CN110526832B - Method for preparing polysubstituted alicyclic compound - Google Patents

Method for preparing polysubstituted alicyclic compound Download PDF

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CN110526832B
CN110526832B CN201910763893.8A CN201910763893A CN110526832B CN 110526832 B CN110526832 B CN 110526832B CN 201910763893 A CN201910763893 A CN 201910763893A CN 110526832 B CN110526832 B CN 110526832B
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李开笑
詹娅玲
张其峰
李东阳
彭勃
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Zhejiang Normal University CJNU
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Abstract

The invention discloses an aryl high valence iodine compound which is activated by an activating reagent and then carries out rearrangement reaction with alpha-tin or silicon substituted nitrile compounds at-70 ℃ to-100 ℃ to obtain electrophilic dearomatization intermediate, and the intermediate reacts with a nucleophilic reagent to obtain the polysubstituted alicyclic compound. The method has the advantages of mild reaction conditions, high reaction speed, good selectivity, high yield, easy product separation, simple operation and the like.

Description

Method for preparing polysubstituted alicyclic compound
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a novel method for preparing a polysubstituted alicyclic compound.
Background
Dearomatization of aromatic compounds, i.e., conversion of aromatic rings in aromatic compounds into alicyclic rings, can achieve rapid conversion of aromatic compounds into alicyclic compounds, and is currently receiving increasing attention as an important synthetic method due to its high economic efficiency in converting readily available aromatic hydrocarbons into complex alicyclic compounds.
Highly functional dearomatization products can be obtained by utilizing a dearomatization method, such as cyano-group, cyanoalkyl (methyl) substituted alicyclic compounds and the like, and a series of functional group derivations can be carried out by using the cyano-group, which is a star group in the pharmaceutical synthetic chemistry. Can be efficiently converted into carboxylic acid (Tetrahedron Lett.2014,55, 3802-.
Because of the great potential of this dearomatization method in the synthesis of natural products and bioactive compounds, it has gradually attracted extensive attention in the synthetic world. Various dearomatization reactions such as birch reduction, phenol oxidation and electrophilic substitution of electron-rich/heteroaromatic hydrocarbons have been reported and have been applied as powerful synthesis tools (angelw. chem. int. ed.2012,51,12662). However, most classical dearomatization processes can only introduce a single functional group into the dearomatized product. Conversely, dearomatization involving double functionalization of aromatics is rarely but particularly attractive (chem. rev.2017,117,13721), which not only destroys the aromaticity of aromatics, but can also introduce multiple functional groups into the product, thus providing valuable polysubstituted cycloaliphatic compounds. However, any method has many problems such as diversity of reaction substrates, limited application range, and harsh reaction conditions.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a novel method for preparing a polysubstituted alicyclic compound, which has the advantages of mild reaction conditions, high reaction speed, good selectivity, high yield, easy product separation, simple operation and the like.
The invention also provides the alicyclic compound prepared by the preparation method.
The technical scheme adopted by the invention is as follows:
a method for preparing polysubstituted alicyclic compound, aryl hypervalent iodine compound is activated by activating reagent, then carries on rearrangement reaction with alpha-tin or silicon substituted nitrile compound under-70-100 deg.C, gets electrophilic dearomatization intermediate, this intermediate reacts with nucleophilic reagent, gets said polysubstituted alicyclic compound;
the structures of the aryl hypervalent iodine compound, the alpha-tin or silicon substituted nitrile compound or the polysubstituted alicyclic compound are respectively as follows:
Figure GDA0002227626850000021
x is selected from C1-C4 alkanoyloxy, substituted C1-C4 alkanoyloxy or two X are one O atom, i.e. with I, I ═ O;
m is selected from 3L-substituted Sn or Si;
nu is a nucleophilic group moiety in a nucleophile;
R1、R2、R3each independently selected from the group consisting of H, halogen, alkyl, halogen-substituted alkyl, alkoxy-substituted alkyl, arene-substituted alkyl, arylvinyloxy-substituted alkyl, arylacyloxy-substituted alkyl, substituted arylacyloxy-substituted alkyl, phenyl, benzyl, haloalkyl, alkoxy, alkanoyloxy-substituted alkyl, substituted alkanoyloxy-substituted alkyl, cyano-substituted alkyl;
Preferably, the aryl hypervalent iodine compound, α -tin or silicon-substituted nitrile compound is preferably:
Figure GDA0002227626850000022
r and 3L are independently selected from H, alkyl, haloalkyl, aryl-substituted alkyl, alkenyl-substituted alkyl, alkanoyloxy-substituted alkyl, arylvinylalkoxy-substituted alkyl, arylacyloxy-substituted alkyl, substituted phenylalkoxy-substituted alkyl, propionaldehyde ethylene glycol-substituted alkyl, TBDPS-OR4-；R4Is selected from alkylene; the nucleophilic reagent is selected from one or more of carbon nucleophilic reagent, heteroatom nucleophilic reagent and hydrogen negative atom. Preferably, each of the 3L's is independently selected from C1-C6 alkyl, aryl, substituted aryl, and the like; more preferred are methyl, isopropyl, tert-butyl, phenyl and the like.
