CN110627610A - Method for synthesizing alkyne by catalyzing asymmetric cross coupling - Google Patents

Method for synthesizing alkyne by catalyzing asymmetric cross coupling Download PDF

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CN110627610A
CN110627610A CN201910808338.2A CN201910808338A CN110627610A CN 110627610 A CN110627610 A CN 110627610A CN 201910808338 A CN201910808338 A CN 201910808338A CN 110627610 A CN110627610 A CN 110627610A
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nmr
cdcl
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phenyl
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CN110627610B (en
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刘心元
董晓阳
张宇峰
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Southwest University of Science and Technology
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Abstract

The invention belongs to the field of asymmetric synthesis, and discloses a method for synthesizing alkyne by catalyzing asymmetric cross-coupling, which comprises the following steps: using cuprous salt and ligand L as catalysts, and adding alkali to react the compound of formula A and the compound of formula B to obtain a compound of formula C:wherein X is selected from halogen, R1Selected from optionally substituted phenyl, optionally substituted heteroaryl, cyano,Wherein R is6Is trialkylsilyl or alkyl, R2Selected from optionally substituted alkyl, optionally substituted cycloalkyl, (CH)2)nR4Wherein n is 0 to 10, R4Selected from phenyl, alkenyl, alkynyl, hydroxyl, aldehyde group, carboxyl, ester group, amino, cyano, benzoyl, alkoxy, aryloxy, halogen, sulfonyl, mercapto, sulfanyl, trialkylsilyl, butyldiphenylsiloxy, and the like,R3Selected from hydrogen or any functional group, ligand L is selected from

Description

Method for synthesizing alkyne by catalyzing asymmetric cross coupling
Technical Field
The invention belongs to the field of asymmetric synthesis, and particularly relates to a method for synthesizing alkyne by catalyzing asymmetric cross coupling.
Background
In the past fifty years, transition metal catalyzed cross-coupling reactions have constructed compounds by forming carbon-carbon and carbon-heterobonds, wherein an alkyne can be obtained by a coupling reaction of an aryl or alkenyl halide with a terminal alkyne using a transition metal catalyst, and subsequently one has expanded the range of electrophilic substrates to alkyl halides, a reaction commonly referred to as Sonogashira coupling reaction, which is a formation of carbon (sp) -carbon (sp)2/sp3) The cross-coupling reaction of bond has been widely used in the fields of organic synthesis, chemical biology, functional materials, natural products, pharmaceutical research, etc.
As an important organic substance, alkynes play an important role in various fields such as organic synthesis, biology, pharmaceutical chemistry, and material science: the alkyne compound is an important synthesis precursor of functional molecules, can be used as an operation handle of a biomarker, and is also a basic component of various photoelectric materials; more importantly, chiral alkynes are key components of many bioactive products and drugs, such as (-) -chamaegynone, dynemicin a (antineoplastic), alfaparostol (veterinary drug for breeding), efavirenz (antiretroviral drug for aids).
Despite the ongoing progress of the Sonogashira coupling reaction, however, the asymmetric Sonogashira coupling reaction remains a blank region of investigation. Use of aryl halogens for enantioselectivity C (sp) -C (sp)2) Cross-coupling to build axial or planar chirality with only moderate enantioselectivity. C (sp) -C (sp) for alkyl halides3) Enantioselective cross-coupling, a process which has not been achieved. In addition, the oxidative addition of alkyl halides and the β -hydrogen elimination of metal alkyl intermediates are difficult compared to aryl or alkenyl halides as substrates. Meanwhile, acetylene is a rich, cheap and widely-used industrial raw material, has the advantage of low cost as a starting material of asymmetric Sonogashira cross-coupling reaction, but is lack of substituent groups and difficult to carry out later conversion, so that acetylene is used as a transition metal of a substrateCatalytic asymmetric conversion is rare and acetylene may suffer from decomposition, polymerization and undesired metathesis with chiral control.
In view of the wide application of acetylene compounds and various practical problems, it is necessary to develop a method for synthesizing acetylene compounds by catalytic asymmetric cross-coupling.
Disclosure of Invention
The invention aims to provide a method for synthesizing acetylene compounds by catalytic asymmetric cross coupling.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing alkyne by catalyzing asymmetric cross coupling comprises the following steps: using cuprous salt and ligand L as catalysts, and adding alkali to react the compound of formula A and the compound of formula B to obtain a compound of formula C:
wherein X is selected from the group consisting of halogen,
R1selected from optionally substituted phenyl, optionally substituted heteroaryl, cyano,
Wherein R is6Is trialkyl silicon base or alkyl,
R2selected from optionally substituted alkyl, optionally substituted cycloalkyl, (CH)2)nR4，
Wherein n is 0-10, R4Selected from phenyl, alkenyl, alkynyl, hydroxyl, aldehyde group, carboxyl, ester group, amino, cyano, benzoyl, alkoxy, aryloxy, halogen, sulfonyl, mercapto, sulfanyl, trialkylsilyl, tert-butyldiphenylsiloxy, and the like,
R3Selected from the group consisting of hydrogen or any functional group,
ligand L is selected from
Wherein R is hydrogen or alkoxy, A is selected from cyclohexyl, naphthyl and optionally substituted phenyl, and R' is hydrogen, phenyl or alkyl.
Further, said R3Selected from the following structures:
the presence of hydrogen in the presence of hydrogen,
an optionally substituted alkyl group, wherein the alkyl group is substituted,
an optionally substituted cycloalkyl group, which is optionally substituted,
an optionally substituted phenyl group, wherein the phenyl group is substituted,
(ii) an optionally substituted heteroaryl group,
an optionally substituted ferrocenyl group, which is optionally substituted,
(CH2)mR5wherein m is 1-5, R5Selected from the group consisting of alkenyl, alkynyl, phenyl, cycloalkyl, halogen, alkoxy, aryloxy, hydroxy, aldehyde, carboxyl, ester, cyano, amide, sulfonyl, sulfonic, mercapto, sulfanyl, phthalimido, carbazolyl, trialkylsilyl, and mixtures thereof,
An acetal group.
Further, said R3Selected from the following structures:
the presence of hydrogen in the presence of hydrogen,
an alkyl group, a carboxyl group,
a cycloalkyl group,
a phenyl group,
alkyl, alkynyl, alkenyl, phenyl, alkoxy, amino, halogen, trifluoromethyl, cyano, hydroxyl, aldehyde, carboxyl, ester, nitro, amide, sulfonyl, sulfonic, mercapto, trifluoromethyl or pinacolboron-substituted phenyl,
pyrrolyl, furyl, thienyl, tetrahydropyrrolyl, tetrahydrofuryl, tetrahydrothienyl, pyridyl, naphthyl, pyranyl, oxazolyl, imidazolyl, thiazolyl, pyrimidinyl, quinolinyl, indolyl, isoquinolinyl, carbazolyl, pyridazinyl, pyrazinyl, purinyl, benzoxazolyl, benzothiazolyl, 1, 2-methylenedioxyphenyl, imidazo [1,2-b ] pyridazinyl, pyrazolo [1,5-a ] pyrimidinyl,
an alkoxy-substituted naphthyl group, wherein the naphthyl group is substituted by an alkoxy group,
a ferrocenyl group,
(CH2)mR5wherein m is 1,2,3,4, R5Selected from alkenyl, alkynyl, phenyl, cycloalkyl, halogen, alkoxy, aryloxy, hydroxyl, aldehyde group, carboxyl, ester group, cyano, amide group, sulfonyl, sulfonic group, sulfanyl, phthalimido, carbazolyl, trimethylsilyl, carboxyl, sulfonyl, sulfo-sulfonyl, phthalimido, carbaz,
Further, said R3Selected from the following structures:
the presence of hydrogen in the presence of hydrogen,
an alkyl group, a carboxyl group,
a cycloalkyl group,
a phenyl group,
alkyl, alkoxy, amino, halogen, trifluoromethyl, cyano, aldehyde, ester, nitro, alkenyl, alkynyl or pinacolboron-substituted phenyl,
thienyl, pyridyl, naphthyl, pyrimidinyl, quinolinyl, benzoxazolyl, benzothiazolyl, 1, 2-methylenedioxyphenyl, imidazo [1,2-b ] pyridazinyl, pyrazolo [1,5-a ] pyrimidinyl,
an alkoxy-substituted naphthyl group, wherein the naphthyl group is substituted by an alkoxy group,
a ferrocenyl group,
(CH2)mR5wherein m is 1,2,3,4, R5Selected from phenyl, cyclohexyl, halogen, hydroxyl, ester group, alkoxy, aryloxy, amido, phthalimide group, carbazolyl, trimethylsilyl group,
Further, said R1Selected from the following structures:
an optionally substituted phenyl group, wherein the phenyl group is substituted,
(ii) a heteroaryl group, wherein,
a halogen-substituted pyridyl group, wherein the pyridyl group is substituted with halogen,
the cyano group(s),
wherein R is6Is trialkyl silicon base or alkyl.
Further, said R1Selected from the following structures:
an optionally substituted phenyl group, wherein the phenyl group is substituted,
(ii) a heteroaryl group, wherein,
a halogen-substituted pyridyl group, wherein the pyridyl group is substituted with halogen,
the cyano group(s),
wherein R is6Is trimethylsilyl, triethylsilyl, triisopropylsilyl, methyl, ethyl, propyl or butyl.
Further, said R1Selected from the following structures:
a phenyl group,
alkyl, alkynyl, alkenyl, phenyl, alkoxy, halogen, hydroxyl, aldehyde group, ketone group, carboxyl group, ester group, amide group, amino group, cyano group, acetylamino group, nitro group, sulfonyl group, sulfonic group, mercapto group, sulfanyl group, trifluoromethyl group or pyrazolyl substituted phenyl group,
naphthyl, pyrrolyl, furanyl, thienyl, tetrahydropyrrolyl, tetrahydrofuryl, tetrahydrothienyl, pyridyl, pyranyl, oxazolyl, imidazolyl, thiazolyl, pyrimidinyl, quinolinyl, indolyl, isoquinolinyl, carbazolyl, pyridazinyl, pyrazinyl, purinyl, benzothienyl, benzofuranyl, 1, 2-methylenedioxyphenyl;
a halogen-substituted pyridyl group, wherein the pyridyl group is substituted with halogen,
the cyano group(s),
wherein R is6Is trimethylsilyl, triethylsilyl, triisopropylsilyl, methyl, ethyl, propyl or butyl.
Further, said R1Selected from the following structures:
a phenyl group,
alkyl, alkoxy, halogen, aldehyde, keto, ester, cyano, acetamido, trifluoromethyl or pyrazolyl-substituted phenyl,
naphthyl, pyridyl, thienyl, thiazolyl, pyrimidinyl, quinolinyl, benzothienyl, benzofuranyl, 1, 2-methylenedioxyphenyl,
a halogen-substituted pyridyl group, wherein the pyridyl group is substituted with halogen,
the cyano group(s),
wherein R is6Is trimethylsilyl, triethylsilyl, triisopropylsilyl or tert-butyl.
Further, said R2Selected from the following structures:
an alkyl group, a carboxyl group,
a cycloalkyl group,
(CH2)nR4wherein n is 0 or 1、2、3、4、5，R4Selected from phenyl, alkenyl, alkynyl, hydroxyl, aldehyde group, carboxyl, ester group, amino, cyano, benzoyl, alkoxy, aryloxy, halogen, sulfonyl, mercapto, sulfanyl, trialkylsilyl, tert-butyldiphenylsiloxy, and the like,
Further, said R2Selected from the following structures:
an alkyl group, a carboxyl group,
a cycloalkyl group,
(CH2)nR4wherein n is 0,1, 2,3, R4Selected from phenyl, vinyl, ester, cyano, benzoyl, alkoxy, halogen, phenylsulfonyl, trimethylsilyl, t-butyldiphenylsiloxy, and mixtures thereof,
Further, said R2Selected from the following structures:
an alkyl group, a carboxyl group,
a cycloalkyl group,
(CH2)nR4wherein, when n is 1,2,3, R4Selected from phenyl, vinyl, ester, cyano, benzoyl, alkoxy, halogen, phenylsulfonyl, t-butyldiphenylsiloxy, and mixtures thereof,When n is 0, R4Selected from trimethylsilyl.
Further, R is hydrogen or methoxy, R' is hydrogen, phenyl or butyl, and A is selected from the following structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein R is8Selected from alkyl, alkoxy, trifluoromethyl, halogen, phenyl and phenoxy, m represents an integer of 1-5, when m is more than or equal to 2, more than 2R exist8The same or different.
Further, said a is selected from the following structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein R is8Selected from methyl, propyl, butyl, methoxy, trifluoromethyl, fluorine, phenyl and phenoxy, m represents an integer of 1-5, when m is more than or equal to 2, more than 2R exist8The same or different.
Further, said a is selected from the following structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein, when m is 1, R8Selected from propyl, butyl, methoxy, phenyl, phenoxy; when m is 2, R8Selected from butyl, trifluoromethyl, methoxy, phenyl; when m is 3, R8Selected from methyl, propyl, butyl, methoxy, fluoro; when m is 5, R8Is selected from methyl; when m.gtoreq.2, more than 2R are present8The same or different.
Further, X is selected from chlorine and bromine.
Further, the cuprous salt is selected from CuI, CuCl, CuBr, CuTc, (CuOTf)2·PhCH3。
Further, the alkali is selected from Cs2CO3、Na2CO3、K3PO4、NaOH、KOtBu。
Further, the cuprous salt is used in an amount of at least 5 mol%, the ligand L is used in an amount of at least 7.5 mol%, and the base is used in an amount of at least 200 mol%.
The amount of the cuprous salt, the ligand L, and the base is based on the amount of the raw compound of formula A or the compound of formula B, for example, the amount of the cuprous salt is written in the form of 5 mol%, which means that 0.05mol of the cuprous salt is used per 1mol of the compound of formula A or the compound of formula B; the amount of ligand L used is written in the form of 7.5 mol%, meaning that 0.075mol of ligand L is used per 1mol of compound of formula A or compound of formula B; the amount of base used is written in the form of 200 mol%, meaning that 2mol of base are used per 1mol of compound of formula A or compound of formula B. The amount of the raw material used is relatively small compared with the amount of the compound of formula A or the compound of formula B, for example, the amount of the compound of formula B is 0.2mol, the amount of the compound of formula A is 0.3mol (1.5 equivalents), the amount of cuprous salt is 5 mol%, the amount of the ligand L is 7.5 mol%, and the amount of the base is 200 mol%, so that the amount of the cuprous salt, the ligand L and the base are 0.01mol, 0.015mol and 0.4mol respectively; the amount of the compound of formula A is 0.2mol, the amount of the compound of formula B is 0.3mol (1.5 equivalents), the amount of the cuprous salt is 5 mol%, the amount of the ligand L is 7.5 mol%, and the amount of the base is 200 mol%, so that the amounts of the cuprous salt, the ligand L, and the base are 0.01mol, 0.015mol, and 0.4mol, respectively.
Further, the reaction uses acetonitrile, ethyl acetate, toluene, tetrahydrofuran, methanol, diethyl ether, dichloromethane, dichloroethane or methyl tert-butyl ether as a solvent.
Further, the molar ratio of the compound of the formula A to the compound of the formula B is 1-3: 1; the reaction temperature is room temperature, and the reaction time is at least 16 h.
As used herein, "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl" as defined below. It will be understood by those skilled in the art that, for any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical, not readily synthesized, and/or inherently unstable.
As used herein, "substituted" means that any one or more hydrogens on the designated atom or group is replaced with a (substituent) selected from the designated group, provided that the designated atom's normal valence is not exceeded. If the substituent is oxo (i.e., ═ O), then two hydrogens on the atom are replaced. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is intended to mean a compound that is sufficiently robust to survive isolation from a reaction mixture and subsequent formulation into a reagent that has at least practical use.
The "substitution" of the "substituted phenyl" or "substituted heteroaryl" as used herein is mono-or polysubstituted, and includes the case where the substituent is an alkyl group which may form a ring. For example, "substituted phenyl" includes three possibilities: (1) the benzene ring has a substituent; (2) the benzene ring has two or more same or different substituents; (3) mechanisms in which two adjacent alkyl or hydroxy groups of the benzene ring form a ring to form a benzo-polycyclic ring, e.g.And the like.
As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl.
As used herein, "alkenyl" refers to an unsaturated branched or straight chain alkyl group having at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from an adjacent carbon atom of the parent alkyl group. Alkenyl groups having 2 to 20 carbon atoms are preferred, and alkenyl groups having 2 to 6 carbon atoms are more preferred. The groups may be in either the cis or trans configuration with respect to one or more double bonds. Typical alkenyl groups include, but are not limited to, vinyl; propenyl, such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyl, such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-2-yl, but-1, 3-dien-1-yl, but-1, 3-dien-2-yl.
As used herein, "alkynyl" refers to an unsaturated, branched or straight chain alkyl group having at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the parent alkyl group. Alkynyl groups having 2 to 20 carbon atoms are preferred, and alkynyl groups having 3 to 6 carbon atoms are more preferred. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl groups such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, e.g. but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl.
As used herein, "cycloalkyl" refers to a non-aromatic carbocyclic ring, typically having from 3 to 8 ring carbon atoms. The rings may be saturated or have one or more carbon-carbon double bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl, as well as bridged and caged cyclic groups such as norbornane.
As used herein, "alkoxy" refers to-O- (alkyl) and-O- (cycloalkyl), where alkyl, cycloalkyl are defined herein, and non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-methylpentyloxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups typically have 1 to 7 carbon atoms connected by an oxygen bridge.
The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine.
As used herein, "aryloxy" refers to the group-O-aryl, wherein aryl is as defined herein.
As used herein, "hydroxy" refers to the group-OH.
As used herein, "aldehyde" refers to the group-CHO.
As used herein, "carboxy" refers to the group-COOH.
As used herein, "keto" refers to the groups (alkyl) -c (o) -, (cycloalkyl) -c (o) -, (aryl) -c (o) -, (heteroaryl) -c (o) -, wherein the groups are attached to the parent structure through a carbonyl functionality, and wherein alkyl, cycloalkyl, aryl, heteroaryl are as described herein.
As used herein, "ester group" refers to-C (O) O (alkyl) or-C (O) O (phenyl), wherein alkyl, phenyl are as defined herein. For the ester-substituted phenyl group, it may be formed either from the phenolic hydroxyl group of the phenyl ring and a carboxylic acid, such as PhOCOCH3PhOPiv, or from the carboxyl group of the phenyl ring with an alcohol, e.g. PhCOOCH3。
As used herein, "cyano" refers to-CN.
As used herein, "trifluoromethyl" refers to-CF3。
As used herein, "trialkylsilyl" refers to a silyl group having three alkyl groups attached thereto and having the structureR7Typically, the alkyl group is trimethylsilyl, triethylsilyl, or triisopropylsilyl.
As used herein, "trimethylsilyl" refers to-Si (CH)3)3。
As used herein, "t-butyldiphenylsiloxy" means
As used herein, "nitro" refers to-NO2。
"sulfonyl" as used herein refers to the following group: -S (O)2) - (alkyl), -S (O)2) - (aryl), -S (O)2) - (heteroaryl), -S (O)2) - (amino). Alkyl, aryl, heteroaryl, amino are as defined herein.
As used herein, "sulfonic acid group" means-SO3H。
"benzoyl" as used herein refers to C6H5(C＝O)-。
As used herein, "sulfanyl" refers to the following groups: -S- (alkyl), -S- (aryl), -S- (heteroaryl), alkyl, aryl, heteroaryl are as defined herein.
As used herein, "mercapto" refers to-SH.
As used herein, "ferrocenyl" refers to
As used herein, "phenyl" refers to
"naphthyl" as used herein refers to
"carbazolyl" as used herein means
As used herein, "phthalimido" refers to
As used herein, "amido" refers to the group-CONRbRcWherein R isbSelected from H hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, RcSelected from alkyl, cycloalkyl, aryl, heteroaryl; or RbAnd RcAnd together with the nitrogen to which they are attached form an optionally substituted 5-to 8-membered nitrogen-containing heterocycloalkyl group optionally containing 1 or 2 additional heteroatoms selected from O, N and S in the heterocycloalkyl ring. Alkyl, cycloalkyl, aryl, heteroaryl are defined herein.
As used herein, "amino" refers to-NH2。
As used herein, "aryl" refers to a 6-membered carbocyclic aromatic ring, such as benzene; bicyclic ring systems in which at least one ring is carbocyclic and aromatic, such as naphthalene, indane and 1,2,3, 4-tetrahydronaphthalene; and tricyclic ring systems in which at least one ring is carbocyclic and aromatic, such as fluorene.
For example, aryl includes a 6-membered carbocyclic aromatic ring fused to a 5-to 7-membered heterocycloalkyl ring containing one or more heteroatoms selected from N, O and S. For such fused bicyclic ring systems in which only one ring is a carbocyclic aromatic ring, the point of attachment may be on the carbocyclic aromatic ring or the heterocycloalkyl ring. Divalent groups that form self-substituted benzene derivatives and have a free valence at the ring atom are referred to as substituted phenylene groups. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose names end in a "radical" by removal of one hydrogen atom from a carbon atom having a free valence are named by adding a "ene" to the name of the corresponding monovalent radical, e.g., a naphthyl radical having two points of attachment is called naphthylene. However, aryl does not in any way include or overlap with heteroaryl, which is individually defined below. Thus, if one or more carbocyclic aromatic rings are fused to a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl rather than aryl, as defined herein.
As used herein, "heteroaryl" refers to:
a 5-to 7-membered aromatic monocyclic ring containing one or more (e.g., 1 to 4, or in certain embodiments 1 to 3) heteroatoms selected from N, O and S and the remaining ring atoms being carbon;
a bicyclic heterocycloalkyl ring containing one or more (e.g., 1 to 4, or in certain embodiments 1 to 3) heteroatoms selected from N, O and S and the remaining ring atoms being carbon, and wherein at least one heteroatom is present in the aromatic ring;
and tricyclic heterocycloalkyl rings containing one or more (e.g., 1 to 5, or in certain embodiments 1 to 4) heteroatoms selected from N, O and S and the remaining ring atoms are carbon, and wherein at least one heteroatom is present in the aromatic ring;
for example, heteroaryl includes a 5-to 7-membered heterocycloalkyl aromatic ring fused with a 5-to 7-membered cycloalkyl or heterocycloalkyl ring. For such fused bicyclic heteroaryl ring systems wherein only one ring contains one or more heteroatoms, the point of attachment may be on either ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In certain embodiments, the total number of S and O atoms in the heteroaryl group is no more than 2. In certain embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1.
Examples of heteroaryl groups include, but are not limited to (numbered from the attachment position designated as position 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 3-pyrazolinyl, 2, 4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuryl, benzimidazolinyl, indolinyl, pyridazinyl, triazolyl, quinolinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, and 5,6,7, 8-tetrahydroisoquinolinyl. Divalent radicals derived from monovalent heteroaryl radicals whose name ends with "radical" by removing one hydrogen atom from the atom having a free valence are named by adding "ene" to the name of the corresponding monovalent radical, e.g., a pyridyl radical having two points of attachment is pyridylene. Heteroaryl does not include or overlap with aryl, cycloalkyl or heterocycloalkyl, as defined herein.
Substituted heteroaryl groups also include ring systems substituted with one or more oxide (-O-) substituents, such as pyridyl N-oxide.
As used herein, "heterocycloalkyl" refers to a single non-aromatic ring, typically having 3 to 8 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and combinations comprising at least one of the foregoing heteroatoms. The rings may be saturated or have one or more carbon-carbon double bonds. Suitable heterocycloalkyl groups include, for example (numbered from the attachment position designated as position 1), 2-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, and 2, 5-piperazinyl. Also contemplated are morpholino groups, including 2-morpholino and 3-morpholino (oxygen is designated as the 1-position in the numbering). Substituted heterocycloalkyl also includes ring systems substituted with one or more oxo (═ O) or oxide (-O-) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1, 1-dioxo-1-thiomorpholinyl.
"heterocycloalkyl" also includes bicyclic ring systems in which one non-aromatic ring (typically having 3 to 8 ring atoms) contains at least 2 carbon atoms in addition to 1 to 3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and combinations comprising at least one of the foregoing heteroatoms; and the other ring (typically having 3 to 8 ring atoms) optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and is non-aromatic.
As used herein, unless otherwise expressly defined, the term "substituted phenyl, heteroaryl, alkyl, cycloalkyl, ferrocenyl, wherein one or more (e.g., up to 5, e.g., up to 3) hydrogen atoms are replaced by a substituent independently selected from:
alkyl, alkynyl, alkenyl, phenyl, alkoxy, amino, halogen, trifluoromethyl, cyano, hydroxyl, aldehyde group, carboxyl, keto, ester group, nitro, amide group, sulfonyl, sulfonic group, mercapto, sulfanyl, trifluoromethyl, pyrazolyl, acetamido, pinacolboron.
As used herein, the following words and phrases are generally intended to have the meanings as set forth below, except where the context in which they are used indicates otherwise.
The following abbreviations and terms have the indicated meanings throughout:
(CuOTf)2·PhCH3a complex of copper trifluoromethanesulfonate and toluene; CuTc refers to cuprous thiophene-2-carboxylate; TFA means trifluoroacetic acid; TFAA means trifluoroacetic anhydride; PhI (TFA)2Refers to (bis (trifluoroacetoxy) iodo) benzene; cp is cyclopentadiene; pin means pinacol; PMP refers to p-methoxybenzene; phth refers to phthaloyl; TMS means trimethylsilyl; ac means acetyl; ts represents p-toluenesulfonyl; TBDPS means t-butyl-diphenylsilyl; piv means pivaloyl; DCC refers to dicyclohexylcarbodiimide; DMAP refers to 4-dimethylaminopyridine; EtOAc or EA refers to ethyl acetate; EtOH refers to ethanol; et (Et)2O means diethyl ether; g means gram; h or hr means hours; HPLC meansHigh pressure liquid chromatography; m/z refers to mass to charge ratio; MeOH refers to methanol; MeCN means acetonitrile; min means minutes; minor refers to minor; major refers to the major product; mg means mg; mmol means millimole; ph denotes phenyl; THF means tetrahydrofuran; TLC refers to thin layer chromatography; UV refers to ultraviolet; DCE refers to dichloroethane; MTBE methyl tert-butyl ether; cy means cyclohexyl, 1-Naph means 1-naphthyl, 2-Naph means 2-naphthyl.
The invention has the following beneficial effects:
1. the invention takes chiral cinchona alkaloid-based nitrogen phosphorus ligand and copper salt as catalysts, and is used for Sonogashira C (sp) -C (sp) of various terminal alkynes and racemic alkyl halides3) Asymmetric cross-coupling reaction is adopted to construct chiral C-C bonds, the reaction is suitable for various alkynes which are widely applied in industry, such as acetylene and propine, and chiral terminal alkyne products are obtained, so that a foundation is laid for industrial synthesis application, and the method has a good industrial application prospect.
2. The method of the invention can be used for synthesizing more than twenty kinds of pharmaceutical compounds and natural products with biological activity or functionality.
3. The method has the advantages of simple reaction operation, mild conditions, high catalytic efficiency, small catalyst dosage, wide substrate application range, high yield and good enantioselectivity.
Detailed Description
The present invention will be further described with reference to the following specific examples.
Unless otherwise indicated, chemicals were purchased from commercial products and were not further purified. Most of the reactions were carried out using Schlenk tubes under argon atmosphere. CuI was purchased from Sigma-Aldrich, and CuTc was purchased from Alfa Aesar and Bide. Anhydrous diethyl ether (Et)2O) was purchased from shanghai lingfeng chemicals, ltd, and used without further treatment. Thin Layer Chromatography (TLC) used 60GF254 silica gel plates. The silica gel column chromatography uses Qingdao marine silica gel (particle size 0.040-0.063 mm). TLC color development was performed with UV light (254nm), iodine or acidic KMnO4And (3) solution.1H NMR、13C NMR and19f NMR was characterized using a Bruker 400MHz or 500MHz NMR spectrometer with deuterated chloroform, deuterated methanol or deuterated methanol as solventDeuterated DMSO using Tetramethylsilane (TMS) as an internal standard. Chemical shifts are in ppm and coupling constants are in Hz. In that1In H NMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, p represents quintet, m represents multiplet, br represents broad. In that13In C NMR, δ represents a chemical shift. Mass spectral data were obtained using Bruker Apex IV RTMS. The enantiomeric excess values were determined by an agilent chiral HPLC instrument and a Hatachi detector. Specific optical rotation was measured by Rudolph-Autopol I.
Example 1
Synthesis of acetylene substrates
General procedure 1: to a mixture of aryl bromide (1.0mmol, 1.0 equiv.), bis (triphenylphosphine) palladium (II) chloride (35.1mg, 0.050mmol, 5.0 mol% equiv.), and trimethylethynylsilicon (196.0mg, 2.0mmol, 2.0 equiv.) in triethylamine (4.0mL) was added copper (I) iodide (9.5mg, 0.050mmol, 5.0 mol% equiv.) under argon, then heated to 50 ℃ for 24 hours. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give trimethylsilylethynyl aromatic compound. The crude product was then dissolved in anhydrous THF (1.0mL) under argon and cooled to 0 ℃. Tetra-n-butylammonium fluoride (1.5mL, 1.0M in THF, 1.5 equiv.) is added dropwise to the solution, then allowed to warm to room temperature and stirred for 0.5 h. After completion of the reaction (monitored by TLC), the solvent was removed by evaporator and purified by silica gel column chromatography to give the alkynyl product.
General procedure 2: to dimethylformamide (10.0mL) of aryl halide (bromide or chloride) (1.0mmol, 1.0 equivalent), triisopropylethynylsilicon (364.8mg, 2.0mmol, 2.0 equivalent), bis (triphenylphosphine) palladium (II) chloride (35.1mg, 0.050mmol) was added copper iodide (9.5mg, 0.050mmol, 5.0 mol%) and triethylamine (0.3mL, 2.0mmol, 2.0 equivalent) under an argon atmosphere, and the mixture was stirred at 40 ℃ for 24 hours. After completion of the reaction (monitored by TLC), the reaction was quenched with water. The mixture was poured into EtOAc and extracted three times with EtOAc, then the organic layer was washed with brine, washed with Na2SO4Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the corresponding product. The crude product was dissolved in MeOH (2.0mL) with K2CO3(0.28g, 2.0mmol, 2.0 equiv.) and stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete consumption of starting material and the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography to give the corresponding aryl acetylene.
Starting from p-bromophenylethylene (182.0mg, 1.0mmol, 1.0 eq), the reaction mixture was purified by silica gel column chromatography using general method 1 (petroleum ether ═ 100) to give product S22 as a colorless oil (84.5mg, 66% yield over two steps). The product was unstable in air and turned red in a short time, so it was stored in-20 ℃ CH2Cl2In (1).
1H NMR(400MHz,CDCl3)δ7.52(d,J＝8.4Hz,2H),7.41(d,J＝8.1Hz,2H),6.75(dd,J＝17.6,10.9Hz,1H),5.83(dd,J＝17.6,0.9Hz,1H),5.36(dd,J＝10.9,0.9Hz,1H),3.18(s,1H)。13C NMR(100MHz,CDCl3) δ 138.0,136.2,132.4,126.2,121.4,115.1,83.7, 77.9. HRMS (ESI) m/z accurate mass calculation C10H9[M+H]+129.0699, found 129.0699.
Starting from 5-bromo-1, 3-benzodioxole (200.0mg, 1.0mmol, 1.0 equiv.) using general method 1, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 20/1) to give the product S25 as a brown amorphous powder (67.2mg, 46% yield in two steps).
1H NMR(400MHz,CDCl3)δ7.05(d,J＝8.0Hz,1H),6.96(s,1H),6.78(d,J＝8.0Hz,1H),6.00(s,2H),3.00(s,1H)。13C NMR(100MHz,CDCl3)δ148.3,147.4,126.9,115.3,112.0,108.4,101.4,83.6,75.6. HRMS (ESI) m/z accurate mass calculation C9H7O2[M+H]+147.0441, found 147.0440.
Using 2-chlorobenzoxazole (153.0mg, 1.0mmol, 1.0 equiv.) as a starting material, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 10/1) using general method 2 to give product S28 as a brown amorphous powder (108.7mg, 76% yield in two steps).
1H NMR(400MHz,CDCl3)δ7.82–7.74(m,1H),7.58–7.53(m,1H),7.50–7.35(m,2H),3.41(s,1H)。13C NMR(100MHz,CDCl3) δ 150.2,146.4,140.4,126.8,125.2,120.7,110.8,81.8, 71.7. HRMS (ESI) m/z accurate mass calculation C9H6NO[M+H]+144.0444, found 144.0443.
Using 2-bromobenzothiazole (212.9mg, 1.0mmol, 1.0 equiv.) as starting material, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 20/1) using general method 2 to give product S29 as a yellow amorphous powder (130.4mg, 82% yield over two steps).
1H NMR(400MHz,CDCl3)δ8.13–8.07(m,1H),7.91–7.85(m,1H),7.59–7.43(m,2H),3.62(s,1H)。13C NMR(100MHz,CDCl3) δ 152.6,147.5,135.2,126.8,126.6,123.9,121.4,84.0, 76.8. HRMS (ESI) m/z accurate mass calculation C9H6NS[M+H]+160.0215, found 160.0214.
Using 5-chloropyrazolo [1,5-a ] pyrimidine (153.0mg, 1.0mmol, 1.0 eq.) as starting material, the reaction mixture was purified by silica gel column chromatography using general method 2 (petroleum ether/ethyl acetate ═ 5/1) to give product S33 as a white amorphous powder (107.3mg, 75% yield over two steps).
1H NMR(400MHz,CDCl3)δ8.62(d,J＝7.1Hz,1H),8.13(d,J＝2.3Hz,1H),6.93–6.86(m,1H),6.71–6.69(m,1H),3.00–2.83(m,1H)。13C NMR(100MHz,CDCl3) δ 148.1,145.7,141.9,134.4,111.2,104.4,97.6, 96.5. HRMS (ESI) m/z accurate mass calculation C8H6N3[M+H]+144.0556, found 144.0556.
To 5-hexynoic acid (123.2mg, 1.1mmol, 1.1 equiv.), 1-ethyl-3- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI, 230.0mg, 1.2mmol, 1.2 equiv.) and 4-Dimethylaminopyridine (DMAP) (12.2mg, 0.10mmol, 0.10 equiv.) in CH at 0 ℃ under an argon blanket2Cl2To a solution (2.0mL) was added 4-methoxyaniline (123.0mg, 1.0mmol, 1.0 equiv) in one portion. The reaction was allowed to warm to room temperature and stirred overnight. After completion of the reaction (monitored by TLC), saturated NaHCO3Quench, extract three times with EtOAc, wash the organic phase with brine, and MgSO4Dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 1/2) to give the alkynyl product S40 as a white amorphous powder (173.6mg, 80% yield).
1H NMR(400MHz,CDCl3)δ7.57(brs,1H),7.39(d,J＝9.0Hz,2H),6.83(d,J＝9.0Hz,2H),3.77(s,3H),2.46(t,J＝7.2Hz,2H),2.29(td,J＝7.2,2.7Hz,2H),2.00(t,J＝2.7Hz,1H),1.94-1.87(m,2H)。13C NMR(100MHz,CDCl3) δ 170.6,156.4,131.0,121.9,114.1,83.5,69.4,55.5,35.8,24.1, 17.9. HRMS (ESI) m/z accurate mass calculation C13H16NO2[M+H]+218.1176, found 218.1175.
To isoindoline-1, 3-dione (147.0mg, 1.0mmol, 1.0 equiv.) and K under argon2CO3(276.0mg, 2.0mmol, 2.0 equiv.) of DMF (5.0mL) was added 4-bromo-n-butyne (158.4mg, 1.2mmol, 1.2 equiv.) and stirred at room temperature overnight. After this time, quench the reaction with water, extract three times with EtOAc, wash the organic layer with brine, and Na2SO4Dried and concentrated in vacuo. The product S41 was obtained as a white amorphous powder by silica gel column chromatography (petroleum ether/ethyl acetate 1/1) (161.1mg, 81% yield).
1H NMR(400MHz,CDCl3)δ7.91–7.82(m,2H),7.78–7.68(m,2H),3.97–3.79(m,2H),2.69–2.55(m,2H),1.97(t,J＝2.6Hz,1H)。13C NMR(100MHz,CDCl3) δ 168.0,134.0,132.0,123.4,80.3,70.3,36.5, 18.3. HRMS (ESI) m/z accurate mass calculation C12H10NO2[M+H]+200.0706, found 200.0706.
S43 was synthesized as a white solid (1.12g, 97% yield) using 2, 2-diphenylacetonitrile (5.0mmol, 0.97g, 1.0 equiv.) according to the literature reported method (S.Chang et al, Catalytic one-pot synthesis of cyclic amides by virtues of chromatography and analysis of chromatography interaction of atomic proportions.J.Am.chem.Soc.128, 12366-12367 (2006)).
1H NMR(400MHz,CDCl3)δ7.46–7.27(m,10H),3.25(s,2H),2.12(s,1H)。13C NMR(100MHz,CDCl3) δ 138.9,128.9,128.4,127.1,121.6,78.3,73.3,51.2, 30.9. HRMS (ESI) m/z accurate mass calculation C17H14N[M+H]+232.1121, found 232.1119.
Phenol (94.0mg, 1.0mmol, 1.0 equiv.) and K were added under argon2CO3(276.0mg, 2.0mmol, 2.0 equiv.) of DMF (5.0mL) was added 3-bromopropyne (142.8mg, 1.2mmol, 1.2 equiv.) and stirred at room temperature overnight. After this time, the reaction was quenched with water, extracted three times with EtOAc, the organic layer was washed with brine, and Na was added2SO4Dried and concentrated in vacuo to afford the product S47 as a yellow oil by silica gel column chromatography (petroleum ether/ethyl acetate-100/1) (120.1mg, 91% yield).
1H NMR(400MHz,CDCl3)δ7.40–7.30(m,2H),7.11–6.95(m,3H),4.73(d,J＝2.4Hz,2H),2.55(t,J＝2.4Hz,1H)。13C NMR(100MHz,CDCl3) δ 157.6,129.5,121.6,114.9,78.7,75.5, 55.8. HRMS (ESI) m/z accurate mass calculation C9H9O[M+H]+133.0648, found 133.0649.
4-tert-Butylphenol (166.0mg, 1.0mmol, 1.0 equiv.) and K were added under argon2CO3(276.0mg, 2.0mmol, 2.0 equiv.) to a mixture of DMF (5.0mL) was added 3-bromopropyne (142.8mg, 1.2mmol, 1.2 equiv.) and stirred at room temperature overnight. The reaction was then quenched with water, extracted three times with EtOAc, the organic layer was washed with brine, and Na2SO4Dried and concentrated in vacuo to afford the product S48 as a yellow oil by silica gel column chromatography (petroleum ether/ethyl acetate-100/1) (179.5mg, 88% yield).
1H NMR(400MHz,CDCl3)δ7.64–7.55(m,1H),7.48–7.41(m,1H),7.26–7.18(m,2H),3.67(d,J＝2.7Hz,2H),2.27(t,J＝2.7Hz,1H),1.55(s,9H)。13C NMR(100MHz,CDCl3) δ 150.4,134.3,133.2,127.1,126.64,126.60,79.8,71.7,36.6,30.7, 24.5. HRMS (ESI) m/z accurate mass calculation C13H17S[M+H]+205.1045, found 205.1045.
Example 2
Synthesis of alkyl halogen substrates
General procedure 3: to a solution of ketone (3.0mmol, 1.0 equiv.) in EtOH (9.0mL) was added NaBH4(136.8mg, 3.6mmol, 1.2 equivalents), the mixture is stirred at room temperature for 0.5 to 2 hours. After completion of the reaction (monitored by TLC), the reaction was quenched with water and quenched with CH2Cl2Diluting and using CH2Cl2Extraction was carried out three times. The organic layer was washed with brine, washed with Na2SO4Drying, filtration and concentration in vacuo afforded the corresponding hydroxy compound without further purification.
Under the protection of argon, hydroxyl compound is dissolved in CH2Cl2Cooling to 0 deg.C, then adding PBr3(0.20mL, 2.1mmol, 0.70 equiv.). After completion of the reaction (monitored by TLC), the reaction was quenched with water and CH2Cl2The combined organic phases were washed with brine, filtered through a pad of silica gel and concentrated in vacuo to give the corresponding crude product, which was used directly in the next step without further purification or stored in a refrigerator (the product was easily decomposed in air or on silica gel).
Using propiophenone (0.40g, 3.0mmol, 1.0 equiv.) as the starting material, S2 was obtained in two steps using general method 3 as a colorless oil (0.56g, 94% yield).
1H NMR(400MHz,CDCl3)δ7.41–7.36(m,2H),7.35–7.31(m,2H),7.30–7.24(m,1H),4.88(t,J＝7.4Hz,1H),2.36–2.23(m,1H),2.22–2.10(m,1H),1.00(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.2,128.8,128.4,127.4,57.7,33.4, 13.1. HRMS (ESI) m/z accurate mass calculation C9H11[M–Br]+119.0855, found 119.0853.
Starting from 1-phenyl-1-butanone (0.44g, 3.0mmol, 1.0 equiv.) using general procedure 3, two steps gave S57 as a colorless oil (0.61g, 95% yield).
1H NMR(400MHz,CDCl3)δ7.41–7.37(m,2H),7.35–7.31(m,2H),7.30–7.24(m,1H),4.97(t,J＝7.6Hz,1H),2.34–2.21(m,1H),2.17–2.04(m,1H),1.58–1.42(m,1H),1.41–1.24(m,1H),0.93(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.4,128.8,128.4,127.4,55.6,42.1,21.6, 13.5. HRMS (ESI) m/z accurate mass calculation C10H13[M–Br]+133.1012, found 133.1009.
Starting from 1-phenyl-1-pentanone (0.49g, 3.0mmol, 1.0 equiv), using general method 3, two steps gave S58 as a colorless oil (0.63g, 93% yield).
1H NMR(400MHz,CDCl3)δ7.40–7.35(m,2H),7.34–7.28(m,2H),7.28–7.22(m,1H),4.94(dd,J＝8.4,7.2Hz,1H),2.33–2.22(m,1H),2.18–2.07(m,1H),1.50–1.39(m,1H),1.38–1.31(m,2H),1.29–1.22(m,1H),0.88(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.4,128.7,128.3,127.3,55.9,39.8,30.5,22.1, 14.0. HRMS (ESI) m/z accurate mass calculation C11H15[M–Br]+147.1168, found 147.1167.