Preferably, the aryl hypervalent iodine compound, the α -tin or silicon substituted nitrile compound or the polysubstituted alicyclic compound have the following structures, respectively:
Figure GDA0002227626850000031
nu is a nucleophilic group moiety in a nucleophile;
R1selected from the group consisting of H, halogen, alkyl, halogen-substituted alkyl, alkoxy-substituted alkyl, arene-substituted alkyl, arylvinyloxy-substituted alkyl, arylacyloxy-substituted alkyl, substituted arylacyloxy-substituted alkyl, benzyl, haloalkyl, alkoxy, alkanoyloxy-substituted alkyl, substituted alkanoyloxy-substituted alkyl, cyano-substituted alkyl; r 2Selected from H, alkyl; r is3Selected from the group consisting of hydrogen, halogen, alkyl, benzyl, phenyl, halogen substituted alkyl, phenylacyloxy substituted alkyl; r is selected from H, alkyl, halogenated alkyl, aryl substituted alkyl, alkenyl substituted alkyl, alkyl acyloxy substituted alkyl, aryl vinyl acyloxy substituted alkyl, aryl acyloxy substituted alkyl, substituted phenyl acyloxy substituted alkyl, propionaldehyde ethylene acetal substituted alkyl, TBDPS-OR4-；R4Is selected from alkylene; the nucleophilic reagent is selected from one or more of carbon nucleophilic reagent, heteroatom nucleophilic reagent and hydrogen negative atom.
The compound represented by the formula (5) (aryl hypervalent iodine compound) includes not only a racemate but also one or more of chiral isomers or diastereomers thereof. The polysubstituted cycloaliphatic compound is preferably:
Figure GDA0002227626850000032
when Nu is other than H, the polysubstituted cycloaliphatic compound is preferably:
Figure GDA0002227626850000041
taking trisilane activating reagent as an activating agent, DCM as a reaction solvent and-78 ℃ as an example, the general formula of the reaction is as follows:
Figure GDA0002227626850000042
in the present invention, the halogen is preferably F, Cl, Br, or the like; the alkyl group is preferably a C1-C7 alkyl group including, but not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, n-pentyl or a homologue thereof at a different substitution position, n-hexyl or a homologue thereof at a different substitution position, n-heptyl or a homologue thereof at a different substitution position, and the like. "substituted alkyl" means an alkyl group wherein one or more H atoms are replaced by another atom. Substituents include, but are not limited to, halogen, nitro, hydroxy, C 1-C6Alkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, alkoxycarbonyl, alkylamido, hydroxyalkylamido, or amino or mono-or poly-substituted amino, wherein the substituents of the amino groups, which may be the same or different, are selected from hydrogen and C1-C6Alkyl radical, C1-C6Hydroxyalkyl radical, C1-C6Alkoxy radical, C3-C10Cycloalkyl, 3-to 10-membered heterocyclyl. The "halogen-substituted alkyl group" may be a single halogen-substituted alkyl group, a plurality of halogen-substituted alkyl groups, or a mixture thereofAre a plurality of different halogen-substituted alkyl groups. In the alkoxy group, the alkyl group is defined as the "alkyl group" above. The "aryl" is obtained by removing one H from an aromatic ring, which refers to an all-carbon monocyclic or fused polycyclic group of 5 to 12 carbon atoms, having a completely conjugated pi-electron system. Non-limiting examples of aromatic rings are: benzene rings, substituted benzene rings, naphthalene rings, substituted naphthalene rings, and anthracene rings. The aromatic ring may be unsubstituted or substituted. The "alkenyl" may be terminal alkenyl, or an intermediate double bond structure, or the like. The alkyl group in the "alkanoyloxy" is as defined above for the "alkyl group". The substituent of the "substituted phenyl" includes, but is not limited to, halogen (preferably fluorine, chlorine, bromine), nitro, amino, hydroxy, C1-C6 alkyl (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, etc.); the substitution of the benzene ring may be mono-substituted (such as ortho-position, meta-position, para-position substitution), or di-substituted or tri-substituted, etc.
The invention adopts the technical scheme that in the presence of activating reagents such as a silicon reagent or a boron reagent and the like, substituted aryl high-valence iodine shown in a structural formula (1) and an alpha-tin substituted nitrile compound shown in a structural formula (2) are subjected to rearrangement reaction at-78-100 ℃ to obtain a highly electrophilic dearomatization intermediate (3), and then nucleophilic reagents (carbon nucleophilic reagents/heteroatom nucleophilic reagents/hydrogen negative atoms) are used for capturing dearomatization species generated in situ at low temperature to synthesize the polysubstituted alicyclic compound shown in a structural formula (5).
As a further preference, the carbon nucleophile includes trialkyl-substituted silanes, dialkylphenylsilanes, diphenylalkylsilanes, triphenylsilanes, trisubstituted phenylsilanes, trialkoxysilanes, halogen-substituted dialkylsilanes, benzothiophenes, substituted benzothiophenes, benzofurans, substituted benzofurans, N-substituted indoles, benzenesulfonamides, substituted benzenesulfonamides, 2-alkyl terminal alkenes, trialkylsyanosilanes, allyltrialkylsilanes, 1-aryl-1-trialkylsiloxyienes, 1-substituted aryl-1-trialkylsiloxyienes, trialkylsizides, thiophenols, substituted thiophenols. The alkyl group includes methyl, ethyl, propyl, isopropyl, etc.; the halogen includes chlorine, Br, etc.; The substituted phenyl group comprises alkyl substituted phenyl, including but not limited to mono-or poly-substituted methyl substituted phenyl; the substituted benzene sulfonamide can be substituted by C1-C2 alkyl on a benzene ring, can also be substituted by a benzene ring on N, and the like. As a further preference, the nucleophiles used include: dimethylphenylsilane, diphenylmethylsilane, triphenylsilane, triisopropylsilane, trimethoxysilane, chlorodimethylsilane, triethylsilane, 9-borabicyclo [3.3.1 ]]Nonane, benzothiophene, benzofuran, N-Boc protected indole, 4-methylbenzenesulfonamide, 4-methyl-N-phenylbenzenesulfonamide, 2-ethyl-1-butene, TMSCN, allyltrimethylsilane, 1-phenyl-1-trimethylsiloxyethylene, TMSN34-chlorobenzenethiol.
Preferably, the activating reagent comprises boron trifluoride diethyl etherate (BF)3·Et2O), trimethylsilyl trifluoromethanesulfonate (TMSOTf), trifluoromethanesulfonic anhydride (Tf)2O), tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), triethylsilyltrifluoromethanesulfonate (TESOTf), TMSOCOCF3And one or more of other activators capable of activating aryl hypervalent iodine.
Preferably, the reaction solvent comprises: one or more of dichloromethane, trichloromethane, acetonitrile, Tetrahydrofuran (THF), N-dimethylformamide, dibromomethane, 1, 2-dimethoxyethane and 1, 4-dioxane. More preferably, methylene chloride is used. Preferably, dried dichloromethane is selected.
Preferably, the molar ratio of the substituted aryl hypervalent iodine compound (the compound represented by the structural formula (1)) to the α -tin substituted nitrile compound is 1: 1-2; more preferably 1: 1.0 to 1.5; further preferred molar ratios of addition are 1: 1.2; the molar ratio of the aryl hypervalent iodine compound (the compound represented by the structural formula (1)) to the activating reagent is 1: 1-3; more preferably 1: 1.5 to 3; still more preferably 1: 2; the molar ratio of the aryl hypervalent iodine compound (the compound represented by the structural formula (1)) to the nucleophile is 1: 1-3; more preferably 1: 1.5 to 3; still more preferably 1: 2.
Preferably, the activation temperature of the activation reagent is-70 to-90 ℃, and the activation time is 5 to 60 minutes; further preferably-75 to-80 ℃ for 8 to 15 minutes; the rearrangement reaction temperature is-70 to-90 ℃, and the reaction time is 5 to 60 minutes; further preferably-75 to-80 ℃ for 8 to 15 minutes; the temperature for reaction with the nucleophilic reagent is-70 to-90 ℃, and the reaction time is 1 to 20 hours; more preferably-75 to-80 ℃ for 10 to 15 hours.
Preferably, R1Selected from halogen, C1-C2 alkyl, chlorobenzyl, halogenated C1-C2 alkyl (trifluoromethyl, etc.), C1-C2 alkoxy C1-C2 alkyl, C1-C2 alkanoyloxy substituted C1-C2 alkyl, halogen substituted thienyl acyloxy substituted C1-C2 alkyl, styryl acyloxy substituted C1-C2 alkyl, halogen substituted C1-C3 alkanoyloxy substituted C1-C2 alkyl, ester substituted C1-C2 alkanoyloxy substituted C1-C2 alkyl, cyano or cyanomethyl; r 2Selected from C1-C2 alkyl; r is3Selected from hydrogen, halogen, methyl alkyl, chlorobenzyl, phenyl, chloromethyl, chloroethyl, phenyl acyloxy substituted C1-C2 alkyl; r is selected from H, C1-C3 alkyl, halogenated C1-C3 alkyl, aryl substituted C1-C2 alkyl, alkenyl substituted C1-C4 alkyl, thienyl acyloxy substituted C1-C6 alkyl, styryloxy substituted C1-C6 alkyl, substituted phenyl acyloxy substituted C1-C6 alkyl, propionaldehyde acetal substituted C1-C2 alkyl, TBDPS-OR4-，R4Selected from C1-C6 alkyl. The C1-C6 alkyl group comprises methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, n-pentyl, isopentyl, hexyl and the like; the halogen substituted thienyl acyloxy substituted methyl alkyl comprises 2-position and 3-position substitution; by the same definition, substituted phenylacyloxy substituted C1 to C6 alkyl groups include para, ortho or meta substitution. As further preferred, R1Selected from methyl, ethyl, chlorine, chloromethyl, cyano-substituted methyl, cyano, trifluoromethyl, methoxymethyl, acetoxymethyl, styroyloxymethyl, Cl-substituted thienylacyloxymethyl, chloropropylacyloxymethyl, formyloxy-substituted methacryloyloxymethyl; r 2Selected from methyl, ethyl; r3Selected from H, bromine, methyl, phenyl, chloromethyl,A benzoyloxymethyl group; r is selected from H, propyl, chloropropyl, phenethyl, alkenylhexyl, thienylacyloxy-substituted hexyl, styryloxy-substituted hexyl, p-formylphenylacyloxy-substituted hexyl, propionaldehyde ethylene glycol-substituted ethyl, TBDPS-OR4-；R4Is selected from C6H12。
Preferably, the nucleophile comprises dimethylphenylsilane, diphenylmethylsilane, triphenylsilane, triisopropylsilane, trimethoxysilane, chlorodimethylsilane, triethylsilane, 9-borabicyclo [3.3.1 ]]Nonane, benzothiophene, benzofuran, N-Boc protected indole, 4-methylbenzenesulfonamide, 4-methyl-N-phenylbenzenesulfonamide, 2-ethyl-1-butene, TMSCN, allyltrimethylsilane, 1-phenyl-1-trimethylsiloxyethylene, TMSN3And 4-chlorobenzenethiol. Further preferred are triethylsilane, benzothiophene, benzofuran, N-Boc protected indole, 4-methylbenzenesulfonamide, 4-methyl-N-phenylbenzenesulfonamide, 2-ethyl-1-butene, TMSCN, allyltrimethylsilane, 1-phenyl-1-trimethylsiloxyethylene, TMSN34-chlorobenzenethiol.