Starting from 1-phenyl-1-hexanone (0.53g, 3.0mmol, 1.0 equiv.) using general procedure 3, two steps gave S59 as a colorless oil (0.66g, 92% yield).
1H NMR(400MHz,CDCl3)δ7.46–7.41(m,2H),7.41–7.34(m,2H),7.34–7.29(m,1H),5.00(dd,J＝8.0,6.8Hz,1H),2.40–2.26(m,1H),2.24–2.12(m,1H),1.60–1.44(m,1H),1.42–1.28(m,5H),0.96–0.89(m,3H)。13C NMR(100MHz,CDCl3)δ142.4,128.7,128.3,127.3,55.9,40.1,31.2,28.0,22.5,14.1. HRMS (ESI) m/z accurate mass calculation C12H17[M–Br]+161.1325, found 161.1325.
Starting from diphenylethanone (0.59g, 3.0mmol, 1.0 equiv.) using general procedure 3, S60 was obtained in two steps as a colorless oil (0.64g, 82% yield).
1H NMR(400MHz,CDCl3)δ7.36–7.31(m,2H),7.28–7.14(m,6H),7.10–7.05(m,2H),5.10(t,J＝7.6Hz,1H),3.52(dd,J＝14.1,7.8Hz,1H),3.44(dd,J＝14.1,7.4Hz,1H)。13C NMR(100MHz,CDCl3) δ 141.5,138.1,129.3,128.7,128.4,127.6,126.9,55.6, 46.5. HRMS (ESI) m/z accurate mass calculation C14H13[M–Br]+181.1012, found 181.1011.
Starting from 1, 3-diphenyl-1-propanone (0.63g, 3.0mmol, 1.0 equiv), two steps were carried out using general method 3 to give S61 as a colourless oil (0.71g, 86% yield).
1H NMR(400MHz,CDCl3)δ7.35–7.22(m,6H),7.19–7.11(m,4H),4.87(dd,J＝8.4,6.4Hz,1H),2.81–2.72(m,1H),2.71–2.61(m,1H),2.60–2.52(m,1H),2.44–2.34(m,1H)。13C NMR(100MHz,CDCl3) δ 142.0,140.5,128.8,128.6,128.5,127.4,126.3,54.8,41.4, 34.3. HRMS (ESI) m/z accurate mass calculation C15H15[M–Br]+195.1168, found 195.1168.
Starting from 3-methyl-1-phenyl-1-butanone (0.49g, 3.0mmol, 1.0 equiv.) using general method 3, S63 was obtained in two steps as a colorless oil (0.61g, 90% yield).
1H NMR(400MHz,CDCl3)δ7.40–7.35(m,2H),7.33–7.27(m,2H),7.26–7.21(m,1H),5.03(dd,J＝8.4,7.2Hz,1H),2.26–2.12(m,1H),2.02–1.89(m,1H),1.76–1.61(m,1H),0.91(d,J＝5.6Hz,3H),0.90(d,J＝5.6Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.3,128.7,128.3,127.3,54.1,48.8,26.8,22.3, 22.0. HRMS (ESI) m/z accurate mass calculation C11H15[M–Br]+147.1168, found 147.1168.
Starting from 2-methyl-1-phenyl-1-propanone (0.44g, 3.0mmol, 1.0 equiv.) using general procedure 3, S64 was obtained in two steps as a colorless oil (0.58g, 91% yield).
1H NMR(400MHz,CDCl3)δ7.37–7.30(m,4H),7.27–7.24(m,1H),4.71(d,J＝8.4Hz,1H),2.39–2.24(m,1H),1.19(d,J＝6.4Hz,3H),0.85(d,J＝6.8Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.7,128.5,128.1,127.9,64.4,36.7,21.7, 20.6. HRMS (ESI) m/z accurate mass calculation C10H13[M–Br]+133.1012, found 133.1013.
Starting from 2, 2-dimethyl-1-phenyl-1-propanone (0.49g, 3.0mmol, 1.0 equiv.) using general procedure 3, S65 was obtained in two steps as a colorless oil (0.55g, 81% yield).
1H NMR(400MHz,CDCl3)δ7.38–7.32(m,2H),7.29–7.27(m,1H),7.25–7.21(m,2H),4.84(s,1H),1.06(s,9H)。13C NMR(100MHz,CDCl3) δ 140.2,129.2,127.9,127.7,69.1,37.1, 27.7. HRMS (ESI) m/z accurate mass calculation C11H15[M–Br]+147.1168, found 147.1168.
Using cyclobutyl (phenyl) methanone (0.48g, 3.0mmol, 1.0 equiv.) as starting material, S66 was obtained in two steps as colorless oil (0.59g, 88% yield) using general method 3.
1H NMR(400MHz,CDCl3)δ7.44–7.39(m,2H),7.38–7.33(m,2H),7.33–7.27(m,1H),4.96(d,J＝10.8Hz,1H),3.24–3.08(m,1H),2.41–2.27(m,1H),2.10–1.96(m,1H),1.94–1.75(m,3H),1.70–1.59(m,1H)。13C NMR(100MHz,CDCl3) δ 140.6,128.7,128.4,127.7,61.8,43.1,28.7,27.0, 16.2. HRMS (ESI) m/z accurate mass calculation C11H13[M–Br]+145.1012, found 145.1012.
Starting from cyclopentyl (phenyl) methanone (0.52g, 3.0mmol, 1.0 equiv.) using general procedure 3, two steps gave S67 as a colorless oil (0.61g, 85% yield).
1H NMR(400MHz,CDCl3)δ7.39–7.34(m,2H),7.32–7.26(m,2H),7.26–7.20(m,1H),4.76(d,J＝10.0Hz,1H),2.81–2.62(m,1H),2.23–2.06(m,1H),1.75–1.38(m,6H),1.12–0.93(m,1H)。13C NMR(100MHz,CDCl3) δ 142.5,128.6,128.1,127.6,61.9,48.6,33.5,31.5,26.1, 25.2. HRMS (ESI) m/z accurate mass calculation C12H15[M–Br]+159.1168, found 159.1169.
Starting from cyclohexyl (phenyl) methanone (0.56g, 3.0mmol, 1.0 equiv.) using general procedure 3, S68 was obtained in two steps as a white solid (0.68g, 90% yield).
1H NMR(400MHz,CDCl3)δ7.44–7.36(m,4H),7.35–7.30(m,1H),4.80(d,J＝8.8Hz,1H),2.47–2.34(m,1H),2.13–1.98(m,1H),1.95–1.83(m,1H),1.80–1.64(m,2H),1.63–1.52(m,1H),1.44–1.08(m,4H),1.00–0.86(m,1H)。13C NMR(100MHz,CDCl3) δ 141.4,128.4,128.0,127.9,63.3,45.5,32.2,31.0,26.2,26.1, 26.0. HRMS (ESI) m/z accurate mass calculation C13H17[M–Br]+173.1325, found 173.1325.
Starting from ethyl 3-oxo-3-phenylpropionate (0.58g, 3.0mmol, 1.0 eq), two steps were carried out according to general procedure 3 to give S71 as a colorless oil (0.63g, 82% yield).
1H NMR(400MHz,CDCl3)δ7.43–7.39(m,2H),7.37–7.24(m,3H),5.40(dd,J＝8.8,6.0Hz,1H),4.20–4.05(m,2H),3.33(dd,J＝16.1,9.0Hz,1H),3.18(dd,J＝16.1,6.2Hz,1H),1.21(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 169.6,140.8,128.83,128.75,127.2,61.1,48.1,44.9, 14.2. HRMS (ESI) m/z accurate mass calculation C11H14BrO2[M+H]+257.0172, found 257.0170. HRMS (ESI) m/z accurate mass calculation C11H13O2[M–Br]+177.0910, found 177.0910.
Starting from ethyl 4-oxo-4-phenylbutyrate (0.62g, 3.0mmol, 1.0 eq), two steps were carried out using general method 3 to give S72 as a colorless oil (0.69g, 85% yield).
1H NMR(400MHz,CDCl3)δ7.43–7.38(m,2H),7.37–7.32(m,2H),7.32–7.26(m,1H),5.07–5.00(m,1H),4.13(q,J＝7.2Hz,2H),2.66–2.31(m,4H),1.25(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 172.5,141.6,128.9,128.6,127.4,60.7,54.4,35.1,32.9, 14.3. HRMS (ESI) m/z accurate mass calculation C12H16BrO2[M+H]+271.0328, found 271.0331. HRMS (ESI) m/z accurate massCalculating C12H15O2[M–Br]+191.1067, found 191.1065.
Starting from ethyl 5-oxo-5-phenylpentanoate (0.66g, 3.0mmol, 1.0 eq), two steps were carried out using general method 3 to give S73 as a colourless oil (0.75g, 88% yield).
1H NMR(400MHz,CDCl3)δ7.41–7.37(m,2H),7.37–7.31(m,2H),7.31–7.27(m,1H),4.95(dd,J＝8.0,6.8Hz,1H),4.12(q,J＝7.2Hz,2H),2.37–2.25(m,3H),2.24–2.13(m,1H),1.91–1.77(m,1H),1.71–1.58(m,1H),1.25(t,J＝7.0Hz,3H)。13C NMR(100MHz,CDCl3) δ 173.1,142.0,128.8,128.5,127.3,60.5,54.9,39.4,33.5,23.8, 14.4. HRMS (ESI) m/z accurate mass calculation C13H17O2[M–Br]+205.1223, found 205.1222.
Starting from 3-chloro-1-phenyl-1-propanone (0.51g, 3.0mmol, 1.0 equiv.) using general procedure 3, S81 was obtained in two steps as a colorless oil (0.64g, 92% yield).
1H NMR(400MHz,CDCl3)δ7.46–7.25(m,5H),5.21(dd,J＝9.0,5.7Hz,1H),3.82–3.65(m,1H),3.63–3.39(m,1H),2.85–2.60(m,1H),2.56–2.38(m,1H)。13C NMR(100MHz,CDCl3) δ 141.0,129.0,128.8,127.5,51.5,42.9, 42.2. HRMS (ESI) m/z accurate mass calculation C9H10Cl[M–Br]+153.0466, found 153.0466.
Starting from p-methyl propiophenone (0.44g, 3.0mmol, 1.0 equiv), S82 was obtained in two steps using general method 3 as a colorless oil (0.57g, 89% yield).
1H NMR(400MHz,CDCl3)δ7.26(d,J＝8.0Hz,2H),7.12(d,J＝8.0Hz,2H),4.86(t,J＝7.4Hz,1H),2.32(s,3H),2.30–2.21(m,1H),2.19–2.08(m,1H),0.98(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 139.3,138.2,129.4,127.3,57.9,33.3,21.3, 13.2. HRMS (ESI) m/z accurate mass calculation C10H13[M–Br]+133.1012, found 133.1012.
Starting from m-methyl propiophenone (0.44g, 3.0mmol, 1.0 equiv), S83 was obtained in two steps using general method 3 as a colorless oil (0.54g, 85% yield).
1H NMR(400MHz,CDCl3)δ7.22–7.12(m,3H),7.07–7.02(m,1H),4.82(dd,J＝8.0,6.8Hz,1H),2.31(s,3H),2.29–2.19(m,1H),2.18–2.06(m,1H),0.97(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.1,138.3,129.1,128.5,128.0,124.4,57.8,33.3,21.4, 13.1. HRMS (ESI) m/z accurate mass calculation C10H13[M–Br]+133.1012, found 133.1012.
Starting from o-methylacetophenone (0.44g, 3.0mmol, 1.0 equiv.) by general method 3, S84 was obtained in two steps as a colorless oil (0.51g, 80% yield).
1H NMR(400MHz,CDCl3)δ7.48(dd,J＝8.0,1.4Hz,1H),7.24–7.10(m,3H),5.12(dd,J＝8.4,6.8Hz,1H),2.41–2.29(m,4H),2.25–2.12(m,1H),1.03(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 140.0,135.5,130.7,128.2,126.72,126.70,54.0,32.2,19.2, 13.2. HRMS (ESI) m/z accurate mass calculation C10H13[M–Br]+133.1012, found 133.1012.
Starting from 2' -bromoacetophenone (0.59g, 3.0mmol, 1.0 equiv.), in two steps using general procedure 3, S90 was obtained as a colorless oil (0.70g, 89% yield).
1H NMR(400MHz,CDCl3)δ7.66(dd,J＝7.9,1.7Hz,1H),7.55(dd,J＝8.0,1.3Hz,1H),7.35(td,J＝7.6,1.3Hz,1H),7.16–7.12(m,1H),5.61(q,J＝6.9Hz,1H),2.04(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.0,133.2,129.8,128.4,128.2,123.2,47.6, 26.2. HRMS (ESI) m/z accurate mass calculation C8H8Br[M–Br]+182.9804, found 182.9804.
Starting from methyl 3-acetylbenzoate (0.53g, 3.0mmol, 1.0 equiv.) in two steps using general procedure 3, S93 was obtained as a colorless oil (0.68g, 93% yield).
1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.96(d,J＝7.8Hz,1H),7.64(d,J＝7.7Hz,1H),7.42(t,J＝7.7Hz,1H),5.23(q,J＝6.9Hz,1H),3.93(s,3H),2.06(d,J＝7.0Hz,3H)。13C NMR(100MHz,CDCl3) δ 166.7,143.8,131.6,130.7,129.6,129.0,128.0,52.4,48.4, 26.8. HRMS (ESI) m/z accurate mass calculation C10H11O2[M–Br]+163.0754, found 163.0753.
Starting from 3-acetylbenzonitrile (0.44g, 3.0mmol, 1.0 equiv), S94 was obtained in two steps as a colorless oil (0.55g, 88% yield) using general method 3.
1H NMR(400MHz,CDCl3)δ7.71(s,1H),7.67–7.63(m,1H),7.58–7.54(m,1H),7.47–7.42(m,1H),5.15(q,J＝6.9Hz,1H),2.03(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 144.8,131.9,131.5,130.5,129.7,118.4,112.7,46.9, 26.6. HRMS (ESI) m/z accurate mass calculation C9H8N[M–Br]+130.0651, found 130.0652.
Starting from 4- (trifluoromethyl) propiophenone (0.61g, 3.0mmol, 1.0 eq.) by general method 3, in two steps S95 was obtained as a colorless oil (0.75g, 94% yield).
1H NMR(400MHz,CDCl3)δ7.59(d,J＝8.4Hz,2H),7.49(d,J＝8.4Hz,2H),4.87(dd,J＝8.4,6.8Hz,1H),2.34–2.22(m,1H),2.20–2.07(m,1H),1.00(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3)δ146.1,130.4(q,J＝32.5Hz),128.1,125.8(q,J＝3.7Hz),124.1(q,J＝272.1Hz),55.7,33.2,12.9。19F NMR(376MHz,CDCl3) Delta-62.7 (s, 3F). HRMS (ESI) m/z accurate mass calculation C10H10F3[M–Br]+187.0729, found 187.0728.
Starting from 2-acetonaphthone (0.51g, 3.0mmol, 1.0 equiv), S97 was obtained in two steps as a white solid (0.59g, 84% yield) using general method 3.
1H NMR(400MHz,CDCl3)δ7.90–7.77(m,4H),7.59(dd,J＝8.5,1.9Hz,1H),7.53–7.43(m,2H),5.40(q,J＝6.9Hz,1H),2.14(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 140.6,133.3,133.2,128.8,128.2,127.8,126.62,126.60,125.3,125.2,50.1, 26.9. HRMS (ESI) m/z accurate mass calculation C12H11[M–Br]+155.0855, found 155.0855.
Starting from 1- (benzo [ d ] [1,3] dioxol-5-yl) -1-ethanone (0.49g, 3.0mmol, 1.0 equiv.) using general procedure 3, two steps gave S98 as a pale yellow oil (0.56g, 82% yield).
1H NMR(400MHz,CDCl3)δ6.90(s,1H),6.86–6.73(m,2H),5.95(s,2H),4.81(q,J＝6.4Hz,1H),1.46(d,J＝6.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 147.7,146.8,140.0,118.7,108.1,106.1,101.0,70.2, 25.1. HRMS (ESI) m/z accurate mass calculation C9H9O2[M–Br]+119.0597, found 149.0597.
Starting from 3-thienylethanone (0.38g, 3.0mmol, 1.0 equiv.) by general method 3, S104 was obtained in two steps as a light brown oil (0.43g, 76% yield).
1H NMR(400MHz,CDCl3)δ7.33(dd,J＝5.2,2.8Hz,1H),7.31–7.27(m,1H),7.21(dd,J＝5.2,1.2Hz,1H),5.35(q,J＝6.9Hz,1H),2.09(d,J＝6.8Hz,3H)。13C NMR(100MHz,CDCl3) δ 144.4,126.9,126.4,121.7,44.4, 26.7. HRMS (ESI) m/z accurate mass calculation C6H7S[M–Br]+111.0263, found 111.0266.
Starting from 1- (thiazol-4-yl) -1-ethanone (0.38g, 3.0mmol, 1.0 equiv.) using general procedure 3, S107 was obtained in two steps as a yellow oil (0.39g, 68% yield).
1H NMR(400MHz,CDCl3)δ8.84(d,J＝2.0Hz,1H),7.34(d,J＝2.0Hz,1H),5.42(q,J＝6.4Hz,1H),2.14(d,J＝6.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 158.4,153.3,115.1,42.9, 25.4. HRMS (ESI) m/z accurate mass calculation C5H7BrNS[M+H]+191.9477, found 191.9476. HRMS (ESI) m/z accurate mass calculation C5H6NS[M–Br]+112.0215, trueMeasured value 112.0218.
General procedure 4: ethyl magnesium bromide (1.0mol/L in THF, 1.2 equiv.) was added slowly to a solution of the aldehyde (1.0 equiv.) in anhydrous THF at 0 deg.C, and the reaction mixture was then warmed to room temperature and stirred for an additional 1 hour until the aldehyde was completely consumed (monitored by TLC). Quench the reaction with 3.0M HCl and CH2Cl2Extracting three times, mixing the organic phase with Na2SO4Drying, filtering, vacuum concentrating, and purifying by silica gel column chromatography to obtain alcohol compound.
The method a comprises the following steps: carbon tetrabromide (1.5 equivalents) was added in one portion to a THF mixture of alcohol and triphenylphosphine (1.8 equivalents) at 0 deg.C under argon. After stirring for a short time at 0 ℃, the mixture was warmed to room temperature and stirred for a further 25 minutes, the mixture was filtered through a pad of celite and washed with THF, the solution was concentrated in vacuo and purified by flash chromatography to give the corresponding product.
The method b: under vigorous stirring at 0 deg.C, PBr3(0.7 equiv.) CH to alcohol2Cl2Then, the temperature was raised to room temperature. After completion of the reaction (monitored by TLC), the mixture was quenched with water and with CH2Cl2Extraction was carried out three times, the combined organic phases were washed with brine and Na2SO4Dry, filter on silica gel using a funnel, and concentrate in vacuo to give the corresponding crude product, which is used directly in the next step without further purification or stored in a refrigerator (the product readily decomposes on air and silica gel).
Starting from 3-methoxybenzaldehyde (0.41g, 3.0mmol, 1.0 equiv.) by general method 4 and method b, S85 was obtained in two steps as a colorless oil (0.63g, 92% yield).
1H NMR(400MHz,CDCl3)δ7.29(t,J＝8.0Hz,1H),7.07–6.94(m,2H),6.90–6.83(m,1H),4.88(t,J＝7.2Hz,1H),3.85(s,3H),2.40–2.11(m,2H),1.04(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 159.7,143.6,129.7,119.6,113.7,113.0,57.4,55.3,33.3, 13.0. HRMS (ESI) m/z accurate mass calculation C10H13O[M–Br]+149.0961, found 149.0961.
Starting with 4-bromobenzaldehyde (1.1g, 5.0mmol, 1.0 equiv.), S88 was obtained in two steps as a yellow oil (1.1g, 78% yield) using general method 4 and method b.
The characterization data are consistent with the data reported in the literature (J.T. Binder, C.J. cordier, G.C.Fu, Catalytic organic selective cross-linking of secondary alkyl polymers with secondary alkyl monomers: New Girishi reactions of cationic benzyl polymers with acrylic alkyl reagents J.Am.Chem.Soc.134,17003-17006 (2012)).
Starting from 3-bromobenzaldehyde (0.64g, 3.0mmol, 1.0 equiv.), two steps were carried out using general method 4 and method b to give S89 as a yellow oil (0.68g, 82% yield).
1H NMR(400MHz,CDCl3)δ7.57(t,J＝1.8Hz,1H),7.46–7.44(m,1H),7.29–7.26(m,1H),7.25–7.23(m,1H),4.82(dd,J＝8.1,6.7Hz,1H),2.35–2.06(m,2H),1.02(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 144.4,131.4,130.4,130.3,126.1,122.6,55.9,33.2, 13.0. HRMS (ESI) m/z accurate mass calculation C9H10Br[M–Br]+196.9960, found 196.9960.
Starting from 3, 5-bis (trifluoromethyl) benzaldehyde (0.73g, 3.0mmol, 1.0 equiv.) using general method 4 and method b, two steps gave S96 as a colorless oil (0.95g, 95% yield).
1H NMR(400MHz,CDCl3)δ7.86(s,2H),7.83(s,1H),4.92(dd,J＝8.3,6.4Hz,1H),2.39–2.28(m,1H),2.24–2.14(m,1H),1.07(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3)δ144.7,132.1(q,J＝33.5Hz),127.5,123.1(q,J＝272.8Hz),122.2–122.0(m),54.0,33.1,12.7。19F NMR(376MHz,CDCl3) Delta-62.9 (s, 6F). HRMS (ESI) m/z accurate mass calculation C11H9F6[M–Br]+255.0603, found 255.0603.
Starting from nicotinaldehyde (0.32g, 3.0mmol, 1.0 equiv), S100 was obtained in two steps as a pale yellow oil (0.48g, 80% yield) using general procedure 4 and procedure a.
1H NMR(400MHz,CDCl3)δ8.61(d,J＝2.0Hz,1H),8.53(dd,J＝4.8,1.6Hz,1H),7.75(dt,J＝7.6,1.8Hz,1H),7.29(dd,J＝7.6,4.8Hz,1H),4.87(dd,J＝8.4,6.8Hz,1H),2.36–2.23(m,1H),2.21–2.09(m,1H),1.02(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 149.5,148.6,137.9,134.9,123.7,54.0,33.1, 12.9. HRMS (ESI) m/z accurate mass calculation C8H11BrN[M+H]+200.0069, found 200.0066. HRMS (ESI) m/z accurate mass calculation C8H10N[M–Br]+120.0808, found 120.0808.
Starting from 3-carbaldehyde benzothiophene (0.49g, 3.0mmol, 1.0 equiv.), using general procedure 4 and procedure b, S103 was obtained in two steps as a yellow oil (0.53g, 70% yield).
1H NMR(400MHz,CDCl3)δ7.93(d,J＝8.0Hz,1H),7.83(d,J＝8.0Hz,1H),7.44(s,1H),7.44–7.39(m,1H),7.38–7.33(m,1H),5.26(dd,J＝8.3,6.2Hz,1H),2.52–2.29(m,2H),1.11(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 140.6,137.0,136.6,124.8,124.2,124.0,123.0,122.5,50.4,31.6, 13.3. HRMS (ESI) m/z accurate mass calculation C11H11S[M–Br]+175.0576, found 175.0573.
Starting from 3-carbaldehyde benzofuran (0.44g, 3.0mmol, 1.0 equiv.) using general procedure 4 and procedure b, S105 was obtained in two steps as a yellow oil (0.52g, 72% yield).
1H NMR(400MHz,CDCl3)δ7.81–7.77(m,1H),7.67(s,1H),7.54–7.50(m,1H),7.40–7.29(m,2H),5.23–5.09(m,1H),2.54–2.30(m,2H),1.14(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 155.8,141.8,125.9,125.0,122.8,122.4,120.8,111.8,47.9,31.9, 13.2. HRMS (ESI) m/z accurate mass calculation C11H11O[M–Br]+159.0804, found 159.0802.
Starting from 5-carbaldehyde pyrimidine (0.32g, 3.0mmol, 1.0 equiv), general method 4 and method a was used to give S108 as a light yellow oil by silica gel column chromatography (petroleum ether/ethyl acetate ═ 4/1) (0.29g, 48% two step yield).
1H NMR(400MHz,CDCl3)δ9.12(s,1H),8.75(s,2H),4.79(dd,J＝8.2,6.6Hz,1H),2.35–2.22(m,1H),2.21–2.08(m,1H),1.04(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 158.3,155.9,136.0,50.0,32.8, 12.8. HRMS (ESI) m/z accurate mass calculation C7H10BrN2[M+H]+201.0022, found 201.0022. HRMS (ESI) m/z accurate mass calculation C7H9N2[M–Br]+121.0760, found 121.0762.
General procedure 5: add NaBH to a solution of ketone (5.0mmol, 1.0 equiv.) in EtOH (20.0mL) over a period of 0.5-2 hours at room temperature4(228.0mg, 6.0mmol, 1.2 equiv.). After completion of the reaction (monitored by TLC), the reaction was quenched with water and quenched with CH2Cl2Diluting and using CH2Cl2Extraction was carried out three times, the combined organic phases were washed with brine and Na2SO4Drying, filtration and concentration in vacuo gave the corresponding alcohol without further purification.
To a solution of the alcohol (1.0 eq) and triphenylphosphine (1.8 eq) in THF, under argon protection, carbon tetrabromide (1.5 eq) was added in one portion and stirred at 0 ℃ for 5 minutes. The mixture was then warmed to room temperature and stirred for an additional 2 hours. The precipitate was filtered off through a pad of celite and washed with cold THF, the solution was concentrated in vacuo and purified by flash chromatography to give the corresponding bromo compound.
Starting from 1- (6-bromopyridin-3-yl) ethanone (1.0g, 5.0mmol, 1.0 equiv.) using general method 5, chromatography on silica gel (petroleum ether/ethyl acetate ═ 10/1) afforded S101 as a colorless oil (1.1g, 84% two-step yield).
1H NMR(400MHz,CDCl3)δ8.39(d,J＝2.6Hz,1H),7.65(dd,J＝8.3,2.6Hz,1H),7.48(d,J＝8.3Hz,1H),5.13(q,J＝7.0Hz,1H),2.03(d,J＝7.0Hz,3H)。13C NMR(100MHz,CDCl3) δ 148.3,141.8,138.5,137.3,128.4,44.3, 26.6. HRMS (ESI) m/z accurate mass calculation C7H8Br2N[M+H]+263.9018, found 263.9017. HRMS (ESI) m/z accurate mass calculation C7H7BrN[M–Br]+183.9756, found 183.9756.
Starting from 1- (5-bromopyridin-3-yl) ethanone (1.0g, 5.0mmol, 1.0 eq), S102 was obtained as a colorless oil by silica gel column chromatography (petroleum ether/ethyl acetate ═ 10/1) using general method 5 (1.1g, 82% two-step yield).
1H NMR (400MHz, CDCl3) δ 8.56(dd, J ═ 12.2,2.1Hz,2H),7.91(t, J ═ 2.0Hz,1H),5.11(q, J ═ 7.0Hz,1H),2.03(d, J ═ 7.0Hz, 3H). 13C NMR (100MHz, CDCl3) delta 150.7,146.3,140.6,137.2,120.9,44.1, 26.6. HRMS (ESI) m/z accurate mass calculation C7H8Br2N[M+H]+263.9018, found 263.9017. HRMS (ESI) m/z accurate mass calculation C7H7BrN[M–Br]+183.9756, found 183.9756.
Starting from 1-quinolin-3-yl-ethanone (0.86g, 5.0mmol, 1.0 eq) using general method 5, S106 was obtained as a yellowish oil by silica gel column chromatography (petroleum ether/ethyl acetate-10/1) (0.64g, 54% two-step yield).
1H NMR(400MHz,CDCl3)δ9.00(d,J＝2.3Hz,1H),8.15(d,J＝2.3Hz,1H),8.10(d,J＝8.4Hz,1H),7.82(dd,J＝8.2,1.4Hz,1H),7.72(ddd,J＝8.4,6.9,1.5Hz,1H),7.57(ddd,J＝8.1,6.9,1.2Hz,1H),5.39(q,J＝7.0Hz,1H),2.17(d,J＝7.0Hz,3H)。13C NMR(100MHz,CDCl3) δ 150.3,147.8,136.1,133.1,130.1,129.4,128.1,127.6,127.3,46.0, 26.5. HRMS (ESI) m/z accurate mass calculation C11H10N[M–Br]+156.0808, found 156.0807.
General procedure 6: benzaldehyde (0.32g, 3.0mmol, 1.0 equiv.) was dissolved in anhydrous Et under argon2In O, cooled to 0 ℃ and Grignard reagent (3.6mmol, 1.2 equiv.) is added dropwiseInto solution. The reaction mixture was warmed to room temperature and stirred for an additional 1 hour until the aldehyde was completely consumed (monitored by TLC). Thereafter, the reaction was quenched with 3.0M HCl and CH2Cl2Extraction was carried out three times, the combined organic phases were washed with brine and Na2SO4Dried, filtered and concentrated in vacuo and the crude product was used in the next step without further purification.
Dissolving the crude alcohol in CH2Cl2In (1), cooling to 0 ℃, and adding PBr dropwise under vigorous stirring3(0.7 equiv.) and then stirred at 0 ℃ for 3h, after completion of the reaction (monitored by TLC), the reaction was quenched with water and quenched with CH2Cl2Extraction was carried out three times, the combined organic phases were washed with brine and Na2SO4Drying, filtration over short silica gel and concentration in vacuo afforded the corresponding compound without further purification.
Starting from (3-phenylpropyl) magnesium bromide (3.6mL, 3.6mmol, 1.0mol/L in THF, 1.2 equiv.) using general method 6, two steps gave S62 as a colorless oil (0.78g, 90% yield).
1H NMR(400MHz,CDCl3)δ7.39–7.24(m,7H),7.20–7.13(m,3H),4.94(dd,J＝8.0,6.8Hz,1H),2.63(t,J＝7.6Hz,2H),2.36–2.25(m,1H),2.22–2.10(m,1H),1.89–1.76(m,1H),1.69–1.55(m,1H)。13C NMR(100MHz,CDCl3) δ 142.2,141.8,128.8,128.50,128.49,128.4,127.4,126.0,55.5,39.6,35.2, 30.1. HRMS (ESI) m/z accurate mass calculation C16H17[M–Br]+209.1325, found 209.1325.
Using allylmagnesium bromide (3.6mL, 3.6mmol, 1.0mol/L in THF, 1.2 equiv.) as starting material, S69 was obtained in two steps using general method 6 as a colorless oil (0.60g, 95% yield).
1H NMR(400MHz,CDCl3)δ7.43–7.37(m,2H),7.37–7.31(m,2H),7.31–7.25(m,1H),5.82–5.65(m,1H),5.19–5.04(m,2H),4.96(dd,J＝8.0,7.0Hz,1H),3.12–2.86(m,2H)。13C NMR(100MHz,CDCl3) δ 141.7,134.8,128.8,128.5,127.5,118.3,54.2, 44.2. HRMS (ESI) m/z accurate mass calculation C10H11[M–Br]+131.0855, found 131.0856.
Starting from 4-penten-1-yl magnesium bromide (3.6mL, 3.6mmol, 1.0mol/L in THF, 1.2 equiv.) in two steps using general method 6, S70 was obtained as a colorless oil (0.63g, 88% yield).
1H NMR(400MHz,CDCl3)δ7.42–7.38(m,2H),7.37–7.32(m,2H),7.32–7.27(m,1H),5.78(ddt,J＝16.9,10.2,6.7Hz,1H),5.09–4.91(m,3H),2.38–2.23(m,1H),2.23–2.04(m,3H),1.71–1.57(m,1H),1.45–1.37(m,1H)。13C NMR(100MHz,CDCl3) δ 142.2,138.0,128.7,128.3,127.3,115.1,55.5,39.4,33.0, 27.5. HRMS (ESI) m/z accurate mass calculation C12H15[M–Br]+159.1168, found 159.1168.
General procedure 7: to the benzyl derivative (5.0mmol, 1.0 equiv.) of CCl4To a solution (10.0mL) were added N-bromosuccinimide (0.89g, 5.5mmol, 1.1 equiv.) and benzoyl peroxide (36.3mg, 0.15mmol, 0.03 equiv.), and the resulting mixture was refluxed overnight. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature, the precipitate was filtered off through a pad of celite, and CCl was used4(10.0mL) and the solution was concentrated in vacuo to give the corresponding product by silica gel column chromatography.
Using 1-bromo-3-phenylpropane (0.99g, 5.0mmol, 1.0 eq) as starting material, S80 was obtained as a colorless oil by column chromatography on silica gel (petroleum ether ═ 100) using general method 7 (1.2g, 88% yield).
1H NMR(400MHz,CDCl3)δ7.46–7.29(m,5H),5.33–5.03(m,1H),3.62–3.50(m,1H),3.49–3.39(m,1H),2.85–2.73(m,1H),2.63–2.48(m,1H)。13C NMR(100MHz,CDCl3) δ 140.9,129.0,128.9,127.5,52.6,42.2, 31.1. HRMS (ESI) m/z accurate mass calculation C9H10Br[M–Br]+196.9960, found 196.9962.
Using 3-ethylbenzaldehyde (0.67g, 5.0mmol, 1.0 eq) as starting material, S91 was obtained as a colorless oil by column chromatography on silica gel (petroleum ether ═ 100) using general method 7 (0.93g, 88% yield).
1H NMR(400MHz,CDCl3)δ10.02(s,1H),7.94(t,J＝1.8Hz,1H),7.80(dt,J＝7.6,1.4Hz,1H),7.73–7.67(m,1H),7.52(t,J＝7.6Hz,1H),5.24(q,J＝6.9Hz,1H),2.07(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 191.9,144.5,136.9,133.1,129.9,129.6,127.7,47.9, 26.8. HRMS (ESI) m/z accurate mass calculation C9H10BrO[M+H]+212.9910, found 212.9908. HRMS (ESI) m/z accurate mass calculation C9H9O[M–Br]+133.0648, found 133.0648.
S75-2(j. streuff, m. feurer, p. bichovski, g. frey, u.gelrich, endogenous selective titanium (III) -catalyzed recycling of ketones, angle. chem., int. ed.51,8661-8664(2012)) was synthesized according to literature reported methods.
To stirred S75-1 (1) at 0 ℃.1g, 6.3mmol, 1.0 equiv.) in anhydrous Et2To a solution of O (30.0mL) was added dropwise phenylmagnesium bromide (6.3mL, 2.5M in THF, 15.8mmol, 2.5 equiv.). The solution was warmed to room temperature and reacted for 3 hours. The reaction was quenched with 2.0M HCl and Et2O extraction three times, combined organic phases washed with brine, Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petrol ether/ethyl acetate 10/1) to give compound S74-1(1.2g, 75% yield) with characterization data in accordance with literature reports (h. ochiai, t. nishihara, y. tamaru, z. yoshida, titan (iv) -medium-type condensation of detectors and zinc keys with carboxylic electrolytes, j. org. chem.53,1343-1344 (1988)).
Starting from S74-1(0.76g, 3.0mmol, 1.0 equiv), S74 was obtained as a white solid (0.80g, 84% yield) using method b of general method 4.
Compound S74 characterization data:1H NMR(400MHz,CDCl3)δ7.97–7.88(m,2H),7.59–7.53(m,1H),7.49–7.39(m,4H),7.37–7.32(m,2H),7.30–7.27(m,1H),5.05–4.97(m,1H),3.01(t,J＝7.1Hz,2H),2.46–2.17(m,2H),2.01–1.90(m,1H),1.85–1.71(m,1H)。13C NMR(100MHz,CDCl3) δ 199.6,142.0,136.9,133.2,128.9,128.8,128.5,128.1,127.4,55.2,39.5,37.7, 23.0. HRMS (ESI) m/z accurate mass calculation C17H17O[M–Br]+237.1274, found 237.1272.
Using S75-2(0.52g, 3.0mmol, 1.0 equiv.) as a substrate, S75 was obtained in two steps as a colorless oil (0.63g, 88% yield) using general method 3.
Compound S75 characterization data:1H NMR(400MHz,CDCl3)δ7.42–7.33(m,4H),7.32–7.28(m,1H),4.94(dd,J＝8.4,6.0Hz,1H),2.46–2.35(m,3H),2.33–2.22(m,1H),1.98–1.84(m,1H),1.76–1.62(m,1H)。13C NMR(100MHz,CDCl3) δ 141.3,128.9,128.7,127.2,119.1,53.8,38.7,24.2, 16.6. HRMS (ESI) m/z accurate mass calculation C11H13BrN[M+H]+238.0226, found 238.0224. HRMS (ESI) m/z accurate mass calculation C11H12N[M–Br]+158.0964, found 158.0964.
S76-3(J.C.Stowell, M.A.Polito, A surface procedure for processing gamma-halo butyl aldehyde acids.J.Org.Chem.57, 2195-2196 (1992)) was synthesized according to literature reports.
To a solution of alcohol S76-3(2.1g, 12.0mmol, 1.0 equiv.) in CH2Cl2To a mixed solution of (40.0mL) and DMSO (8.0mL) was added 2-iodobenzoic acid (4.0g, 14.4mmol, 1.0 equiv.), and the reaction was heated to 50 ℃ and held for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was hydrolyzed with water, filtered over a pad of celite and washed with CH2Cl2Extraction was carried out three times, the combined organic phases were washed with brine and Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate. RTM. 15/1) to give aldehyde S76-2 as a colorless liquid (1.4g, 67% yield) with characterization data consistent with literature reports (D.Yang, G.C. Micalizio, Convergent and stereospecific synthesis of complex 1-Aza-7-oxolanyl 2.2.1heptanes. J.am. chem. Soc.133,9216-9219 (2011)).
Starting from S76-2(0.79g, 3.0mmol, 1.0 equiv.) by general method 4 and method a using triphenylphosphine (3.6mmol, 1.2 equiv.) and carbon tetrabromide (3.6mmol, 1.2 equiv.) as solvent with CH2Cl2Instead of THF, S76 was obtained.
Characterization data for compound S76-1: as a colorless oil (0.98g, 62% yield).
1H NMR(400MHz,CDCl3)δ7.38–7.29(m,4H),7.27–7.21(m,1H),4.69(td,J＝6.4,2.8Hz,1H),4.45(t,J＝4.6Hz,1H),3.68–3.53(m,2H),3.41(d,J＝10.7Hz,2H),2.88(d,J＝3.2Hz,1H),1.93–1.86(m,2H),1.84–1.64(m,2H),1.18(s,3H),0.71(s,3H)。13C NMR(100MHz,CDCl3)δ144.9,128.4,127.4,125.9,101.9,77.3,74.2,33.4,31.2,30.2,23.1,21.9。
Compound S76 characterization data: as a colorless oil (0.62g, 64% yield).
1H NMR(400MHz,CDCl3)δ7.44–7.24(m,5H),5.03–4.96(m,1H),4.45(t,J＝4.7Hz,1H),3.62–3.54(m,2H),3.39(d,J＝11.1Hz,2H),2.49–2.25(m,2H),1.90–1.79(m,1H),1.71–1.63(m,1H),1.17(s,3H),0.71(s,3H)。13C NMR(100MHz,CDCl3) δ 142.2,128.8,128.4,127.4,101.2,77.3,55.6,34.4,33.6,30.2,23.1, 21.9. HRMS (ESI) m/z accurate mass calculation C15H21O2[M–Br]+233.1536, found 233.1534.
S77-2(C.Uyeda, E.N.Jacobsen, endogenous Claisen reargements with a hydrogen-bond dornor catalyst.J.Am.chem.Soc.130,9228-9229(2008), P.H.Huy, A.M.P.Koskinen, effective, stereogenic access to 3-polyperidols by trap P (OEt) was synthesized according to literature reported methods3cyclodehydration.Org.Lett.15,5178-5181(2013))。
S77-1(P.H.Huy, S.Motsch, S.M.Kappler, formalides as Lewis base catalysts in S) was synthesized according to literature reported methodsN reactions-efficient transformation of alcohols into chlorides,amines,and ethers.Angew.Chem.,Int.Ed.55,10145-10149(2016))。
Using S77-1(1.2g, 3.0mmol, 1.0 equivalent) as a starting material, S77 was obtained as a colorless oil by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) using triphenylphosphine (0.94g, 3.6mmol, 1.2 equivalents) and carbon tetrabromide (1.2g, 3.6mmol, 1.2 equivalents) according to method a of general method 4 (0.84g, 60% yield).
Compound S77 characterization data:1H NMR(400MHz,CDCl3)δ7.69–7.64(m,4H),7.48–7.29(m,11H),5.05–4.92(m,1H)3.79–3.63(m,2H),2.46–2.24(m,2H),1.83–1.69(m,1H),1.67–1.51(m,1H),1.08(s,9H)。13C NMR(100MHz,CDCl3) δ 142.3,135.7,133.9,129.8,128.8,128.4,127.8,127.4,63.1,55.6,36.6,31.2,27.0, 19.3. HRMS (ESI) m/z accurate mass calculation C26H31OSi[M–Br]+387.2139, found 387.2137.
To a mixture of diol (0.83g, 5.0mmol, 1.0 equiv.) in iodomethane (15.0mL) was added Ag in one portion2O (3.5g, 15.0mmol, 3.0 equiv.) and stirred at room temperature overnight. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite, the filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 6/1) to give S78-1 as a colorless liquid (0.45g, 50% yield).
Characterization data for compound S78-1:1H NMR(400MHz,CDCl3)δ7.35–7.28(m,4H),7.26–7.21(m,1H),4.64(td,J＝6.4,3.1Hz,1H),3.38(t,J＝6.1Hz,2H),3.30(s,3H),3.18(d,J＝3.3Hz,1H),1.82–1.76(m,2H),1.74–1.53(m,2H)。13C NMR(100MHz,CDCl3)δ144.9,128.4,127.3,125.9,74.1,72.8,58.6,36.5,26.2。
starting from S78-1(0.36g, 2.0mmol, 1.0 equiv), following general procedure 4, method b gave S78 as a colorless oil (0.48g, 98% yield).
Compound S78 characterization data:1H NMR(400MHz,CDCl3)δ7.42–7.37(m,2H),7.36–7.30(m,2H),7.30–7.24(m,1H),4.98(dd,J＝8.4,6.7Hz,1H),3.44–3.36(m,2H),3.31(s,3H),2.42–2.18(m,2H),1.84–1.71(m,1H),1.66–1.52(m,1H)。13C NMR(100MHz,CDCl3) δ 142.2,128.8,128.5,127.4,71.9,58.7,55.6,36.9, 28.5. HRMS (ESI) m/z accurate mass calculation C11H15O[M–Br]+163.1117, found 163.1110.