The compound shown in the structural formula (1) is an aryl hypervalent iodide compound and comprises (2, 6-dimethylphenyl) iodide diacetate, (2, 6-diethylphenyl) iodide diacetate, (2,4, 6-trimethylphenyl) iodide diacetate, (2, 6-dimethyl-4-bromophenyl) iodide diacetate, (2, 6-diethyl-4-phenylacyloxymethylphenyl) iodide diacetate, (2-methyl-6-ethylphenyl) iodide diacetate, (2-methyl-6-cyanomethylphenyl) iodide diacetate, (2-methyl-6-cyanophenyl) iodide diacetate, (2-styryloxy-substituted methyl-6-methylphenyl) iodide diacetate, (2-chloro-substituted thienylacyloxy-substituted methyl-6-methylphenyl) iododiacetate, (2-carbonyatoalkanoyloxy-substituted methyl-6-methylphenyl) iododiacetate, (3, 5-dimethyl- [1,1' -biphenyl ] -4-yl) iododiacetic acid ethyl ester, (4- (chloromethyl) -2, 6-dimethylphenyl) iododiacetate, (2-chloro-6-methylphenyl) iododiacetate, (6- (chloromethyl) -2-methylphenyl) iododiacetate, (6- (trifluoromethyl) -2-methylphenyl) iododiacetate, (2- (methoxymethyl) -6-methylphenyl) iododiacetate, one or more of (2- (acetoxymethyl) -6-methylphenyl) iodiodiacetate and (2- (((4-chlorobutyryl) oxy) methyl) -6-methylphenyl) iodiodiacetate.
As a further preference, the activator is trimethylsilyl trifluoromethanesulfonate. The adding molar ratio of the aryl hypervalent iodine compound (shown in a formula (1)) to trimethylsilyl trifluoromethanesulfonate is 1: 2. the temperature of the activator is-78 ℃, and the reaction time is 10 min.
The mechanism of the [3,3] -sigma rearrangement of (2, 6-dimethylphenyl) iododiacetate with alpha-tin substituted nitriles to give highly electrophilic dearylation intermediates followed by triethylsilane at low temperature to capture the in situ generated labile dearomatization species is shown below:
Figure GDA0002227626850000071
the activated (2, 6-dimethylphenyl) iodized diacetate is converted into (2, 6-dimethylphenyl) iodized ditrifluoromethanesulfonate 1 with extremely strong electrophilicity, the (2, 6-dimethylphenyl) iodized ditrifluoromethanesulfonate 1 can be subjected to nucleophilic attack by an alpha-tin substituted nitrile compound in a system to obtain an intermediate 2, the trifluoromethanesulfonate dropped off in the reaction process further reacts with tin to break a C-Sn bond to form a rearrangement precursor 5, further [3,3] -sigma rearrangement is carried out to obtain an intermediate 6, and finally an unstable dearomatization species 6 generated in situ is captured by triethylsilane at low temperature to obtain a target product 7. Because the activated iodobenzene has extremely strong electrophilicity, and the synergistic effect of the triflate and the tin enables two species which are not easy to occur to quickly complete the assembly of the rearrangement precursor. By the assembly mode, the reaction time is greatly shortened, and the functional group compatibility of a reaction substrate is greatly improved due to the very high recognition of the alpha-tin substituted nitrile compound to the active intermediate 1. In addition, the highly electrophilic dearylation intermediate generated by rearrangement is captured by nucleophilic reagent at low temperature, and a multi-substituted alicyclic compound can be obtained.
A polysubstituted alicyclic compound having the structure represented by the structural formula (5) defined in any one of the above. Preferably, the structure is as follows:
Figure GDA0002227626850000081
Figure GDA0002227626850000091
preferably, the polysubstituted alicyclic compound includes:
Figure GDA0002227626850000092
further preferred compounds are:
Figure GDA0002227626850000101
compared with the existing method, the method has the advantages that (2, 6-dimethylphenyl) diacetate iodide and alpha-tributylstannyl acetonitrile are subjected to [3,3] -sigma rearrangement to obtain a highly electrophilic dearylation intermediate, and then triethylsilane is used for capturing unstable dearomatization species generated in situ at low temperature to synthesize the polysubstituted alicyclic compound, wherein:
(1) the method has the advantages of mild reaction conditions, high reaction speed, good selectivity, high yield, easy product separation and simple operation;
(2) the raw materials used in the method are cheap and easy to obtain, and the defects that the reaction conditions are strict and the reaction substrates are limited in the traditional method are avoided; the process allows for the continuous introduction of different nucleophiles into the benzene ring, thereby producing a highly functionalized dearomatization product.