S79-1 was synthesized according to literature reported methods (J.C. Cartero, J.Rojo, N.Diaz, C.Hamdouchi, A.Poveda, New one-step process for the synthesis of functionalized 1,6-dioxaspiro 4,5 cancel. tetrahedron51,8507-8524 (1995)).
Using S79-1(0.83g, 3.0mmol, 1.0 equiv.) as starting material, S79 was obtained in two steps as colorless oil (0.96g, 95% yield) using method b of general method 4.
Compound S79 characterization data:1H NMR(400MHz,CDCl3)δ7.93–7.88(m,2H),7.71–7.64(m,1H),7.61–7.55(m,2H),7.36–7.27(m,5H),5.00(dd,J＝8.7,6.3Hz,1H),3.41–3.26(m,1H),3.25–3.07(m,1H),2.75–2.45(m,2H)。13C NMR(100MHz,CDCl3) δ 140.4,139.0,134.1,129.6,129.1,129.0,128.1,127.3,54.8,52.1, 33.1. HRMS (ESI) m/z accurate mass calculation C15H15O2S[M–Br]+259.0787, found 259.0785.
Commercial Lithium Diisopropylamide (LDA) (4.0ml, 8.0mmol, 1.0 equiv., 2.0M in THF/heptane/ethylbenzene) was diluted with anhydrous THF (4.0ml) and hexane (4.0ml) and the mixture was cooled to-100 ℃. A solution of benzyl bromide (1.37g, 8.0mmol, 1.0 equiv.) and chlorotrimethylsilane (TMSCl, 1.04g, 9.6mmol, 1.2 equiv.) in dry THF (4.0ml) was added dropwise. Stirring at-100 deg.C for 1 hr, naturally heating the reaction to-20 deg.C, quenching with water, and separating organic phase. Et for aqueous phase2O extraction three times, combined organic phases washed with 2.0M alkene hydrochloric acid and brine, Na2SO4Dried and concentrated in vacuo. The crude product was purified by distillation under reduced pressure to give S130 as a colorless oil (1.05g, 54% yield).
Compound S130 characterization data:1H NMR(400MHz,CDCl3)δ7.21–7.06(m,5H),4.17(s,1H),0.00(s,9H)。13C NMR(100MHz,CDCl3)δ140.4,128.4,128.0,126.8,43.8,–2.8。
s86-2 was synthesized according to literature reported methods (L.ZHao et al, Fragment-based drug discovery of2-thiazolidinones as inhibitors of the histone readers BRD4 bromodel.J.Med.chem.56, 3833-3851 (2013)).
Starting from S86-2(0.53g, 3.0mmol, 1.0 equiv.) in two steps using general procedure 3, S86 was obtained as a colorless oil (0.42g, 58% yield).
Compound S86 characterization data:1H NMR(400MHz,CDCl3)δ7.62(s,1H),7.52(s,1H),7.43(d,J＝8.3Hz,1H),7.33–7.24(m,1H),7.18(d,J＝7.7Hz,1H),5.16(q,J＝6.9Hz,1H),2.18(s,3H),2.02(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 169.5,144.1,138.2,129.3,122.8,120.2,118.7,49.3,26.8, 24.4. HRMS (ESI) m/z accurate mass calculation C10H12NO[M–Br]+162.0913, found 162.0912.
S87-1(C.J. Bennett et al, functional therapeutic antioxidants and organic stabilizing ability of mycotin and lipophilic chain of vitamin E to effect microbiological inactivation. bioorg.Med.chem.12,2079-2098 (2004)) was synthesized according to literature reports.
Using S87-1(0.82g, 5.0mmol, 1.0 equiv.) as a starting material, S87 was obtained as a colorless oil by column chromatography on silica gel (petroleum ether/ethyl acetate ═ 10/1) using general method 7 (1.0g, 86% yield).
Compound S87 characterization data:1H NMR(400MHz,CDCl3)δ7.38–7.27(m,2H),7.18(t,J＝2.0Hz,1H),7.05–7.00(m,1H),5.18(q,J＝6.9Hz,1H),2.30(s,3H),2.03(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 169.4,150.8,144.9,129.7,124.4,121.7,120.2,48.4,26.8, 21.2. HRMS (ESI) m/z accurate mass calculation C10H11O2[M–Br]+163.0754, found 163.0753.
S92-1 was synthesized according to the methods reported in the literature (M.Uchiyama et al, high enzymatic reduction of systematic diacetylaromatics with hands' S year. tetrahedron: Asymmetry 8,3467-3474 (1997)).
Using S92-1(0.82g, 5.0mmol, 1.0 equiv.) as starting material, general method 3 was employed to give S92 as a colorless oil (1.0g, 89% yield).
Compound S92 characterization data:1H NMR(400MHz,CDCl3)δ8.01(t,J＝1.8Hz,1H),7.86(dt,J＝7.7,1.4Hz,1H),7.65(dt,J＝7.7,1.4Hz,1H),7.45(t,J＝7.7Hz,1H),5.23(q,J＝6.9Hz,1H),2.61(s,3H),2.06(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 197.7,144.0,137.6,131.7,129.2,128.4,126.5,48.5,26.84, 26.82. HRMS (ESI) m/z accurate mass calculation C10H12BrO[M+H]+227.0066, found 227.0066. HRMS (ESI) m/z accurate mass calculation C10H11O[M–Br]+147.0804, found 147.0804.
S99-1(4.8g, 56% yield) was synthesized according to literature reported methods (K.K. Sivaraman et al, Synthesis and structure-activity relationships of phosphorus amides mutants of the M1 and M17 aminopeptides from a microorganism bacterium falciparum.J. Med. chem.56,5213-5217 (2013)).
Starting from S99-1(0.86g, 5.0mmol, 1.0 equiv.), in two steps using general procedure 4 and procedure b, S99 was obtained as a pale yellow oil (1.1g, 86% yield).
Compound S99 characterization data:1H NMR(400MHz,CDCl3)δ7.94(d,J＝2.4Hz,1H),7.75(d,J＝1.6Hz,1H),7.69(d,J＝8.4Hz,2H),7.50(d,J＝8.4Hz,2H),6.49(t,J＝2.4Hz,1H),4.93(t,J＝7.2Hz,1H),2.40–2.27(m,1H),2.27–2.14(m,1H),1.04(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3)δ141.3,140.3,139.8,128.5,126.7,119.3,107.8,56.6,33.3,13.0。HRMS (ESI) m/z accurate mass calculation C12H14BrN2[M+H]+265.0335, found 265.0332. HRMS (ESI) m/z accurate mass calculation C12H13N2[M–Br]+185.1073, found 185.1072.
Reacting NaBH4(0.46g, 12.0mmol, 1.2 equiv.) was added to a solution of phenylcyclopropylmethanone (1.5g, 10.0mmol, 1.0 equiv.) in EtOH (40.0 mL). The mixture was stirred at room temperature for 3 hours and then cooled in an ice bath. The reaction was quenched with water, then most of the solvent was removed under reduced pressure and the aqueous layer was washed with CH2Cl2Extracting, and mixing the organic phase with Na2SO4Dried, filtered and concentrated in vacuo to afford S109-1 as a colorless oil (1.4g, 94% yield). Characterization data are consistent with literature (S.N.Hosseini, J.R.Johnston, F.G.West, Evidence for statistical significance of acrylic oxide imide for the characterization of the Stevens [1,2 ]]-shift.Chem.Commun.53,12654-12656(2017))。
To S109-1(0.89g, 6.0mmol, 1.0 equiv.) of CH under argon protection at 0 deg.C2Cl2(6.0mL) to the solution was added dropwise chlorotrimethylsilane (2.60mL, 30.0mmol, 5.0 equiv.). The reaction mixture was stirred at 0 ℃ for 1 hour, quenched with water and CH2Cl2Extraction was carried out three times, the combined organic layers were washed with brine and Na2SO4Dried and concentrated in vacuo to afford S109 as a colorless oil (0.90g, 90% yield).
Compound S109 characterization data:1H NMR(400MHz,CDCl3)δ7.55–7.29(m,5H),4.32(d,J＝9.2Hz,1H),1.66–1.51(m,1H),0.90–0.80(m,1H),0.76–0.66(m,1H),0.65–0.56(m,1H),0.50–0.39(m,1H)。13C NMR(100MHz,CDCl3) δ 141.8,128.7,128.3,127.2,69.1,20.0,6.6, 6.4. HRMS (ESI) m/z accurate mass calculation C10H11[M–Cl]+131.0855, found 131.0856.
Compounds S131, S132, S133 were synthesized according to literature reported methods (Smith, S.W. & Fu, G.C.Nickel-catalyzed Negishi cross-couplings of second nuclear molecules with second nuclear polypeptides at room temperature 933. Angew.chem.int. Ed.47, 4-9336 (2008). 933).
Compound S131 characterization data:1H NMR(400MHz,CDCl3)δ7.33–7.27(m,2H),7.24–7.17(m,3H),4.49(t,J＝6.7Hz,1H),3.08–2.66(m,2H),2.47–2.15(m,2H),1.09(s,21H)。13C NMR(100MHz,CDCl3) δ 140.4,128.7,126.4,105.7,89.4,41.6,36.7,33.6,18.7, 11.3. HRMS (ESI) m/z accurate mass calculation C20H31Si[M–Br]+299.2190, found 299.2189.
Compound S132 characterization data:1H NMR(400MHz,CDCl3)δ7.39–7.32(m,2H),7.30–7.22(m,3H),4.52(t,J＝6.8Hz,1H),2.92(t,J＝7.6Hz,2H),2.46–2.26(m,2H),1.07(t,J＝7.9Hz,9H),0.68(q,J＝7.9Hz,6H)。13C NMR(100MHz,CDCl3) δ 140.3,128.7,126.4,105.0,90.2,41.4,36.6,33.6,7.6, 4.4. HRMS (ESI) m/z accurate mass calculation C17H25Si[M–Br]+257.1720, found 257.1719.
Compound S133 characterization data:1H NMR(400MHz,CDCl3)δ7.33–7.25(m,2H),7.23–7.16(m,3H),4.48(t,J＝6.7Hz,1H),2.83(t,J＝7.6Hz,2H),2.44–2.04(m,2H),1.23(s,9H)。13C NMR(100MHz,CDCl3) δ 140.5,128.7,128.6,126.3,96.8,77.8,41.9,37.9,33.6,30.9, 27.7. HRMS (ESI) m/z accurate mass calculation C15H19[M–Br]+199.1481, found 199.1480.
To a solution of 4-phenyl-1-butyne (0.80mL, 7.7mmol, 1.0 equiv.) in THF (20mL) at-78 deg.C was added 3.7mL of n-BuLi (3.9mL, 9.3mmol, 1.2 equiv., 2.4M in hexanes) over 5 minutes. After 1h, 3-phenylpropionaldehyde (0.82mL, 7.7mmol, 1.0 eq.) was added dropwise to the mixture. After TLC detection of complete consumption of 4-phenyl-1-butyne, saturated aqueous ammonium chloride solution was added to quench the reaction. The aqueous phase was extracted three times with EtOAc, then the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and filtered, and after concentration, the residue was purified by silica gel column chromatography to give S134-1 as a colorless oil (1.9g, 94% yield).
To a suspension of S134-1(1.1g, 4.1mmol, 1.0 equiv.) in 10mL THF at 0 deg.C was slowly added LiAlH4(312mg, 8.2mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 24 hours and Na was added2SO4·10H2And O, quenching the reaction. The residue was then filtered and the organic solvent removed in vacuo to give S134-2 as a colorless oil (1.02g, 94% yield).
To a solution of S134-2(1.02g, 3.8mmol, 1.0 equiv.) in 10mL CH at 0 deg.C2Cl2Adding PBr into the suspension3(513mg, 1.9mmol, 0.5 equiv.). The reaction mixture was stirred at room temperature for 2 hours, then quenched with water, and the aqueous phase with CH2Cl2Extraction was carried out three times, and then the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and filtered. After removal of the solvent, crude S134 was obtained as a colorless oil (1.06g, 85% yield) which was used in the next step without further purification.
Compound S134 characterization data:
1H NMR(400MHz,CDCl3)δ7.31–7.11(m,10H),5.88–5.57(m,2H),4.55–4.37(m,1H),2.84–2.54(m,4H),2.43–2.33(m,2H),2.30–2.17(m,1H),2.15–1.99(m,1H)。13C NMR(100MHz,CDCl3) δ 141.4,140.7,132.7,132.2,128.6,128.5,128.4,126.2,126.0,55.4,40.8,35.3,33.9, 33.7. HRMS (ESI) m/z accurate mass calculation C19H21[M–Br]+249.1638, found 249.1634.
Will threeMethylcyanosilane (1.63g, 16.5mmol, 1.1 equiv.) was added to cyclohexanecarboxaldehyde (1.68g, 15.0mmol, 1.0 equiv.) and K2CO3(0.41g, 3.0mmol, 0.2 equiv.) of Et2O (30mL) mixture was stirred at room temperature overnight. After completion of the reaction monitored by TLC, saturated NaHCO was used3Quenching with Et2O was extracted three times, the organic phase was washed with brine and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate-5/1) to give product S135-1 as a colorless oil (1.90g, 91% yield).
Characterization data for compound S135-1:1H NMR(400MHz,CDCl3)δ4.25(d,J＝6.4Hz,1H),3.95(brs,1H),1.96–1.63(m,6H),1.34–1.02(m,5H)。13C NMR(100MHz,CDCl3)δ119.5,66.1,42.1,28.2,27.9,25.9,25.43,25.41。
to a solution of S135-1(0.70g, 5.0mmol, 1.0 equiv.) in CH under a vigorous stirring at 0 deg.C under an argon atmosphere2Cl2To a solution (25mL) was added dibromotriphenylphosphine (2.53g, 6.0mmol, 1.2 equiv.) and imidazole (0.41g, 6.0mmol, 1.2 equiv.). The reaction was warmed to room temperature and stirred overnight. After completion of the reaction monitored by TLC, saturated NH was added4Quenching the reaction with Cl, using CH2Cl2The extraction was carried out three times, the organic phase was washed with brine and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate-20/1) to give product S135 as a yellow oil (0.55g, 55% yield).
Compound S135 characterization data:1H NMR(400MHz,CDCl3)δ4.21(d,J＝5.7Hz,1H),2.10–1.93(m,2H),1.92–1.87(m,3H),1.77–1.68(m,1H),1.41–1.12(m,5H)。13C NMR(100MHz,CDCl3)δ116.6,42.7,34.3,30.4,29.5,25.6,25.5。
to a 100mL flask was added N-methylaniline (2.17mL, 20.0mmol), evacuated and backfilled with argon, the flask cooled to 0 ℃ in an ice bath and Et added3N (3.06mL, 22.0mmol) and THF (40 mL). Dissolving orange in waterThe solution was stirred for 5 minutes, then 2-bromobutyryl bromide (2.66mL, 22.0mmol) was added slowly via syringe to form a precipitate. The resulting suspension was stirred at 0 ℃ for 10 minutes and then quenched by the addition of ice water. Et mixture2O (40mL) was extracted three times, the combined organic phases were washed with brine, dried over sodium sulfate and concentrated, and the resulting oil was purified by silica gel column chromatography (petroleum ether/ethyl acetate 15/1) to give product S136 as a colorless oil (4.61g, 90% yield).
Compound S136 characterization data:1H NMR(400MHz,CDCl3)δ7.50–7.36(m,3H),7.29(d,J＝7.6Hz,2H),4.02(t,J＝7.4Hz,1H),3.31(s,3H),2.25–2.05(m,1H),2.02–1.85(m,1H),0.89(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 169.1,143.0,130.1,128.5,127.3,45.9,38.1,28.7, 12.2. HRMS (ESI) m/z accurate mass calculation C11H15BrNO[M+H]+256.0332, found 256.0328.
Example 3
And (3) screening reaction conditions: to an oven-dried Schlenk tube equipped with a magnetic stir bar, copper salt (10 mol% equiv.), ligand L8(15 mol%), base (2.0 equiv.), and solvent (1.0mL) were added under argon. Then, (1-bromoethyl) benzene (0.05mmol) and phenylacetylene (0.075mmol) were added successively to the mixture and reacted at 29 ℃ for 24 h. After completion of the reaction (monitored by TLC), the precipitate was filtered off and washed with solvent, then the solution was evaporated and purified by silica gel column chromatography (petroleum ether ═ 100) to give product 1 with yields and ee values as shown in the table below.
Characterization data for product 1: is colorless oil, [ alpha ]]D 27＝-29(c 1.4,CH2Cl2)。
HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝12.30min,tR(major)＝17.52min。1H NMR(400MHz,CDCl3)δ7.52–7.41(m,4H),7.36(t,J＝7.6Hz,2H),7.32–7.27(m,3H),7.26–7.24(m,1H),4.00(q,J＝7.1Hz,1H),1.59(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 143.3,131.6,128.6,128.2,127.8,127.0126.7,123.7, 92.6,82.4,32.5, 24.6. HRMS (ESI) m/z accurate mass calculation C16H15[M+H]+207.1168, found 207.1161.
Example 4
Following the procedure of example 3, (1-bromoethyl) benzene (0.05mmol), phenylacetylene (0.075mmol), CuTc (10 mol%), ligand L9(15 mol%) in 1.0mL Et2In O, 83% yield, 85% ee.
Example 5
Following the procedure of example 3, (1-bromoethyl) benzene (0.05mmol), phenylacetylene (0.075mmol), CuTc (10 mol%), ligand L10(15 mol%) in 1.0mL Et2In O, 50% yield, 89% ee.
Example 6
Following the procedure of example 3, (1-bromoethyl) benzene (0.05mmol), phenylacetylene (0.075mmol), CuTc (10 mol%), ligand L11(15 mol%) in 1.0mL Et2In O, 82% yield, 80% ee.
Example 7
Following the procedure of example 3, (1-bromoethyl) benzene (0.05mmol), phenylacetylene (0.075mmol), CuTc (10 mol%), ligand L12(15 mol%) in 1.0mL Et2In O, 75% yield, 75% ee.
Example 8
Following the procedure of example 3, (1-bromoethyl) benzene (0.05mmol), phenylacetylene (0.075mmol), CuTc (10 mol%), ligand L13(15 mol%) in 1.0mL Et2In O, 90% yield, 94% ee.
Example 9
Following the procedure of example 3, (1-bromoethyl)Benzene (0.05mmol), phenylacetylene (0.075mmol), CuTc (5 mol%), ligand L13(7.5 mol%) in 1.0mL Et2In O, 82% yield, 94% ee.
Example 10
Following the procedure of example 3, (1-bromoethyl) benzene (37.0mg, 0.20mmol, 1.0 equiv.), phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv.), CuTc (1.9mg, 0.010mmol, 5.0 mol% equiv.), ligand L13(12.5mg, 0.015mmol, 7.5 mol% equiv.), Cs2CO3(130.4mg, 0.40mmol, 2.0 equiv.) in anhydrous Et2O (4.0mL) for 48h, 30.9mg product, 75% yield, 94% ee.
Through the condition screening of the embodiment 3-10, a general reaction method is obtained:
general procedure a:
to an oven-dried Schlenk tube equipped with a magnetic stir bar, CuTc (1.9mg, 0.010mmol, 5.0 mol% equivalent), ligand L13(12.5mg, 0.015mmol, 7.5 mol% equivalent), Cs were added under argon protection2CO3(130.4mg, 0.40mmol, 2.0 equiv.) and anhydrous Et2O (4.0 mL). Then, the alkyl halide (0.30mmol, 1.5 equivalents) and the alkyne (0.20mmol, 1.0 equivalent) were added to the mixture in order, and stirred at room temperature for 24 to 72 hours. After completion of the reaction (monitored by TLC), the precipitate was filtered off and treated with Et2O or petroleum ether, followed by evaporation of the solution and purification by silica gel column chromatography to give the desired product.
General procedure B:
to an oven-dried Schlenk tube equipped with a magnetic stir bar, CuTc (1.9mg, 0.010mmol, 5.0 mol% equivalent), ligand L13(12.5mg, 0.015mmol, 7.5 mol% equivalent), Cs were added under argon protection2CO3(130.4mg, 0.40mmol, 2.0 equiv.) and anhydrous Et2O (4.0 mL). Then, the alkyl halide (0.20mmol, 1.0 equivalent) and the alkyne (0.30mmol, 1.5 equivalent) were added to the mixture in order, and stirred at room temperature for 16 to 72 hours. After completion of the reaction (monitored by TLC), filtration was carried outThe precipitate is taken up in Et2Washing with O or petroleum ether, then concentrating the solution and purifying by silica gel column chromatography to give the desired product.
General procedure C (benzyl bromide cross-coupling with acetylene gas):
CuTc (1.91mg, 0.010mmol, 5.0 mol% equivalent), ligand L13(12.5mg, 0.015mmol, 7.5 mol% equivalent), and Cs2CO3(130.4mg, 0.40mmol, 2.0 equiv.) was charged to an oven-dried 25mL Schlenk flask with a magnetic stir bar and the air was vented in vacuo. Benzyl bromide (0.20mmol, 1.0 equiv.) was dissolved in diethyl ether (4.0mL) and injected into a Schlenk flask via a syringe, and then acetylene gas was filled into the flask via a balloon (approximately 1 day). Stirring was carried out at room temperature for 18 hours and monitored by TLC until complete consumption of starting material, the reaction mixture was diluted with petroleum ether, filtered on silica gel and concentrated in vacuo, and the residue was purified by silica gel column chromatography to give the corresponding product.
Notably, most of the products were not stable in air after purification and had to be stored in solvent (CH) at-10 ℃ after NMR, HPLC or HRMS ASAP characterization2Cl2Or Et2O) in (A). At the same time, the reaction is sensitive to water and air, and Schlenk tubes and reagents must be dried before use.
Preparation of racemate:
CuTc (1.9mg, 0.010mmol, 5.0 mol% equiv) and Lrac (3.8mg, 0.010mmol, 10.0 mol% equiv) were used as catalyst and ligand at room temperature or 40 ℃ in anhydrous Et2O (4.0mL) for 16 to 72 hours, followed by the same procedure as described above to prepare the racemate. After completion of the reaction (monitored by TLC), the precipitate was filtered off and treated with Et2O wash, then concentrate and purify by silica gel column chromatography to give the desired product.
Examples 11-65 are extensions of alkyne substrates:
aryl alkynes with different substituents, such as mono-substituted benzene rings, di-substituted benzene rings, naphthalene rings and ferrocene rings with electron donating or electron withdrawing substituents at different positions (ortho, meta or para), can be used to obtain corresponding products 2-26 smoothly, with a yield of 65-98% and an ee value of 91-98%. For heteroarylalkynes, such as pyridine, benzo [ d ] oxazole, benzothiazole, quinoline, pyrimidine, imidazopyridazine, pyrazolopyrimidine, thiophene, all can be used as substrates to obtain the products in excellent yields and enantioselectivities. For alkyl alkynes, unfunctionalized aliphatic alkynes and alkyl alkynes with alkenes, cyclopropane, halogens, amides, imides, carbazoles, nitriles, acetals, hydroxyls, ester groups, ethers, thioethers are all suitable substrates with high chemo-and enantioselectivity, and silylalkynes give the product in almost quantitative yield and 95% ee. When industrial alkyne, namely propyne and acetylene is selected, the product is obtained with excellent yield and ee value. Propyne was used in 88% yield and an ee value of 97%. Chiral terminal alkyne compounds can be obtained by using acetylene, and the compounds can be used for click reaction to obtain cycloaddition products and can also be used for asymmetric Sonogashira coupling reaction again.
Example 11
Starting from (1-bromopropyl) benzene S2(39.8mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 48 hours using general method B to give product 2 as a colorless oil (33.0mg, 75% yield, 97% ee).
[α]D 27＝-14(c 1.5,CH2Cl2). HPLC conditions Chiralcel ODH (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝10.57min,tR(major)＝15.33min。1H NMR(400MHz,CDCl3)δ7.49–7.44(m,3H),7.43(s,1H),7.35(t,J＝7.6Hz,2H),7.33–7.29(m,3H),7.28–7.24(m,1H),3.81(t,J＝6.8Hz,1H),2.00–1.79(m,2H),1.07(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.0,131.7,128.4,128.2,127.7,127.6,126.7,123.9,91.5,83.4,40.0,31.7, 11.9. HRMS (ESI) m/z accurate mass calculation C17H17[M+H]+221.1325, found 221.1323.
Example 12
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 4-phenylacetylene methyl ether (26.4mg, 0.20mmol, 1.0 equivalent) using general procedure a, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 3 as a colorless oil (33.0mg, 66% yield, 95% ee).
[α]D 25＝-5.0(c 1.4,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 1.0mL/min, λ 254nm), tR(minor)＝18.67min,tR(major)＝19.31min。1H NMR(400MHz,CDCl3)δ7.44–7.36(m,4H),7.33(t,J＝7.5Hz,2H),7.26–7.20(m,1H),6.87–6.77(m,2H),3.80(s,3H),3.79–3.74(m,1H),1.93–1.77(m,2H),1.05(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 159.2,142.3,133.0,128.4,127.6,126.6,116.0,113.8,89.9,83.1,55.3,40.0,31.8, 11.9. HRMS (ESI) m/z accurate mass calculation C18H19O[M+H]+251.1430, found 251.1429.
Example 13
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 3-phenylacetylene methyl ether (26.4mg, 0.20mmol, 1.0 equivalent) using general procedure a, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 4 as a colorless oil (47.0mg, 94% yield, 96% ee).
[α]D 27＝–6.5(c 2.9,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 1.0mL/min, λ 254nm), tR(minor)＝8.78min,tR(major)＝10.58min。1H NMR(400MHz,CDCl3)δ7.52–7.43(m,2H),7.43–7.35(m,2H),7.32–7.22(m,2H),7.10–7.07(m,1H),7.07–7.00(m,1H),6.93–6.86(m,1H),3.91–3.76(m,1H),3.84(s,3H),2.06–1.77(m,2H),1.11(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 159.2,141.9,129.2,128.4,127.5,126.6,124.8,124.2,116.5,114.3,91.3,83.2,55.2,39.9,31.6, 11.9. HRMS (ESI) m/z accurate mass calculation C18H19O[M+H]+251.1430, found 251.1434.
Example 14
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and 2-phenylacetylene methyl ether (26.4mg, 0.20mmol, 1.0 equiv) using general procedure a, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 5 as a colourless oil (42.0mg, 84% yield, 97% ee).
[α]D 27＝–2.8(c 3.9,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 0.3mL/min, λ 254nm), tR(minor)＝22.55min,tR(major)＝33.92min。1H NMR(400MHz,CDCl3)δ7.49–7.44(m,2H),7.42(dd,J＝7.5,1.8Hz,1H),7.37–7.29(m,2H),7.28–7.20(m,2H),6.94–6.82(m,2H),3.91–3.82(m,1H),3.87(s,3H),1.98–1.79(m,2H),1.07(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 160.1,142.1,133.5,129.0,128.3,127.6,126.5,120.3,113.0,110.6,95.6,79.6,55.8,40.2,31.8, 11.7. HRMS (ESI) m/z accurate mass calculation C18H19O[M+H]+251.1430, found 251.1433.
Example 15
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 4-tolylacetylene (23.2mg, 0.20mmol, 1.0 equiv.) using general procedure a, after 16 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 6 as a colorless oil (36.6mg, 78% yield, 97% ee).
[α]D 27＝–11(c 1.7,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 0.5mL/min, λ 254nm), tR(minor)＝26.02min,tR(major)＝30.94min。1H NMR(400MHz,CDCl3)δ7.47(d,J＝7.8Hz,2H),7.43–7.34(m,4H),7.31–7.25(m,1H),7.15(d,J＝7.9Hz,2H),3.83(t,J＝7.0Hz,1H),2.38(s,3H),1.97–1.82(m,2H),1.10(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.1,137.7,131.5,128.9,128.4,127.5,126.6,120.7,90.6,83.4,40.0,31.7,21.4, 11.8. HRMS (ESI) m/z accurate mass calculation C18H19[M+H]+235.1481, found 235.1481.
Example 16
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 4-phenylethynylamine (23.4mg, 0.20mmol, 1.0 equivalent), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) using general method a until complete consumption of starting material by TLC to give product 7 as a colorless oil (41.0mg, 87% yield, 97% ee).
[α]D 27＝–18(c 4.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 97/3, flow rate 1.0mL/min, λ 254nm), tR(minor)＝35.08min,tR(major)＝37.23min。1H NMR(400MHz,CDCl3)δ7.51–7.41(m,2H),7.41–7.32(m,2H),7.32–7.24(m,3H),6.67–6.57(m,2H),3.85–3.66(m,3H),1.93–1.81(m,2H),1.08(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 146.1,142.4,132.8,128.3,127.6,126.5,114.7,113.4,88.9,83.6,40.0,31.8, 11.9. HRMS (ESI) m/z accurate mass calculation C17H18N[M+H]+236.1434, found 236.1432.
Example 17
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 4-fluoroacetylene (24.0mg, 0.20mmol, 1.0 equiv.), the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 16 hours using general procedure a to give product 8 as a colorless oil (39.6mg, 83% yield, 96% ee).
[α]D 27＝–19(c 0.40,CH2Cl2). HPLC conditions Chiralcel OJH (n-hexane/isopropanol 100/0, flow rate 1.0mL/min, λ 254nm), tR(minor)＝16.85min,tR(major)＝18.97min。1H NMR(400MHz,CDCl3)δ7.46–7.37(m,4H),7.37–7.29(m,2H),7.28–7.21(m,1H),7.04–6.94(m,2H),3.83–3.71(m,1H),1.94–1.77(m,2H),1.05(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ162.2(d,J＝248.4Hz),141.9,133.4(d,J＝8.4Hz),128.4,127.5,126.7,119.9(d,J＝3.4Hz),115.4(d,J＝22.1Hz),91.1(d,J＝1.5Hz),82.2,39.9,31.6,11.9。19F NMR(376MHz,CDCl3) Delta-112.02-112.12 (m, 1F). HRMS (ESI) m/z accurate mass calculation C17H16F[M+H]+239.1231, found 239.1229.
Example 18
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 3-fluoroacetylene (24.0mg, 0.20mmol, 1.0 equiv.), the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 16 hours using general procedure a to give product 9 as a colorless oil (46.5mg, 98% yield, 96% ee).
[α]D 27＝–13(c 1.5,CH2Cl2). HPLC conditions Chiralcel ODH (99.8/0.2 n-hexane/isopropanol, flow rate 0.5mL/min, 254nm @), t ═ tR(minor)＝8.53min,tR(major)＝9.20min。1H NMR(400MHz,CDCl3)δ7.42–7.37(m,2H),7.37–7.30(m,2H),7.28–7.19(m,3H),7.17–7.11(m,1H),7.02–6.94(m,1H),3.78(t,J＝7.2Hz,1H),1.94–1.79(m,2H),1.05(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ162.4(d,J＝246.1Hz),141.7,129.7(d,J＝8.7Hz),128.5,127.5,126.8,125.7(d,J＝9.5Hz),118.4(d,J＝22.5Hz),115.0(d,J＝21.2Hz),92.6,82.2(d,J＝3.4Hz),39.9,31.5,11.8。19F NMR(376MHz,CDCl3) Delta-113.3 (td, J ═ 9.0,5.3Hz, 1F). HRMS (ESI) m/z accurate mass calculation C17H16F[M+H]+239.1231, found 239.1230.
Example 19
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 2-fluoroacetylene (24.0mg, 0.20mmol, 1.0 equiv.), the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 18 hours using general procedure a to give product 10 as a colorless oil (44.6mg, 94% yield, 97% ee).
[α]D 27＝–11(c 2.6,CH2Cl2). HPLC conditions Chiralcel ODH (99.8/0.2 n-hexane/isopropanol, flow rate 0.5mL/min, 254nm @), t ═ tR(minor)＝10.49min,tR(major)＝11.32min。1H NMR(400MHz,CDCl3)δ7.47–7.39(m,3H),7.38–7.30(m,2H),7.29–7.21(m,2H),7.09–7.02(m,2H),3.83(t,J＝7.0Hz,1H),1.93–1.81(m,2H),1.07(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ162.9(d,J＝250.6Hz),141.6,133.5(d,J＝1.4Hz),129.3(d,J＝7.9Hz),128.4,127.5,126.7,123.8(d,J＝3.7Hz),115.4(d,J＝21.1Hz),112.3(d,J＝15.8Hz),96.9(d,J＝3.3Hz),76.7,40.1,31.6,11.7。19F NMR(376MHz,CDCl3) Delta-110.46- -110.55 (m, 1F). HRMS (ESI) m/z accurate mass calculation C17H16F[M+H]+239.1231, found 239.1225.
Example 20
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 4-chlorophenylacetylene (27.3mg, 0.20mmol, 1.0 equiv.), the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 18 hours using general procedure a to give product 11 as a colorless oil (41.0mg, 81% yield, 97% ee).
[α]D 27＝–5.4(c 3.3,CH2Cl2). HPLC conditions are Chiralcel OJH (99.5/0.5 n-hexane/isopropanol, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝13.57min,tR(major)＝15.78min。1H NMR(400MHz,CDCl3)δ7.44–7.29(m,6H),7.29–7.22(m,3H),3.77(t,J＝7.0Hz,1H),1.94–1.78(m,2H),1.04(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.7,133.6,132.9,128.51,128.50,127.5,126.7,122.3,92.5,82.2,40.0,31.5, 11.9. HRMS (ESI) m/z accurate mass calculation C17H16Cl[M+H]+255.0935, found 255.0937.
Example 21
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 3-chlorophenylacetylene (27.3mg, 0.20mmol, 1.0 equiv.), the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 18 hours using general procedure a to give product 12 as a colorless oil (50.0mg, 98% yield, 94% ee).
[α]D 27＝–10(c 2.8,CH2Cl2). HPLC conditionsChiralcel ODH (n-hexane/isopropanol 100/0, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝10.43min,tR(major)＝11.49min。1H NMR(400MHz,CDCl3)δ7.47–7.28(m,6H),7.28–7.17(m,3H),3.77(t,J＝6.8Hz,1H),1.94–1.77(m,2H),1.04(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.6,134.0,131.5,129.8,129.4,128.5,128.0,127.5,126.8,125.5,92.9,82.0,39.9,31.5, 11.8. HRMS (ESI) m/z accurate mass calculation C17H16Cl[M+H]+255.0935, found 255.0933.
Example 22
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 4-bromophenylacetylene (36.2mg, 0.20mmol, 1.0 equiv.) the reaction mixture was purified by column chromatography on silica gel (cyclohexane ═ 100) after 18 hours using general procedure a to give product 13 as a colorless oil (57.0mg, 96% yield, 97% ee).
[α]D 27＝–8.2(c 4.4,CH2Cl2). HPLC conditions are Chiralcel OJH (99.5/0.5 n-hexane/isopropanol, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝14.73min,tR(major)＝17.19min。1H NMR(400MHz,CDCl3)δ7.45–7.37(m,4H),7.37–7.27(m,4H),7.27–7.22(m,1H),3.76(t,J＝7.0Hz,1H),1.92–1.77(m,2H),1.04(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.7,133.1,131.4,128.5,127.5,126.7,122.8,121.8,92.8,82.3,40.0,31.5, 11.9. HRMS (ESI) m/z accurate mass calculation C17H16Br[M+H]+299.0435and 301.0415, found 299.0428and 301.0408.
Example 23
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 3-bromophenylacetylene (36.2mg, 0.20mmol, 1.0 equiv.) the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 18 hours using general procedure a to give product 14 as a colorless oil (57.0mg, 96% yield, 94% ee).
[α]D 27＝–8.2(c 4.4,CH2Cl2). HPLC conditions Chiralcel ODH (n-hexane/isopropanol 100/0, flow rate 1.0mL/min, λ 254nm), tR(minor)＝10.43min,tR(major)＝11.49min。1H NMR(400MHz,CDCl3)δ7.65–7.54(m,1H),7.46–7.29(m,6H),7.29–7.21(m,1H),7.18–7.10(m,1H),3.77(t,J＝7.0Hz,1H),1.93–1.78(m,2H),1.04(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.6,134.4,130.9,130.2,129.6,128.5,127.5,126.7,125.8,122.0,93.0,81.9,39.9,31.5, 11.8. HRMS (ESI) m/z accurate mass calculation C17H16Br[M+H]+299.0435, found 299.0430.
Example 24
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 4-trifluoromethylphenylacetylene (34.0mg, 0.20mmol, 1.0 equiv.) the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 16 hours using general procedure a to give product 15 as a colorless oil (48.1mg, 84% yield, 97% ee).
[α]D 27＝–2.4(c 4.0,CH2Cl2). HPLC conditions Chiralcel IG (n-hexane/isopropanol 100/0, flow rate 0.3mL/min, λ 254nm), tR(minor)＝15.70min,tR(major)＝17.38min。1H NMR(400MHz,CDCl3)δ7.57–7.50(m,4H),7.44–7.38(m,2H),7.38–7.31(m,2H),7.29–7.23(m,1H),3.80(t,J＝7.0Hz,1H),1.95–1.80(m,2H),1.06(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ141.5,131.9,129.5(q,J＝32.5Hz),128.6,127.7(d,J＝1.4Hz),127.5,126.9,125.2(q,J＝3.7Hz),124.0(q,J＝272.1Hz),94.3,82.2,40.0,31.5,11.9。19F NMR(376MHz,CDCl3) Delta-62.7 (s, 3F). HRMS (ESI) m/z accurate mass calculation C18H16F3[M+H]+289.1199, found 289.1192.
Example 25
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and 4-cyanophenylacetylene (25.4mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) after 16 hours using general procedure a to give product 16 as a colorless oil (47.7mg, 97% yield, 96% ee).
[α]D 27＝–19(c 3.0,CH2Cl2). HPLC conditions Chiralcel AS3 (n-hexane/isopropanol 95/5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝15.37min,tR(major)＝20.43min。1H NMR(400MHz,CDCl3)δ7.61(d,J＝8.2Hz,2H),7.54(d,J＝8.2Hz,2H),7.46–7.36(m,4H),7.33–7.27(m,1H),3.84(t,J＝7.1Hz,1H),1.98–1.86(m,2H),1.09(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.1,132.1,131.9,128.7,128.5,127.4,126.9,118.5,111.0,96.6,81.9,40.0,31.3, 11.8. HRMS (ESI) m/z accurate mass calculation C18H16N[M+H]+246.1277, found 246.1274.
Example 26
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and 4-phenylacetylene carboxaldehyde (26.0mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) after 16h using general procedure a to give product 17 as a colorless oil (48.0mg, 97% yield, 96% ee).
[α]D 27＝–22(c 4.0,CH2Cl2). HPLC conditions Chiralcel IE (n-hexane/isopropanol 99/1, flow rate 0.3mL/min, λ 254nm), tR(minor)＝40.38min,tR(major)＝44.14min。1H NMR(400MHz,CDCl3)δ10.02(s,1H),7.90–7.80(m,2H),7.66–7.58(m,2H),7.49–7.34(m,4H),7.34–7.27(m,1H),3.85(t,J＝7.0Hz,1H),2.03–1.82(m,2H),1.10(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 191.5,141.4,135.1,132.2,130.3,129.5,128.6,127.5,126.9,96.2,82.7,40.1,31.5, 11.9. HRMS (ESI) m/z accurate mass calculation C18H17O[M+H]+249.1274, found 249.1273.
Example 27
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and 2-phenylacetylene carboxaldehyde (26.0mg, 0.20mmol, 1.0 equiv) using general procedure a, after 36 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 18 as a colorless oil (39.0mg, 79% yield, 91% ee).
[α]D 27＝–23(c 1.5,CH2Cl2). HPLC conditions Chiralcel IE (n-hexane/isopropanol 99/1, flow rate 0.4mL/min, λ 254nm), tR(minor)＝19.32min,tR(major)＝20.77min。1H NMR(400MHz,CDCl3)δ10.58(d,J＝0.7Hz,1H),7.97–7.85(m,1H),7.60–7.45(m,2H),7.44–7.31(m,5H),7.29–7.23(m,1H),3.85(t,J＝7.1Hz,1H),1.99–1.85(m,2H),1.07(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 191.9,141.2,136.0,133.7,133.4,128.6,128.1,127.5,127.4,127.0,126.9,99.2,78.9,40.2,31.4, 11.9. HRMS (ESI) m/z accurate mass calculation C18H17O[M+H]+249.1274, found 249.1279.
Example 28
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and methyl 4-phenylacetenecarboxylate (32.0mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 50/1) after 16h using general procedure a to give product 19 as a colorless oil (51.2mg, 92% yield, 96% ee).
[α]D 27＝–26(c 1.6,CH2Cl2). HPLC conditions Chiralcel IF (n-hexane/isopropanol 99/1, flow rate 0.3mL/min, λ 254nm), tR(minor)＝29.10min,tR(major)＝32.49min。1H NMR(400MHz,CDCl3)δ8.00–7.94(m,2H),7.54–7.47(m,2H),7.45–7.38(m,2H),7.37–7.29(m,2H),7.28–7.22(m,1H),3.90(s,3H),3.80(t,J＝7.0Hz,1H),1.94–1.82(m,2H),1.05(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 166.7,141.6,131.6,129.4,129.1,128.7,128.5,127.5,126.8,95.0,82.8,52.2,40.1,31.5, 11.9. HRMS (ESI) m/z accurate mass calculation C19H19O2[M+H]+279.1380, found 279.1378.
Example 29
Using (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 4-nitrophenylacetylene (29.4mg, 0.20mmol, 1.0 equivalents) as starting materials at-10 ℃, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 30/1) after 72 hours using general procedure a to afford product 20 as a colorless oil (50.0mg, 94% yield, 98% ee).
[α]D 27＝–20(c 3.3,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 0.3mL/min, lambda 230nm), tR(minor)＝29.20min,tR(major)＝31.13min。1H NMR(400MHz,CDCl3)δ8.20–8.11(m,2H),7.60–7.54(m,2H),7.47–7.36(m,4H),7.35–7.26(m,1H),3.86(t,J＝7.1Hz,1H),2.02–1.86(m,2H),1.10(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 146.8,141.1,132.4,130.9,128.6,127.5,127.0,123.5,97.7,81.8,40.2,31.4, 11.9. HRMS (ESI) m/z accurate mass calculation C17H16NO2[M+H]+266.1176, found 266.1176.
Example 30
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and 2- (4-phenylethynyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (45.6mg, 0.20mmol, 1.0 equiv), after 16h using general procedure a, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 30/1) to give product 21 as a colorless oil (65.0mg, 94% yield, 96% ee).