(3) The obtained product contains iodine, can be further subjected to coupling reaction, and develops a new synthetic way for synthesizing the multi-substituted alicyclic compound with wider functional groups.
Meanwhile, the prepared aliphatic compound of cyclohexadiene is an important organic synthesis intermediate, and the compound serving as an organic chemical raw material is widely used in chemical industry, such as adamantane synthesis, polyester synthesis and the like, and has important industrial application and wide application prospect.
Detailed Description
Example 1
Figure GDA0002227626850000102
N2To a stirred solution of (2, 6-dimethylphenyl) iododiacetate (70mg, 0.2mmol) in DCM (2mL) at-78 deg.C under protection was added TMSOTf (72. mu.L, 0.4mmol) and the mixture was stirred for 10 min. Then, 2- (tributylstannyl) acetonitrile (75 μ L, 0.24mmol) was added to the mixture at-78 ℃, and then the mixture was stirred for 10 minutes. Et was added to the mixture at-78 deg.C3SiH (64. mu.L, 0.4mmol), and after stirring for 12h, the mixture was passed through a short silica gel column and concentrated in vacuo. The resulting residue was separated by column chromatography (Rf 0.30, developing solvent: petroleum ether/ethyl acetate 10/1, v/v) to give the polysubstituted alicyclic compound as a pale yellow oily liquid in a yield of 72%.
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ5.94–5.76(m,1H),5.62–5.58(m,1H),2.94–2.76(m,2H),2.74(d,J＝16.6Hz,1H),2.42(d,J＝16.6Hz,1H),1.96(s,3H),1.31(s,3H).
13C NMR(151MHz,CDCl3):δ139.6,128.0,124.7,117.6,108.0,43.5,34.4,33.2,30.8,30.4.
IR(neat):3027,2965,2922,2853,2807,2242,1680,1416,911,733.
EI-MS:calculated for[C10H12IN]:273.1,found:273.0.
example 2
Figure GDA0002227626850000111
Following the procedure of example 1, 2, 6-diethylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate, and the resulting residue was isolated by column chromatography (Rf ═ 0.35, developing solvent: petroleum ether/ethyl acetate ═ 10/1, v/v) to give the polysubstituted alicyclic compound and as a pale yellow oily liquid in 81% yield. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ5.99–5.95(m,1H),5.43–5.39(m,1H),2.95–2.77(m,2H),2.74(d,J＝16.6Hz,1H),2.35(d,J＝16.6Hz,1H),2.33–2.26(m,2H),1.80–1.72(m,1H),1.35–1.21(m,1H),1.04(t,J＝7.6Hz,3H),0.74(t,J＝7.3Hz,3H).
13C NMR(151MHz,CDCl3):δ146.4,127.0,126.3,117.5,105.9,47.6,37.0,34.6,32.9,32.4,12.0,8.9.
IR(neat):2967,2931,2873,2247,1655,1633,1455,1293,835,736.
EI-MS:calculated for[C12H16IN]:301.0,found:300.9.
Example 3
Figure GDA0002227626850000121
Following the procedure of example 1, (2,4, 6-trimethylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate. The resulting residue was separated by column chromatography (Rf 0.33, developing solvent: petroleum ether/ethyl acetate 10/1, v/v) to give the polysubstituted alicyclic compound as a pale yellow oily liquid in 55% yield. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ5.33–5.29(m,1H),2.84–2.62(m,3H),2.41(d,J＝16.5Hz,1H),1.96(s,3H),1.73(s,3H),1.27(s,3H).
13C NMR(151MHz,CDCl3):δ139.3,132.3,122.9,117.8,107.9,44.4,39.1,33.3,31.0,30.0,22.1.
IR(neat):2969,2924,2857,2803,2250,1638,1447,1414,1374,902,862.
EI-MS:calculated for[C9H12I(M-CH2CN)]:247.1,found:247.0。
example 4
Figure GDA0002227626850000122
Following the procedure of example 1, (2, 6-dimethyl-4-bromophenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate. The resulting residue was separated by column chromatography (Rf 0.33, developing solvent: petroleum ether/ethyl acetate 10/1, v/v) to give the polysubstituted alicyclic compound and as a pale yellow oily liquid in a yield of 57%. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ5.99–5.96(m,1H),3.17(dd,J＝76.2,22.1Hz,2H),2.73(d,J＝16.7Hz,1H),2.47(d,J＝16.7Hz,1H),1.96(s,3H),1.34(s,3H).
13C NMR(151MHz,CDCl3):δ138.8,128.8,120.1,116.9,106.3,47.0,42.6,32.7,30.3,29.6.
IR(neat):2973,2927,2874,2803,2247,1734,1416,1241,905,737.
EI-MS:calculated for[C10H11BrIN]:350.9,found:350.9.
example 5
Figure GDA0002227626850000131
Following the procedure of example 1, (2, 6-dimethyl-4-phenylacyloxymethylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate. The resulting residue was separated by column chromatography (Rf 0.33, developing solvent: petroleum ether/ethyl acetate 5/1, v/v) to give the polysubstituted alicyclic compound as a pale yellow oily liquid in 62% yield. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ8.07–8.04(m,2H),7.64–7.52(m,1H),7.52–7.36(m,2H),5.74(s,1H),4.80(s,2H),3.04–2.82(m,2H),2.76(d,J＝16.6Hz,1H),2.48(d,J＝16.6Hz,1H),2.00(s,3H),1.34(s,3H).
13C NMR(151MHz,CDCl3):δ166.3,138.8,133.3,131.4,130.0,129.8,128.6,126.4,117.3,107.1,66.9,44.2,35.1,33.0,30.6,30.1.
IR(neat):2973,2924,2875,2246,1715,1600,1449,1265,1107,734,709.
HRMS(ESI-TOF):calculated for[C18H18INO2Na(M+Na+)]:430.0274,found:430.0274.
Example 6
Figure GDA0002227626850000132
Following the procedure of example 1, (2-methyl-6-ethylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate. The resulting residue was separated by column chromatography (Rf 0.30, developing solvent: petroleum ether/ethyl acetate 10/1, v/v) to give two polysubstituted alicyclic compounds as pale yellow oily liquids (3 ha)Et/3haMe55/45), overall yield was 79%. The target product was characterized as follows:
1H NMR(600MHz,CDCl3),3ha(a mixture of 3haEt and 3haMe,3haEt/3haMe＝55/45):δ5.98–5.92(m,0.55H),5.86–5.83(m,0.45H),5.59–5.56(m,0.45H),5.44–5.38(m,0.55H),2.96–2.86(m,1.09H),2.83–2.70(m,2.17H),2.42–2.33(m,1.10H),2.33–2.22(m,1.00H),1.98(s,1.65H),1.79–1.72(m,0.58H),1.36–1.23(m,2.14H),1.03(t,J＝7.6Hz,1.46H),0.73(t,J＝7.3Hz,1.70H).
13C NMR(151MHz,CDCl3),3ha(a mixture of 3haEt and 3haMe,3haEt/3haMe＝55/45):δ144.4,141.3,127.9,126.8,126.3,124.9,117.6,117.5,107.3,106.5,47.6,43.4,36.9,34.63,34.58,33.2,32.8,32.0,30.9,30.4,11.8,9.0.
IR(neat):2966,2929,2873,2247,1658,1453,1286,898,828,735.
EI-MS:calculated for[C11H14IN]:287.0,found:287.0.
example 7
Figure GDA0002227626850000141
Following the procedure of example 1, (2-methyl-6-cyanomethylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate. The resulting residue was separated by column chromatography (Rf 0.30, developing solvent: petroleum ether/ethyl acetate 3/1, v/v) to give the polysubstituted alicyclic compound as a pale yellow oily liquid in 60% yield. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ5.92–5.86(m,1H),5.65–5.60(m,1H),3.56(d,J＝17.9Hz,1H),3.38(d,J＝18.0Hz,1H),3.04–3.00(m,2H),2.74(d,J＝16.7Hz,1H),2.44(d,J＝16.7Hz,1H),1.34(s,3H).
13C NMR(151MHz,CDCl3):δ133.0,127.6,123.7,116.9,116.3,112.8,44.1,33.0,32.9,32.6,30.7.
IR(neat):3464,2971,2929,2874,2250,1662,1412,737.
EI-MS:calculated for[C11H11IN2(M-CH2CN)]:258.1,found:257.9.
example 8
Figure GDA0002227626850000142
Following the procedure of example 1, (2-methyl-6-cyanophenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate. The resulting residue was separated by column chromatography (Rf 0.22, developing solvent: petroleum ether/ethyl acetate 3/1, v/v) to give the polysubstituted alicyclic compound as a pale yellow oily liquid in 56% yield. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ5.98–5.90(m,1H),5.71–5.63(m,1H),3.15–2.90(m,2H),2.73(d,J＝16.7Hz,1H),2.49(d,J＝16.7Hz,1H),1.36(s,3H).
13C NMR(151MHz,CDCl3):δ126.6,123.5,123.2,122.9,119.8,116.2,43.4,32.9,32.1,30.4.
IR(neat):3038,2973,2929,2247,2218,1453,1417,908,736.
EI-MS:calculated for[C10H9IN2]:284.0,found:283.8.
Example 9
Figure GDA0002227626850000151
Following the procedure of example 1, (2-styryloxy-substituted methyl-6-methylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate. The resulting residue was separated by column chromatography (Rf 0.40, developing solvent: petroleum ether/ethyl acetate 3/1, v/v) to give the polysubstituted alicyclic compound and as a pale yellow oily liquid in 54% yield. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ7.73(d,J＝16.0Hz,1H),7.56–7.51(m,2H),7.44–7.36(m,3H),6.47(d,J＝16.0Hz,1H),5.93–5.85(m,1H),5.69–5.62(m,1H),4.92(dd,J＝45.1,13.3Hz,2H),3.03–2.85(m,2H),2.76(d,J＝16.6Hz,1H),2.47(d,J＝16.6Hz,1H),1.35(s,3H).