[α]D 27＝–29(c 1.5,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 0.5mL/min, λ 254nm), tR(major)＝18.44min,tR(minor)＝22.31min。1H NMR(400MHz,CDCl3)δ7.73(d,J＝7.8Hz,2H),7.48–7.38(m,4H),7.37–7.30(m,2H),7.27–7.20(m,1H),3.79(t,J＝7.0Hz,1H),1.92–1.81(m,2H),1.34(s,12H),1.05(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3)δ141.9,134.5,130.8,128.4,127.5,126.7,126.6,92.9,83.9,83.5,40.0,31.6,24.9,11.9。11B NMR(128MHz,CDCl3) δ 31.5. HRMS (ESI) m/z accurate mass calculation C23H28BO2[M+H]+347.2177, found 347.2175.
Example 31
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 4-vinylphenylacetylene S22(25.6mg, 0.20mmol, 1.0 equiv.) following 36 hours of general procedure a, the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 22 as a colorless oil (38.0mg, 77% yield, 96% ee).
[α]D 27＝+0.61(c 1.8,CH2Cl2). HPLC conditions Chiralcel IG (n-hexane/isopropanol 99/1, flow rate 0.5mL/min, λ 254nm), tR(major)＝7.88min,tR(minor)＝8.50min。1H NMR(400MHz,CDCl3)δ7.49–7.41(m,4H),7.40–7.33(m,4H),7.32–7.24(m,1H),6.72(dd,J＝17.6,10.9Hz,1H),5.78(d,J＝17.6Hz,1H),5.30(d,J＝10.9Hz,1H),3.82(t,J＝7.0Hz,1H),1.97–1.80(m,2H),1.09(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.0,136.9,136.3,131.8,128.4,127.6,126.7,126.0,123.2,114.4,92.2,83.4,40.1,31.7, 11.9. HRMS (ESI) m/z accurate mass calculation C19H19[M+H]+247.1481, found 247.1481.
Example 32
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and 1, 4-tolane (25.2mg, 0.20mmol, 1.0 equiv), after 36 hours using general procedure a, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 99/1) to give product 23 as a colorless oil (31.7mg, 65% yield, 96% ee).
[α]D 27＝–0.90(c 4.0,CH2Cl2). HPLC conditions Chiralcel AY3 (n-hexane/isopropanol 100/0, flow rate 0.6mL/min, λ 254nm), tR(minor)＝13.38min,tR(major)＝15.93min。1H NMR(400MHz,CDCl3)δ7.48–7.41(m,6H),7.41–7.35(m,2H),7.32–7.26(m,1H),3.83(t,J＝7.6Hz,1H),3.18(s,1H),1.96–1.85(m,2H),1.09(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.7,132.0,131.6,128.5,127.5,126.8,124.4,121.3,93.8,83.4,82.9,78.5,40.1,31.6, 11.9. HRMS (ESI) m/z accurate mass calculation C19H17[M+H]+245.1325, found 245.1321.
Example 33
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 2-ethynyl-6-methoxynaphthalene (36.4mg, 0.20mmol, 1.0 equiv.) using general procedure a, after 36 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 24 as an amorphous powder (56.0mg, 93% yield, 97% ee).
[α]D 27＝–17(c 0.67,CH2Cl2). HPLC conditions Chiralcel OJ3 (n-hexane/isopropanol 98/2, flow rate 1.0mL/min, λ 254nm), tR(major)＝31.22min,tR(minor)＝44.53min。1H NMR(400MHz,CDCl3)δ7.88(s,1H),7.66(t,J＝8.6Hz,2H),7.51–7.42(m,3H),7.39–7.29(m,2H),7.28–7.22(m,1H),7.13(dd,J＝8.9,2.5Hz,1H),7.09(d,J＝2.4Hz,1H),3.90(s,3H),3.83(t,J＝7.0Hz,1H),1.97–1.83(m,2H),1.09(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 158.0,142.1,133.8,131.0,129.3,129.1,128.5,128.4,127.6,126.6,119.2,118.8,105.7,91.0,83.8,55.3,40.1,31.7, 11.9. HRMS (ESI) m/z accurate mass calculation C22H21O[M+H]+301.1587, found 301.1584.
Example 34
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and S25(29.2mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) after 72 hours using general procedure a to give product 25 as a colorless oil (39.7mg, 75% yield, 98% ee).
[α]D 27＝–6.2(c 1.4,CH2Cl2). HPLC conditions Chiralcel OJ3 (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(minor)＝19.52min,tR(major)＝27.61min。1H NMR(400MHz,CDCl3)δ7.43–7.37(m,2H),7.36–7.29(m,2H),7.27–7.20(m,1H),6.96(dd,J＝8.0,1.6Hz,1H),6.90(d,J＝1.6Hz,1H),6.73(d,J＝8.0Hz,1H),5.94(s,2H),3.75(dd,J＝7.7,6.3Hz,1H),1.93–1.75(m,2H),1.04(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 147.4,147.3,142.1,128.4,127.6,126.6,126.0,117.1,111.8,108.3,101.2,89.7,83.1,40.0,31.7, 11.9. HRMS (ESI) m/z accurate mass calculation C18H17O2[M+H]+265.1223, found 265.1222.
Example 35
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 1-ethynylferrocene (42.0mg, 0.20mmol, 1.0 equivalent), the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 28 hours using general procedure a to give product 26 as a colorless oil (58.0mg, 88% yield, 98% ee).
[α]D 27＝–0.25(c 4.0,CH2Cl2). HPLC conditions Chiralcel OJ3 (n-hexane/isopropanol 99/1, flow rate 0.3mL/min, λ 254nm), tR(major)＝36.68min,tR(minor)＝43.21min。1H NMR(400MHz,CDCl3)δ7.50–7.43(m,2H),7.42–7.35(m,2H),7.32–7.25(m,1H),4.48–4.41(m,2H),4.24(s,5H),4.21–4.19(m,2H),3.73(dd,J＝8.0,6.0Hz,1H),1.96–1.78(m,2H),1.10(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.4,128.4,127.6,126.6,87.5,81.3,71.3,69.8,68.3,66.3,40.1,31.8, 11.9. HRMS (ESI) m/z accurate mass calculation C21H20Fe[M]+328.0909, found 328.0906.
Example 36
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and 3-ethynylpyridine (20.6mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) after 36 hours using general procedure a to give product 27 as a colorless oil (38.0mg, 86% yield, 95% ee).
[α]D 27＝–15.6(c 0.66,CH2Cl2). HPLC conditions Chiralcel OJH (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(major)＝12.39min,tR(minor)＝13.45min。1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.51(s,1H),7.72(dt,J＝7.9,1.8Hz,1H),7.44–7.38(m,2H),7.38–7.31(m,2H),7.29–7.20(m,2H),3.80(t,J＝7.1Hz,1H),1.94–1.82(m,2H),1.06(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 152.4,148.1,141.4,138.5,128.5,127.5,126.8,122.9,95.2,80.0,40.0,31.5, 11.9. HRMS (ESI) m/z accurate mass calculation C16H16N[M+H]+222.1277, found 222.1277.
Example 37
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and S28(28.6mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 30/1) after 18 hours using general method a to give product 28 as a colorless oil (45.9mg, 88% yield, 97% ee).
[α]D 27＝–1.2(c 1.9,CH2Cl2). HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 99/1, flow rate 0.5mL/min,. lambda.254 nm), tR(minor)＝19.70min,tR(major)＝29.06min。1H NMR(400MHz,CDCl3)δ7.75–7.71(m,1H),7.53–7.49(m,1H),7.43–7.32(m,6H),7.31–7.27(m,1H),3.87(t,J＝7.1Hz,1H),2.03–1.90(m,2H),1.09(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ150.2,147.7,140.9,139.7,128.7,127.6,127.2,126.1,124.9,120.3,110.5,97.1,71.9,39.9,30.9,11.8. HRMS (ESI) m/z accurate mass calculation C18H16NO[M+H]+262.1226, found 262.1226.
Example 38
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and S29(31.8mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 30/1) after 18 hours using general method a to give product 29 as a colorless oil (55.0mg, 99% yield, 96% ee).
[α]D 27＝–12(c 3.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 98/2, flow rate 0.3mL/min, λ 254nm), tR(major)＝32.68min,tR(minor)＝35.49min。1H NMR(400MHz,CDCl3)δ8.11–8.05(m,1H),7.89–7.82(m,1H),7.56–7.50(m,1H),7.48–7.42(m,3H),7.42–7.35(m,2H),7.34–7.27(m,1H),3.91(t,J＝7.1Hz,1H),2.07–1.90(m,2H),1.11(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 152.8,149.0,140.2,135.2,128.7,127.6,127.1,126.6,126.0,123.5,121.3,99.6,77.1,40.2,31.1, 11.9. HRMS (ESI) m/z accurate mass calculation C18H16NS[M+H]+278.0998, found 278.0998.
Example 39
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and 4-ethynylquinoline (30.6mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) after 36 hours using general procedure a to give product 30 as a colorless oil (54.0mg, 99% yield, 94% ee).
[α]D 27＝–10(c 2.5,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 98/2, flow rate 0.3mL/min, λ 254nm), tR(major)＝29.85min,tR(minor)＝32.12min。1H NMR(400MHz,CDCl3)δ8.84(d,J＝4.5Hz,1H),8.33–8.23(m,1H),8.10(d,J＝8.3Hz,1H),7.72(ddd,J＝8.4,6.9,1.5Hz,1H),7.58(ddd,J＝8.2,6.9,1.2Hz,1H),7.51–7.43(m,3H),7.41–7.34(m,2H),7.32–7.23(m,1H),3.96(t,J＝7.0Hz,1H),1.98(p,J＝7.3Hz,2H),1.13(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 149.8,148.1,141.2,130.4,129.82,129.76,128.7,128.2,127.6,127.1,127.0,126.1,123.8,101.8,79.4,40.4,31.6, 12.0. HRMS (ESI) m/z accurate mass calculation C20H18N[M+H]+272.1434, found 272.1433.
Example 40
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and 2-ethynylpyrimidine (20.8mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) after 16 hours using general procedure a to give product 31 as a colorless oil (43.0mg, 97% yield, 97% ee).
[α]D 27＝–3.8(c 2.1,CH2Cl2). HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 90/10, flow rate 1.0mL/min,. lambda.254 nm), tR(major)＝8.09min,tR(minor)＝10.38min。1H NMR(400MHz,CDCl3)δ8.70(d,J＝5.0Hz,2H),7.44–7.42(m,2H),7.36–7.31(m,2H),7.27–7.19(m,2H),3.84(t,J＝7.2Hz,1H),2.01–1.87(m,2H),1.07(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 157.2,153.3,140.5,128.6,127.6,126.9,119.6,91.4,82.4,39.8,31.1, 11.9. HRMS (ESI) m/z accurate mass calculation C15H15N2[M+H]+223.1230, found 223.1229.
EXAMPLE 41
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv.) and 3-ethynylimidazo [1,2-b ] pyridazine (28.6mg, 0.20mmol, 1.0 equiv.), the reaction mixture is purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1) after 16 hours using general method a to give product 32 as a colorless oil (47.5mg, 91% yield, 96% ee).
[α]D 27＝+7.8(c 2.5,CH2Cl2). HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 95/5, flow rate 0.5mL/min,. lambda.254 nm), tR(minor)＝33.91min,tR(major)＝40.60min。1H NMR(400MHz,CDCl3)δ8.42(dd,J＝4.4,1.6Hz,1H),7.96–7.92(m,2H),7.49–7.45(m,2H),7.38–7.33(m,2H),7.28–7.23(m,1H),7.04(dd,J＝9.1,4.4Hz,1H),3.97(t,J＝7.0Hz,1H),1.96(p,J＝7.3Hz,2H),1.10(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 143.6,141.2,139.1,137.8,128.5,127.6,126.8,125.7,117.1,113.6,101.5,70.0,40.4,31.5, 11.9. HRMS (ESI) m/z accurate mass calculation C17H16N3[M+H]+262.1339, found 262.1337.
Example 42
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and S33(28.6mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1) after 16 hours using general procedure a to give product 33 as a colorless oil (51.7mg, 99% yield, 96% ee).
[α]D 27＝–28(c 2.3,CH2Cl2). HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 95/5, flow rate 0.5mL/min,. lambda.254 nm), tR(minor)＝29.14min,tR(major)＝32.46min。1H NMR(400MHz,CDCl3)δ8.57(dd,J＝7.2,1.0Hz,1H),8.11(d,J＝2.3Hz,1H),7.45–7.39(m,2H),7.37–7.32(m,2H),7.28–7.23(m,1H),6.84(d,J＝7.2Hz,1H),6.67(dd,J＝2.3,0.9Hz,1H),3.84(t,J＝7.1Hz,1H),2.02–1.87(m,2H),1.07(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 148.1,145.6,142.6,140.5,134.5,128.6,127.6,127.0,110.9,97.3,96.1,82.0,40.0,31.1, 11.9. HRMS (ESI) m/z accurate mass calculation C17H16N3[M+H]+262.1339, found 262.1337.
Example 43
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 2-ethynylthiophene (21.2mg, 0.20mmol, 1.0 equivalent), the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 18 hours using general procedure a to give product 34 as a colorless oil (41.0mg, 91% yield, 97% ee).
[α]D 27＝–13(c 1.1,CH2Cl2). HPLC conditions Chiralcel ODH (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝11.86min,tR(major)＝12.84min。1H NMR(400MHz,CDCl3)δ7.42–7.37(m,2H),7.36–7.29(m,2H),7.27–7.22(m,1H),7.22–7.13(m,2H),6.95(dd,J＝5.2,3.6Hz,1H),3.79(t,J＝7.0Hz,1H),1.93–1.78(m,2H),1.04(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.6,131.2,128.4,127.5,126.8,126.7,126.2,123.9,95.4,76.4,40.2,31.5, 11.9. HRMS (ESI) m/z accurate mass calculation C15H15S[M+H]+227.0889, found 227.0889.
Example 44
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 3-benzene-1-propyne (23.2mg, 0.20mmol, 1.0 equivalent), the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 72 hours using general procedure a to give product 35 as a colorless oil (43.0mg, 92% yield, 96% ee).
[α]D 27＝–2.3(c 3.3,CH2Cl2). HPLC conditions Chiralcel OJ3 (n-hexane/isopropanol 99/1, flow rate 0.6mL/min, λ 214nm), tR(major)＝15.50min,tR(minor)＝17.04min。1H NMR(400MHz,CDCl3)δ7.41–7.35(m,4H),7.35–7.28(m,4H),7.25–7.19(m,2H),3.68(d,J＝1.8Hz,2H),3.65–3.58(m,1H),1.84–1.73(m,2H),1.00(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.5,137.4,128.4,128.3,127.8,127.5,126.5,126.4,84.0,80.5,39.6,31.8,25.3, 11.9. HRMS (ESI) m/z accurate mass calculation C18H19[M+H]+235.1481, found 235.1481.
Example 45
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 3-cyclohexylpropyne (24.4mg, 0.20mmol, 1.0 equivalent), KOtBu (44.8mg, 0.40mmol, 2.0 equiv.) in place of Cs2CO3The reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 36 hours using general procedure a to give product 36 as a colorless oil (42.2mg, 88% yield, 98% ee).
[α]D 27＝+0.50(c 0.40,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 0.3mL/min,. lambda.214 nm), tR(minor)＝19.98min,tR(major)＝26.49min。1H NMR(400MHz,CDCl3)δ7.42–7.31(m,4H),7.27–7.21(m,1H),3.64–3.56(m,1H),2.17(dd,J＝6.6,2.3Hz,2H),1.92–1.64(m,7H),1.58–1.45(m,1H),1.36–1.06(m,5H),1.02(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.9,128.3,127.5,126.4,82.4,82.1,39.5,37.7,32.8,32.0,26.7,26.4,26.2, 11.9. HRMS (ESI) m/z precisionMass calculation C18H25[M+H]+241.1951, found 241.1950.
Example 46
Starting from (1-bromopropyl) benzene S2(39.6mg, 0.20mmol, 1.0 eq) and 1-ethynyl-1-cyclohexene (31.8mg, 0.30mmol, 1.5 eq) using general procedure B, after 72 hours the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) to give product 37 as a colourless oil (33.1mg, 74% yield, 97% ee).
[α]D 27＝–4.0(c 2.4,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 0.2mL/min, lambda 230nm), tR(minor)＝23.22min,tR(major)＝24.85min。1H NMR(400MHz,CDCl3)δ7.42–7.32(m,4H),7.28–7.22(m,1H),6.15–6.09(m,1H),3.75–3.67(m,1H),2.23–2.16(m,2H),2.16–2.08(m,2H),1.86–1.75(m,2H),1.70–1.59(m,4H),1.03(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.4,133.5,128.3,127.5,126.4,120.9,88.5,85.2,39.8,31.8,29.6,25.6,22.4,21.6, 11.8. HRMS (ESI) m/z accurate mass calculation C17H21[M+H]+225.1638, found 225.1638.
Example 47
Starting from (1-bromopropyl) benzene S2(39.6mg, 0.20mmol, 1.0 equiv) and cyclopropylacetylene (19.8mg, 0.30mmol, 1.5 equiv), the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 72 hours using general procedure B to give product 38 as a colorless oil (29.8mg, 81% yield, 97% ee).
[α]D 27＝+1.3(c 2.3,CH2Cl2). HPLC conditions Chiralcel IG (n-hexane/isopropanol 100/0, flow rate 0.3mL/min, lambda214nm),tR(minor)＝17.83min,tR(major)＝22.16min。1H NMR(400MHz,CDCl3)δ7.37–7.30(m,4H),7.26–7.20(m,1H),3.53(ddd,J＝7.9,6.0,1.8Hz,1H),1.83–1.65(m,2H),1.36–1.26(m,1H),0.98(t,J＝7.4Hz,3H),0.81–0.74(m,2H),0.72–0.64(m,2H)。13C NMR(100MHz,CDCl3) δ 142.7,128.3,127.5,126.4,86.3,76.9,39.4,31.8,11.8,8.24,8.17, -0.3. HRMS (ESI) m/z accurate mass calculation C14H17[M+H]+185.1325, found 185.1325.
Example 48
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 6-chlorohexyne (23.3mg, 0.20mmol, 1.0 equivalent), the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 48 hours using general procedure a to give product 39 as a colorless oil (41.0mg, 88% yield, 97% ee).
[α]D 27＝+1.3(c 2.3,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 0.5mL/min,. lambda.214 nm), tR(minor)＝22.13min,tR(major)＝29.06min。1H NMR(400MHz,CDCl3)δ7.40–7.30(m,4H),7.28–7.21(m,1H),3.60(t,J＝6.6Hz,2H),3.59–3.52(m,1H),2.32(td,J＝7.0,2.2Hz,2H),2.00–1.89(m,2H),1.83–1.67(m,4H),1.00(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.6,128.3,127.4,126.5,82.4,82.2,44.7,39.5,31.8,31.6,26.2,18.2, 11.8. HRMS (ESI) m/z accurate mass calculation C15H20Cl[M+H]+235.1248, found 235.1247.
Example 49
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and S40(43.4mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) after 72 hours using general procedure a to give product 40 as a colorless oil (52.0mg, 78% yield, 97% ee).
[α]D 27＝+4.1(c 1.0,CH2Cl2). HPLC conditions Chiralcel IG (n-hexane/isopropanol 95/5, flow rate 0.5mL/min, λ 254nm), tR(minor)＝32.97min,tR(major)＝44.03min。1H NMR(400MHz,CDCl3)δ7.42–7.29(m,6H),7.28–7.22(m,1H),7.13(brs,1H),6.89–6.83(m,2H),3.81(s,3H),3.61–3.53(m,1H),2.49(t,J＝7.3Hz,2H),2.39(td,J＝6.8,2.2Hz,2H),1.97(p,J＝7.0Hz,2H),1.83–1.72(m,2H),1.01(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 170.6,156.3,142.6,130.9,128.4,127.4,126.6,121.7,114.1,83.2,81.9,55.5,39.5,36.1,31.7,24.7,18.2, 11.9. HRMS (ESI) m/z accurate mass calculation C22H26NO2[M+H]+336.1958, found 336.1957.
Example 50
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and S41(39.8mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) after 72 hours using general procedure a to give product 41 as a colorless oil (61.0mg, 96% yield, 98% ee).
[α]D 27＝–1.2(c 4.4,CH2Cl2). HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 99/1, flow rate 1.0mL/min,. lambda.214 nm), tR(minor)＝15.77min,tR(major)＝17.71min。1H NMR(400MHz,CDCl3)δ7.92–7.83(m,2H),7.78–7.69(m,2H),7.31–7.14(m,5H),3.91(t,J＝7.1Hz,2H),3.52–3.44(m,1H),2.69(td,J＝7.1,2.2Hz,2H),1.77–1.59(m,2H),0.88(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3)δ168.1,142.2,133.9,132.1,128.2,127.4,126.4,123.3,83.9,78.7,39.3,37.1,31.5,18.7,11.7. HRMS (ESI) m/z accurate mass calculation C21H20NO2[M+H]+318.1489, found 318.1487.
Example 51
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and 3- (N-carbazole) propyne (41.0mg, 0.20mmol, 1.0), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 30/1) after 18 hours using general procedure a to give product 42 as a colorless oil (63.0mg, 98% yield, 98% ee).
[α]D 27＝+28(c 3.1,CH2Cl2). HPLC conditions Chiralcel IG (n-hexane/isopropanol 99/1, flow rate 0.3mL/min, λ 254nm), tR(minor)＝26.12min,tR(major)＝34.75min。1H NMR(400MHz,CDCl3)δ8.17(d,J＝7.8Hz,2H),7.65–7.49(m,4H),7.41–7.21(m,7H),5.15(d,J＝2.1Hz,2H),3.62–3.51(m,1H),1.85–1.63(m,2H),0.93(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.6,140.1,128.4,127.5,126.7,125.8,123.2,120.4,119.3,109.0,86.1,77.0,39.3,33.0,31.3, 11.7. HRMS (ESI) m/z accurate mass calculation C24H22N[M+H]+324.1747, found 324.1745.
Example 52
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and S43(46.2mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) after 18 hours using general procedure a to give product 43 as a colorless oil (69.0mg, 99% yield, 96% ee).
[α]D 27＝–8.0(c 1.9,CH2Cl2)。HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 98/2, flow rate 1.0mL/min,. lambda.214 nm), tR(major)＝12.24min,tR(minor)＝15.72min。1H NMR(400MHz,CDCl3)δ7.52–7.33(m,10H),7.31–7.19(m,3H),7.19–7.13(m,2H),3.55–3.47(m,1H),3.36(d,J＝2.1Hz,2H),1.78–1.57(m,2H),0.88(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.8,139.3,139.2,128.8,128.3,128.18,128.16,127.5,127.3,127.2,126.5,122.0,86.9,77.3,51.8,39.4,31.6,31.5, 11.6. HRMS (ESI) m/z accurate mass calculation C26H24N[M+H]+350.1903, found 350.1902.
Example 53
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 3, 3-diethoxy-1-propyne (25.6mg, 0.20mmol, 1.0 equivalent), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) after 18 hours using general procedure a to give product 44 as a colorless oil (45.0mg, 91% yield, 96% ee).
[α]D 27＝–2.0(c 2.8,CH2Cl2). HPLC conditions Chiralcel IG (n-hexane/isopropanol 99/1, flow rate 0.3mL/min, λ 214nm), tR(major)＝16.70min,tR(minor)＝22.81min。1H NMR(400MHz,CDCl3)δ7.38–7.30(m,4H),7.30–7.22(m,1H),5.37(d,J＝1.4Hz,1H),3.87–3.73(m,2H),3.71–3.56(m,3H),1.83(p,J＝7.3Hz,2H),1.26(td,J＝7.1,3.3Hz,6H),1.01(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.3,128.4,127.5,126.7,91.6,87.5,78.6,60.73,60.66,39.3,31.3,15.15,15.13, 11.8. HRMS (ESI) m/z accurate mass calculation C16H23O2[M+H]+247.1693, found 247.1693.
Example 54
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equivalents) and 3-butyn-1-ol (14mg, 0.20mmol, 1.0 equivalent), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) after 36 hours using general method a to give product 45 as a colorless oil (34.0mg, 90% yield, 98% ee).
[α]D 27＝+1.6(c 2.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 98/2, flow rate 0.5mL/min,. lambda.214 nm), tR(major)＝34.03min,tR(minor)＝44.67min。1H NMR(400MHz,CDCl3)δ7.42–7.27(m,4H),7.26–7.18(m,1H),3.79–3.66(m,2H),3.60–3.50(m,1H),2.52(td,J＝6.2,2.2Hz,2H),1.85–1.65(m,3H),0.97(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.3,128.4,127.4,126.6,84.2,79.2,61.4,39.4,31.7,23.3, 11.8. HRMS (ESI) m/z accurate mass calculation C13H17O[M+H]+189.1274, found 189.1274.
Example 55
Starting from (1-bromopropyl) benzene S2(39.6mg, 0.20mmol, 1.0 equiv.) and propynyl acetate (29.4mg, 0.30mmol, 1.5 equiv.) the general procedure B was followed. After 18 h, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 46 as a colorless oil (42.3mg, 98% yield, 97% ee).
[α]D 27＝+3.9(c 2.9,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 0.3mL/min,. lambda.214 nm), tR(major)＝26.51min,tR(minor)＝30.44min。1H NMR(400MHz,CDCl3)δ7.35–7.29(m,4H),7.27–7.20(m,1H),4.74(d,J＝2.1Hz,2H),3.64–3.56(m,1H),2.09(s,3H),1.78(p,J＝7.2Hz,2H),0.97(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ170.4,141.4,128.5,127.5,126.7,88.8,76.8,52.8,39.4,31.3,20.8,11.8. HRMS (ESI) m/z accurate mass calculation C14H17O2[M+H]+217.1223, found 217.1225.
Example 56
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and S47(26.4mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/1) after 18 hours using general procedure a to give product 47 as a colorless oil (49.5mg, 98% yield, 96% ee).
[α]D 27＝+0.50(c 4.5,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 0.5mL/min,. lambda.214 nm), tR(minor)＝15.24min,tR(major)＝17.36min。1H NMR(400MHz,CDCl3)δ7.38–7.30(m,6H),7.30–7.22(m,1H),7.09–6.99(m,3H),4.81(d,J＝1.9Hz,2H),3.70–3.59(m,1H),1.89–1.72(m,2H),0.99(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 157.8,141.5,129.4,128.4,127.5,126.7,121.3,115.2,89.5,77.9,56.5,39.5,31.4, 11.7. HRMS (ESI) m/z accurate mass calculation C18H19O[M+H]+251.1430, found 251.1431.
Example 57
Starting from (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) and S48(40.8mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 18 hours using general procedure a to give product 48 as a colorless oil (61.0mg, 95% yield, 97% ee).
[α]D 27＝–3.9(c 2.3,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol)100/0 flow rate 1.0mL/min,. lambda.214 nm), tR(minor)＝26.53min,tR(major)＝30.94min。1H NMR(400MHz,CDCl3)δ7.66–7.61(m,1H),7.48–7.44(m,1H),7.35–7.17(m,7H),3.78(d,J＝2.2Hz,2H),3.58(ddt,J＝8.2,6.0,2.2Hz,1H),1.84–1.69(m,2H),1.56(s,9H),0.96(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 150.3,141.9,134.6,133.2,128.3,127.5,126.8,126.6,126.5,126.4,85.3,78.6,39.5,36.6,31.5,30.7,25.0, 11.8. HRMS (ESI) m/z accurate mass calculation C22H27S[M+H]+323.1828, found 323.1825.
Example 58
Starting from 1- (1-bromoethyl) -4-isobutylbenzene (48.0mg, 0.20mmol, 1.0 equiv.) and silicon trimethylethynylene (29.4mg, 0.30mmol, 1.5 equiv.), after 18 hours using general procedure B, the reaction mixture was filtered and washed with petroleum ether without further purification to give product 49 as a colorless oil (51.0mg, 99% yield).
1H NMR(400MHz,CDCl3)δ7.36(d,J＝8.1Hz,2H),7.17(d,J＝8.1Hz,2H),3.84(q,J＝7.1Hz,1H),2.53(d,J＝7.2Hz,2H),1.93(dp,J＝13.5,6.8Hz,1H),1.54(d,J＝7.1Hz,3H),0.98(d,J＝6.7Hz,7H),0.26(s,9H)。13C NMR(100MHz,CDCl3)δ140.3,139.9,129.2,126.6,109.8,86.0,45.1,32.5,30.3,24.7,22.48,22.46,0.3。
Crude 49 was dissolved in methanol (1.0mL) with K2CO3(55.2mg, 0.40mmol, 2.0 equiv.) and stirred at room temperature for 3 hours. The reaction was monitored by TLC until complete consumption of starting material, and the mixture was concentrated in vacuo and purified by column chromatography to give product 49' as a colorless oil (33.9mg, 91% yield, 95% ee).
[α]D 27＝–5.2(c 6.9,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 0.3mL/min,. lambda.214 nm), tR(major)＝18.13min,tR(minor)＝23.43min。1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.0Hz,2H),7.14(d,J＝8.1Hz,2H),3.78(qd,J＝7.2,2.5Hz,1H),2.49(d,J＝7.1Hz,2H),2.28(d,J＝2.5Hz,1H),1.87(tp,J＝12.9,6.6Hz,1H),1.53(d,J＝7.2Hz,3H),0.93(d,J＝6.7Hz,6H)。13C NMR(100MHz,CDCl3) δ 140.2,139.9,129.3,126.5,87.4,69.9,45.0,31.2,30.2,24.2,22.40, 22.39. HRMS (ESI) m/z accurate mass calculation C14H19[M+H]+187.1481, found 187.1482.
Example 59
Starting from (1-bromopropyl) benzene S2(39.6mg, 0.20mmol, 1.0 equiv) and propyne (0.5mL, 1.0M in THF, 0.50mmol, 2.5 equiv), the reaction mixture was purified by silica gel column chromatography (cyclohexane ═ 100) after 28 hours using general procedure B to give product 50 as a colorless oil (27.8mg, 88% yield, 97% ee).
[α]D 27＝+19(c 0.80,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 0.3mL/min,. lambda.214 nm), tR(minor)＝24.67min,tR(major)＝26.48min。1H NMR(400MHz,CDCl3)δ7.40–7.30(m,4H),7.27–7.21(m,1H),3.60–3.47(m,1H),1.90(d,J＝2.4Hz,3H),1.84–1.68(m,2H),1.00(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.7,128.3,127.5,126.4,80.8,78.3,39.5,31.7,11.9, 3.7. HRMS (ESI) m/z accurate mass calculation C12H15[M+H]+159.1168, found 159.1169.
Example 60
Starting from 1- (3- (1-bromoethyl) phenyl) ethanone (45.2mg, 0.20mmol, 1.0 equiv.) and acetylene gas, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 20/1) after 18 hours using general method C to give product 51 as a colorless oil (33.0mg, 96% yield, 96% ee).
[α]D 27＝+15(c 1.0,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.3/0.7, flow rate 0.3mL/min,. lambda.254 nm), tR(minor)＝38.82min,tR(major)＝43.46min。1H NMR(400MHz,CDCl3)δ8.00(t,J＝1.8Hz,1H),7.89–7.83(m,1H),7.68–7.61(m,1H),7.46(t,J＝7.7Hz,1H),3.86(qd,J＝7.2,2.5Hz,1H),2.64(s,3H),2.33(d,J＝2.5Hz,1H),1.56(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 198.1,143.3,137.5,131.6,128.9,127.0,126.7,86.4,70.8,31.6,26.7, 24.2. HRMS (ESI) m/z accurate mass calculation C12H13O[M+H]+173.0961, found 173.0961.
Example 61
Using 5-bromo-5-phenylpentanenitrile S75(47.4mg, 0.20mmol, 1.0 equiv.) and acetylene gas as starting materials, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/1) after 18 hours using general method C to give product 52 as a colorless oil (28.2mg, 77% yield, 95% ee).
[α]D 27＝+8.6(c 1.2,CH2Cl2). HPLC conditions Chiralcel IG (n-hexane/isopropanol 85/15, flow rate 0.5mL/min, λ 214nm), tR(minor)＝11.88min,tR(major)＝12.52min。1H NMR(400MHz,CDCl3)δ7.41–7.25(m,5H),3.73(ddd,J＝8.3,5.8,2.5Hz,1H),2.39(t,J＝6.9Hz,2H),2.34(d,J＝2.5Hz,1H),2.01–1.75(m,4H)。13C NMR(100MHz,CDCl3) δ 140.3,128.7,127.3,127.2,119.3,84.6,72.0,36.9,36.8,23.0, 16.9. HRMS (ESI) m/z accurate mass calculation C13H14N[M+H]+184.1121, found 184.1120.
Example 62
Starting from 2- (1-bromoethyl) naphthalene S97(46.8mg, 0.20mmol, 1.0 equiv.) and acetylene gas, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/1) after 18 hours using general method C to give product 56 as a colorless oil (25.6mg, 71% yield, 93% ee).
[α]D 27＝+1.2(c 2.2,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 0.3mL/min, λ 254nm), tR(minor)＝18.49min,tR(major)＝21.05min。1H NMR(400MHz,CDCl3)δ7.97–7.78(m,4H),7.60–7.41(m,3H),3.97(qd,J＝7.1,2.5Hz,1H),2.36(d,J＝2.5Hz,1H),1.63(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 140.0,133.5,132.4,128.3,127.8,127.6,126.1,125.7,125.4,125.1,87.1,70.4,31.8, 24.1. HRMS (ESI) m/z accurate mass calculation C14H13[M+H]+181.1012, found 181.1011.
Example 63
Starting from S92(47.4mg, 0.20mmol, 1.0 equiv) and acetylene gas, the reaction mixture was filtered and concentrated after 18 hours without further purification using general procedure C. The residue was dissolved in toluene (2.0mL) under argon and p-toluenesulfonyl azide (39.4mg, 0.20mmol, 1.0 equiv.) and CuTc (1.91mg, 0.010mmol, 5.0 mol% equiv.) were added and after 3 hours the reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether/ethyl acetate 2/1) to give product 54 as a yellow amorphous powder (59.8mg, 81% over two steps, 95% ee).
[α]D 27＝+8.2(c 0.60,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 90/10, flow rate 0.4mL/min, λ 240nm), tR(minor)＝63.56min,tR(major)＝67.30min。1H NMR(400MHz,CDCl3)δ7.99(d,J＝8.4Hz,2H),7.88–7.82(m,2H),7.77(s,1H),7.49(dt,J＝7.7,1.6Hz,1H),7.46–7.41(m,1H),7.40(d,J＝8.2Hz,2H),4.34(q,J＝7.2Hz,1H),2.60(s,3H),2.46(s,3H),1.72(d,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 198.0,151.7,147.3,144.1,137.6,133.0,132.3,130.4,129.1,128.7,127.2,127.0,120.3,37.0,26.7,21.9, 21.1. HRMS (ESI) m/z accurate mass calculation C19H20N3O3S[M+H]+370.1220, found 370.1217.
Example 64
Starting from S92(47.4mg, 0.20mmol, 1.0 equiv) and acetylene gas, the reaction mixture was filtered and concentrated after 18 hours using general method C and the residue was used in the next step without further purification. To a mixture of chiral ligand L13(12.5mg, 0.015mmol, 7.5 mol% equiv), CuTc (1.91mg, 0.010mmol, 5.0 mol% equiv) and anhydrous cesium carbonate (130.4mg, 0.40mmol, 2.0 equiv) in diethyl ether (4.0ml) under argon protection were added the above residue and (1-bromopropyl) benzene S2(59.4mg, 0.30mmol, 1.5 equiv) in sequence and stirred at room temperature for 72h, after completion of the reaction the mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 55 as a colourless oil (39.4mg, two step yield 68%, 95% ee).
[α]D 27＝+2.8(c 1.8,CH2Cl2). HPLC conditions Chiralcel AZ3 (n-hexane/isopropanol 98/2, flow rate 0.4mL/min, λ 240nm), tR(major)＝18.96min,tR(minor)＝24.70min。1H NMR(400MHz,CDCl3)δ8.05(s,1H),7.85(d,J＝7.8Hz,1H),7.65(d,J＝7.7Hz,1H),7.48–7.42(m,1H),7.42–7.37(m,2H),7.37–7.31(m,2H),7.28–7.22(m,1H),3.92(q,J＝7.0Hz,1H),3.66(t,J＝6.9Hz,1H),2.61(s,3H),1.89–1.75(m,2H),1.56(d,J＝7.1Hz,3H),1.04(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 198.2,144.6,142.4,137.4,131.7,128.7,128.4,127.5,126.9,126.58,126.55,85.2,84.5,39.5,32.0,31.8,26.7,24.9, 11.9. HRMS (ESI) m/z accurate mass calculation C21H23O[M+H]+291.1743, found 291.1740.
Example 65
Starting from S92(47.4mg, 0.20mmol, 1.0 equiv) and acetylene gas, the reaction mixture was filtered and concentrated after 18 hours using general method C and the residue was used in the next step without further purification. To a mixture of chiral ligand L13(12.5mg, 0.015mmol, 7.5 mol% equiv), CuTc (1.91mg, 0.01mmol, 5.0 mol% equiv) and anhydrous cesium carbonate (130.4mg, 0.4mmol, 2.0 equiv) in diethyl ether (4.0mL) under argon protection were added the residue and S103(76.2mg, 0.30mmol, 1.5 equiv) in that order and stirred at room temperature for 72h, after completion of the reaction, the mixture was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 56 as a yellow oil (33.9mg, 49% over two steps, 95% ee).
[α]D 27＝+6.4(c 0.50,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 0.5mL/min, λ 254nm), tR(minor)＝29.15min,tR(major)＝46.89min。1H NMR(400MHz,CDCl3)δ8.02(t,J＝1.9Hz,1H),7.92–7.82(m,3H),7.67–7.61(m,1H),7.44(t,J＝7.7Hz,1H),7.41–7.35(m,3H),4.10–4.03(m,1H),3.92(qd,J＝7.2,2.1Hz,1H),2.56(s,3H),2.10–1.84(m,2H),1.56(d,J＝7.1Hz,3H),1.11(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 198.2,144.4,140.9,137.5,137.4,136.5,131.7,128.8,126.8,126.6,124.2,123.8,123.0,122.5,122.0,85.0,83.7,33.7,32.0,29.0,26.7,24.8, 11.9. HRMS (ESI) m/z accurate mass calculationC23H23OS[M+H]+347.1464, found 347.1463.
Examples 66-126 are extensions of alkyl halide substrates
Taking unfunctionalized benzyl bromide as a substrate, and obtaining products 1 and 57-59 with good results (65-77% yield, 94-96% ee); larger groups are introduced around the chiral center, and the effect of the steric hindrance effect on the yield and the enantioselectivity is not obvious (products 60-68); by introducing various functional groups such as terminal olefin, ester, ketone, nitrile, acetal, silyl ether, ether and sulfone, the reaction is not influenced (products 69-79), and better enantioselectivity can be obtained (products 80 and 81) when halogen is introduced; various electron-withdrawing groups or electron-donating groups are introduced into different positions (ortho position, meta position, para position, 3, 4-or 3,5-) of a benzene ring of the alkyl bromide, or the benzene ring is replaced by a naphthalene ring, and the product 82-99 is obtained with the yield of 38-95% and the ee of 84-97%. In addition, introducing heterocycles into alkyl bromide, such as pyridine, benzo [ b ] thiophene, benzofuran, quinoline, thiazole and pyrimidine, are feasible substrates, and obtaining 100-108 products; using alkyl chloride as substrate, products 1 and 109 were also obtained smoothly with a slight increase in catalyst usage.
General procedure B:
to an oven-dried Schlenk tube equipped with a magnetic stir bar, CuTc (1.9mg, 0.010mmol, 5.0 mol% equivalent), ligand L13(12.5mg, 0.015mmol, 7.5 mol% equivalent), Cs were added under argon protection2CO3(130.4mg, 0.40mmol, 2.0 equiv.) and anhydrous Et2O (4.0 mL). Then, the alkyl halide (0.20mmol, 1.0 equivalent) and the alkyne (0.30mmol, 1.5 equivalent) were sequentially added to the mixture, and stirred at room temperature for 24 to 72 hours. After completion of the reaction (monitored by TLC), the precipitate was filtered off and treated with Et2Washing with O or petroleum ether, then concentrating the solution and purifying by silica gel column chromatography to give the desired product.
General procedure D:
to an oven-dried Schlenk tube equipped with a magnetic stir bar, CuTc (3.8mg, 0.020mmol, 10.0 mol% equiv.), ligand L13(25.1mg, 0.03mmol, 15.0 mol% equiv.), Cs were added under argon protection2CO3(130.4mg, 0.40mmol, 2.0 equiv.) and anhydrous Et2O (4.0 mL). Then, an alkyl halide (0.20mmol, 1.0 equivalent) and an alkyne (0.30mmol, 1.5 equivalent) were sequentially added to the mixture, and stirred at room temperature for 24 to 72 hours. After completion of the reaction (monitored by TLC), the precipitate was filtered off and treated with Et2Washing with O or petroleum ether, then concentrating the solution and purifying by silica gel column chromatography to give the desired product.
Notably, most of the products were not stable in air after purification and had to be stored in solvent (CH) at-10 ℃ after NMR, HPLC or HRMS ASAP characterization2Cl2Or Et2O) in (A). At the same time, the reaction is sensitive to water and air, and Schlenk tubes and reagents must be dried before use.
Preparation of racemate:
following the same procedure described above, CuTc (1.9mg, 0.010mmol, 5.0 mol%) and Lrac (3.76mg, 0.010mmol, 10.0 mol%) were used as catalyst and ligand, anhydrous Et at room temperature or 40 deg.C2Preparation of racemate in O (4.0mL), reaction for 24-72 hours, after completion of the reaction (monitored by TLC), the precipitate was filtered off and Et was used2O wash, then concentrate and purify by silica gel column chromatography to give the desired product.
Example 66
Starting from (1-chloroethyl) benzene (28.1mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 72 hours using general procedure D to give product 1 as a colorless oil (28.9mg, 70% yield, 94% ee).
[α]D 27＝-30(c 1.2,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝11.99min,tR(major)＝16.61min。
Example 67
Starting from (1-bromobutyl) benzene S57(42.6mg, 0.20mmol, 1.0 equiv.) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv.) the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 48 hours using general method B to give product 57 as a colorless oil (36.0mg, 77% yield, 96% ee).