13C NMR(151MHz,CDCl3):δ166.6,145.8,138.1,134.3,130.6,129.1,128.3,127.7,124.4,117.4,117.2,109.9,73.2,43.4,33.1,31.1,30.6.
IR(neat):3082,3060,2972,2877,2247,1709,1634,1157,980,767,734.
HRMS(ESI-TOF):calculated for[C19H18INO2Na(M+Na+)]:442.0274,found:442.0273.
example 10
Figure GDA0002227626850000152
Following the procedure of example 1, (2-chloro-substituted thien-5-ylacetoxy-substituted methyl-6-methylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate. The resulting residue was separated by column chromatography (Rf 0.40, developing solvent: petroleum ether/ethyl acetate 3/1, v/v) to give the polysubstituted alicyclic compound as a pale yellow oily liquid in a yield of 70%. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ7.62(d,J＝4.0Hz,1H),6.94(d,J＝4.0Hz,1H),5.91–5.86(m,1H),5.67–5.62(m,1H),4.97(dd,J＝42.8,13.3Hz,2H),3.04–2.82(m,2H),2.75(d,J＝16.6Hz,1H),2.46(d,J＝16.6Hz,1H),1.34(s,3H).
13C NMR(151MHz,CDCl3):δ160.8,138.0,137.6,133.6,131.2,127.7,127.6,124.3,117.1,110.2,73.6,43.4,33.0,31.0,30.5.
IR(neat):3096,2969,2877,2245,1706,1420,1243,1085,1059,740.
HRMS(ESI-TOF):calculated for[C15H13ClINO2SNa(M+Na+)]:455.9292,found:455.9292.
example 11
Figure GDA0002227626850000161
Following the procedure of example 1, (2-carbomethoxyalkanoyloxy-substituted-methylalkyl-6-methylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate. The resulting residue was separated by column chromatography (Rf 0.31, developing solvent: petroleum ether/ethyl acetate 3/1, v/v) to give the polysubstituted alicyclic compound and as a pale yellow oily liquid in 51% yield. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ5.91–5.85(m,1H),5.66–5.60(m,1H),4.87(dd,J＝45.8,13.1Hz,2H),4.64(s,2H),2.95–2.76(m,2H),2.74(d,J＝16.6Hz,1H),2.44(d,J＝16.6Hz,1H),2.16(s,3H),1.32(s,3H).
13C NMR(151MHz,CDCl3):δ170.5,167.6,137.4,127.6,124.3,117.1,110.8,73.8,60.7,43.5,33.0,31.0,30.6,20.6.
IR(neat):2961,2964,2245,1260,1180,1079,841,736.
HRMS(ESI-TOF):calculated for[C14H16INO4Na(M+Na+)]:412.0016,found:412.0014.
Example 12
Figure GDA0002227626850000162
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate instead of (2, 6-dimethylphenyl) iododiacetate, 2- (tributylstannyl) valeronitrile instead of 2- (tributylstannyl) acetonitrile; the resulting residue was isolated by column chromatography (Rf 0.31, developing solvent: petroleum ether/ethyl acetate 20/1, v/v) to give a mixture of two diastereomers (86/14dr) and a yield of 70% for both as a light yellow oily liquid. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ6.02–5.92(m,1H,mixture),5.57–5.53(m,0.14H,minor),5.35–5.29(m,0.86H,major),2.99–2.92(m,1.83H,mixture),2.81–2.76(m,1.21H,mixture),2.34–2.27(m,2H,mixture),1.70–1.63(m,2.43H,mixture),1.60–1.50(m,1.58H,mixture),1.44–1.36(m,2H,mixture),1.06–1.01(m,3H,mixture),0.95(m,3H,mixture),0.73(m,3H,mixture).
13C NMR(151MHz,CDCl3):δ146.3(minor),146.1(major),128.3(minor),129.0(major),126.9(minor),125.0(major),120.8(minor),120.4(major),107.8(major),107.0(minor),50.2(minor),49.8(major),44.8(major),43.2(minor),37.2(major),37.1(minor),33.6(minor),32.7(major),32.0(major),30.6(minor),30.2(minor),28.2(major),21.6(major),20.8(minor),13.8(major),13.7(minor),11.9(minor),11.8(major),9.0(major),8.4(minor).
IR(neat):3330,2963,2931,2872,2853,2236,1677,1457,1262,755,737.
HRMS(ESI-TOF):calculated for[C15H22INNa(M+Na+)]:366.0689,found:366.0693.
example 13
Figure GDA0002227626850000171
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate instead of (2, 6-dimethylphenyl) iododiacetate, 4-phenyl-2- (tributylstannyl) butyronitrile instead of 2- (tributylstannyl) acetonitrile; the resulting residue was separated by column chromatography to give the two diastereomeric products (73/27dr) in 50% and 18% yields, respectively, as light yellow oily liquids. The target product was characterized as follows:
(major) light yellow oily liquid, 40.1mg, 50% (Rf ═ 0.25, eluent: PE/EtOAc ═ 20/1).