[α]D 27＝-10(c 2.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝9.04min,tR(major)＝13.82min。1H NMR(400MHz,CDCl3)δ7.47–7.39(m,4H),7.33(t,J＝7.6Hz,2H),7.30–7.20(m,4H),3.84(dd,J＝8.2,6.3Hz,1H),1.89–1.71(m,2H),1.63–1.42(m,2H),0.95(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.4,131.7,128.5,128.2,127.7,127.5,126.7,123.9,91.7,83.2,40.9,38.2,20.7, 13.9. HRMS (ESI) m/z accurate mass calculation C18H19[M+H]+235.1481, found 235.1479.
Example 68
Starting from (1-bromopentyl) benzene S58(45.4mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 48 hours using general procedure B to give product 58 as a colorless oil (34.7mg, 70% yield, 96% ee).
[α]D 27＝-9.4(c 2.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝8.83min,tR(major)＝14.51min。1H NMR(400MHz,CDCl3)δ7.47–7.42(m,3H),7.41(d,J＝0.5Hz,1H),7.33(t,J＝7.6Hz,2H),7.30–7.26(m,3H),7.26–7.20(m,1H),3.83(t,J＝7.2Hz,1H),1.91–1.75(m,2H),1.58–1.40(m,2H),1.40–1.28(m,2H),0.90(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.4,131.7,128.5,128.2,127.7,127.5,126.7,123.9,91.8,83.2,38.48,38.47,29.7,22.5, 14.1. HRMS (ESI) m/z accurate mass calculation C19H21[M+H]+249.1638, found 249.1632.
Example 69
Starting from (1-bromohexyl) benzene S59(48.2mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 60 hours using general procedure B to give product 59 as a colorless oil (34.1mg, 65% yield, 96% ee).
[α]D 27＝-7.5(c 2.3,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝8.91min,tR(major)＝15.15min。1H NMR(400MHz,CDCl3)δ7.47–7.42(m,3H),7.40(d,J＝0.7Hz,1H),7.33(t,J＝7.5Hz,2H),7.30–7.25(m,3H),7.25–7.20(m,1H),3.83(dd,J＝7.9,6.5Hz,1H),1.88–1.71(m,2H),1.61–1.39(m,2H),1.35–1.23(m,4H),0.93–0.80(m,3H)。13C NMR(100MHz,CDCl3) δ 142.4,131.7,128.5,128.2,127.7,127.5,126.7,123.9,91.8,83.2,38.7,38.5,31.6,27.2,22.6, 14.1. HRMS (ESI) m/z accurate mass calculation C20H23[M+H]+263.1794, found 263.1794.
Example 70
Starting from S60(52.2mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 60 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 60 as a colorless oil (35.0mg, 62% yield, 92% ee).
[α]D 27＝+35(c 1.5,CH2Cl2). HPLC conditions Chiralcel OJH (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(major)＝11.76min,tR(minor)＝14.37min。1H NMR(400MHz,CDCl3)δ7.40–7.35(m,3H),7.34(d,J＝0.9Hz,1H),7.31(dd,J＝6.9,1.8Hz,2H),7.29–7.23(m,6H),7.23–7.20(m,1H),7.20–7.15(m,2H),4.07(t,J＝7.3Hz,1H),3.10(d,J＝7.3Hz,2H)。13C NMR(100MHz,CDCl3) δ 141.4,139.0,131.6,129.6,128.5,128.3,128.1,127.9,127.8,127.0,126.5,123.7,91.1,84.4,45.2, 40.9. HRMS (ESI) m/z accurate mass calculation C22H19[M+H]+283.1481, found 283.1477.
Example 71
Starting from S61(55.0mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 61 as a colorless oil (42.0mg, 71% yield, 94% ee).
[α]D 27＝+31(c 2.4,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝26.12min,tR(major)＝27.24min。1H NMR(400MHz,CDCl3)δ7.48–7.45(m,2H),7.41(d,J＝7.8Hz,2H),7.38–7.27(m,6H),7.26(d,J＝1.6Hz,1H),7.24–7.15(m,4H),3.84(t,J＝7.2Hz,1H),2.93–2.74(m,2H),2.27–1.99(m,2H)。13C NMR(100MHz,CDCl3) δ 141.9,141.7,131.7,128.6,128.5,128.3,127.9,127.6,126.9,126.0,123.8,91.2,83.9,40.2,37.8, 33.7. HRMS (ESI) m/z accurate mass calculation C23H21[M+H]+283.1638, found 283.1633.
Example 72
Starting from S62(57.8mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 62 as a colorless oil (32.2mg, 52% yield, 95% ee).
[α]D 27＝+1.0(c 1.8,CH2Cl2). HPLC conditions Chiralcel IB (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(minor)＝4.65min,tR(major)＝6.81min。1H NMR(400MHz,CDCl3)δ7.47–7.41(m,2H),7.40(d,J＝1.4Hz,1H),7.39–7.37(m,1H),7.32(t,J＝7.5Hz,2H),7.29–7.20(m,6H),7.19–7.13(m,3H),3.86(t,J＝6.7Hz,1H),2.74–2.55(m,2H),1.97–1.72(m,4H)。13C NMR(100MHz,CDCl3) δ 142.3,142.1,131.7,128.6,128.5,128.4,128.3,127.8,127.5,126.8,125.8,123.8,91.5,83.4,38.4,38.2,35.6, 29.2. HRMS (ESI) m/z accurate mass calculation C24H23[M+H]+311.1794, found 311.1793.
Example 73
Using S63(45.4mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) as starting materials, the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 48 hours using general method B to give product 63 as a colorless oil (34.7mg, 70% yield, 96% ee).
[α]D 27＝-11(c 2.3,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝8.18min,tR(major)＝11.86min。1H NMR(400MHz,CDCl3)δ7.46–7.39(m,4H),7.33(t,J＝7.5Hz,2H),7.30–7.21(m,4H),3.88(dd,J＝9.7,6.1Hz,1H),1.99–1.85(m,1H),1.80(ddd,J＝13.2,9.7,5.4Hz,1H),1.57(ddd,J＝13.2,8.5,6.1Hz,1H),0.98(dd,J＝8.4,6.6Hz,6H)。13C NMR(100MHz,CDCl3) δ 142.7,131.7,128.6,128.2,127.7,127.5,126.7,123.9,91.7,83.0,48.1,36.6,26.2,23.1, 21.9. HRMS (ESI) m/z accurate mass calculation C19H21[M+H]+249.1638, found 249.1634.
Example 74
Starting from S64(42.6mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), ligand L8 instead of ligand L13, the reaction mixture was purified by column chromatography on silica gel (petroleum ether ═ 100) after 24h using general procedure B to give product 64 as a colorless oil (37.9mg, 81% yield, 98% ee).
[α]D 27＝-34(c 1.0,CH2Cl2). HPLC conditions Chiralcel ODH (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝9.14min,tR(major)＝10.67min。1H NMR(400MHz,CDCl3)δ7.49–7.43(m,2H),7.40(d,J＝7.4Hz,2H),7.35–7.27(m,5H),7.24(t,J＝7.2Hz,1H),3.73(d,J＝5.9Hz,1H),2.05(dq,J＝13.1,6.5Hz,1H),1.04(d,J＝6.7Hz,3H),0.99(d,J＝6.7Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.1,131.7,128.25,128.22,127.7,126.6,124.0,90.2,84.3,45.8,35.2,21.3, 18.7. HRMS (ESI) m/z accurate mass calculation C18H19[M+H]+235.1481, found 235.1478.
Example 75
Starting from S65(45.4mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 65 as a colorless oil (14.9mg, 30% yield, 96% ee).
[α]D 27＝-15(c 1.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 0.5mL/min,. lambda.254 nm), tR(minor)＝15.55min,tR(major)＝16.04min。1H NMR(400MHz,CDCl3)δ7.47–7.41(m,2H),7.39–7.34(m,2H),7.34–7.26(m,5H),7.26–7.22(m,1H),3.62(s,1H),1.04(s,9H)。13C NMR(100MHz,CDCl3) δ 139.4,131.6,129.7,128.2,127.6,126.7,124.0,91.4,83.7,50.3,35.5, 27.8. HRMS (ESI) m/z accurate mass calculation C19H21[M+H]+249.1638, found 249.1632.
Example 76
Using S66(45.0mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) as starting materials, following 48 hours using general procedure B, the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 66 as a colorless oil (35.9mg, 73% yield, 96% ee).
[α]D 27＝+19(c 2.1,CH2Cl2). HPLC conditions Chiralcel IC (n-hexane/isopropanol 99.8/0.2, flow rate 1.0mL/min,. lambda.254 nm), tR(major)＝5.15min,tR(minor)＝5.62min。1H NMR(400MHz,CDCl3)δ7.48–7.40(m,2H),7.37(d,J＝7.4Hz,2H),7.34–7.26(m,5H),7.25–7.19(m,1H),3.80(d,J＝7.7Hz,1H),2.67(h,J＝8.1Hz,1H),2.13–2.00(m,2H),1.99–1.88(m,2H),1.86–1.75(m,2H)。13C NMR(100MHz,CDCl3) δ 140.8,131.8,128.4,128.2,127.8,127.6,126.7,123.9,90.2,83.7,44.1,42.2,26.7,26.0, 17.6. HRMS (ESI) m/z accurate mass calculation C19H19[M+H]+247.1481, found 247.1486.
Example 77
Starting from S67(47.8mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), ligand L8 instead of ligand L13, the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 48 hours using general procedure B to give product 67 as a colorless oil (41.1mg, 79% yield, 96% ee).
[α]D 27＝-1.1(c 2.9,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝9.22min,tR(major)＝10.57min。1H NMR(400MHz,CDCl3)δ7.48–7.40(m,3H),7.39(s,1H),7.35–7.25(m,5H),7.25–7.21(m,1H),3.78(d,J＝7.3Hz,1H),2.32–2.17(m,1H),2.33–2.18(m,1H),1.85–1.72(m,1H),1.72–1.54(m,5H),1.47–1.38(m,1H)。13C NMR(100MHz,CDCl3) δ 142.0,131.7,128.3,128.2,127.9,127.7,126.6,124.0,91.2,83.3,47.3,43.3,31.2,30.0,25.4, 25.2. HRMS (ESI) m/z accurate mass calculation C20H21[M+H]+261.1638, found 261.1636.
Example 78
Starting from S68(50.6mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), ligand L8 instead of ligand L13, the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 48 hours using general procedure B to give product 68 as a colorless oil (44.9mg, 82% yield, 98% ee).
[α]D 27＝-10(c 1.6,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝8.62min,tR(major)＝11.41min。1H NMR(400MHz,CDCl3)δ7.47–7.41(m,2H),7.41–7.35(m,2H),7.35–7.26(m,5H),7.26–7.21(m,1H),3.68(d,J＝6.2Hz,1H),1.86(s,1H),1.80–1.75(m,2H),1.70–1.55(m,3H),1.27–1.09(m,5H)。13C NMR(100MHz,CDCl3) δ 140.9,131.7,128.4,128.25,128.22,127.7,126.6,124.0,90.8,84.1,45.2,44.7,31.7,29.6,26.5,26.4, 26.3. HRMS (ESI) m/z accurate mass calculation C21H23[M+H]+275.1794, found 275.1793.
Example 79
Using S69(42.2mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) as starting materials, the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 48 hours using general method B to give product 69 as a colorless oil (29.7mg, 64% yield, 96% ee).
[α]D 27＝-2.2(c 1.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝11.62min,tR(major)＝13.43min。1H NMR(400MHz,CDCl3)δ7.50–7.40(m,4H),7.34(t,J＝7.6Hz,2H),7.31–7.26(m,3H),7.26–7.23(m,1H),5.92(ddt,J＝17.1,10.2,7.0Hz,1H),5.15–5.02(m,2H),3.92(t,J＝7.1Hz,1H),2.59(t,J＝7.1Hz,2H)。13C NMR(100MHz,CDCl3) δ 141.4,135.5,131.7,128.5,128.2,127.8,127.6,126.9,123.7,117.1,91.0,83.8,42.8, 38.6. HRMS (ESI) m/z accurate mass calculation C18H17[M+H]+233.1325, found 233.1321.
Example 80
Starting from S70(47.8mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 70 as a colorless oil (39.1mg, 75% yield, 96% ee).
[α]D 27＝-6.0(c 2.3,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝10.61min,tR(major)＝21.67min。1H NMR(400MHz,CDCl3)δ7.46–7.41(m,3H),7.40(s,1H),7.33(t,J＝7.5Hz,2H),7.30–7.26(m,3H),7.26–7.17(m,1H),5.80(ddt,J＝16.9,10.2,6.7Hz,1H),5.01(ddd,J＝17.1,3.4,1.6Hz,1H),4.97–4.92(m,1H),3.84(t,J＝7.2Hz,1H),2.18–2.04(m,2H),1.90–1.77(m,2H),1.73–1.43(m,2H)。13C NMR(100MHz,CDCl3) δ 142.2,138.6,131.7,128.5,128.2,127.8,127.5,126.7,123.8,114.7,91.5,83.3,38.3,38.1,33.5, 26.7. HRMS (ESI) m/z accurate mass calculation C20H21[M+H]+261.1638, found 261.1638.
Example 81
Using ethyl 3-bromo-3-phenylpropionate S71(51.4mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) as starting materials, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) after 72 hours using general method B to give product 71 as a colorless oil (18.9mg, 34% yield, 92% ee).
[α]D 27＝-12(c 0.80,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 95/5, flow rate 1.0mL/min, λ 254nm), tR(major)＝5.17min,tR(minor)＝7.75min。1H NMR(400MHz,CDCl3)δ7.45(d,J＝7.4Hz,2H),7.43–7.38(m,2H),7.34(t,J＝7.5Hz,2H),7.31–7.25(m,4H),4.38(t,J＝7.6Hz,1H),4.19–4.10(m,2H),2.90(dd,J＝15.1,8.4Hz,1H),2.79(dd,J＝15.1,6.9Hz,1H),1.22(t,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3) δ 170.9,140.5,131.7,128.7,128.2,128.0,127.5,127.3,123.3,89.9,83.6,60.7,43.4,34.9, 14.2. HRMS (ESI) m/z accurate mass calculation C19H19O2[M+H]+279.1380, found 279.1377.
Example 82
Starting from ethyl 4-bromo-4-phenylbutyrate S72(54.2mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 72 as a colorless oil (50.2mg, 86% yield, 86% ee).
[α]D 27＝-1.7(c 4.5,CH2Cl2). HPLC conditions Chiralcel IC (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(minor)＝8.56min,tR(major)＝10.32min。1H NMR(400MHz,CDCl3)δ7.51–7.43(m,4H),7.36(t,J＝7.5Hz,2H),7.34–7.24(m,4H),4.13(q,J＝7.1Hz,2H),3.98(dd,J＝8.4,5.9Hz,1H),2.66–2.45(m,2H),2.28–2.08(m,2H),1.26(t,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3) δ 173.2,141.2,131.7,128.6,128.3,128.0,127.6,127.0,123.5,90.3,84.1,60.5,37.6,33.4,32.0, 14.3. HRMS (ESI) m/z accurate mass calculation C20H21O2[M+H]+293.1536, found 293.1533.
Example 83
Starting from ethyl 5-bromo-5-phenylpentanoate S73(57.1mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) after 48 hours using general method B to give product 73 as a colorless oil (45.9mg, 75% yield, 92% ee).
[α]D 27＝-7.0(c 3.8,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(minor)＝7.93min,tR(major)＝11.48min。1H NMR(400MHz,CDCl3)δ7.45(d,J＝4.1Hz,1H),7.44–7.42(m,2H),7.41(s,1H),7.33(t,J＝7.5Hz,2H),7.30–7.27(m,3H),7.26–7.21(m,1H),4.11(q,J＝7.1Hz,2H),3.86(t,J＝6.5Hz,1H),2.35(t,J＝6.9Hz,2H),1.95–1.78(m,4H),1.23(t,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3) δ 173.4,141.8,131.7,128.6,128.2,127.8,127.5,126.8,123.7,91.0,83.6,60.3,38.2,37.9,34.0,22.9, 14.3. HRMS (ESI) m/z accurate mass calculation C21H23O2[M+H]+307.1693, found 307.1687.
Example 84
Starting from S74(63.4mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 15/1) to give product 74 as a colorless oil (56.8mg, 84% yield, 92% ee).
[α]D 27＝-3.6(c 3.6,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 90/10, flow rate 1.0mL/min, λ 254nm), tR(minor)＝9.16min,tR(major)＝18.19min。1H NMR(400MHz,CDCl3)δ7.98–7.94(m,2H),7.55(ddd,J＝6.8,4.0,1.2Hz,1H),7.50–7.42(m,6H),7.36(t,J＝7.5Hz,2H),7.33–7.27(m,3H),7.27–7.24(m,1H),3.94(t,J＝6.7Hz,1H),3.11–2.93(m,2H),2.10–1.87(m,4H)。13C NMR(100MHz,CDCl3)δ200.0,141.9,137.0,133.0,131.7,128.61,128.60,128.2,128.1,127.8,127.5,126.8,123.7,91.2,83.7,38.3,38.2,38.1,22.3. HRMS (ESI) m/z accurate mass calculation C25H23O[M+H]+339.1743, found 339.1743.
Example 85
Using 5-bromo-5-phenylpentanenitrile S75(47.6mg, 0.20mmol, 1.0 equiv.) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv.) as starting materials, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 8/1) after 72 hours using general method B to give product 75 as a colorless oil (43.0mg, 83% yield, 94% ee).
[α]D 27＝-7.6(c 3.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 85/15, flow rate 1.0mL/min, λ 254nm), tR(minor)＝9.97min,tR(major)＝14.98min。1H NMR(400MHz,CDCl3)δ7.47-7.39(m,4H),7.35(t,J＝7.6Hz,2H),7.30-7.28(m,3H),7.27-7.23(m,1H),3.90(dd,J＝7.8,6.0Hz,1H),2.36(t,J＝7.0Hz,2H),2.02-1.92(m,2H),1.91-1.78(m,2H)。13C NMR(100MHz,CDCl3) δ 141.0,131.7,128.7,128.3,128.1,127.4,127.1,123.3,119.5,90.1,84.2,37.7,37.2,23.2, 17.0. HRMS (ESI) m/z accurate mass calculation C19H18N[M+H]+260.1434, found 260.1437.
Example 86
Starting from S76(62.6mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 76 as a colorless oil (49.4mg, 74% yield, 94% ee).
[α]D 27＝-2.1(c 3.5,CH2Cl2). HPLC conditions Chiralcel IB (99.5/0.5 n-hexane/isopropanol, flow rate 1.0mL/min, 254nm), tR(minor)＝17.29min,tR(major)＝18.52min。1H NMR(400MHz,CDCl3)δ7.47–7.40(m,4H),7.33(t,J＝7.6Hz,2H),7.30–7.21(m,4H),4.45(t,J＝4.6Hz,1H),3.92–3.83(m,1H),3.60(d,J＝3.1Hz,1H),3.58(d,J＝2.9Hz,1H),3.41(d,J＝3.0Hz,1H),3.38(d,J＝3.0Hz,1H),2.04–1.88(m,3H),1.88–1.75(m,1H),1.18(s,3H),0.70(s,3H)。13C NMR(100MHz,CDCl3) δ 141.9,131.7,128.5,128.2,127.7,127.6,126.8,123.7,101.9,91.1,83.6,77.2,38.2,32.9,32.7,30.2,23.0, 21.9. HRMS (ESI) m/z accurate mass calculation C23H27O2[M+H]+335.2006, found 335.1998.
Example 87
Using S77(93.4mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) as starting materials, the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 48 hours using general method B to give product 77 as a colorless oil (81.1mg, 83% yield, 95% ee).
[α]D 27＝-2.2(c 2.2,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.3/0.7, flow rate 0.5mL/min,. lambda.254 nm), tR(minor)＝7.80min,tR(major)＝9.81min。1H NMR(400MHz,CDCl3)δ7.69–7.61(m,4H),7.43–7.41(m,3H),7.39(d,J＝5.3Hz,3H),7.36–7.31(m,6H),7.30–7.21(m,4H),3.87(t,J＝7.6Hz,1H),3.79–3.63(m,2H),2.01–1.85(m,2H),1.85–1.68(m,2H),1.04(s,9H)。13C NMR(100MHz,CDCl3) δ 142.1,135.6,134.01,134.00,131.7,129.6,128.5,128.2,127.7,127.6,127.5,126.7,123.8,91.5,83.4,63.6,38.0,34.9,30.3,26.9, 19.3. HRMS (ESI) m/z accurate mass calculation C34H37OSi[M+H]+489.2608, found 489.2600.
Example 88
Using S78(48.6mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) as starting materials, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 50/1) after 48 hours using general method B to give product 78 as a colorless oil (43.8mg, 83% yield, 95% ee).
[α]D 27＝-11(c 3.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 97/3, flow rate 0.3mL/min, λ 254nm), tR(minor)＝14.89min,tR(major)＝16.42min。1H NMR(400MHz,CDCl3)δ7.46–7.40(m,4H),7.33(t,J＝7.5Hz,2H),7.30–7.20(m,4H),3.87(dd,J＝7.8,6.2Hz,1H),3.46–3.35(m,2H),3.31(s,3H),1.98–1.69(m,4H)。13C NMR(100MHz,CDCl3) δ 142.0,131.7,128.5,128.2,127.8,127.5,126.8,123.8,91.3,83.5,72.5,58.6,38.2,35.3, 27.6. HRMS (ESI) m/z accurate mass calculation C19H21O[M+H]+265.1587, found 265.1585.
Example 89
Starting from S79(67.8mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 8/1) to give product 79 as a colourless oil (66.2mg, 92% yield, 80% ee).
[α]D 27＝-0.60(c 5.5,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 85/15, flow rate 1.0mL/min, λ 254nm), tR(minor)＝9.02min,tR(major)＝10.32min。1H NMR(400MHz,CDCl3)δ7.89(s,1H),7.88(t,J＝1.6Hz,1H),7.69–7.59(m,1H),7.54(t,J＝7.6Hz,2H),7.42–7.37(m,2H),7.37–7.31(m,4H),7.31–7.29(m,3H),7.29–7.23(m,1H),4.00(dd,J＝8.2,5.8Hz,1H),3.36–3.21(m,2H),2.33–2.08(m,2H)。13C NMR(100MHz,CDCl3) δ 139.8,139.0,133.8,131.7,129.4,128.8,128.33,128.28,128.0,127.44,127.38,122.9,88.8,84.9,54.0,36.9, 31.1. HRMS (ESI) m/z accurate mass calculation C23H21O2S[M+H]+361.1257, found 361.1255.
Example 90
Starting from S80(55.6mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 80 as a colorless oil (45.9mg, 77% yield, 96% ee).
[α]D 27＝+8.8(c 3.3,CH2Cl2). HPLC conditions Chiralcel OJH (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(major)＝9.15min,tR(minor)＝10.66min。1H NMR(400MHz,CDCl3)δ7.49–7.44(m,2H),7.44(d,J＝2.6Hz,2H),7.36(t,J＝7.5Hz,2H),7.33–7.25(m,4H),4.13(dd,J＝8.5,6.2Hz,1H),3.64(ddd,J＝10.0,7.7,6.6Hz,1H),3.48(dt,J＝10.1,6.2Hz,1H),2.44–2.21(m,2H)。13C NMR(100MHz,CDCl3) δ 140.6,131.7,128.8,128.3,128.1,127.6,127.2,123.3,89.7,84.1,41.2,36.9, 31.3. HRMS (ESI) m/z accurate mass calculation C17H16Br[M+H]+299.0430, found 299.0426.
Example 91
Starting from S81(54.9mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 81 as a colorless oil (39.6mg, 78% yield, 97% ee).
[α]D 27＝+6.2(c 3.5,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝16.07min,tR(major)＝16.95min。1H NMR(400MHz,CDCl3)δ7.48–7.41(m,4H),7.35(t,J＝7.6Hz,2H),7.32–7.24(m,4H),4.14(dd,J＝8.5,6.3Hz,1H),3.78(ddd,J＝10.9,7.6,6.3Hz,1H),3.64–3.55(m,1H),2.35–2.16(m,2H)。13C NMR(100MHz,CDCl3) δ 140.7,131.7,128.8,128.3,128.1,127.6,127.2,123.3,89.8,84.0,42.7,41.1, 35.7. HRMS (ESI) m/z accurate mass calculation C17H16Cl[M+H]+255.0935, found 255.0933.
Example 92
Starting from S130(72.6mg, 0.30mmol, 1.5 equiv) and S42(41.0mg, 0.20mmol, 1.0 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/EtOAc 20/1) after 48 hours using general method a to give product 130 as a colorless oil (63.1mg, 86% yield, 97% ee).
[α]D 27＝–3.7(c 1.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 0.5mL/min, λ 254nm), tR(major)＝18.73min,tR(minor)＝20.47min。1H NMR(400MHz,CDCl3)δ8.15(d,J＝7.8Hz,2H),7.62–7.50(m,4H),7.34–7.29(m,2H),7.28–7.22(m,2H),7.17–7.08(m,3H),5.18(d,J＝2.2Hz,2H),3.09(t,J＝2.4Hz,1H),-0.11(s,9H)。13C NMR(100MHz,CDCl3) δ 140.2,138.9,128.1,126.9,125.8,125.1,123.3,120.4,119.3,109.1,84.6,76.8,33.1,29.3, -3.4. HRMS (ESI) m/z accurate mass calculation C25H26NSi[M+H]+368.1829, found 368.1827.
Example 93
Starting from S82(42.6mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 82 as a colorless oil (39.8mg, 85% yield, 96% ee).
[α]D 27＝-2.6(c 2.6,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝9.24min,tR(major)＝15.76min。1H NMR(400MHz,CDCl3)δ7.45(d,J＝4.5Hz,1H),7.43(d,J＝1.9Hz,1H),7.34–7.26(m,5H),7.15(d,J＝7.9Hz,2H),3.75(t,J＝7.0Hz,1H),2.34(s,3H),1.90–1.79(m,2H),1.05(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 139.1,136.2,131.7,129.1,128.2,127.7,127.4,123.9,91.7,83.2,39.6,31.7,21.1, 11.9. HRMS (ESI) m/z accurate mass calculation C18H19[M+H]+235.1481, found 235.1480.
Example 94
Starting from S83(42.6mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 83 as a colorless oil (37.0mg, 79% yield, 93% ee).
[α]D 27＝-10(c 2.8,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝10.82min,tR(major)＝13.69min。1H NMR(500MHz,CDCl3)δ7.49-7.44(m,2H),7.33-7.28(m,3H),7.26-7.21(m,3H),7.10–7.04(m,1H),3.76(dd,J＝7.6,6.4Hz,1H),2.38(s,3H),1.93–1.81(m,2H),1.07(t,J＝7.3Hz,3H)。13C NMR(125MHz,CDCl3) δ 142.0,138.0,131.7,128.34,128.31,128.2,127.7,127.4,124.6,123.9,91.7,83.3,39.9,31.7,21.5, 12.0. HRMS (ESI) m/z accurate mass calculation C18H19[M+H]+235.1481, found 235.1481.
Example 95
Using S84(42.6mg, 0.20mmol, 1.0 eq), phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) as starting material, ligand L8 in place of ligand L13, the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 72 hours using general procedure B to give product 84 as a colorless oil (20.1mg, 43% yield, 95% ee).
[α]D 27＝-11(c 0.80,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(major)＝8.66min,tR(minor)＝10.85min。1H NMR(400MHz,CDCl3)δ7.58(d,J＝7.5Hz,1H),7.48–7.37(m,2H),7.34–7.27(m,3H),7.25–7.18(m,1H),7.18–7.13(m,2H),3.97(dd,J＝8.3,5.8Hz,1H),2.39(s,3H),1.91–1.74(m,2H),1.12(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 140.3,134.9,131.6,130.4,128.2,127.7,126.6,126.2,123.9,91.9,82.7,36.5,30.1,19.3, 12.2. HRMS (ESI) m/z accurate mass calculation C18H19[M+H]+235.1481, found 235.1480.
Example 96
Starting from S85(45.8mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) using general method B, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 100/1) to give product 85 as a colorless oil (35.0mg, 70% yield, 96% ee).
[α]D 27＝-6.8(c 1.4,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(minor)＝4.89min,tR(major)＝5.55min。1H NMR(400MHz,CDCl3)δ7.53–7.40(m,2H),7.39–7.27(m,4H),7.03(d,J＝6.1Hz,2H),6.85–6.77(m,1H),3.84(s,3H),3.79(t,J＝7.0Hz,1H),1.97–1.83(m,2H),1.09(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 159.7,143.7,131.7,129.4,128.2,127.7,123.9,120.0,113.5,111.9,91.4,83.5,55.2,40.0,31.6, 11.9. HRMS (ESI) m/z accurate mass calculation C18H19O[M+H]+251.1430, found 251.1425.
Example 97
Starting from S86(48.4mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to give product 86 as a colorless oil (47.3mg, 90% yield, 90% ee).
[α]D 27＝-4.4(c 3.9,CH2Cl2). HPLC conditions Chiralcel IC (n-hexane/isopropanol 90/10, flow rate 1.0mL/min, λ 254nm), tR(minor)＝12.96min,tR(major)＝14.66min。1H NMR(400MHz,CDCl3)δ7.54(s,1H),7.49–7.43(m,3H),7.40(s,1H),7.33–7.26(m,4H),7.19(d,J＝7.7Hz,1H),3.96(q,J＝7.1Hz,1H),2.16(s,3H),1.57(d,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3) δ 168.4,144.3,138.1,131.7,129.2,128.2,127.8,123.6,122.9,118.4,118.3,92.3,82.6,32.4,24.6, 24.4. HRMS (ESI) m/z accurate mass calculation C18H18NO[M+H]+264.1383, found 264.1382.
Example 98
Starting from S87(48.6mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 87 as a colorless oil (50.1mg, 95% yield, 92% ee).
[α]D 27＝-10(c 4.5,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(minor)＝7.84min,tR(major)＝8.48min。1H NMR(400MHz,CDCl3)δ7.47(d,J＝4.3Hz,1H),7.45(t,J＝2.7Hz,1H),7.39–7.33(m,2H),7.33–7.29(m,3H),7.21(d,J＝1.8Hz,1H),7.03–6.99(m,1H),4.01(q,J＝7.1Hz,1H),2.31(s,3H),1.60(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 169.5,150.9,145.0,131.7,129.5,128.3,127.9,124.5,123.6,120.2,119.9,92.0,82.8,32.3,24.3, 21.2. HRMS (ESI) m/z accurate mass calculation C18H17O2[M+H]+265.1223, found 265.1221.
Example 99
Starting from S88(55.6mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 88 as a colorless oil (50.0mg, 84% yield, 96% ee).
[α]D 27＝-6.5(c 4.5,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝12.93min,tR(major)＝23.05min。1H NMR(400MHz,CDCl3)δ7.49–7.47(m,1H),7.46(d,J＝2.1Hz,2H),7.44(t,J＝2.8Hz,1H),7.31(t,J＝3.7Hz,3H),7.29(d,J＝2.4Hz,2H),3.76(t,J＝7.2Hz,,1H),1.91–1.75(m,2H),1.05(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.1,131.7,131.5,129.3,128.3,127.9,123.6,120.5,90.7,83.7,39.4,31.5, 11.7. HRMS (ESI) m/z accurate mass calculation C17H16Br[M+H]+299.0430, found 299.0430.
Example 100
Using S89(55.6mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) as starting materials, following 48 hours using general method B, the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 89 as a colorless oil (36.9mg, 62% yield, 95% ee).
[α]D 27＝-3.0(c 2.5,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝12.81min,tR(major)＝16.94min。1H NMR(400MHz,CDCl3)δ7.57(t,J＝1.7Hz,1H),7.48–7.46(m,1H),7.45(t,J＝2.8Hz,1H),7.41–7.37(m,1H),7.35(d,J＝7.7Hz,1H),7.33–7.28(m,3H),7.21(t,J＝7.8Hz,1H),3.76(t,J＝7.6Hz,1H),1.97–1.72(m,2H),1.06(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 144.3,131.7,130.7,130.0,129.8,128.3,127.9,126.3,123.5,122.5,90.5,83.9,39.6,31.6, 11.8. HRMS (ESI) m/z accurate mass calculation C17H16Br[M+H]+299.0430, found 299.0425.
Example 101
Starting from S90(52.8mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 90 as a colorless oil (21.6mg, 38% yield, 95% ee).
[α]D 27＝-19(c 1.3,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(major)＝8.23min,tR(minor)＝9.18min。1H NMR(400MHz,CDCl3)δ7.78(dd,J＝7.8,1.6Hz,1H),7.56(dd,J＝8.0,0.9Hz,1H),7.48(d,J＝4.1Hz,1H),7.46(t,J＝2.8Hz,1H),7.38–7.29(m,4H),7.13(td,J＝7.8,1.6Hz,1H),4.45(q,J＝7.0Hz,1H),1.57(d,J＝7.0Hz,3H)。13C NMR(100MHz,CDCl3) δ 142.4,132.9,131.7,128.8,128.4,128.3,127.9,123.6,123.1,92.0,82.6,32.4, 23.1. HRMS (ESI) m/z accurate mass calculation C16H14Br[M+H]+285.0273, found 285.0277.
Example 102
Starting from 3- (1-bromoethyl) benzaldehyde S91(42.6mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), the reaction mixture was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20/1) after 48 hours using general method B to give product 91 as a colorless oil (31.8mg, 68% yield, 90% ee).
[α]D 27＝-5.5(c 2.7,CH2Cl2). HPLC conditions Chiralcel IC (n-hexane/isopropanol 97/3, flow rate 1.0mL/min, λ 254nm), tR(major)＝8.80min,tR(minor)＝9.63min。1H NMR(400MHz,CDCl3)δ10.04(s,1H),7.97(s,1H),7.85–7.71(m,2H),7.52(t,J＝7.6Hz,1H),7.48–7.46(m,1H),7.45(t,J＝2.7Hz,1H),7.35–7.26(m,3H),4.08(q,J＝7.1Hz,1H),1.62(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 192.3,144.5,136.8,133.2,131.7,129.3,128.4,128.3,128.1,128.0,123.4,91.6,83.1,32.3, 24.3. HRMS (ESI) m/z accurate mass calculation C17H15O[M+H]+235.1117, found 235.1115.
Example 103
Starting from S92(45.4mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 92 as a colorless oil (47.1mg, 95% yield, 93% ee).
[α]D 27＝-13(c 4.4,CH2Cl2). HPLC conditions Chiralcel OJ3 (n-hexane/isopropanol 95/5, flow rate 1.0mL/min, λ 254nm), tR(minor)＝17.45min,tR(major)＝20.28min。1H NMR(400MHz,CDCl3)δ8.05(t,J＝1.7Hz,1H),7.85(d,J＝7.7Hz,1H),7.69(d,J＝7.7Hz,1H),7.53–7.41(m,3H),7.39–7.27(m,3H),4.06(q,J＝7.1Hz,1H),2.63(s,3H),1.61(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 198.1,144.0,137.5,131.8,131.6,128.9,128.3,128.0,126.9,126.8,123.5,91.9,83.0,32.4,26.8, 24.4. HRMS (ESI) m/z accurate mass calculation C18H17O[M+H]+249.1274, found 249.1272.
Example 104
Using S93(48.6mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) as starting materials, following 48 hours in general procedure B, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 93 as a colorless oil (48.0mg, 91% yield, 89% ee).
[α]D 27＝-9.3(c 3.7,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(minor)＝7.82min,tR(major)＝9.38min。1H NMR(400MHz,CDCl3)δ8.13(s,1H),7.94(d,J＝7.7Hz,1H),7.69(d,J＝7.7Hz,1H).7.47–7.41(m,3H),7.38–7.28(m,3H),4.05(q,J＝7.1Hz,1H),3.93(s,3H),1.61(d,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3) δ 167.1,143.7,131.7,131.6,130.5,128.7,128.3,128.2,128.0,127.9,123.5,91.9,82.9,52.2,32.4, 24.4. HRMS (ESI) m/z accurate mass calculation C18H17O2[M+H]+265.1223, found 265.1221.
Example 105
Starting from S94(42.0mg, 0.20mmol, 1.0 eq) and 9- (prop-2-yn-1-yl) -9H-carbazole (61.5mg, 0.30mmol), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) after 48 hours using general method B to give product 94 as a colorless oil (58.8mg, 88% yield, 84% ee).
[α]D 27＝+15(c 3.9,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 90/10, flow rate 1.0mL/min, λ 254nm), tR(minor)＝16.97min,tR(major)＝18.84min。1H NMR(400MHz,CDCl3)δ8.13(t,J＝0.9Hz,1H),8.11(t,J＝0.9Hz,1H),7.60(t,J＝1.7Hz,1H),7.55–7.44(m,6H),7.33(t,J＝7.8Hz,1H),7.31–7.26(m,2H),5.11(d,J＝2.0Hz,2H),3.72(qt,J＝7.0,1.7Hz,1H),1.40(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 144.2,139.9,131.5,130.5,129.3,125.9,123.3,120.5,119.5,118.8,112.6,108.8,85.6,77.4,32.8,31.5, 23.9. HRMS (ESI) m/z accurate mass calculation C24H19N2[M+H]+335.1543, found 335.1542.
Example 106
Using S95(53.4mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) as starting materials, the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 48 hours using general method B to give product 95 as a colorless oil (39.7mg, 69% yield, 96% ee).
[α]D 27＝-11(c 2.8,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝11.52min,tR(major)＝19.36min。1H NMR(500MHz,CDCl3)δ7.61(d,J＝8.2Hz,2H),7.55(d,J＝8.2Hz,2H),7.47(d,J＝3.7Hz,1H),7.45(t,J＝2.9Hz,1H),7.36–7.29(m,3H),3.86(t,J＝5.6Hz,1H),1.96–1.82(m,2H),1.07(t,J＝7.3Hz,3H)。13C NMR(125MHz,CDCl3)δ146.1,131.7,129.0(q,J＝32.5Hz),128.3,128.0,127.9,125.4(q,J＝3.7Hz),124.3(q,J＝274.6Hz),123.4,90.3,84.0,39.8,31.5,11.8。19F NMR(376MHz,CDCl3) Delta-62.3 (s, 3F). HRMS (ESI) m/z accurate mass calculation C18H16F3[M+H]+289.1199, found 289.1201.
Example 107
Starting from S96(67.0mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 96 as a colorless oil (52.7mg, 74% yield, 94% ee).
[α]D 27＝-1.2(c 2.3,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(major)＝7.36min,tR(minor)＝17.39min。1H NMR(400MHz,CDCl3)δ7.89(s,2H),7.79(s,1H),7.54–7.43(m,2H),7.36–7.30(m,3H),3.95(dd,J＝8.0,6.0Hz,1H),2.04–1.75(m,2H),1.10(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3)δ144.6,131.74(q,J＝32.5Hz),131.68,128.4,128.3,127.8,123.4(q,J＝274.6Hz),123.0,121.0–120.8(m),89.0,84.9,39.8,31.5,11.7。19F NMR(376MHz,CDCl3)δ–62.8(s,6F). HRMS (ESI) m/z accurate mass calculation C19H15F6[M+H]+357.1072, found 357.1065.
Example 108
Starting from S97(47.0mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 97 as a colorless oil (43.0mg, 84% yield, 90% ee).
[α]D 27＝-16(c 3.3,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 97/3, flow rate 1.0mL/min, λ 254nm), tR(minor)＝4.82min,tR(major)＝5.08min。1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.88–7.83(m,3H),7.61(dd,J＝8.5,1.7Hz,1H),7.56–7.43(m,4H),7.40–7.28(m,3H),4.18(q,J＝7.1Hz,1H),1.70(d,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3) δ 140.7,133.6,132.5,131.7,128.34,128.29,127.9,127.8,127.7,126.1,125.6,125.2,123.8,92.6,82.7,32.7, 24.4. HRMS (ESI) m/z accurate mass calculation C20H17[M+H]+257.1325, found 257.1322.
Example 109
Starting from S98(45.8mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 98 as a colorless oil (25.0mg, 50% yield, 91% ee).
[α]D 27＝-0.77(c 1.8,CH2Cl2). HPLC conditions Chiralcel IA (n-hexane/isopropanol 100/0, flow rate 1.0mL/min, λ 254nm), tR(major)＝20.33min,tR(minor)＝23.58min。1H NMR(400MHz,CDCl3)δ7.50–7.43(m,2H),7.35–7.29(m,3H),7.00(d,J＝1.6Hz,1H),6.92(dd,J＝8.0,1.6Hz,1H),6.81(d,J＝8.0Hz,1H),5.98(s,2H),3.94(q,J＝7.2Hz,1H),1.58(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 147.7,146.3,137.4,131.6,128.2,127.8,123.7,119.9,108.2,107.6,101.0,92.6,82.4,32.2, 24.7. HRMS (ESI) m/z accurate mass calculation C17H15O2[M+H]+251.1067, found 251.1065.
Example 110
Using S99(52.8mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) as starting materials, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) after 48 hours using general method B to give product 99 as a colorless oil (45.8mg, 80% yield, 96% ee).
[α]D 27＝-1.6(c 4.3,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 95/5, flow rate 0.5mL/min, λ 254nm), tR(minor)＝17.73min,tR(major)＝19.99min。1H NMR(400MHz,CDCl3)δ7.91(d,J＝2.3Hz,1H),7.72(d,J＝1.2Hz,1H),7.67(d,J＝8.5Hz,2H),7.50(d,J＝8.5Hz,2H),7.47(d,J＝4.2Hz,1H),7.46(d,J＝1.9Hz,1H),7.36–7.27(m,3H),6.46(t,J＝2.0Hz,1H),3.84(t,J＝6.9Hz,1H),1.95–1.78(m,2H),1.07(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 141.0,140.4,138.9,131.7,128.6,128.2,127.8,126.7,123.7,119.3,107.5,91.0,83.7,39.4,31.6, 11.7. HRMS (ESI) m/z accurate mass calculation C20H19N2[M+H]+287.1543, found 287.1541.
Example 111
Starting from 3- (1-bromopropyl) pyridine S100(40.0mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 15/1) after 48 hours using general method B to give product 100 as a colorless oil (34.0mg, 77% yield, 97% ee).
[α]D 27＝-1.6(c 1.9,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 95/5, flow rate 1.0mL/min, λ 254nm), tR(minor)＝8.01min,tR(major)＝9.10min。1H NMR(400MHz,CDCl3)δ8.65(d,J＝1.9Hz,1H),8.50(dd,J＝4.7,1.4Hz,1H),7.76(dt,J＝7.9,1.9Hz,1H),7.48–7.40(m,2H),7.34–7.25(m,4H),3.82(t,J＝7.2Hz,1H),1.95–1.76(m,2H),1.07(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 149.2,148.2,137.5,135.1,131.7,128.3,128.0,123.4,123.3,89.9,84.0,37.5,31.4, 11.7. HRMS (ESI) m/z accurate mass calculation C16H16N[M+H]+222.1277, found 222.1276.
Example 112
Starting from 2-bromo-5- (1-bromoethyl) pyridine S101(53.0mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method B, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 101 as a colorless oil (37.6mg, 66% yield, 93% ee).
[α]D 27＝-0.96(c 2.6,CH2Cl2). HPLC conditions Chiralcel IC (n-hexane/isopropanol 95/5, flow rate 1.0mL/min, λ 254nm), tR(minor)＝8.41min,tR(major)＝9.24min。1H NMR(400MHz,CDCl3)δ8.44(d,J＝2.6Hz,1H),7.67(dd,J＝8.2,2.6Hz,1H),7.50–7.39(m,3H),7.35–7.27(m,3H),3.98(q,J＝7.1Hz,1H),1.58(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3)δ149.0,140.3,138.2,137.4,131.6,128.3,128.2,128.0,123.0,90.4,83.4,29.6,24.1. HRMS (ESI) m/z accurate mass calculation C15H13BrN[M+H]+286.0226, found 286.0224.
Example 113
Starting from 3-bromo-5- (1-bromoethyl) pyridine S102(53.0mg, 0.20mmol, 1.0 eq) and 3- (N-carbazol) propyne (61.5mg, 0.30mmol, 1.5 eq), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) after 48 hours using general method B to give product 102 as a colorless oil (59.9mg, 77% yield, 87% ee).
[α]D 27＝+31(c 2.6,CH2Cl2). HPLC conditions Chiralcel ID (n-hexane/isopropanol 95/5, flow rate 0.6mL/min, λ 254nm), tR(major)＝26.47min,tR(minor)＝31.05min。1H NMR(400MHz,CDCl3)δ8.54(d,J＝2.2Hz,1H),8.43(d,J＝1.9Hz,1H),8.12(dt,J＝7.8,0.9Hz,2H),7.75(td,J＝2.1,0.6Hz,1H),7.56–7.46(m,4H),7.32–7.27(m,2H),5.09(d,J＝2.1Hz,2H),3.78–3.64(m,1H),1.41(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 149.3,146.8,140.1,140.0,137.1,126.0,123.3,120.8,120.5,119.6,108.8,85.0,77.6,32.8,29.3, 23.8. HRMS (ESI) m/z accurate mass calculation C22H18BrN2[M+H]+389.0648, found 389.0641.
Example 114
Starting from S103(51.0mg, 0.20mmol, 1.0 eq) and 3- (N-carbazol) propyne (61.5mg, 0.30mmol, 1.5 eq) using general method B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 20/1) to give product 103 as a colourless oil (59.1mg, 78% yield, 99% ee).
[α]D 27＝+19(c 3.0,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 95/5, flow rate 1.0mL/min, λ 254nm), tR(major)＝17.41min,tR(minor)＝20.76min。1H NMR(400MHz,CDCl3)δ8.17(dd,J＝7.8,1.3Hz,2H),7.88(dd,J＝7.2,1.5Hz,1H),7.77(d,J＝8.0Hz,1H),7.59–7.49(m,4H),7.40–7.29(m,4H),7.24(s,1H),5.13(d,J＝2.0Hz,2H),3.95(td,J＝5.6,2.4Hz,1H),2.00–1.77(m,2H),0.99(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 140.8,140.1,137.4,135.6,125.8,124.3,123.9,123.3,123.0,122.7,121.9,120.4,119.4,108.9,85.2,76.8,33.5,32.9,28.6, 11.8. HRMS (ESI) m/z accurate mass calculation C26H22NS[M+H]+380.1467, found 380.1461.
Example 115
Starting from 3- (1-bromoethyl) thiophene S104(38.2mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) after 48 hours using general procedure B to give product 104 as a colorless oil (36.9mg, 87% yield, 92% ee).
[α]D 27＝-9.3(c 1.4,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 0.4mL/min, λ 254nm), tR(minor)＝11.03min,tR(major)＝11.95min。1H NMR(400MHz,CDCl3)δ7.50–7.46(m,2H),7.35–7.31(m,4H),7.28–7.25(m,1H),7.17(dd,J＝4.9Hz,1H),4.09(q,J＝7.2Hz,1H),1.63(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 143.7,131.6,128.2,127.8,126.9,125.9,123.6,120.3,92.4,81.8,27.9, 23.2. HRMS (ESI) m/z accurate mass calculation C14H13S[M+H]+213.0732, found 213.0729.
Example 116
Starting from 3- (1-bromopropyl) benzofuran S105(47.8mg, 0.20mmol, 1.0 equiv) and 3- (N-carbazol) propyne (61.5mg, 0.30mmol, 1.5 equiv), the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 20/1) after 48 hours using general method B to give product 105 as a colourless oil (55.2mg, 76% yield, 98% ee).
[α]D 27＝+28(c 1.5,CH2Cl2). HPLC conditions Chiralcel AS3 (n-hexane/isopropanol 97/3, flow rate 0.7mL/min,. lambda.254 nm), tR(minor)＝9.36min,tR(major)＝10.04min。1H NMR(400MHz,CDCl3)δ8.24–8.09(m,2H),7.59–7.48(m,6H),7.44(s,1H),7.36–7.29(m,3H),7.23–7.15(m,1H),5.13(d,J＝2.0Hz,2H),3.83–3.69(m,1H),1.99–1.76(m,2H),0.99(td,J＝7.2,1.6Hz,3H)。13C NMR(100MHz,CDCl3) δ 155.6,141.7,140.0,126.6,125.8,124.3,123.3,122.4,120.44,120.40,120.1,119.4,111.6,108.9,84.7,76.4,32.8,29.4,28.3, 11.6. HRMS (ESI) m/z accurate mass calculation C26H22NO[M+H]+364.1696, found 364.1688.
Example 117
Starting from 3- (1-bromoethyl) quinoline S106(47.2mg, 0.20mmol, 1.0 eq) and phenylacetylene (30.6mg, 0.30mmol, 1.5 eq) using general method D, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 10/1) to give product 106 as a colourless oil (32.9mg, 64% yield, 90% ee).
[α]D 27＝+6.7(c 2.1,CH2Cl2). HPLC conditions Chiralcel IC (n-hexane/isopropanol 97/3, flow rate 1.0mL/min, λ 254nm), tR(minor)＝14.05min,tR(major)＝18.30min。1H NMR(400MHz,CDCl3)δ9.01(d,J＝2.1Hz,1H),8.21(d,J＝2.1Hz,1H),8.12(d,J＝8.4Hz,1H),7.82(d,J＝8.1Hz,1H),7.69(ddd,J＝8.4,6.9,1.4Hz,1H),7.57–7.52(m,1H),7.52–7.44(m,2H),7.39–7.27(m,3H),4.21(q,J＝7.1Hz,1H),1.70(d,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3) δ 150.6,147.2,135.9,133.1,131.7129.2,129.1,128.3,128.1,128.0,127.7,126.8,123.3, 91.1,83.4,30.4, 24.1. HRMS (ESI) m/z accurate mass calculation C19H16N[M+H]+258.1277, found 258.1276.
Example 118
Starting from 4- (1-bromoethyl) thiazole S107(38.4mg, 0.20mmol, 1.0 equiv.) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv.) using general procedure B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 20/1) to give product 107 as a colorless oil (26.0mg, 61% yield, 82% ee).
[α]D 27＝-6.1(c 2.4,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 95/5, flow rate 1.0mL/min, λ 254nm), tR(minor)＝6.00min,tR(major)＝7.02min。1H NMR(400MHz,CDCl3)δ8.78(d,J＝2.0Hz,1H),7.47(d,J＝3.7Hz,1H),7.45(t,J＝2.9Hz,1H),7.37–7.34(m,1H),7.33–7.27(m,3H),4.25(q,J＝7.1Hz,1H),1.69(d,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3) δ 158.7,153.1,131.7,128.2,128.0,123.4,113.6,91.2,82.4,29.3, 22.1. HRMS (ESI) m/z accurate mass calculation C13H12NS[M+H]+214.0685, found 214.0684.
Example 119
Starting from 5- (1-bromopropyl) pyrimidine S108(40.2mg, 0.20mmol, 1.0 equiv.) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv.) using general procedure B, after 48 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 10/1) to give product 108 as a colorless oil (31.1mg, 70% yield, 97% ee).
[α]D 27＝-1.1(c 2.8,CH2Cl2). HPLC conditions Chiralcel IC (n-hexane/isopropanol 90/10, flow rate 1.0mL/min, λ 254nm), tR(minor)＝11.17min,tR(major)＝13.73min。1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.80(s,2H),7.51–7.38(m,2H),7.34–7.27(m,3H),3.84(dd,J＝7.6,6.4Hz,1H),1.96–1.79(m,2H),1.09(t,J＝7.3Hz,3H)。13C NMR(100MHz,CDCl3) δ 157.4,156.1,135.2,131.7,128.4,128.3,122.8,88.2,84.8,35.4,31.1, 11.6. HRMS (ESI) m/z accurate mass calculation C15H15N2[M+H]+223.1230, found 223.1230.
Example 120
Starting from S109(33.3mg, 0.20mmol, 1.0 equiv) and phenylacetylene (30.6mg, 0.30mmol, 1.5 equiv) using general method D, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 109 as a colorless oil (24.1mg, 52% yield, 92% ee).
[α]D 27＝+21(c 0.63,CH2Cl2). HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 99.5/0.5, flow rate 0.8mL/min,. lambda.254 nm), tR(minor)＝7.57min,tR(major)＝8.65min。1H NMR(400MHz,CDCl3)δ7.51–7.46(m,2H),7.46–7.41(m,2H),7.38–7.33(m,2H),7.31–7.26(m,4H),3.69(d,J＝6.6Hz,1H),1.24–1.19(m,1H),0.71–0.42(m,4H)。13C NMR(100MHz,CDCl3) δ 142.2,131.8,128.6,128.3,127.9,127.7,127.0,123.8,89.7,83.4,41.5,17.6,4.2, 3.3. HRMS (ESI) m/z accurate mass calculation C18H17[M+H]+233.1325, found 233.1320.
Example 121
General procedure A was used, S131(83.8mg, 0.30mmol, 1.5 equiv.), S42(41.1mg, 0.20mmol, 1.0 equiv.), CuTc (3.0mg, 0.016mmol, 8.0 mol%) and ligand L13(20.1mg, 0.024mmol, 12 mol%) in CH2Cl2(4mL) for 40h and the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give product 131 as a pale yellow oil (93.7mg, 93% yield, 96% ee).
[α]D 27＝-6.4(c 3.0,CH2Cl2). HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 99/1, flow rate 0.3mL/min,. lambda.254 nm), tR(minor)＝16.73min,tR(major)＝17.38min。1H NMR(400MHz,CDCl3)δ8.09(dt,J＝7.8,1.0Hz,2H),7.73–7.39(m,4H),7.31–7.09(m,5H),7.09–6.83(m,2H),5.05(d,J＝2.1Hz,2H),3.59–3.13(m,1H),2.84–2.54(m,2H),1.91(q,J＝7.5Hz,2H),1.05(s,21H)。13C NMR(100MHz,CDCl3) δ 141.1,140.1,128.7,128.5,126.1,125.9,123.3,120.5,119.5,109.0,105.5,82.5,82.3,75.4,37.6,33.0,32.9,23.9,18.8, 11.3. HRMS (ESI) m/z accurate mass calculation C35H42NSi[M+H]+504.3081, found 504.3079.
Example 122
General procedure A was used, S132(101.2mg, 0.30mmol, 1.5 equiv.), S42(41.1mg, 0.20mmol, 1.0 equiv.), CuTc (3.0mg, 0.016mmol, 8.0 mol%) and ligand L13(20.1mg, 0.024mmol, 12 mol%) in CH2Cl2(4mL) for 40h and the reaction mixture was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20/1) to give product 132 as a pale yellow oil (76.6mg, 83% yield, 92% ee).
[α]D 27＝-5.7(c 2.7,CH2Cl2). HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 99/1, flow rate 0.3mL/min,. lambda.214 nm), tR(minor)＝18.78min,tR(major)＝21.28min。1H NMR(400MHz,CDCl3)δ8.09(dt,J＝7.8,0.9Hz,2H),7.54–7.43(m,4H),7.29–7.17(m,4H),7.17–7.11(m,1H),7.04–6.99(m,2H),5.06(d,J＝2.1Hz,2H),3.37–3.23(m,1H),2.77–2.60(m,2H),1.91(q,J＝7.5Hz,2H),0.97(t,J＝7.9Hz,9H),0.58(q,J＝8.0Hz,6H)。13C NMR(100MHz,CDCl3) δ 141.0,140.1,128.7,128.5,126.1,125.9,123.3,120.5,119.5,109.0,104.9,83.5,82.4,75.6,37.5,32.9,23.8,7.6, 4.5. HRMS (ESI) m/z accurate mass calculation C32H36NSi[M+H]+462.2612, found 462.2608.
Example 123
General procedure A was used, S133(83.8mg, 0.30mmol, 1.5 equiv.), S42(41.1mg, 0.20mmol, 1.0 equiv.), CuTc (3.0mg, 0.016mmol, 8.0 mol%) and ligand L13(20.1mg, 0.024mmol, 12 mol%) in CH2Cl2(4mL) for 40h and the reaction mixture was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20/1) to give product 133 as a pale yellow oil (67.8mg, 84% yield, 91% ee).
[α]D 27＝-5.8(c 2.3,CH2Cl2). HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 97/3, flow rate 0.4mL/min, λ 254nm), tR(minor)＝11.79min,tR(major)＝14.11min。1H NMR(400MHz,CDCl3)δ8.08(dt,J＝7.8,1.0Hz,2H),7.53–7.42(m,4H),7.27–7.16(m,4H),7.16–7.10(m,1H),7.04–6.96(m,2H),5.02(d,J＝2.1Hz,2H),3.27–3.16(m,1H),2.72–2.57(m,2H),1.86(q,J＝7.5Hz,2H),1.19(s,9H)。13C NMR(100MHz,CDCl3) δ 141.2,140.1,128.7,128.4,126.0,125.9,123.3,120.5,119.5,109.1,90.4,83.5,76.2,75.0,37.8,33.0,31.2,27.5, 22.7. HRMS (ESI) m/z accurate mass calculation C30H30N[M+H]+404.2373, found value 404.2370。
Example 124
General methods B, S134(65.8mg, 0.20mmol, 1.0 equiv.), S13(72.4mg, 0.40mmol, 2.0 equiv.), Cu (PPh) were used3)3Br (9.3mg, 0.010mmol, 5.0 mol%) was reacted in 1, 4-dioxane (4mL) for 24h and the reaction mixture was purified by silica gel column chromatography (petroleum ether ═ 100) to give product 134 as a colorless oil (83mg, 95% yield, E: Z ═ 4:1, main product 76% ee).
[α]D 27＝-8.2(c 1.2,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(major)＝11.16min,tR(minor)＝20.55min。1H NMR(400MHz,CDCl3)δ7.43(d,J＝8.4Hz,2H),7.30–7.23(m,6H),7.21–7.16(m,6H),5.77(dtd,J＝15.0,6.7,1.3Hz,1H),5.55–5.23(m,1H),3.20(q,J＝6.8Hz,1H),2.89–2.61(m,4H),2.53–2.24(m,2H),2.01–1.73(m,2H)。13C NMR(100MHz,CDCl3) δ 141.79,141.75,133.1,131.4,130.9,129.8,128.53,128.50,128.4,128.3,125.9,125.8,122.8,121.8,92.3,82.5,77.3,37.3,35.8,34.5,34.1, 33.2. HRMS (ESI) m/z accurate mass calculation C27H26Br[M+H]+429.1212, found 429.1208.
Example 125
Using general procedure a, S135(60.3mg, 0.30mmol, 1.5 equiv), S42(41.0mg, 0.20mmol, 1.0 equiv) were reacted at-40 ℃ for 72h and the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) to give product 135 as a colorless oil (39.8mg, 61% yield, 77% ee).
[α]D 27＝-2.8(c 1.1,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol)95/5 flow rate 1.0mL/min, λ 230nm), tR(major)＝24.98min,tR(minor)＝34.36min。1H NMR(400MHz,CDCl3)δ8.13(d,J＝7.7Hz,2H),7.57–7.45(m,4H),7.34–7.28(m,2H),5.11–5.07(m,2H),3.37–7.27(m,1H),1.84–1.62(m,6H),1.25–1.04(m,5H)。13C NMR(100MHz,CDCl3) δ 139.9,125.9,123.3,120.5,119.7,116.6,108.8,79.1,75.6,40.7,32.5,30.0,29.9,29.8,25.6, 25.5. HRMS (ESI) m/z accurate mass calculation C23H23N2[M+H]+327.1856, found 327.1850.
Example 126
Using general procedure B, S136(51.2mg, 0.20mmol, 1.0 eq), S42(61.5mg, 0.30mmol, 1.5 eq), CuTc (3.0mg, 0.016mmol, 8.0 mol% eq) and ligand L13(20.1mg, 0.024mmol, 12.0 mol% eq) were reacted for 40 hours and the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1) to give product 136 as a colorless oil (70.2mg, 92% yield, 86% ee).
[α]D 27＝-143.4(c 2.2,CH2Cl2). HPLC conditions Chiralcel IG (n-hexane/isopropanol 90/10, flow rate 0.8mL/min, λ 214nm), tR(major)＝20.76min,tR(minor)＝23.44min。1H NMR(400MHz,CDCl3)δ8.10(dt,J＝7.8,1.0Hz,2H),7.52–7.44(m,4H),7.29–7.23(m,2H),7.14(tt,J＝7.4,1.3Hz,1H),7.03(t,J＝7.4Hz,2H),6.94–6.87(m,2H),5.00(t,J＝2.0Hz,2H),3.19(s,3H),3.00–2.89(m,1H),1.84–1.72(m,1H),1.68–1.59(m,1H),0.77(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3) δ 169.9,143.1,140.0,129.7,127.9,127.2,125.8,123.2,120.4,119.4,109.0,82.6,76.4,37.8,37.1,32.8,25.8, 11.8. HRMS (ESI) m/z accurate mass calculation C26H25N2O[M+H]+381.1961, found 381.1957.
Examples 127-131 are methods of the invention for the synthesis of biologically active molecules
The synthetic method of the present invention can be used for the synthesis of various bioactive molecules, such as L-menthol (compound 110), estrone (compound 111), sulbactam (compound 112) and biotin (compound 113), and compound 114, and the alkynylated products can be obtained with high stereoselectivity despite the difference in chiral center and molecular structure.
Example 127
To 5-oxo-phenylpentanoic acid (1.92g, 10.0mmol, 1.0 equiv.) in CH at room temperature2Cl2(8.0mL) and CH3CN (8.0mL) was added to the mixed solution in this order L-menthol (1.56g, 10.0mmol, 1.0 equiv.), dicyclohexylcarbodiimide (2.20g, 11.0mmol, 1.1 equiv.) and DMAP (122.0mg, 1.0mmol, 0.1 equiv.). The reaction mixture was stirred overnight. Water was added and the mixture was extracted three times with EtOAc, the combined organic layers were filtered through a short pad of silica gel and washed with the eluent (petroleum ether/ethyl acetate-2/1) and the filtrate was evaporated under reduced pressure to give the crude product S110-2(2.10g) as a colourless oil which was used without further purification.
To a cooled solution of S110-2(1.00g, crude product) in methanol (15.0mL) at 0 deg.C was added NaBH4(240.0mg, 6.4 mmol). The reaction mixture was stirred for 30 minutes and then saturated NH was used4Quenching with Cl and CH2Cl2The product was extracted three times from the aqueous layer and the combined organic layers were washed with anhydrous Na2SO4Drying, filtering and concentrating to obtain the crude product, which is dissolved in anhydrous CH2Cl2Neutralizing and cooling to 0 deg.C, adding PBr to the cooled solution3(0.58g, 2.1mmol, 0.7 equiv.). The reaction mixture was stirred for 30 min and quenched with water, CH2Cl2The product was extracted three times from the aqueous layer and the combined organic layers were passed over anhydrous Na2SO4Drying, filtration and concentration gave a crude product which was purified by flash column chromatography to give S110-1 as a viscous oil (0.80g, mixture of diastereomers)Material, total yield 40%).
Characterization data for compound S110-1:
1H NMR(400MHz,CDCl3)δ7.41–7.28(m,5H),4.98–4.94(m,1H),4.76–4.65(m,1H),2.36–2.29(m,3H),2.24–2.15(m,1H),2.00–1.94(m,2H),1.90–1.81(m,2H),1.72–1.61(m,3H),1.55–1.33(m,2H),1.14–0.86(m,8H),0.75(t,J＝5.5Hz,3H)。13C NMR(100MHz,CDCl3) δ 172.6,141.9,141.8,128.7,128.4,127.2,74.2,60.4,54.8,54.7,46.9,40.9,39.2(5),39.2(2),34.2,33.7,33.7,31.3,26.2,26.2,23.8,23.7,23.3,22.0,20.7, 16.2. HRMS (ESI) m/z accurate mass calculation C21H31O2[M–Br]+315.2319, found 315.2313.
Starting from S110-1(80.0mg, 0.20mmol, 1.0 equiv) and phenylacetylene (31.0mg, 0.30mmol, 1.5 equiv) by general method B, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 9/1) to give product 110 as a colorless oil (62.0mg, 75% yield, dr)>20: 1). Diastereomer ratio by1H NMR spectroscopy.
Compound 110 characterization data:
[α]D 27＝–15(c 4.6,CH2Cl2)。1H NMR(400MHz,CDCl3)δ7.52–7.42(m,4H),7.40–7.27(m,6H),4.71(td,J＝10.9,4.4Hz,1H),3.97–3.85(m,1H),2.42–2.33(m,2H),2.04–1.98(m,1H),1.98–1.82(m,5H),1.74–1.66(m,2H),1.57–1.46(m,1H),1.44–1.35(m,1H),1.14–0.96(m,2H),0.93(d,J＝6.5Hz,3H),0.90(d,J＝7.0Hz,3H),0.87–0.82(m,1H),0.77(d,J＝7.0Hz,3H)。13C NMR(100MHz,CDCl3) δ 172.9,141.8,131.6,128.5,128.2,127.8,127.4,126.8,123.6,90.9,83.6,74.1,47.0,40.9,38.1,37.9,34.3,34.2,31.4,26.2,23.4,23.0,22.0,20.7, 16.2. HRMS (ESI) m/z accurate mass calculation C29H37O2[M+H]+417.2788, found 417.2778.
Example 128
S111-2(L.Crespin, L.Biancalana, T.Morack, D.C.Blakemore, S.V.Ley, One-pot acid-catalyzed ring-opening/cycling/oxidation of azidines with N-trisylhydrazines: access to 1,2, 4-trisazines.org.Lett.19, 1084-1087 (2017)) was synthesized according to the literature report
To a stirred mixture of S111-2(0.56g, 2.0mmol, 1.0 equiv.) and silica gel (1.0g) in CH at room temperature2Cl2(5.0mL) of the solution was added PBr3Solution (0.54g, 2.0mmol, 1.0 eq in 2.0mL CH)2Cl2In (1). The reaction mixture was stirred for 20 minutes, filtered and washed with CH2Cl2Washed with saturated NaHCO3The filtrate was washed with brine. The organic layer was washed with anhydrous Na2SO4Drying, filtration and evaporation gave product S111-1 as a viscous solid (0.71g, 95% yield, d.r ═ 1: 1).
Characterization data for compound S111-1:
1H NMR(400MHz,CDCl3)δ7.31–7.23(m,2H),7.20(s,1H),5.24–5.20(m,1H),2.96–2.93(m,2H),2.57–1.95(m,10H),1.71–1.43(m,6H),0.93(s,3H)。13C NMR(100MHz,CDCl3) δ 220.9,140.7,140.1,136.9,136.8,127.3,125.7,124.2,124.1,50.4,49.8,49.7,47.9,44.4,38.0,35.8,31.5,29.4,26.7,26.7,26.4,25.6,21.6, 13.8. HRMS (ESI) m/z accurate mass calculation C20H25O[M–Br]+281.1900, found 281.1893.
Starting from S111-1(72.0mg, 0.20mmol, 1.0 equiv) and phenylacetylene (31.0mg, 0.30mmol, 1.5 equiv) using general procedure B, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate 9/1) to give product 111 as a colourless oil (66.0mg, 87% yield, dr > 20: 1).
Characterization data for compound 111:
[α]D 27＝+46(c 3.2,CH2Cl2)。1H NMR(400MHz,CDCl3)δ7.53–7.42(m,2H),7.36–7.26(m,5H),7.22(s,1H),3.96(q,J＝7.1Hz,1H),2.98(dd,J＝9.0,4.2Hz,2H),2.63–2.44(m,2H),2.34(td,J＝10.9,4.3Hz,1H),2.23–2.15(m,1H),2.13–1.98(m,3H),1.72–1.44(m,9H),0.95(s,3H)。13C NMR(100MHz,CDCl3) δ 220.9,140.8,138.1,136.6,131.6,128.2,127.7,127.5,125.6,124.4,123.8,92.8,82.2,50.5,48.0,44.3,38.2,35.9,32.0,31.6,29.5,26.5,25.7,24.4,21.6, 13.8. HRMS (ESI) m/z accurate mass calculation C28H31O[M+H]+383.2369, found 383.2364.
Example 129
To a solution of sulbactam (70.0mg, 0.30mmol, 1.0 equiv.) in DMF (2.0mL) was added K2CO3(42.0mg, 0.30mmol, 1.0 equiv.) and S112-2(83.0mg, 0.30mmol, 1.0 equiv.). The reaction mixture was stirred for 3 hours and quenched with water. Et was added2O, the organic layer was washed twice with water, and the combined organic layers were passed over anhydrous Na2SO4Drying, filtration and concentration gave the crude product which was purified by flash column chromatography to give product S112-1 as a viscous oil (88.0mg, mixture of diastereomers, 70% yield).
Characterization data for compound S112-1:
1H NMR(400MHz,CDCl3)δ7.47(d,J＝8.2Hz,2H),7.36(d,J＝8.2Hz,2H),5.29–5.14(m,3H),4.62(dd,J＝4.3,2.1Hz,1H),4.43(s,1H),3.59–3.36(m,2H),2.05(d,J＝6.9Hz,3H),1.58(s,3H),1.31(s,3H)。13C NMR(101MHz,CDCl3) δ 170.8,166.8,144.1,134.4,129.1,127.3,67.6,63.2,62.8,61.1,48.6,38.3,26.7,20.2, 18.6. HRMS (ESI) m/z accurate mass calculation C17H21BrNO5S[M+H]+430.0318, found 430.0308.
Starting from S112-1(43.0mg, 0.10mmol, 1.0 eq) and 4-ethynylbenzonitrile (16.0mg, 0.15mmol, 1.5 eq) using general method B, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 80/20) to give product 112 as a colorless oil (24.0mg, 50% yield, dr > 20: 1).
Compound 112 characterization data:
[α]D 27＝+132(c 1.1,CH2Cl2)。1H NMR(400MHz,CDCl3)δ7.66–7.57(m,2H),7.57–7.50(m,2H),7.47(d,J＝8.2Hz,2H),7.38(d,J＝8.2Hz,2H),5.34–5.15(m,2H),4.62(dd,J＝4.1,2.2Hz,1H),4.43(s,1H),4.04(q,J＝7.1Hz,1H),3.58–3.38(m,2H),1.66–1.57(m,6H),1.33(s,3H)。13C NMR(100MHz,CDCl3) δ 170.7,166.8,143.5,133.0,132.1,131.9,129.2,128.4,127.3,118.5,111.2,96.9,81.3,67.8,63.2,62.7,61.10,38.35,32.3,24.0,20.1, 18.6. HRMS (ESI) m/z accurate mass calculation C26H25N2O5S[M+H]+477.1479, found 477.1464.
Example 130
To biotin (0.97g, 4.0mmol, 1.0 equiv.) and 3-hydroxyacetophenone (0.60g, 4.4mmol, 1.1 equiv.) in CH at room temperature2Cl2To a solution (20.0mL) were added DCC (0.90g, 4.4mmol, 1.1 equiv.) and DMAP (50.0mg, 0.40mmol, 0.1 equiv.) in that order. The reaction mixture was stirred for 12 hours, then quenched with water and extracted three times with EtOAc, and the combined organic layers were extracted with saturated NaHCO3Washing with solution, salt solution, and anhydrous Na2SO4Drying, filtration and concentration gave a residue which was filtered through a short pad of silica gel and washed with EtOAc to remove the solvent to give crude product S113-2(0.80g) which was used without further purification.
To a cooled solution of S113-2(0.80g, crude product) in methanol (15.0mL) at 0 deg.C was added NaBH4(80.0mg, 2.1 mmol). The reaction mixture was stirred for 30 minutes and then saturated NH was used4Cl quenching and CH addition2Cl2Extracting three times, mixing the organic layers with anhydrous Na2SO4Drying, filtering and concentrating to obtain the crude product, which is dissolved in anhydrous CH2Cl2(15.0mL) inAnd cooled to 0 deg.C, and PBr was added to the cooled solution3(0.19g, 0.7mmol) and stirred for 30 min. After completion of the reaction, the reaction was quenched with water and CH2Cl2Extracting three times, mixing the organic layers with anhydrous Na2SO4Drying, filtration and concentration gave the crude product which was purified by flash column chromatography to give S113-1 as a viscous oil (0.20g, 10% overall yield).
Characterization data for compound S113-1:
1H NMR(400MHz,CDCl3)δ7.40–7.26(m,2H),7.19(s,J＝1.9Hz,1H),7.05–7.02(m,1H),6.06(s,0.75H),5.89(s,0.25H),5.48(s,1H),5.20(q,J＝6.9Hz,0.75H),5.09(q,J＝6.9Hz,0.25H),4.53–4.50(m,1H),4.35–4.30(m,1H),3.24–3.14(m,1H),2.94–2.89(m,1H),2.76–2.72(m,1H),2.61(t,J＝7.5Hz,1.5H),2.35(t,J＝7.5Hz,0.5H),2.05(d,J＝6.9Hz,2H),1.85(d,J＝6.9Hz,1H),1.83–1.65(m,4H),1.60–1.46(m,2H)。13C NMR(100MHz,CDCl3) δ 172.1,163.8,150.7,144.8,129.6,124.2,121.6,120.1,62.0,60.1,55.5,48.4,40.6,34.0,28.4,28.3,26.7, 24.7. HRMS (ESI) m/z accurate mass calculation C18H24BrN2O3S[M+H]+427.0686, found 427.0679.
Starting from S113-1(43.0mg, 0.10mmol, 1.0 equiv.) and phenylacetylene (15.3mg, 0.15mmol, 1.5 equiv.) by general method B, after 72 hours the reaction mixture is purified by column chromatography on silica gel (CH)2Cl2MeOH 98/2) to give product 113 as a colorless oil (11.0mg, 25% yield, dr)>20：1)。
Compound 113 characterization data:
[α]D 27＝+12(c 0.90,CH2Cl2)。1H NMR(500MHz,CDCl3)δ7.46(dd,J＝6.6,2.9Hz,2H),7.39–7.30(m,5H),7.18(s,1H),7.00(d,J＝7.7Hz,1H),5.65(s,1H),5.13(s,1H),4.51(d,J＝12.7Hz,1H),4.33(d,J＝12.5Hz,1H),4.01(q,J＝7.1Hz,1H),3.20(t,J＝6.7Hz,1H),2.92(dd,J＝12.9,5.2Hz,1H),2.75(d,J＝12.8Hz,1H),2.62(t,J＝7.4Hz,2H),1.87–1.76(m,4H),1.62–1.53(m,5H)。13C NMR(126MHz,CDCl3) δ 172.2,163.4,150.8,145.0,131.7,129.5,128.2,127.9,124.5,123.5,120.1,119.9,92.0,82.7,62.0,60.1,55.4,40.6,34.0,32.3,28.4,28.3,24.7, 24.3. HRMS (ESI) m/z accurate mass calculation C26H29N2O3S[M+H]+449.1893, found 449.1884.
Example 131
To 4-ethoxycarbonylphenylboronic acid (2.3 g, 12.0mmol, 1.2 equiv.), 4' -bromophenylpentanone (2.41g, 10.0mmol, 1.0 equiv.), and K under the protection of argon gas2CO3(4.14g, 30.0mmol, 3.0 equiv.) in H2Pd/C (100.0mg, 10% w/w) was added to a mixed solution of O (15.0mL) and 1, 4-dioxane (15.0mL), and the mixture was refluxed for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, diluted with EtOAc and water, and then extracted three times with EtOAc. The combined organic layers were washed with brine, washed with Na2SO4Drying, filtration and concentration in vacuo afforded the coupled product S114-3 as a white solid (2.5g, 81%).
Starting from S114-3(1.6g, 5.0mmol, 1.0 equiv.), using general method 4 and method b, S114-1 was obtained as a white solid (1.7g, 92% yield over two steps).
Characterization data for compound S114-1:
1H NMR(400MHz,CDCl3)δ8.14(d,J＝8.2Hz,2H),7.68(d,J＝8.2Hz,2H),7.62(d,J＝8.2Hz,2H),7.51(d,J＝8.2Hz,2H),5.03(t,J＝7.6Hz,1H),4.43(q,J＝7.2Hz,2H),2.41–2.28(m,1H),2.26–2.15(m,1H),1.61–1.26(m,7H),0.94(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 166.4,144.8,142.3,139.9,130.1,129.5,127.9,127.6,126.9,61.0,55.2,39.6,30.4,22.1,14.4, 13.9. HRMS (ESI) m/z accurate mass calculation C20H24BrO2[M+H]+375.0954, found 375.0954. HRMS (ESI) m/z accurate mass calculation C20H23O2[M–Br]+295.1693, found 295.1693.
Using phenylacetylene (30.6mg, 0.30mmol, 1.5 equivalents) and compound S114-1(75.0mg, 0.20mmol) as starting materials, following 48 hours using general method B, the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 20/1) to give product 114 as a colorless oil (65.7mg, 83% yield, 96% ee).
Compound 114 characterization data:
[α]D 27＝-3.5(c 3.4,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99/1, flow rate 1.0mL/min, λ 254nm), tR(minor)＝7.76min,tR(major)＝10.88min。1H NMR(400MHz,CDCl3)δ8.10(d,J＝8.1Hz,2H),7.65(d,J＝8.3Hz,2H),7.59(d,J＝8.2Hz,2H),7.51(d,J＝8.1Hz,2H),7.47–7.45(m,2H),7.33–7.24(m,3H),4.39(q,J＝7.1Hz,2H),3.88(t,J＝7.2Hz,1H),1.94–1.79(m,2H),1.59–1.44(m,2H),1.40(t,J＝7.1Hz,4H),1.38–1.32(m,1H),0.92(t,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 166.6,145.3,142.5,138.4,131.7,130.1,129.2,128.3,128.1,127.8,127.4,126.9,123.8,91.5,83.4,61.0,38.4,38.2,29.7,22.5,14.4, 14.1. HRMS (ESI) m/z accurate mass calculation C28H29O2[M+H]+397.2162, found 397.2162.
Examples 132-135 use of the methods of the invention for the Synthesis of pharmaceuticals
The method comprises the steps of preparing chiral alkyne (R) -115 and chiral alkyne (S) -115 by using acetylene gas as a raw material through an asymmetric Sonogashira coupling reaction, and oxidizing to obtain the common non-steroidal anti-inflammatory drug ibuprofen. The Sonogashira coupling product 116 is subjected to alkaline alcoholysis, alkylation and alkaline hydrolysis to obtain a G protein coupled receptor GPR40 agonist AMG 837. Examples 125, 126 illustrate the great potential of commercial alkyne feedstocks (acetylene, propyne) for future industrial applications. Metabotropic glutamate receptor modulators (compound 117) and the recently reported dihydrofolate reductase (DHFR) inhibitor UCP1172 against drug-resistant bacteria were obtained with high enantioselectivity by the method of the present invention.
Example 132
4-isobutylacetophenone S115-1(176.1mg, 1.0mmol, 1.0 equiv.) was dissolved in ethanol (5.0mL), the mixture was cooled to 0 ℃ with stirring and the NaBH carefully added4(76.0mg, 2.0mmol, 2.0 equiv.) was added to the mixture. The reaction was stirred at 0 ℃ until the starting material was consumed (monitored by TLC) and then saturated NH was added4The reaction was quenched with Cl, extracted three times with ethyl acetate, and the organic layer with Na2SO4Drying, the residue was filtered through a pad of silica gel and concentrated to give the crude product S115-2 as a colorless oil (171.0mg, 96% yield).
Characterization data for compound S115-2:
1H NMR(400MHz,CDCl3)δ7.30(d,J＝8.0Hz,2H),7.16(d,J＝7.8Hz,2H),4.96–4.82(m,1H),2.50(d,J＝7.1Hz,2H),1.98–1.81(m,1H),1.52(d,J＝6.5Hz,3H),0.93(d,J＝6.6Hz,6H)。13C NMR(100MHz,CDCl3)δ143.1,141.0,129.2,125.2,70.3,45.1,30.3,25.0,22.4。
s115-2(178.0mg, 1.0mmol, 1.0 equiv.) was dissolved in CH under argon2Cl2(5.0mL) and cooled to 0 ℃. Phosphorus tribromide (189.7mg, 0.70mmol, 0.7 eq) was added dropwise with vigorous stirring, then warmed to room temperature and stirred overnight. The reaction was quenched with water, extracted three times with petroleum ether, the organic layer was washed with brine and filtered through a pad of silica gel. After concentration, the residue S115-3 was a colorless liquid (220.8mg, 92% yield), which was used in the next step without further purification.
Characterization data for compound S115-3:
1H NMR(400MHz,CDCl3)δ7.37(d,J＝8.2Hz,2H),7.15(d,J＝7.9Hz,2H),5.26(q,J＝6.9Hz,1H),2.49(d,J＝7.2Hz,2H),2.08(d,J＝6.9Hz,3H),1.89(dp,J＝13.6,6.7Hz,1H),0.94(d,J＝6.6Hz,6H)。13C NMR(100MHz,CDCl3) δ 142.1,140.5,129.4,126.6,50.0,45.1,30.2,26.8, 22.4. HRMS (ESI) m/z accurate mass calculation C12H17[M–Br]+161.1325 found 161.1324。
Purification by silica gel column chromatography using S115-3(48.0mg, 0.20mmol, 1.0 eq) using general method C afforded (S) -115 as a colorless oil (32.0mg, 86% over two yields, 96% ee).
Characterization data for compound (S) -115:
[α]D 25＝+2.3(c 0.90,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 0.3mL/min,. lambda.214 nm), tR(major)＝15.56min,tR(minor)＝21.37min。1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.0Hz,2H),7.14(d,J＝8.1Hz,2H),3.78(qd,J＝7.2,2.5Hz,1H),2.49(d,J＝7.1Hz,2H),2.28(d,J＝2.5Hz,1H),1.87(tp,J＝12.9,6.6Hz,1H),1.53(d,J＝7.2Hz,3H),0.93(d,J＝6.7Hz,6H)。13C NMR(100MHz,CDCl3) δ 140.2,139.9,129.3,126.5,87.4,69.9,45.0,31.2,30.2,24.2,22.40, 22.39. HRMS (ESI) m/z accurate mass calculation C14H19[M+H]+187.1481, found 187.1482.
Starting from S115-3(48.0mg, 0.20mmol, 1.0 equiv) and ligand L15 in place of ligand L13, (R) -115 was obtained as a colorless oil by silica gel column chromatography (cyclohexane ═ 100) using general method C (30.0mg, two-step yield 81%, 83% ee).
Characterization data for compound (R) -115:
[α]D 25＝–5.2(c 6.9,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 100/0, flow rate 0.3mL/min,. lambda.214 nm), tR(minor)＝15.81min,tR(major)＝21.57min。1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.0Hz,2H),7.14(d,J＝8.1Hz,2H),3.78(qd,J＝7.2,2.5Hz,1H),2.49(d,J＝7.1Hz,2H),2.28(d,J＝2.5Hz,1H),1.87(tp,J＝12.9,6.6Hz,1H),1.53(d,J＝7.2Hz,3H),0.93(d,J＝6.7Hz,6H)。13C NMR(100MHz,CDCl3) δ 140.2,139.9,129.3,126.5,87.4,69.9,45.0,31.2,30.2,24.2,22.40, 22.39. HRMS (ESI) m/z accurate mass calculation C14H19[M+H]+187.1481, found 187.1482.
To RuCl3(1.5mg, 0.010mmol, 5.0 mol% equiv.) and sodium periodate (171.0mg, 0.80mmol, 4.0 equiv.) in CCl4To a mixed solution of (0.4mL) and water (0.6mL) was added a solution of compound 115(37.2mg, 0.20mmol, 1.0 equiv.) in MeCN (0.4mL) in one portion. Stirring was carried out at room temperature for 2 hours, the reaction mixture was concentrated by evaporation and purified by silica gel column chromatography (petroleum ether/ethyl acetate 2: 1) to give the product.
From (S) -115, (R) -ibuprofen was obtained as a white solid (37.1mg, 90% yield).
[α]D 25＝–40(c 4.1,CH2Cl2)。1H NMR(400MHz,CDCl3)δ7.26(d,J＝8.0Hz,2H),7.14(d,J＝7.9Hz,2H),3.74(q,J＝7.1Hz,1H),2.49(d,J＝7.1Hz,2H),1.89(dp,J＝13.6,6.8Hz,1H),1.54(d,J＝7.2Hz,3H),0.94(d,J＝6.6Hz,6H)。13C NMR(100MHz,CDCl3) δ 181.0,140.9,137.0,129.4,127.3,45.1,45.0,30.2,22.4, 18.1. HRMS (ESI) m/z accurate mass calculation C13H19O2[M+H]+207.1380, found 207.1379.
Using (R) -115 as the starting material, the same procedure as for (R) -ibuprofen was used to give (S) -ibuprofen as a white solid (34.2mg, 83% yield).
[α]D 25＝+40(c 1.1,CH2Cl2)。1H NMR(400MHz,CDCl3)δ7.26(d,J＝8.0Hz,2H),7.14(d,J＝7.9Hz,2H),3.74(q,J＝7.1Hz,1H),2.49(d,J＝7.1Hz,2H),1.89(dp,J＝13.6,6.8Hz,1H),1.54(d,J＝7.2Hz,3H),0.94(d,J＝6.6Hz,6H)。13C NMR(100MHz,CDCl3) δ 181.0,140.9,137.0,129.4,127.3,45.1,45.0,30.2,22.4, 18.1. HRMS (ESI) m/z accurate mass calculation C13H19O2[M+H]+207.1380, found 207.1379.
To a solution of (R) -ibuprofen (41.2mg, 0.20mmol, 1.0 equiv) in methanol (1.0mL) was added SOCl dropwise at 0 deg.C2(119.0mg, 1.0mmol, 5.0 equiv.), then warmed to room temperature and stirred for an additional 3 hours. After completion of the reaction, the solvent was removed by evaporation and purified by silica gel column chromatography (petroleum ether/ethyl acetate)Ester 20:1) the residue was purified to give the product (R) -S115-4 as a colorless oil (44.0mg, quantitative yield, 95% ee).
Characterization data for compound (R) -S115-4:
[α]D 25＝–91(c 6.9,CH2Cl2). HPLC conditions Chiralcel OJ3 (n-hexane/isopropanol 99/1, flow rate 0.5mL/min, λ 214nm), tR(minor)＝16.04min,tR(major)＝20.30min。1H NMR(400MHz,CDCl3)δ7.25(d,J＝8.2Hz,1H),7.14(d,J＝8.2Hz,1H),3.75(q,J＝7.2Hz,1H),3.69(s,2H),2.50(d,J＝7.2Hz,1H),1.54(d,J＝7.2Hz,2H),0.95(d,J＝6.7Hz,3H)。13C NMR(100MHz,CDCl3) δ 175.2,140.5,137.8,129.4,127.2,51.9,45.09,45.05,30.2,22.4, 18.7. HRMS (ESI) m/z accurate mass calculation C14H21O2[M+H]+221.1536, found 221.1535.
Using (S) -ibuprofen as a starting material, the same procedure as for (R) -S115-4 was carried out to give (S) -S115-4 as a colorless oil (44.0mg, quantitative yield, 82% ee).
Characterization data for compound (S) -S115-4:
[α]D 25＝+53(c 7.1,CH2Cl2). HPLC conditions Chiralcel OJ3 (n-hexane/isopropanol 99/1, flow rate 0.5mL/min, λ 214nm), tR(major)＝12.97min,tR(minor)＝14.34min。1H NMR(400MHz,CDCl3)δ7.25(d,J＝8.2Hz,1H),7.14(d,J＝8.2Hz,1H),3.75(q,J＝7.2Hz,1H),3.69(s,2H),2.50(d,J＝7.2Hz,1H),1.54(d,J＝7.2Hz,2H),0.95(d,J＝6.7Hz,3H)。13C NMR(100MHz,CDCl3) δ 175.2,140.5,137.8,129.4,127.2,51.9,45.09,45.05,30.2,22.4, 18.7. HRMS (ESI) m/z accurate mass calculation C14H21O2[M+H]+221.1536, found 221.1535.
Determination of absolute configuration
The absolute configuration was determined by comparison with the standard (S) -ibuprofen derivative methyl (S) -2- (4-isobutylphenyl) propionate, which indicated that S155-4 was the R configuration using ligand L13 and S155-4 was the S configuration using ligand L15.
Sample (I) Absolute configuration ee％
1 Standard article S -99
2 (R)-S155-4 R 94
3 (S)-S155-4 S -82
Example 133
S116-4(B.M.Trost, J.T.Masters, B.R.Taft, J. -P.Lumb, asymmetry synthesis of cardiac β -alkyl carbonyl and sulfo derivatives via sequential palladium and linker analysis. chem.Sci.7,6217-6231 (2016)) was synthesized according to literature reports
At the temperature of 0 ℃, the temperature of the mixture is controlled,to a solution of 4-hydroxybenzaldehyde (3.7g, 30.0mmol, 1.0 equiv) in THF (30.0mL) was added Et in sequence3N (6.2mL, 45.0mmol, 1.5 equiv.) and pivaloyl chloride (5.5mL, 45.0mmol, 1.5 equiv.). The reaction mixture was then warmed to room temperature and stirred for 2 hours. After the reaction is completed, the reaction is saturated with NH4Quenched with Cl and extracted three times with EtOAc and the organic layer with anhydrous Na2SO4Drying, filtration, evaporation in vacuo and purification by silica gel column chromatography (petroleum ether/ethyl acetate: 8/1) gave the desired product S116-7(6.1g, 98% yield).
TMSCl (70. mu.L, 0.50mmol) was added to a suspension of activated Zn powder (1.10g, 17.0mmol, 1.7 equiv.) in dry THF (20.0mL) and refluxed for 30 min. Thereafter, ethyl bromoacetate (1.30mL, 12.0mmol, 1.2 equiv.) was added dropwise to the suspension at 40 ℃ and after stirring for 30 minutes, S116-7(2.10g, 10.0mmol, 1.0 equiv.) was slowly added to the suspension and stirred at room temperature for 8 hours. After the reaction was complete, the mixture was washed with saturated NH4Quenched with Cl and extracted three times with EtOAc and the organic layer with anhydrous Na2SO4Drying, filtration, evaporation and purification by silica gel column chromatography (petroleum ether/ethyl acetate-5/1) gave the desired product S116-8(1.30g, 43% yield). Characterization data are consistent with the literature (H.M.Nelson, B.D.Williams, J.Miro, F.D.Toste, Enantioselective 1,1-aryl of keys: polymeric phase transfer with Pd catalysis.J.Am.chem.Soc.137,3213-3216 (2015)).
To S116-8(588.0mg, 2.0mmol, 1.0 equiv.) in CH at 0 deg.C2Cl2(6.0mL) solution to which PBr was slowly added3(0.13mL, 1.4 mmol). The reaction mixture was then warmed to room temperature and stirred for an additional 3 hours. After the reaction was completed, saturated Na was used2CO3Quenching the reaction and using CH2Cl2Extraction was carried out three times, and the organic layer was washed with brine and anhydrous Na2SO4Drying, filtration through a pad of silica gel and concentration in vacuo afforded the crude product S116-9(678.3mg, 95% yield) which was used in the next step without further purification.
Characterization data for compound S116-9:
1H NMR(400MHz,CDCl3)δ7.43(d,J＝8.5Hz,2H),7.04(d,J＝8.5Hz,2H),5.40(dd,J＝8.8,6.4Hz,1H),4.20–4.06(m,2H),3.32(dd,J＝16.2,8.9Hz,1H),3.18(dd,J＝16.1,6.3Hz,1H),1.35(s,9H),1.23(t,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3) δ 176.8,169.5,151.1,138.1,128.3,121.9,61.1,47.2,45.0,39.1,27.1, 14.1. HRMS (ESI) m/z accurate mass calculation C16H21O4[M–Br]+277.1434, found 277.1429.
To an oven-dried Schlenk tube equipped with a magnetic stir bar, CuTc (15.2mg, 0.080mmol, 20.0 mol%), ligand L16(97.0mg, 0.12mmol, 30.0 mol%), Cs were added under argon protection2CO3(260.8mg, 0.80mmol, 2.0 equiv.) and anhydrous Et2O (8.0mL), then S116-9(143.0mg, 0.40mmol, 1.0 equiv.) and propyne (2.0mL, 2.0mmol, 5.0 equiv., 1.0mol/L in THF) were added sequentially. After stirring at room temperature for 72 hours, the reaction mixture was filtered to remove solids and Et2O rinse, then evaporate the solution and purify by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give a mixture, products 116 and 116' cannot be separated.
The mixture of 116 and 116' was dissolved in EtOH (4.0mL) and K was added all at once2CO3Powder (165.6mg, 1.2mmol, 3.0 equiv.) and stirred at room temperature for 4 h. After completion of the reaction, the mixture was diluted with EtOAc and washed with 1.0M HCl, then brine. Separating the organic layer with Na2SO4Drying, filtration and evaporation gave a mixture of S116-10 and S116-10', which could not be isolated.
To a mixture of S116-10 and S116-10' in acetone (4.0mL) was added S116-4(138.6mg, 0.44mmol, 1.1 equiv.) and Cs2CO3Powder (143.4mg, 0.44mmol, 1.1 mm)Amount), and then stirred at room temperature for 24 hours. After completion of the reaction, the solvent was removed in vacuo, and the residue was diluted with water and EtOAc and extracted three times with EtOAc. The combined organic phases were washed with brine, washed with Na2SO4Dried, filtered and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 20/1) to give the product S116-11(50.3mg, three-step yield 27%, 83% ee).
Characterization data for compound S116-11:
[α]D 27＝+4.5(c 0.71,CH2Cl2). HPLC conditions Chiralcel IB (n-hexane/isopropanol 98/2, flow rate 1.0mL/min, λ 254nm), tR(minor)＝10.77min,tR(major)＝11.98min。1H NMR(400MHz,CDCl3)δ7.70(s,4H),7.66(s,1H),7.56(d,J＝7.1Hz,1H),7.53–7.43(m,2H),7.31(d,J＝8.6Hz,2H),6.95(d,J＝8.5Hz,2H),5.12(s,2H),4.19–4.01(m,3H),2.75(dd,J＝15.1,8.4Hz,1H),2.65(dd,J＝15.1,7.0Hz,1H),1.83(d,J＝2.2Hz,3H),1.22(t,J＝7.1Hz,3H)。13C NMR(100MHz,CDCl3)δ171.2,157.7,144.4,140.2,137.9,133.8,129.5(q,J＝32.4Hz),129.3,128.5,127.5,127.3,126.9,126.3,125.8(q,J＝3.7Hz),124.3(q,J＝271.9Hz),114.9,79.6,78.8,69.9,60.6,43.6,33.5,14.2,3.7。19F NMR(376MHz,CDCl3) Delta-62.4 (s, 3F). HRMS (ESI) m/z accurate mass calculation C28H26F3O3[M+H]+467.1829, found 467.1820.
Compound S116-11(30.0mg, 0.064mmol) was stirred in a mixture of 10% NaOH (0.07mL) and EtOH (1.0mL) for 5 hours at room temperature. After the reaction is finished, adjusting the pH to 1-2 by using 3.0M HCl, and using CH for a water phase2Cl2Extracting, and then subjecting the organic layer to Na2SO4Drying, filtration, concentration and purification by silica gel column chromatography (petroleum ether/ethyl acetate: 1/1) gave the desired product AMG 837(25.9mg, 92% yield).
Compound AMG 837 characterization data:
[α]D 27＝+4.3(c 0.75,CH2Cl2)。1H NMR(400MHz,CDCl3)δ7.71(s,4H),7.67(s,1H),7.57(d,J＝6.8Hz,1H),7.55–7.44(.,2H),7.34(d,J＝8.0Hz,2H),6.98(d,J＝7.9Hz,2H),5.13(s,2H),4.08(s,1H),2.83(dd,J＝15.6,8.4Hz,1H),2.73(dd,J＝15.7,6.6Hz,1H),1.85(s,3H)。13C NMR(100MHz,CDCl3)δ177.3,157.8,144.4,140.2,137.9,133.4,129.5(q,J＝32.0Hz),129.3,128.5,127.5,127.3,126.9,126.4,125.8(q,J＝3.6Hz),124.3(q,J＝270.3Hz),115.0,79.4,79.2,69.9,43.3,33.2,3.7。19F NMR(376MHz,CDCl3) Delta-62.3 (s, 3F). HRMS (ESI) m/z accurate mass calculation C26H22 F3O3[M+H]+439.1516, found 439.1506.
Determination of absolute configuration
Sample (I) ee/％ Configuration(s) [α]D 27
1 S116-11 (Synthesis) –83 S +4.5(c 0.71,CH2Cl2)
2 S116-11 (Standard) –99 S +5.5(c 2.8,CH2Cl2)
3 AMG 837 (Synthesis) –83 S +4.3(c 0.75,CH2Cl2)
4 AMG 837 (Standard) –99 S +7.5(c 0.91,CH2Cl2)
S configuration: [ alpha ] to]D 22＝+10.9(c 0.44，CHCl3，>99％ee)。
Determined by comparison with AMG 837(S configuration). AMG 837 was synthesized with ligand L16 and compared to a commercial standard sample to demonstrate the generation of the S configuration using ligand L16.
Example 134
Starting from (1-bromoethyl) benzene S1(55.2mg, 0.30mmol, 1.5 equiv.) and S33(28.6mg, 0.20mmol, 1.0 equiv.) using general procedure a, after 72 hours the reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 2/1) to give product 117 as a colorless oil (34.1mg, 69% yield, 93% ee).
Compound 117 characterization data:
[α]D 27＝–8.1(c 0.70,CH2Cl2). HPLC conditions Chiralcel AD3 (n-hexane/isopropanol 95/5, flow rate 0.3mL/min,. lambda.254 nm), tR(minor)＝52.07min,tR(major)＝54.80min。1H NMR(400MHz,CDCl3)δ8.59(d,J＝7.2Hz,1H),8.18–8.07(m,1H),7.45(d,J＝8.1Hz,2H),7.37(t,J＝7.5Hz,2H),7.30–7.25(m,1H),6.86(d,J＝7.0Hz,1H),6.68(s,1H),4.05(q,J＝7.2Hz,1H),1.64(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 148.1,145.7,142.5,141.8,134.5,128.8,127.1,127.0,110.8,97.3,97.0,81.0,32.5, 23.8. HRMS (ESI) m/z accurate mass calculation C16H13N3[M+H]+248.1182, found 248.1180.
Example 135
2, 4-diamino-6-ethylpyrimidine (0.54g, 3.9mmol, 1.0 equiv.) and N-iodosuccinimide (884.0mg, 3.9mmol, 1.0 equiv.) were added to methanol (10.0mL), stirred at room temperature for 30 minutes, and after completion of the reaction, the reaction mixture was concentrated and purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 1/1) to give product S118-2 as a white solid (0.73g, 70% yield).
Characterization data for compound S118-2:
1H NMR(400MHz,CDCl3)δ5.52(brs,2H),5.12(brs,2H),2.72(q,J＝7.5Hz,2H),1.20(t,J＝7.6Hz,3H)。13C NMR(100MHz,CDCl3)δ178.4,172.8,162.7,162.1,34.4,12.4。
starting from S118-2(0.66g, 2.5mmol, 1.0 eq), the alkynyl product S118-3 was obtained as a brown powder (0.27g, 66% yield) by silica gel column chromatography (petroleum ether/ethyl acetate 1/4) according to general procedure 2.
Characterization data for compound S118-3:
1H NMR(400MHz,CD3OD)δ3.84(s,1H),2.54(q,J＝7.7Hz,2H),1.10(t,J＝7.7Hz,3H)。13C NMR(100MHz,CD3OD) δ 173.1,165.1,161.2,88.2,86.4,76.2,28.7, 11.7. HRMS (ESI) m/z accurate mass calculation C8H14N4[M+H]+163.0978, found 163.0977.
Methyl magnesium bromide (3.6mL, 1.0mol/L in THF, 3.6mmol, 1.2 equiv.) was added slowly to a solution of 3-bromo-5-methoxybenzaldehyde (0.68g, 3.0mmol, 1.0 equiv.) in anhydrous THF at 0 deg.C under nitrogen, and the reaction mixture was warmed to room temperature and stirred for 1 hour until the aldehyde was consumed (monitored by TLC). Quench the reaction with 3.0M HCl and CH2Cl2Extraction was carried out three times, the combined organic phases were washed with brine and Na2SO4Dried, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1) to give S118-4 as a colorless oil (0.63g, 90% yield).
Characterization data for compound S118-4:
1H NMR(400MHz,CDCl3)δ7.10(s,1H),6.98–6.93(m,1H),6.87–6.83(m,1H),4.82(q,J＝6.4Hz,1H),3.80(s,3H),1.46(d,J＝6.5Hz,3H)。13C NMR(100MHz,CDCl3)δ160.5,149.1,122.8,120.9,115.9,110.2,69.8,55.5,25.2。
to 4-methoxycarbonylphenylboronic acid (0.43g, 2.4mmol, 1.2 equiv.), S118-4(0.46g, 2.0), Cs were added under an argon atmosphere2CO3(1.3g, 4.0mmol, 2.0 equiv.) of 1, 4-dioxane (10.0mL) was added Pd/C (100mg, 10% w/w), and the mixture was heated at 100 ℃ for 4 hours. After completion of the reaction, cooled to rt, diluted with EtOAc and water, then extracted three times with EtOAc, the organic layer washed with brine, washed with Na2SO4Dried, filtered and concentrated in vacuo. The product S118-5 was obtained as a white solid by silica gel column chromatography (petroleum ether/ethyl acetate 5/1) (0.46g, 81% yield).
Characterization data for compound S118-5:
1H NMR(400MHz,CDCl3)δ8.11–8.02(m,2H),7.70–7.56(m,2H),7.20(s,1H),7.04(s,1H),6.97(s,1H),4.98–4.91(m,1H),3.98–3.92(m,3H),3.90–3.85(m,3H),1.57–1.55(m,3H)。13C NMR(100MHz,CDCl3)δ167.0,160.3,148.3,145.4,141.6,130.1,129.0,127.1,116.8,112.0,110.6,70.3,55.4,52.2,25.4。
PBr was washed at 0 deg.C3(0.30g, 1.1mmol, 0.7 equiv.) CH was added to a solution of S118-5 (0.46g, 1.6mmol, 1.0 equiv.)2Cl2(9.0mL) solution. After completion of the reaction (monitored by TLC), the reaction was quenched with water and quenched with CH2Cl2Extracting three times, and subjecting the combined organic phase to Na2SO4Dried and concentrated in vacuo to afford the corresponding crude product S118-6 without further purification (0.50g, 90% yield).
Characterization data for compound S118-6:
1H NMR(400MHz,CDCl3)δ8.08(d,J＝7.9Hz,2H),7.70–7.58(m,2H),7.26(d,J＝1.5Hz,1H),7.10–7.05(m,2H),5.21(q,J＝6.2Hz,1H),3.92(s,3H),3.84(s,3H),2.06(d,J＝6.7Hz,3H)。13C NMR(100MHz,CDCl3)δ166.8,160.2,145.3,144.9,141.7,130.1,129.2,127.1,118.2,112.9,112.2,55.4,52.1,49.2,26.9。
starting from compound S118-6(34.8mg, 0.10mmol, 1.0 eq) and the alkynyl compound S118-3(24.3mg, 0.15mmol, 1.5 eq) using general method B, after 72 hours the reaction mixture was purified by silica gel column chromatography (ethyl acetate 100) to give a mixture of product 118 (92% ee) and S118-3. NMR data and HPLC data of compound 118 were obtained by a small amount of preparative TLC.
Compound 118 characterization data:
HPLC conditions Chiralcel IA (n-hexane/isopropanol 60/40, flow rate 0.7mL/min, λ 270nm), tR(minor)＝31.69min,tR(major)＝45.12min。1H NMR(400MHz,CDCl3)δ8.10(d,J＝7.6Hz,2H),7.65(d,J＝7.6Hz,2H),7.25(s,1H),7.03(d,J＝5.3Hz,2H),5.40–5.30(m,4H),4.09(q,J＝7.1Hz,1H),3.94(s,3H),3.88(s,3H),2.72(q,J＝7.6Hz,2H),1.64(d,J＝7.0Hz,3H),1.24(t,J＝7.4Hz,3H)。13C NMR(100MHz,CDCl3)δ172.2,166.9,164.2,160.4,160.0,145.5,145.4,141.9,130.1,129.2,127.1,118.4,112.3,111.3,101.6,90.6,75.0,55.5,52.2,33.2,29.1,24.7,12.6。HRMS(ESI) m/z accurate mass calculation C25H27N4O3[M+H]+431.2078, found 431.2078.
To a mixture of the crude product 118 (half of the product prepared in the last step) in THF (0.5mL) and water (0.5mL) was added LiOH. H.under vigorous stirring2O (10.5mg, 0.25mmol, 5.0 equiv.) and stirred at room temperature for 5 hours. After completion of the reaction (monitored by TLC), the mixture was diluted with EtOAc and water, extracted three times with EtOAc, the organic layer was washed with brine, concentrated in vacuo, and purified by silica gel column chromatography (methanol/ethyl acetate ═ 1/50) to give the product UCP1172 as a white powder (12.3mg, two step yield 59%).
UCP1172 characterization data:
[α]D 27＝–2.2(c 0.090,CH2Cl2)。1H NMR(400MHz,DMSO-d6)δ8.03(d,J＝7.8Hz,2H),7.71(d,J＝7.8Hz,2H),7.36(s,1H),7.11(s,1H),7.06(s,1H),6.27(brs,2H),6.17(brs,2H),4.15(q,J＝6.9Hz,1H),3.84(s,3H),2.56(q,J＝7.6Hz,2H),1.56(d,J＝7.1Hz,3H),1.11(t,J＝7.6Hz,3H)。13C NMR(100MHz,DMSO-d6) δ 172.1,164.7,161.7,160.4,146.4,141.6,130.3,126.8,118.3,112.6,110.9,100.9,88.2,76.6,55.7,32.8,29.4,25.1, 12.9. HRMS (ESI) m/z accurate mass calculation C24H25N4O3[M+H]+417.1921, found 417.1922.
Example 136
The coupled product (R) -119 is readily hydrogenated and hydrolyzed to the compound (S) -120, which is a key intermediate in the synthesis of the natural products (+) -ar-curcumene, (+) -nuciferal, (+) -erologinee, (+) -ar-himachalene. (R) -120 is obtained through (R) -119, and a compound 121 is obtained through oxidation and can be used for synthesizing a natural product (+) -laevigatin.
Starting from p-toluoylene (1.34g, 10.0mmol, 1.0 equiv.) by general method 3, the crude (±) -S119-3 was obtained as a colorless oil (1.78g, 90% yield).
Characterization data for compound (+ -) -S119-3:
1H NMR(400MHz,CDCl3)δ7.41(d,J＝7.6Hz,2H),7.23(d,J＝7.8Hz,2H),5.29(q,J＝6.9Hz,1H),2.42(s,3H),2.12(dd,J＝7.0,0.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 140.4,138.3,129.4,126.8,49.9,26.9, 21.3. HRMS (ESI) m/z accurate mass calculation C9H11[M–Br]+119.0855, found 119.0853.
Starting from S119-3(39.6mg, 0.20mmol, 1.0 eq) and 3, 3-diethoxy-1-propyne (38.4mg, 0.30mmol, 1.5 eq) according to general method B, after 36 hours the reaction mixture is filtered through a pad of silica gel and Et2O rinse, then concentrated in vacuo to give the crude product (R) -119 as a colorless oil (47.2mg, 96% yield, 93% ee).
Characterization data for compound (R) -119:
[α]D 27＝–2.6(c 1.8,CH2Cl2). HPLC conditions Chiralcel IG (n-hexane/isopropanol 98/2, flow rate 1.0mL/min, lambda 210nm), tR(major)＝4.82min,tR(minor)＝5.86min。1H NMR(400MHz,CDCl3)δ7.28(d,J＝7.6Hz,2H),7.15(d,J＝7.6Hz,2H),5.34(s,1H),3.84–3.74(m,3H),3.66–3.58(m,2H),2.35(s,3H),1.51(d,J＝7.2Hz,3H),1.31–1.23(m,6H)。13C NMR (100MHz, CDCl3) delta 139.6,136.3,129.2,126.8,91.6,88.8,77.5,60.7,31.4,24.2,21.0, 15.2. HRMS (ESI) m/z accurate mass calculation C16H22NaO2[M+Na]+269.1512, found 269.1510.
Starting from S119-3(39.6mg, 0.20mmol, 1.0 equiv.) and 3, 3-diethoxy-1-propyne (38.4mg, 0.30mmol, 1.5 equiv.), ligand L15 instead of ligand L13, the crude product (S) -119 was obtained as a colorless oil after 36 hours (47.2mg, 94% yield, 87% ee) by general method B.
Characterization data for compound (S) -119:
[α]D 27＝+16(c 2.7,CH2Cl2). HPLC condition Chiralcel IG (flow rate 1.0mL/min, λ 210nm, n-hexane/isopropanol 98/2), tR(minor)＝4.74min,tR(major)＝5.71min。
To Pd/C (50.0mg, 10% w/w) and Cs under an argon atmosphere2CO3(130.0mg, 0.40mmol, 2.0 equiv.) to a mixture in EtOH (2.0mL) was added (R) -119(49.2mg, 0.20mmol, 1.0 equiv.), then the argon was replaced with hydrogen through a balloon, and the mixture was stirred at room temperature for 12 hours under a hydrogen atmosphere. After completion of the reaction, the reaction was filtered and washed with EtOAc, and the solution was concentrated in vacuo without further purification. The residue was dissolved in THF (1.0mL) and H2O (1.0mL) was added, then two drops of 1.0M HCl were added, then stirred until the starting material was completely consumed (monitored by TLC). The reaction mixture was diluted with EtOAc, washed with water and brine, over MgSO4Dried, filtered and concentrated in vacuo. (S) -120 was obtained as a colorless oil by silica gel column chromatography (petroleum ether/ethyl acetate 5/1) (31.7mg, 90% yield, 90% ee).
Compound (S) -120 characterization data:
[α]D 27＝+34(c 1.8,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝12.30min,tR(major)＝17.52min。1H NMR(400MHz,CDCl3)δ9.70(t,J＝1.6Hz,1H),7.14(d,J＝8.0Hz,2H),7.08(d,J＝8.0Hz,2H),2.76–2.66(m,1H),2.40–2.29(m,2H),2.34(s,3H),2.03–1.81(m,2H),1.29(d,J＝6.8Hz,3H)。13C NMR(100MHz,CDCl3) δ 202.5,143.0,135.8,129.2,126.9,42.2,38.9,30.4,22.4, 21.0. HRMS (ESI) m/z accurate mass calculation C12H16NaO[M+Na]+199.1093, found 199.1094.
Using (S) -119(49.2mg, 0.20mmol, 1.0 equivalent) as a starting material, the same procedure as for (S) -120 was followed to give (R) -120 as a colorless oil (32.4mg, 92% yield, 87% ee).
Characterization data for compound (R) -120:
[α]D 27＝–11(c 1.2,CH2Cl2). HPLC conditionsChiralcel OD3 (n-hexane/isopropanol 99.5/0.5, flow rate 1.0mL/min,. lambda.254 nm), tR(minor)＝12.30min,tR(major)＝17.52min。
To aldehyde (R) -120(26.4mg, 0.15mmol, 1.0 equiv.) in THF and H with vigorous stirring2O(THF/H2O-3/1, v/v, 8.0mL) was added to AgNO3(63.8mg, 0.38mmol, 2.5 equiv.) of H2O (1.0mL) solution. Aqueous NaOH (2.5mL, 10% m/v) was then added dropwise to the mixture at room temperature. After 2 hours, the reaction mixture was filtered and washed with water. The filtrate was taken up in Et2O extraction was carried out three times and the organic layer was separated. The aqueous phase was acidified to pH 1 with hydrochloric acid (12.0mol/L) at 0 ℃ and CH2Cl2And extracting for four times. The combined organic layers were washed with brine, over anhydrous Na2SO4Dried and concentrated in vacuo. Chromatography on silica gel (CH)2Cl2MeOH 10/1) to give 121(21.6mg, 75% yield) as a yellow oil.
Compound 121 characterization data:
[α]D 27＝–14(c 1.8,CH2Cl2)。1H NMR(400MHz,CDCl3)δ7.06–7.01(m,2H),7.01–6.96(m,2H),2.67–2.56(m,1H),2.24(s,3H),2.18–2.11(m,2H),1.90–1.72(m,2H),1.18(d,J＝7.2Hz,3H)。13C NMR(100MHz,CDCl3) δ 180.3,143.0,135.8,129.2,126.9,38.9,33.0,32.3,22.3, 21.0. HRMS (ESI) m/z accurate mass calculation C12H16NaO[M+Na]+215.1043, found 215.1044.
Example 137
The coupled product (R) -122 can be hydrolyzed, Pinnick oxidized, hydrogenated, Friedel-Crafts acylated to obtain the compound 123, and then (-) -7-methoxy-1, 2-dihydrocadylene and (+) - (1S,4R) -7-methoxyalamine can be synthesized according to the existing literature report. Diastereoselective hydroxylation of compound 123 gives compound 124, a precursor for the synthesis of (+) -heroin.
Synthesis of intermediate 122
At-78 deg.C, adding CH3MgCl (2.0mL, 3.0M in THF, 6.0mmol, 1.2 equiv.) was added slowly to a solution of 3-methoxy-4-methylbenzaldehyde S122-1(0.75g, 5.0mmol, 1.0 equiv.) in THF. Then warmed to room temperature and stirred for 1 hour until the aldehyde was completely consumed (monitored by TLC). Quench the reaction with 3.0M HCl and CH2Cl2Extraction was carried out three times, the combined organic phases were washed with brine and Na2SO4Drying, filtration, concentration in vacuo, and purification by silica gel chromatography (petroleum ether/ethyl acetate 5/1) gave S122-2 as a colorless oil (0.80g, 96% yield).
Characterization data for compound S122-2:
1H NMR(400MHz,CDCl3)δ7.09(d,J＝7.6Hz,1H),6.88(d,J＝1.6Hz,1H),6.83(dd,J＝7.6,1.6Hz,1H),4.85(q,J＝6.4Hz,1H),3.84(s,3H),2.21(d,J＝0.8Hz,3H),1.49(d,J＝6.5Hz,3H)。13C NMR(100MHz,CDCl3)δ157.9,145.0,130.6,125.9,117.2,107.1,70.5,55.4,25.3,16.1。
PBr was washed at 0 deg.C3(0.20mL, 2.1mmol, 0.70 equiv.) is added dropwise to S122-2(0.50g, 3.0mmol, 1.0 equiv.) in CH2Cl2(10.0ml) the reaction mixture was stirred at this temperature for 2 hours, then quenched with water and CH2Cl2Extraction was carried out three times. The combined organic phases are passed over Na2SO4Drying, filtration through a pad of silica gel and concentration in vacuo afforded the crude product S122-3(0.64g, 93% yield) as a white solid without further purification.
Characterization data for compound S122-3:
1H NMR(400MHz,CDCl3)δ7.09(d,J＝7.5Hz,1H),6.94(dd,J＝7.5,1.8Hz,1H),6.91(d,J＝1.7Hz,1H),5.22(q,J＝6.9Hz,1H),3.86(s,3H),2.21(s,3H),2.06(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 157.9,142.2,130.7,127.3,118.5,108.6,55.4,50.4,27.0, 16.2. HRMS (ESI) m/z accurate mass calculation C10H13O[M–Br]+149.0961, found 149.0966.
To a 10mL Schlenk tube were added CuTc (1.91mg, 0.010mmol, 5.0 mol% equiv.), ligand L13(12.5mg, 0.015mmol, 7.5 mol% equiv.), and Cs2CO3(130.4mg, 0.40mmol, 2.0 equiv.), the air is evacuated in vacuo and refilled with argon three times. Addition of anhydrous Et while bubbling argon2O (4.0mL), then S122-3(45.6mg, 0.20mmol, 1.0 equiv.) and 3, 3-diethoxy-1-propyne (38.4mg, 0.30mmol, 1.5 equiv.) were added in that order. The reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction (monitored by TLC), insoluble solids were removed by filtration through a suction funnel on silica gel, using CH2Cl2Washed and concentrated in vacuo to give the crude product (R) -122 (94% ee) without further purification.
Characterization data for compound (R) -122:
HPLC conditions Chiralcel IG (n-hexane/isopropanol 99/1, flow rate 0.4mL/min, λ 254nm), tR(major)＝13.59min,tR(minor)＝14.94min。Crude 1H NMR(400MHz,CDCl3)δ7.10(d,J＝7.5Hz,1H),6.92–6.85(m,2H),5.36(s,1H),3.87(s,3H),3.85–3.74(m,3H),3.71–3.56(m,2H),2.23(s,3H),1.54(d,J＝7.2Hz,3H),1.27(td,J＝7.1,3.0Hz,8H)。Crude13C NMR(100MHz,CDCl3)δ157.8,141.5,130.6,125.0,118.6,108.7,91.6,88.9,60.7,60.7,55.2,31.8,24.2,15.9,15.2。
To a solution of (R) -122 in THF (2.0mL) at 0 deg.C was added 1.0M HCl (0.1mL) dropwise and stirred at 0 deg.C for 6 hours. After completion of the reaction (monitored by TLC), the mixture was concentrated in vacuo and the crude S122-4 was used in the next step without further purification.
S122-4 (prepared in the previous step) was dissolved in H2O (2.0mL) and tBuOH (2.0mL) were added2-methyl-2-butene (0.28g, 4.0mmol, 20.0 equiv.), NaH2PO4(0.12g, 1.0mmol, 5.0 equiv.) and NaClO2(68.0mg, 80% purity, 0.60mmol, 3.0 equiv.). The reaction was stirred at room temperature until the starting material was completely consumed, diluted with EtOAc and extracted three times with EtOAc. The organic layer was washed with brine, Na2SO4Dry dried and concentrated in vacuo, without any purification, the crude S122-5 was used in the next step.
To a two-necked flask with hydrogen balloon, palladium on carbon (containing 10% Pd and 50% water), a mixed solution of S122-5 (prepared in the previous step) in THF (1.0mL) and water (1.0mL) was added by syringe and stirred at room temperature overnight. After completion of the reaction (monitored by TLC), the mixture was filtered and concentrated in vacuo to give the crude product (S) -S122-6, which was used in the next step without further purification.
A mixture of trifluoroacetic acid (22.8mg, 0.20mmol, 1.0 equiv.) and trifluoroacetic anhydride (168.0mg, 0.80mmol, 4.0 equiv.) was added to a flask containing (S) -S122-6 (prepared in the previous step) at 0 deg.C under argon protection. After completion of the reaction (monitored by TLC), saturated NaHCO was used at 0 deg.C3Quench the reaction and use Et2And extracting for three times. The organic layer was washed with brine and Na2SO4Drying, filtration, concentration in vacuo, and purification by silica gel column chromatography (petroleum ether/ethyl acetate: 5/1) gave 123 as a white powder (16.3mg, 80% over five steps, 89% ee).
Compound 123 characterization data:
[α]D 25＝–22(c 0.40,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 98/2, flow rate 0.3mL/min, λ 270nm), tR(major)＝29.56min,tR(minor)＝32.48min。1H NMR(400MHz,CDCl3)δ7.85(s,1H),6.70(s,1H),3.92(s,3H),3.14–3.00(m,1H),2.66(dddd,J＝78.8,17.3,8.6,4.9Hz,2H),2.30–2.23(m,1H),2.22(s,3H),1.98–1.84(m,1H),1.41(d,J＝6.6Hz,3H)。13C NMR(100MHz,CDCl3)δ197.5,162.2,149.5,129.6,125.5,124.8,107.6,55.5,35.9,33.1,30.8,20.8,15.8。HRMS(ESI)m/z accurate mass calculation C13H17O2[M+H]+205.1223, found 205.1222.
To a mixture of 123(21.0mg, 0.10mol, 1.0 equiv.) and KOH (56.0mg, 1.0mmol, 10.0 equiv.) in methanol (0.5mL) was added PhI (OCOCOCF) at 0 deg.C under argon shield3)2(51.6mg, 0.12mmol, 1.2 eq), then allowed to warm to room temperature naturally and stirred for 3 hours. After completion of the reaction (monitored by TLC), the mixture was concentrated by evaporation and purified by silica gel column chromatography (petroleum ether/ethyl acetate 5/1) to give the product as a white solid as two isomeric mixtures 124 and 124' (syn: anti about 6.7: 1). (combined yield 56%, cis major isomer 124 89% ee, trans minor isomer 124' 87% ee).
[α]D 25＝+21(c 0.20,CH2Cl2). HPLC conditions (syn-major isomer) Chiralcel OZ3 (n-hexane/isopropanol 95/5, flow rate 0.5mL/min,. lambda.254 nm), tR(major)＝37.34min,tR(minor)＝42.80min。1H NMR(syn-major isomer)(400MHz,CDCl3)δ7.86(s,1H),6.80(s,1H),4.36(dd,J＝13.4,5.3Hz,1H),3.94(s,3H),3.24–3.13(m,1H),2.51(dt,J＝12.5,4.7Hz,1H),2.24(s,3H),1.78(q,J＝12.6Hz,1H),1.48(d,J＝6.8Hz,3H)。13C NMR(syn-major isomer)(100MHz,CDCl3)δ198.5,162.9,149.1,129.7,126.1,107.0,73.0,55.5,40.8,31.6,20.5,15.8。
HPLC conditions (anti-minor isomer) Chiralcel OZ3 (n-hexane/isopropanol 95/5, flow rate 0.5mL/min,. lambda.254 nm), tR(major)＝39.90min,tR(minor)＝44.85min。1H NMR(anti-minor isomer)(400MHz,CDCl3) δ 7.81(s,1H),6.62(s,1H),4.61(dd, J ═ 13.4,5.6Hz,1H),3.92(s,3H), 3.32-3.23 (m,1H), 2.42-2.34 (m,1H),2.23(s,3H),1.64(m,1H),1.50(d, J ═ 7.0Hz, 3H). HRMS (ESI) m/z accurate mass calculation C13H17O3[M+H]+221.1172, found 221.1170.
Example 138
From the compound 122, the synthesis is carried out to obtain 126 and 127 through route adjustment, and products such as (+) -methylisteegone A, (-) -aristeegone B and the like can be continuously synthesized.
Using S122-3(91.2mg, 0.40mmol, 1.0 equivalent) as a starting material, ligand L16(24.2mg, 0.030mmol), 7.5 mol% equivalent) was used in place of ligand L13, and (S) -122 was obtained as a colorless oil by silica gel column chromatography (petroleum ether ═ 100) in the same manner as for (R) -122 (99.5mg, 90% yield, 84% ee).
Characterization data for compound (S) -122:
[α]D 27＝–4.9(c 1.6,CH2Cl2). HPLC conditions Chiralcel IG (n-hexane/isopropanol 99/1, flow rate 0.4mL/min, λ 214nm), tR(minor)＝13.79min,tR(major)＝15.32min。1H NMR(400MHz,CDCl3)δ7.07(d,J＝7.5Hz,1H),6.86(s,1H),6.84(d,J＝7.7Hz,1H),5.32(s,1H),3.83(s,3H),3.81–3.70(m,3H),3.66–3.53(m,2H),2.18(s,3H),1.50(d,J＝7.2Hz,3H),1.23(td,J＝7.1,3.1Hz,6H)。13C NMR(100MHz,CDCl3) δ 157.9,141.6,130.7,125.1,118.7,108.9,91.7,89.0,77.7,60.84,60.81,55.4,31.9,24.3,16.0, 15.3. HRMS (ESI) m/z accurate mass calculation C17H25O3[M+H]+277.1798, found 277.1796.
(S) -122(83.0mg, 0.30mmol, 1.0 equiv.), Cs2CO3A mixture of (48.9mg, 0.15mmol, 0.50 equiv.) and Pd/C (20.0mg, 10% w/w) in THF/MeOH (1: 3, v/v, 10.0mL) was hydrogenated (balloon pressure) for 24 h. The mixture was then filtered through a short pad of celite and rinsed with EtOAc, which after concentration gave crude product 125 as a colorless oil (80.0mg, 95% yield) without further purification.
To a stirred solution of 125(56.0mg, 0.20mmol, 1.0 equiv.) in THF (6.0mL) at room temperature was added 2.0M HCl (2.0mL) dropwise and the mixture was stirred at room temperatureStirring was carried out at 35 ℃ for 1 hour. At 0 deg.C, with saturated NaHCO3The reaction was quenched and extracted three times with EtOAc, and the combined organic phases were washed with brine, washed with Na2SO4Drying, filtration, concentration in vacuo and purification by silica gel column chromatography (petroleum ether/ethyl acetate: 15/1) gave product 126(33.0mg, 88% yield, 83% ee) as a colorless oil.
Compound 126 characterization data:
[α]D 27＝+29(c 0.42,CH2Cl2). HPLC conditions Chiralcel OJ3 (n-hexane/isopropanol 99/1, flow rate 0.3mL/min, λ 270nm), tR(minor)＝26.19min,tR(major)＝35.32min。1H NMR(400MHz,CDCl3)δ6.84(s,1H),6.67(s,1H),6.37(d,J＝9.5Hz,1H),5.85–5.75(m,1H),3.84(s,3H),2.95–2.82(m,1H),2.50–2.40(m,1H),2.18(s,3H),2.15–2.03(m,1H),1.23(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 157.0,139.5,128.8,126.9,126.0,124.3,124.1,108.7,55.6,32.2,31.3,20.5, 15.9. HRMS (ESI) m/z accurate mass calculation C13H17O[M+H]+189.1274, found 189.1274.
To a stirred solution of 125(78.0mg, 0.28mmol, 1.0 equiv.) in THF (10.0mL) at 0 deg.C was added 0.5M HCl (3.0mL) dropwise and stirred at that temperature for 4 hours. At 0 deg.C, by saturated NaHCO3The reaction was quenched and extracted with EtOAc and the combined organic phases were washed with brine, Na2SO4Drying, filtration, concentration in vacuo and purification by silica gel column chromatography (petroleum ether/ethyl acetate 10/1) gave 127(46.2mg, 80% yield, 85% ee) as a colorless oil.
Compound 127 characterization data:
[α]D 27＝–12(c 2.8,CH2Cl2). HPLC conditions Chiralcel OJ3 (n-hexane/isopropanol 99/1, flow rate 0.3mL/min, lambda. 280nm), tR(major)＝42.70min,tR(minor)＝47.03min。1H NMR(400MHz,CDCl3)δ9.69(s,1H),7.06(d,J＝7.2Hz,1H),6.67(d,J＝7.2Hz,1H),6.63(s,1H),3.83(s,3H),2.73–2.64(m,1H),2.41–2.26(m,2H),2.19(s,3H),2.00–1.79(m,2H),1.28(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 202.7,157.9,145.1,130.7,124.6,118.7,108.9,55.4,42.4,39.5,30.5,22.6, 16.0. HRMS (ESI) m/z accurate mass calculation C13H19O2[M+H]+207.1380, found 207.1381.
At 127(41.0mg, 0.20mmol, 1.0 equiv.) of CH3CN/tBuOH/H2To the O (2: 2: 1, 10.0mL) mixed solution was added NaH in order2PO4(72.0mg, 0.60mmol, 3.0 equiv.), NaClO2(89.5mg, 1.2mmol, 6.0 equiv.). After stirring at room temperature for 2 hours, the mixture was diluted with EtOAc and saturated Na2S2O3And washed with brine and Na2SO4Dried and concentrated in vacuo. By silica gel column Chromatography (CH)2Cl210/MeOH: 1) the residue was purified to give the product (R) -S122-6(40.0mg, 90% yield) as a colorless oil, with characterization data consistent with literature reports:
[α]D 27＝–19(c 1.8,CH2Cl2)。1H NMR(400MHz,CDCl3)δ7.05(d,J＝7.4Hz,1H),6.68(d,J＝7.5Hz,1H),6.64(s,1H),3.82(s,3H),2.76–2.64(m,1H),2.25(t,J＝7.6Hz,2H),2.18(s,3H),2.00–1.83(m,2H),1.27(d,J＝7.4Hz,4H)。13C NMR(100MHz,CDCl3) δ 179.7,157.9,145.1,130.7,124.6,118.8,109.0,55.4,39.5,33.1,32.4,22.4, 16.0. HRMS (ESI) m/z accurate mass calculation C13H19O3[M+H]+223.1329, found 223.1327.
Using (R) -S122-6(44.4mg, 0.20mmol, 1.0 equiv.) as starting material and the same procedure as 123, (+) -methylisteeledione A (32.6mg, 80% yield, 89% ee) was obtained as a white solid, with characterization data consistent with those reported in the literature:
[α]D 27＝+14(c 0.50,CH2Cl2). HPLC conditions Chiralcel OD3 (n-hexane/isopropanol 98/2, flow rate 0.4mL/min, λ 254nm), tR(minor)＝19.97min,tR(major)＝21.44min。1H NMR(400MHz,CDCl3)δ6.84(s,1H),6.67(s,1H),6.37(d,J＝9.5Hz,1H),5.85–5.75(m,1H),3.84(s,3H),2.95–2.82(m,1H),2.50–2.40(m,1H),2.18(s,3H),2.15–2.03(m,1H),1.23(d,J＝6.9Hz,3H)。13C NMR(100MHz,CDCl3) δ 157.0,139.5,128.8,126.9,126.0,124.3,124.1,108.7,55.6,32.2,31.3,20.5, 15.9. HRMS (ESI) m/z accurate mass calculation C13H17O2[M+H]+205.1223, found 205.1222.
(+) -Methyliseletegone A (36.8mg, 0.18mmol, 1.0 equiv.) was used as the starting material to give (-) -aristoelegenin B as a white solid by semi-preparative HPLC using the same procedure as 124 (27.0mg, 68% yield, 81% ee).
[α]D 27＝–0.50(c 1.0,CH2Cl2). HPLC conditions Chiralcel OJ3 (n-hexane/isopropanol 90/10, flow rate 0.8mL/min, λ 270nm), tR(major)＝12.27min,tR(minor)＝14.60min。1H NMR(400MHz,CDCl3)δ7.83(s,1H),6.77(s,1H),4.33(dd,J＝13.5,5.3Hz,1H),3.96–3.88(m,4H),3.25–3.06(m,1H),2.54–2.43(m,1H),2.21(s,3H),1.76(q,J＝12.6Hz,1H),1.45(d,J＝6.8Hz,3H)。13C NMR(100MHz,CDCl3) δ 198.7,163.1,149.2,129.9,126.2,122.9,107.1,73.1,55.6,41.0,31.8,20.7, 15.9. HRMS (ESI) m/z accurate mass calculation C13H17O3[M+H]+221.1172, found 221.1170.
Example 139
The coupling product 128 obtained by using acetylene gas as a raw material can be converted into a compound 129, and then natural products (+) -bisacumol, (+) -dihydrocurumene and (+) -turmerone can be synthesized.
Starting from S119-3(39.6mg, 0.20mmol, 1.0 equiv.) using general procedure C, crude product 128 was obtained as a colorless oil (23.3mg, 81% yield) without further purification.
In a glove box, CpRu (MeCN)3]PF6(CAS No.930601-66-4)(2.4mg, 0.0040mmol, 2.0 mol% equiv.) and 5,5 '-bis (trifluoromethyl) -2,2' -bipyridine L (1.2mg, 0.0040mmol, 2.0 mol% equiv.) were added to a Schlenk tube, after which the Schlenk was removed and a mixed solution of crude product 128 in NMP (0.8mL) and water (0.2mL) was added to the tube under argon and stirred at 25 ℃ overnight. After completion of the reaction (monitored by TLC), the mixture was diluted with EtOAc and washed with brine, Na2SO4Dried, filtered and concentrated in vacuo to afford the product 129 as a colorless oil by silica gel column chromatography (petroleum ether/ethyl acetate: 20/1) (22.0mg, two steps 68%) with data for characterization:
[α]D 27＝+40(c 0.4,CH2Cl2)。1H NMR(400MHz,CDCl3)δ9.73(t,J＝2.1Hz,1H),7.14(s,4H),3.39–3.23(m,1H),2.79–2.60(m,2H),2.34(s,3H),1.32(d,J＝6.8Hz,3H)。13C NMR(100MHz,CDCl3) δ 202.1,142.4,136.1,129.3,126.6,51.8,33.9,22.3, 21.0. HRMS (ESI) m/z accurate mass calculation C11H14NaO[M+Na]+185.0937, found 185.0938.
Since aldehyde 129 is unstable in air, the ee value is detected by reducing the product S129-1.
To a solution of aldehyde 129(16.2mg, 0.10mmol, 1.0 equiv.) in EtOH (1.0mL) was added NaBH4(7.6mg, 0.20mmol, 2.0 equiv.) and stirred at room temperature for 3 hours. After completion of the reaction (monitored by TLC), the reaction was quenched with water, extracted three times with EtOAc, the organic layer was washed with brine, washed with Na2SO4Dry, filter and concentrate in vacuo to give the product S129-1 as a colorless oil by silica gel column chromatography (petroleum ether/ethyl acetate 5/1) (14.9mg, 91% yield, 98% ee).
[α]D 27＝+13(c 0.31,CH2Cl2). HPLC conditions Chiralcel AY3 (n-hexane/isopropanol 99/1, flow rate 0.5mL/min, lambda. 214nm), tR(minor)＝20.81min,tR(major)＝22.80min。1H NMR(400MHz,CDCl3)δ7.11(s,4H),3.62–3.49(m,2H),2.91–2.80(m,1H),2.32(s,3H),1.91–1.77(m,2H),1.26(d,J＝7.0Hz,3H)。13C NMR(100MHz,CDCl3) δ 143.8,135.6,129.2,126.8,61.3,41.0,36.1,22.6, 21.0. HRMS (ESI) m/z accurate mass calculation C11H16NaO[M+Na]+187.1093, found 187.1093.
Example 140
Structure and synthesis of ligand L
To verify the suitability of the ligand structure, ligands of the following structures were used in the template reaction of example 3, with the following yields and enantioselectivities:
the above results show that the ligand L has good yield and excellent enantioselectivity for the reaction of the present invention, and can be synthesized according to the following route:
step 1: diethyl phosphite (1.0mmol) was slowly added dropwise to a stirred solution of Grignard reagent S1(3.0mmol) in tetrahydrofuran at 0 ℃. The reaction mixture was then warmed to room temperature and stirred for 12 hours. After complete conversion (monitored by TLC), the crude mixture was directly purified by silica gel column chromatography (50: 1 ratio of petroleum ether to ethyl acetate) to give pure S2 (50-80% yield).
Step 2: to a stirred solution of S2(1.0mmol) in toluene was added copper triflate (0.1mmol) and 1,1,3, 3-tetramethyldisiloxane TMDS (2.0mmol) at room temperature. The reaction mixture was stirred and heated to reflux for 12 hours. After cooling to room temperature, the toluene solvent was removed under reduced pressure to give crude product S3, which was directly subjected to the next reaction.
And step 3: dissolving the crude product S3 obtained in the last step into tetrahydrofuran, cooling to-78 ℃, and stirring. KHMDS (1.0mmol) was added to the reaction at this temperature, and the reaction was stirred for 30 minutes at room temperature. Then cooling to-78 ℃, adding the o-fluorobenzoic acid methyl ester into the reaction system, slowly heating to room temperature for reaction, and stirring for 24 hours. The mixture was quenched with dilute hydrochloric acid (1M). The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 20:1) to give S4 (40-60% yield).
And 4, step 4: lithium hydroxide (2.0mmol) was added to a mixed solution of S4(1.0mmol) in tetrahydrofuran and water, and the reaction system was heated to 70 ℃ and refluxed for 24 hours, and then cooled. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 1:1) to give S5 (70-80% yield).
And 5: to a solution of S5(1.0mmol) and quinine-derived S6(1.0mmol) (S6 and several other derivatives of amines of the backbone synthesis references: Chinese chem. Lett.2014,25,557.) in dichloromethane were added EDCI (1.2mmol) and DMAP (0.1 mmol). The reaction was stirred at room temperature for 24 hours and quenched by addition of water. The organic layer was separated, dried, filtered and concentrated in vacuo. The residue thus obtained was purified by silica gel column chromatography (ratio of petroleum ether to ethyl acetate 1:2) to obtain ligand 1 (60-80% yield).
Characterization data for ligand 1:1H NMR(400MHz,CDCl3)δ8.69(d,J＝4.4Hz,1H),7.98(d,J＝9.2Hz,1H),7.71(s,1H),7.63-7.15(m,23H),7.06-6.95(m,1H),6.02-5.64(m,2H),5.12-4.97(m,2H),3.92(s,3H),3.77(s,1H),3.49(s,1H),3.30-3.20(m,1H),3.04-2.88(m,1H),2.84-2.70(m,1H),2.48-2.31(m,1H),1.88-1.55(m,4H),1.10-0.92(m,1H)；13C NMR(100MHz,CDCl3)δ169.2,158.2,147.6,144.9,141.4,141.3,140.4,139.1,136.1,134.4,134.3,134.2,134.1,131.7,130.7,129.0,128.9,127.7,127.2,127.1,127.0,122.2,116.1,102.1,56.1,55.0,41.4,38.2,27.2,26.4,25.6；31P NMR(162MHz,CDCl3)δ-11.3。
characterization data for ligand 2:1H NMR(400MHz,CDCl3)δ8.69(d,J＝4.4Hz,1H),8.01(d,J＝9.2Hz,1H),7.71(d,J＝2.4Hz,1H),7.66-7.58(m,1H),7.43-7.27(m,9H),7.17-6.80(m,15H),5.83-5.64(m,1H),5.64-5.36(m,1H),5.09-4.90(m,2H),3.97(s,3H),3.36-3.00(m,3H),2.73-2.57(m,2H),2.41-2.19(m,1H),1.76-1.54(m,3H),1.51-1.37(m,1H),1.03-0.81(m,1H)；13C NMR(100MHz,CDCl3)δ169.0,158.5,158.3,157.9,156.3,156.2,147.6,144.8,141.2,135.5,135.33,135.28,135.1,134.1,129.9,124.02,123.97,121.8,119.8,119.7,118.4,118.3,118.2,114.8,102.3,56.0,55.8,41.2,39.5,27.8,27.5,26.3；31P NMR(162MHz,CDCl3)δ-13.4。
characterization data for ligand 3:1H NMR(400MHz,CDCl3)δ8.65(d,J＝4.4Hz,1H),8.01(d,J＝9.2Hz,1H),7.70(d,J＝2.6Hz,1H),7.66-7.58(m,1H),7.38-7.25(m,8H),7.08(t,J＝7.8Hz,2H),7.02(t,J＝7.8Hz,2H),6.98-6.95(m,1H),5.74-5.65(m,1H),5.47(brs,1H),4.97-4.93(m,2H),3.97(s,3H),3.15-2.94(m,3H),2.59-2.45(m,2H),2.25-2.19(m,1H),1.61-1.54(m,3H),1.43-1.32(m,1H),1.30(s,9H),1.29(s,9H),0.92-0.87(m,1H)；13C NMR(100MHz,CDCl3)δ169.0,157.7,151.7,151.5,147.6,144.7,141.8(d,J＝27.9Hz),141.5,135.7(d,J＝20.8Hz),134.4,133.7(d,J＝9.8Hz),133.6,133.43,133.36,133.2,133.6,130.1,128.7,128.5,125.7(d,J＝6.8Hz),125.5(d,J＝6.8Hz),121.7,114.5,102.2,56.0,55.7,48.9,41.0,39.6,34.7,34.6,33.9,31.31,31.30,28.0,27.4,26.2,25.6,25.0；31P NMR(162MHz,CDCl3)δ-14.4。
characterization data for ligand 4:1H NMR(400MHz,CDCl3)δ8.53(s,1H),7.99(d,J＝9.2Hz,1H),7.69(s,1H),7.59(s,1H),7.44-7.20(m,9H),7.12-7.00(m,2H),6.99-6.88(m,1H),6.88-6.71(m,1H),5.74-5.53(m,1H),5.34(br,1H),5.00-4.83(m,2H),3.94(s,1H),3.75-3.53(m,2H),3.20-2.14(m,8H),1.74-1.49(m,4H),1.13-0.96(m,12H)；13C NMR(100MHz,CDCl3)δ168.7,157.7,147.8,144.6,141.3,135.1,133.9,131.7,129.4,128.7,126.2,125.70,125.66,125.6,121.3,114.4,102.2,55.8,55.6,41.0,39.6,31.5,31.4,31.3,31.1,28.0,27.4,27.0,24.0；31P NMR(162MHz,CDCl3):δ-30.4。
characterization data for ligand 5:1H NMR(400MHz,CDCl3)δ8.67(d,J＝3.8Hz,1H),7.99(d,J＝9.0Hz,1H),7.72-7.61(m,2H),7.39-7.21(m,5H),6.95(s,1H),6.43-6.25(m,6H),5.77-5.65(m,1H),5.47(s,1H),5.02-4.91(m,2H),3.97(s,3H),3.67(s,12H),3.21-3.07(m,2H),3.05-2.89(m,1H),2.70-2.59(m,1H),2.56-2.46(m,1H),2.23(s,2H),1.63-1.55(m,2H),1.44-1.36(m,1H),0.94-0.82(m,1H)；13C NMR(101MHz,CDCl3)δ168.8,160.7,160.62,160.60,160.5,157.7,157.6,147.4,144.6,141.3,141.1,138.9,134.2,131.4,130.3,128.9,128.2,121.5,114.4,111.45,111.41,111.24,111.19,102.0,100.8,100.7,55.7,55.6,55.2,40.9,39.4,27.8,27.3,26.1；31P NMR(162MHz,CDCl3)δ-6.57。
characterization data for ligand 6:1H NMR(400MHz,CDCl3)δ8.61(d,J＝4.4Hz,1H),7.94(d,J＝9.2Hz,1H),7.78(s,1H),7.74-7.65(m,2H),7.56-7.48(m,12H),7.46-7.27(m,18H),7.18-7.12(m,1H),5.67-5.52(m,1H),5.44(brs,1H),4.93-4.80(m,2H),3.89(s,3H),3.20-2.81(m,3H),2.60-2.49(m,1H),2.47-2.39(m,1H),2.22-2.12(m,1H),1.67-1.44(m,3H),1.39-1.29(m,1H),0.95-0.81(m,1H)；13C NMR(100MHz,CDCl3)δ171.3,169.0,157.8,147.7,144.8,142.0,141.9,141.4,140.7,140.0,138.8,138.6,138.5,135.3,134.6,131.6,131.4,130.7,128.9,128.5,127.7,127.3,126.9,126.7,121.6,114.5,102.2,55.9,55.7,41.0,39.6,28.0,27.4,21.2；31P NMR(162MHz,CDCl3):δ-8.6。
characterization data for ligand 7:1H NMR(400MHz,CDCl3)δ10.08(s,1H),8.15(s,1H),8.04(s,1H),7.94(d,J＝9.2Hz,1H),7.69–7.66(m,1H),7.47–7.43(m,1H),7.35–7.31(m,2H),7.27–7.23(m,1H),7.06(s,2H),7.00(d,J＝2.9Hz,2H),6.63(s,1H),5.70–5.57(m,2H),4.95–4.87(m,2H),3.99(s,3H),3.24–3.16(m,2H),3.04–2.97(m,1H),2.90(dt,J＝9.2,6.9Hz,2H),2.73–2.58(m,2H),2.25(s,1H),2.10(s,1H),1.61(s,3H),1.34–1.17(m,24H),1.05–0.93(m,5H),0.75–0.42(m,12H)；13C NMR(101MHz,CDCl3)δ167.3,157.7,154.4,154.2,153.1,152.9,150.9,149.5,147.7,146.6,144.3,141.4,136.7,136.5,134.2,131.8,131.4,130.0,129.6,128.6,128.2,122.7,121.2,119.3,114.3,101.6,60.3,55.9,55.5,51.8,41.1,39.7,34.1,34.0,32.2,32.0,28.1,27.4,25.5,24.2,23.8,23.8,23.7；31P NMR(162MHz,CDCl3)δ-40.16。
characterization data for ligand 9:1H NMR(400MHz,CDCl3)δ8.73-8.58(m,1H),8.08-7.92(m,1H),7.73-7.61(m,2H),7.40-7.21(m,5H),7.09-6.93(m,4H),6.89-6.71(m,5H),5.79-5.66(m,1H),5.62-5.30(m,1H),5.06-4.89(m,2H),3.97(s,3H),3.76(s,6H),3.11-2.94(m,3H),2.70-2.54(m,2H),2.29-2.19(m,1H),1.67-1.50(m,3H),1.48-1.38(m,1H),0.92-0.79(m,1H)；13C NMR(101MHz,CDCl3)δ168.7,160.0,159.9,157.6,147.4,144.6,141.3,135.2,135.0,134.9,134.7,133.5,131.3,130.0,128.3,121.5,114.3,114.2,114.1,114.03,113.95,102.1,55.8,55.6,55.00,54.98,40.9,39.4,27.7,27.3,26.1；31P NMR(162MHz,CDCl3):δ-13.74。
characterization data for ligand 10:1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.36(d,J＝4.6Hz,1H),7.97(d,J＝9.2Hz,1H),7.90(t,J＝6.5Hz,1H),7.68(d,J＝2.8Hz,1H),7.37–7.31(m,2H),7.24–7.14(m,2H),6.87(d,J＝3.1Hz,2H),6.77(d,J＝3.2Hz,2H),6.60(s,1H),5.75(ddd,J＝17.5,10.4,7.4Hz,1H),5.53(d,J＝10.8Hz,1H),5.03–4.94(m,2H),3.96(s,3H),3.24(qd,J＝10.5,6.1Hz,2H),2.91(d,J＝9.3Hz,1H),2.77–2.65(m,2H),2.31(d,J＝2.8Hz,6H),2.11(s,6H),1.94(s,6H),1.82(d,J＝31.5Hz,2H),1.61(ddq,J＝16.0,6.6,3.0Hz,2H),1.44–1.33(m,1H),0.93–0.84(m,1H)；13C NMR(101MHz,CDCl3)δ168.1,157.7,147.6,144.5,143.6,143.5,142.6,142.4,141.6,138.9,138.1,133.3,131.5,130.3,130.3,130.2,130.2,130.0,128.4,121.4,114.4,101.8,41.2,39.7,28.0,27.5,26.0,23.0,22.9,22.6,22.5,21.0,20.9；31P NMR(162MHz,CDCl3)δ-30.28。
characterization data for ligand 11:1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.51-8.39(m,1H),8.17-8.04(m,1H),7.77-7.65(m,3H),7.61-7.55(m,1H),7.44-7.33(m,3H),7.29-7.22(m,2H),7.15-7.06(m,2H),7.02-6.94(m,2H),6.92-6.83(m,1H),5.66-5.55(m,1H),5.52-5.32(m,1H),4.93-4.84(m,2H),3.10-2.94(m,2H),2.90-2.73(m,1H),2.59-2.51(m,1H),2.45-2.37(m,1H),2.29-2.11(m,2H),1.61-1.47(m,3H),1.26-1.17(m,36H),0.93-0.87(m,1H)；13C NMR(101MHz,CDCl3)δ171.0,150.83,150.77,150.70,150.6,150.1,148.31,141.32,136.0,134.2,130.2,130.0,128.8,128.6,128.1,127.9,127.7,126.4,123.4,122.4,122.3,114.4,55.9,40.6,39.6,34.9,34.8,31.3,31.3,27.8,27.2,25.4；31P NMR(162MHz,CDCl3)δ-8.84。
characterization data for ligand 12:1H NMR(400MHz,CDCl3)δ8.67(d,J＝4.3Hz,1H),8.01(d,J＝9.1Hz,1H),7.87(s,1H),7.80–7.68(m,3H),7.60(dd,J＝24.6,5.9Hz,4H),7.39(dd,J＝21.2,6.8Hz,4H),6.85(s,1H),5.75(dt,J＝17.3,8.9Hz,1H),5.48(s,1H),5.09–4.88(m,2H),3.90(s,3H),3.36–3.06(m,3H),2.84–2.61(m,2H),2.33(s,1H),1.62(dd,J＝43.9,20.1Hz,4H),1.05-0.95(m,1H)；13C NMR(101MHz,CDCl3)δ167.7,157.9,147.4,144.7,141.6,141.4,141.2,140.9,140.7,139.9,139.7,134.4,134.2,133.6,133.4,133.1,132.9,132.4,132.2,132.1,132.1,132.0,131.9,131.8,131.7,131.6,131.6,131.5,131.4,131.3,131.21,131.15,130.1,128.6,128.5,127.73,127.69,127.1,127.0,124.4,124.3,122.9,122.8,121.7,121.6,118.9,118.9,114.6,102.1,56.0,55.5,41.0,39.4,27.7,27.3,26.5；19F NMR(376MHz,CDCl3)δ-62.97,-63.00；31P NMR(162MHz,CDCl3)δ-7.28。
characterization data for ligand 13:1H NMR(400MHz,CDCl3)δ8.58(d,J＝4.4Hz,1H),8.01(d,J＝9.2Hz,1H),7.70(d,J＝2.3Hz,2H),7.63(s,1H),7.44–7.35(m,4H),7.34–7.29(m,1H),7.18(s,1H),7.13–7.07(m,2H),7.00(dd,J＝7.9,1.7Hz,2H),6.90(dd,J＝7.1,3.9Hz,1H),5.67(ddd,J＝17.5,10.3,7.6Hz,1H),5.44(s,1H),5.02–4.87(m,2H),4.00(s,3H),3.06(dd,J＝13.8,10.1Hz,2H),2.86(s,1H),2.58(s,1H),2.52–2.42(m,1H),2.19(d,J＝22.4Hz,2H),1.65–1.51(m,3H),1.23(d,J＝15.7Hz,36H),0.95(dd,J＝13.1,6.5Hz,1H)；13C NMR(101MHz,CDCl3)δ168.8,157.6,150.7,150.6,147.6,144.5,141.4,136.0,135.9,134.2,131.6,130.0,128.6,128.1,127.9,127.7,122.4,122.3,121.3,114.4,102.0,60.3,56.0,55.6,40.8,39.6,34.9,34.8,31.4,31.3,28.0,27.3,25.6,21.0,14.2；31P NMR(162MHz,CDCl3)δ-8.63。
characterization data for ligand 14:1H NMR(400MHz,CDCl3)δ8.64(s,1H),8.43(d,J＝4.8Hz,1H),7.97(d,J＝9.2Hz,1H),7.94-7.84(m,1H),7.68(d,J＝2.8Hz,1H),7.40-7.30(m,2H),7.25-7.12(m,2H),6.80-6.39(m,5H),5.89-5.68(m,1H),5.60(br,1H),5.15-4.87(m,2H),3.95(s,3H),3.81(s,6H),3.41-3.19(m,2H),2.86-2.67(m,2H),2.11(s,6H),1.92(s,6H),1.74-1.51(m,4H),0.95-0.78(m,3H)；31P NMR(162MHz,CDCl3)δ-31.6。
characterization data for ligand 16:1H NMR(400MHz,CDCl3)δ8.46(d,J＝4.4Hz,1H),7.94(d,J＝9.2Hz,1H),7.80(t,J＝8.6Hz,2H),7.76-7.64(m,7H),7.62(d,J＝2.4Hz,1H),7.52-7.38(m,5H),7.33-7.18(m,6H),7.00-6.97(m,1H),5.67-5.59(m,1H),5.39(brs,1H),4.93-4.87(m,2H),3.90(s,3H),3.04-2.90(m,3H),2.54-2.47(m,1H),2.35-2.31(m,1H),2.20-2.17(m,1H),1.59-1.57(m,1H),1.50-1.47(m,2H),1.36-1.31(m,1H),0.84-0.79(m,1H)；13C NMR(100MHz,CDCl3)δ168.8,157.6,147.3,144.6,141.4,141.2,134.43,134.36,134.3,134.2,134.1(d,J＝4Hz),133.8,133.4,133.34,133.25,133.23,133.15,131.4,130.3,130.1,130.0,128.9,128.5,128.1,128.0,127.9(d,J＝7.3Hz),127.6(d,J＝8Hz),126.7(d,J＝10.4Hz),126.3(d,J＝8.4Hz),121.5,114.4,102.0,55.6,40.9,39.3,27.7,27.3,26.0；31P NMR(162MHz,CDCl3)δ-9.4。
characterization data for ligand 17:1H NMR(400MHz,CDCl3)δ8.55(d,J＝4.6Hz,1H),7.92(d,J＝9.2Hz,1H),7.67–7.56(m,3H),7.54(d,J＝9.7Hz,1H),7.51–7.45(m,1H),7.43–7.34(m,1H),7.33–7.21(m,4H),6.96(d,J＝7.6Hz,2H),6.87(d,J＝7.7Hz,2H),6.80–6.73(m,1H),5.58(ddd,J＝17.5,10.3,7.6Hz,1H),5.36(s,1H),4.91–4.76(m,2H),3.91(s,3H),3.60(d,J＝4.3Hz,6H),2.99(dd,J＝13.9,10.0Hz,2H),2.83(s,1H),2.57–2.32(m,2H),2.14(d,J＝5.4Hz,1H),1.78(s,2H),1.51(d,J＝22.4Hz,3H),1.22(d,J＝11.9Hz,36H)；31PNMR(162MHz,)δ-11.22。
characterization data for ligand 18:1H NMR(400MHz,CDCl3):δ8.79(d,J＝4.4Hz,1H),8.05(d,J＝9.2Hz,1H),7.79(d,J＝4Hz,1H),7.64(s,1H),7.50-7.39(m,6H),7.24-7.18(m,2H),7.04-6.99(m,1H),6.10-6.05(m,1H),5.91-5.83(m,1H),5.37-5.24(m,3H),4.14-4.07(m,2H),3.93(s,4H),3.61-3.55(m,1H),3.36-3.32(m,1H),2.76(s,1H),2.04-2.03(m,3H),1.14-1.11(m,1H)；13C NMR(100MHz,CDCl3) Delta 169.0,158.5,152.6-152.3(m),150.2-149.9(m),147.8,144.6,140.9(d, J ═ 7.1Hz),140.1,136.5,133.5,132.9(d, J ═ 12.7Hz),131.8,129.6(d, J ═ 13.2Hz),129.2 (d, J ═ 9.8Hz),127.8,125.5,124.4,122.0,120.3,117.8,117.1-116.8(m),116.2-115.9(m),101.1,58.8,55.9,53.4,48.4,42.8,36.7,26.6,24.9, 24.4;19F NMR(376MHz,CDCl3)δ-129.5,-129.8,-151.4；31P NMR(162MHz,CDCl3):δ29.9。
characterization data for ligand 19:1H NMR(400MHz,CDCl3)δ8.99(d,J＝5.8Hz,1H),8.21(d,J＝4.4Hz,1H),8.02-7.96(m,1H),7.92(d,J＝9.2Hz,1H),7.68(d,J＝2.5Hz,1H),7.33-7.27(m,2H),7.23-7.15(m,2H),6.30(s,1H),5.78-5.68(m,1H),5.54(d,J＝9.0Hz,1H),4.98(d,J＝8.3Hz,1H),4.94(s,1H),3.96(s,3H),3.30-3.19(m,2H),2.85(d,J＝7.2Hz,1H),2.76-2.66(m,2H),2.27(s,6H),2.25-2.21(m,1H),2.17(s,12H),2.07(s,6H),1.94(s,6H),1.62-1.51(m,3H),1.33(t,J＝11.7Hz,1H),0.81(dd,J＝13.6,6.7Hz,1H)；13C NMR(101MHz,CDCl3)δ167.7,157.,147.3,145.1,144.2,141.5,138.8,138.7,137.4,137.2,137.1,136.8,136.3,135.2,133.1,133.0,132.9,132.9,131.2,130.9,130.1,128.6,127.7,121.2,114.2,101.7,55.9,55.5,41.0,39.5,27.8,27.3,25.9,19.9,19.8,19.7,19.5,17.2,17.1,17.00,16.98；31P NMR(162MHz,CDCl3)δ-23.94。
characterization data for ligand 20:1H NMR(400MHz,CDCl3)δ8.44-8.21(m,3H),7.92(d,J＝9.2Hz,1H),7.86-7.70(m,5H),7.65(d,J＝1.8Hz,1H),7.49-7.25(m,8H),7.19(t,J＝7.5Hz,1H),7.12(td,J＝7.6,0.7Hz,1H),7.01(s,2H),6.91-6.85(m,2H),5.64-5.31(m,2H),4.90-4.80(m,2H),3.86(s,3H),3.13(s,1H),3.01-2.92(m,1H),2.90-2.43(m,2H),2.40-2.20(m,1H),2.15(s,1H),1.57-1.41(m,3H),1.32-1.25(m,1H),0.77(d,J＝6.5Hz,1H)；13C NMR(101MHz,CDCl3)δ168.7,157.5,147.2,144.3,141.0,135.2,135.1,135.04,134.99,134.8,133.32,133.28,132.6,131.3,130.2,129.6,129.5,129.0,128.5,128.4,126.3,126.2,126.2,126.05,125.97,125.94,125.87,125.6,125.5,121.3,114.2,101.7,55.4,40.7,39.2,27.6,27.1,25.7,25.6；31P NMR(162MHz,CDCl3)δ-28.24。
characterization data for ligand 21:1H NMR(400MHz,CDCl3)δ8.92–8.69(m,1H),8.55(s,1H),8.05(d,J＝9.2Hz,1H),7.85(s,1H),7.74(s,1H),7.56–7.38(m,3H),7.37–7.29(m,2H),6.13(s,1H),5.84(s,1H),5.29–5.05(m,2H),4.06(s,4H),3.52(s,2H),3.15(s,1H),2.68(s,1H),2.01–1.54(m,14H),1.44–0.79(m,12H)；13C NMR(100MHz,CDCl3)δ170.6,158.4,147.9,144.9,144.4,144.0,143.5,140.0,137.4,137.3,132.5,131.7,129.0,125.4,122.2,119.9,117.5,102.1,59.2,56.0,54.2,53.5,49.2,42.2,37.3,34.5(d,J＝12Hz),33.8(d,J＝12Hz),30.7–30.3(4C),29.7,29.3,27.1–26.9(4C),26.3,26.2,25.2；31P NMR(162MHz,CDCl3)δ-8.7。
characterization data for ligand 22:1H NMR(400MHz,CDCl3)δ8.25(d,J＝7.1Hz,2H),8.14-8.04(m,2H),7.71-7.63(m,2H),7.47-7.34(m,6H),7.29-7.12(m,13H),7.01-6.95(m,1H),5.81-5.33(m,2H),4.96-4.88(m,2H),3.97(s,3H),3.19-2.81(m,3H),2.63-2.52(m,1H),2.40-2.31(m,1H),2.23-2.15(m,1H),1.62-1.49(m,3H),1.40(t,J＝11.6Hz,1H),1.02-0.90(m,1H)；13C NMR(101MHz,CDCl3)δ168.9,157.5,154.6,142.0,141.8,141.3,140.0,136.9,136.8,134.4,133.6,133.4,133.2,131.8,130.0,128.8,128.64,128.58,128.54,128.45,128.37,128.32,128.2,127.42,127.40,121.5,114.3,99.8,60.2,55.7,55.5,40.8,39.4,27.8,27.2,26.0；31P NMR(162MHz,CDCl3)δ-12.34。
characterization data for ligand 23:1H NMR(400MHz,CDCl3):δ7.98(d,J＝7.5Hz,1H),7.74-7.60(m,2H),7.44-7.11(m,15H),6.96(s,1H),5.91-5.19(m,2H),5.04-4.86(m,2H),4.24-4.01(m,1H),3.94(s,3H),3.17-2.90(m,4H),2.69-2.43(m,2H),2.30-2.12(sm,1H),2.03-1.97(m,1H),1.91-1.72(m,2H),1.65-1.38(m,6H),1.26-1.18(m,1H),0.99-0.88(m,3H)；13C NMR(101MHz,CDCl3):δ168.6,159.5,156.8,144.2,141.8,141.5,141.1,137.1,136.9,136.8,134.1,133.4,133.3,133.2,133.1,130.6,129.8,128.5,128.3,128.2,128.1,128.0,127.9,120.9,114.0,102.1,60.0,55.5,55.3,40.7,39.2,38.6,32.0,27.6,27.1,26.0,22.4,20.7,13.8；31P NMR(162MHz,CDCl3):δ-11.60。
the above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims (18)

1. A method for synthesizing alkyne by catalyzing asymmetric cross coupling is characterized by comprising the following steps: using cuprous salt and ligand L as catalysts, and adding alkali to react the compound of formula A and the compound of formula B to obtain a compound of formula C:
wherein X is selected from the group consisting of halogen,
R1selected from optionally substituted phenyl, optionally substituted heteroaryl, cyano,
Wherein R is6Is trialkyl silicon base or alkyl,
R2selected from optionally substituted alkyl, optionally substituted cycloalkyl, (CH)2)nR4，
Wherein n is 0-10, R4Selected from phenyl, alkenyl, alkynyl, hydroxyl, aldehyde group, carboxyl, ester group, amino, cyano, benzoyl, alkoxy, aryloxy, halogen, sulfonyl, mercapto, sulfanyl, trialkylsilyl, tert-butyldiphenylsiloxy, and the like,
R3Selected from the group consisting of hydrogen or any functional group,
ligandsL is selected from
Wherein R is hydrogen or alkoxy, A is selected from cyclohexyl, naphthyl and optionally substituted phenyl, and R' is hydrogen, phenyl or alkyl.
2. The method of claim 1, wherein R is3Selected from the following structures:
the presence of hydrogen in the presence of hydrogen,
an optionally substituted alkyl group, wherein the alkyl group is substituted,
an optionally substituted cycloalkyl group, which is optionally substituted,
an optionally substituted phenyl group, wherein the phenyl group is substituted,
(ii) an optionally substituted heteroaryl group,
an optionally substituted ferrocenyl group, which is optionally substituted,
(CH2)mR5wherein m is 1-5, R5Selected from the group consisting of alkenyl, alkynyl, phenyl, cycloalkyl, halogen, alkoxy, aryloxy, hydroxy, aldehyde, carboxyl, ester, cyano, amide, sulfonyl, sulfonic, mercapto, sulfanyl, phthalimido, carbazolyl, trialkylsilyl, and mixtures thereof,
An acetal group.
3. The method of claim 2, wherein R is3Selected from the following structures:
the presence of hydrogen in the presence of hydrogen,
an alkyl group, a carboxyl group,
a cycloalkyl group,
a phenyl group,
alkyl, alkynyl, alkenyl, phenyl, alkoxy, amino, halogen, trifluoromethyl, cyano, hydroxyl, aldehyde, carboxyl, ester, nitro, amide, sulfonyl, sulfonic, mercapto, trifluoromethyl or pinacolboron-substituted phenyl,
pyrrolyl, furyl, thienyl, tetrahydropyrrolyl, tetrahydrofuryl, tetrahydrothienyl, pyridyl, naphthyl, pyranyl, oxazolyl, imidazolyl, thiazolyl, pyrimidinyl, quinolinyl, indolyl, isoquinolinyl, carbazolyl, pyridazinyl, pyrazinyl, purinyl, benzoxazolyl, benzothiazolyl, 1, 2-methylenedioxyphenyl, imidazo [1,2-b ] pyridazinyl, pyrazolo [1,5-a ] pyrimidinyl,
an alkoxy-substituted naphthyl group, wherein the naphthyl group is substituted by an alkoxy group,
a ferrocenyl group,
(CH2)mR5wherein m is 1,2,3,4, R5Selected from alkenyl, alkynyl, phenyl, cycloalkyl, halogen, alkoxy, aryloxy, hydroxyl, aldehyde group, carboxyl, ester group, cyano, amide group, sulfonyl, sulfonic group, sulfanyl, phthalimido, carbazolyl, trimethylsilyl, carboxyl, sulfonyl, sulfo-sulfonyl, phthalimido, carbaz,
4. The method of claim 3, wherein R is3Selected from the following structures:
the presence of hydrogen in the presence of hydrogen,
an alkyl group, a carboxyl group,
a cycloalkyl group,
a phenyl group,
alkyl, alkoxy, amino, halogen, trifluoromethyl, cyano, aldehyde, ester, nitro, alkenyl, alkynyl or pinacolboron-substituted phenyl,
thienyl, pyridyl, naphthyl, pyrimidinyl, quinolinyl, benzoxazolyl, benzothiazolyl, 1, 2-methylenedioxyphenyl, imidazo [1,2-b ] pyridazinyl, pyrazolo [1,5-a ] pyrimidinyl,
an alkoxy-substituted naphthyl group, wherein the naphthyl group is substituted by an alkoxy group,
a ferrocenyl group,
(CH2)mR5wherein m is 1,2,3,4, R5Selected from phenyl, cyclohexyl, halogen, hydroxyl, ester group, alkoxy, aryloxy, amido, phthalimide group, carbazolyl, trimethylsilyl group,
5. The method of claim 1, wherein R is1Selected from the following structures:
an optionally substituted phenyl group, wherein the phenyl group is substituted,
(ii) a heteroaryl group, wherein,
a halogen-substituted pyridyl group, wherein the pyridyl group is substituted with halogen,
the cyano group(s),
wherein R is6Is trialkyl silicon base or alkyl.
6. The method of claim 5, wherein R is1Selected from the following structures:
a phenyl group,
alkyl, alkynyl, alkenyl, phenyl, alkoxy, halogen, hydroxyl, aldehyde group, ketone group, carboxyl group, ester group, amide group, amino group, cyano group, acetylamino group, nitro group, sulfonyl group, sulfonic group, mercapto group, sulfanyl group, trifluoromethyl group or pyrazolyl substituted phenyl group,
naphthyl, pyrrolyl, furanyl, thienyl, tetrahydropyrrolyl, tetrahydrofuryl, tetrahydrothienyl, pyridyl, pyranyl, oxazolyl, imidazolyl, thiazolyl, pyrimidinyl, quinolinyl, indolyl, isoquinolinyl, carbazolyl, pyridazinyl, pyrazinyl, purinyl, benzothienyl, benzofuranyl, 1, 2-methylenedioxyphenyl,
a halogen-substituted pyridyl group, wherein the pyridyl group is substituted with halogen,
the cyano group(s),
wherein R is6Is trimethylsilyl, triethylsilyl, triisopropylsilyl, methyl, ethyl, propyl or butyl.
7. The method of claim 6, wherein R is1Selected from the following structures:
a phenyl group,
alkyl, alkoxy, halogen, aldehyde, keto, ester, cyano, acetamido, trifluoromethyl or pyrazolyl-substituted phenyl,
naphthyl, pyridyl, thienyl, thiazolyl, pyrimidinyl, quinolinyl, benzothienyl, benzofuranyl, 1, 2-methylenedioxyphenyl,
a halogen-substituted pyridyl group, wherein the pyridyl group is substituted with halogen,
the cyano group(s),
wherein R is6Is trimethylsilyl, triethylsilyl, triisopropylsilyl or tert-butyl.
8. The method of claim 1, wherein R is2Selected from the following structures:
an alkyl group, a carboxyl group,
a cycloalkyl group,
(CH2)nR4wherein n ═0、1、2、3、4、5，R4Selected from phenyl, alkenyl, alkynyl, hydroxyl, aldehyde group, carboxyl, ester group, amino, cyano, benzoyl, alkoxy, aryloxy, halogen, sulfonyl, mercapto, sulfanyl, trialkylsilyl, tert-butyldiphenylsiloxy, and the like,
9. The method of claim 8, wherein R is2Selected from the following structures:
an alkyl group, a carboxyl group,
a cycloalkyl group,
(CH2)nR4wherein n is 0,1, 2,3, R4Selected from phenyl, vinyl, ester, cyano, benzoyl, alkoxy, halogen, phenylsulfonyl, trimethylsilyl, t-butyldiphenylsiloxy, and mixtures thereof,
10. The method of claim 1, wherein R is hydrogen or methoxy, R' is hydrogen, phenyl or butyl, and A is selected from the following structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein R is8Selected from alkyl, alkoxy, trifluoromethyl, halogen, phenyl and phenoxy, m represents an integer of 1-5, when m is more than or equal to 2, more than 2R exist8The same or different.
11. The method of claim 10, wherein a is selected from the following structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein R is8Selected from methyl, propyl, butyl, methoxy, trifluoromethyl, fluorine, phenyl and phenoxy, m represents an integer of 1-5, when m is more than or equal to 2, more than 2R exist8The same or different.
12. The method of claim 11, wherein a is selected from the following structures:
a cyclohexyl group which is a group having a ring-opening structure,
a naphthyl group,
a phenyl group,
wherein, when m is 1, R8Selected from propyl, butyl, methoxy, phenyl, phenoxy; when m is 2, R8Selected from butyl, trifluoromethyl, methoxy, phenyl; when m is 3, R8Selected from methyl, propyl, butyl, methoxy, fluoro; when m is 5, R8Is selected from methyl; when m.gtoreq.2, more than 2R are present8The same or different.
13. The method of claim 1, wherein X is selected from chlorine, bromine.
14. The method according to any one of claims 1 to 13, wherein the cuprous salt is selected from the group consisting of CuI, CuCl, CuBr, CuTc, (CuOTf)2·PhCH3。
15. The method according to any one of claims 1 to 13, wherein the base is selected from Cs2CO3、Na2CO3、K3PO4、NaOH、KOtBu。
16. The process according to any one of claims 1 to 13, wherein the cuprous salt is present in an amount of at least 5 mol%, the ligand L is present in an amount of at least 7.5 mol% and the base is present in an amount of at least 200 mol%.
17. The method according to any one of claims 1 to 13, wherein the reaction is carried out using acetonitrile, ethyl acetate, toluene, tetrahydrofuran, methanol, diethyl ether, dichloromethane, dichloroethane, or methyl tert-butyl ether as a solvent.
18. The method according to any one of claims 1 to 13, wherein the molar ratio of the compound of formula a to the compound of formula B is 1 to 3: 1; the reaction temperature is room temperature, and the reaction time is at least 16 h.
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