1H NMR(600MHz,CDCl3):δ7.36–7.29(m,2H),7.25–7.19(m,3.1Hz,3H),6.02–5.97(m,1H),5.31–5.24(m,1H),3.06–2.88(m,3H),2.82–2.75(m,1.5Hz,1H),2.71–2.63(m,1H),2.31(q,J＝7.6Hz,2H),1.93–1.86(m,2H),1.63(dd,J＝13.5,7.3Hz,1H),1.39–1.30(m,1H),1.05(t,J＝7.6Hz,3H),0.72(t,J＝7.3Hz,3H).
13C NMR(151MHz,CDCl3):δ146.2,140.5,128.8,128.6,128.1,126.6,124.9,120.3,107.4,49.8,44.4,37.2,34.3,32.7,32.1,28.3,11.8,9.0.
IR(neat):3402,3026,2965,2930,2870,2237,1676,1454,748,700.
HRMS(ESI-TOF):calculated for[C20H24INNa(M+Na+)]:428.0845,found:428.0829.
(minor) light yellow oily liquid, 14.8mg, 18% (Rf ═ 0.22, eluent: PE/EtOAc ═ 20/1).
1H NMR(600MHz,CDCl3):δ7.32–7.27(m,2H),7.23–7.18(m,3H),5.97–5.92(m,1H),5.60–5.50(m,1H),2.96–2.87(m,2H),2.81–2.75(m,2H),2.70–2.62(m,1H),2.30–2.21(m,2H),1.74–1.64(m,4H),1.00(t,J＝7.5Hz,3H),0.70(t,J＝7.3Hz,3H).
13C NMR(151MHz,CDCl3):δ146.5,140.5,128.8,128.7,127.1,126.4,124.9,120.6,106.7,50.3,43.0,37.1,33.8,33.6,32.7,30.2,11.9,8.4.
IR(neat):3334,3027,2965,2930,2871,2239,1655,1454,747,700.
HRMS(ESI-TOF):calculated for[C20H24INNa(M+Na+)]:428.0845,found:428.0835.
Example 14
Figure GDA0002227626850000181
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate and 2- (tributylstannyl) oct-7-enenitrile was substituted for 2- (tributylstannyl) acetonitrile. The resulting residue was separated by column chromatography to give the two diastereomeric products (84/16dr) in 74% and 14% yields, respectively, as light yellow oily liquids. The target product was characterized as follows:
(major) pale yellow oily liquid, 57.0mg, 74% (Rf 0.33, eluent: PE/EtOAc 20/1).
1H NMR(600MHz,CDCl3):δ6.01–5.97(m,1H),5.84–5.75(m,1H),5.35–5.27(m,1H),5.06–4.92(m,2H),3.02–2.89(m,2H),2.82–2.75(m,1H),2.35–2.27(m,2H),2.14–2.02(m,2H),1.72–1.62(m,2H),1.60–1.56(m,2H),1.49–1.37(m,4H),1.05(t,J＝7.6Hz,3H),0.74(t,J＝7.3Hz,3H).13C NMR(151MHz,CDCl3):δ146.1,138.5,128.0,124.9,120.4,114.9,107.7,49.9,45.0,37.2,33.6,32.7,32.0,28.6,27.8,26.1,11.8,9.0.
IR(neat):3075,2966,2929,2869,2236,1677,1640,1458,907,756.
HRMS(ESI-TOF):calculated for[C18H26INNa(M+Na+)]:406.1002,found:406.0993.
(minor) light yellow oily liquid, 11mg, 14% (Rf ═ 0.31, eluent: PE/EtOAc ═ 20/1).
1H NMR(600MHz,CDCl3):δ5.98–5.93(m,1H),5.82–5.76(m,1H),5.58–5.52(m,1H),5.05–4.92(m,2H),2.33–2.24(m,1H),2.85–2.78(m,2H),2.34–2.23(m,2H),2.09–2.05(m,2H),1.77–1.65(m,2H),1.47–1.34(m,6H),1.01(t,J＝7.3Hz,3H),0.72(t,J＝7.3Hz,3H).
13C NMR(151MHz,CDCl3):δ146.4,138.7,127.0,124.9,120.8,114.8,107.0,50.3,43.5,37.1,33.62,33.59,32.8,28.4,28.0,27.0,11.9,8.4.
IR(neat):3074,2964,2928,2860,2234,1678,1639,1456,907,755.
HRMS(ESI-TOF):calculated for[C18H26INNa(M+Na+)]:406.1002,found:406.0991.
Example 15
Figure GDA0002227626850000191
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate instead of (2, 6-dimethylphenyl) iododiacetate, and 8- ((tert-butyldiphenylsilyl) oxy) -2- (tributylstannyl) octanenitrile instead of 2- (tributylstannyl) acetonitrile. The resulting residue was separated by column chromatography (Rf 0.35, developing solvent: petroleum ether/ethyl acetate 20/1, v/v) to give a mixture of the two diastereomers ((86/14dr) and a light yellow oily liquid in 65% yield.
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ7.69(d,J＝6.8Hz,4.27H,mixture),7.45–7.39(m,5.78H,mixture),6.05–5.95(m,1H,mixture),5.57(d,J＝10.0Hz,0.14H,minor),5.33(d,J＝9.7Hz,0.86H,major),3.68(t,J＝6.3Hz,2H,mixture),3.02–2.91(m,1.87H,mixture),2.83–2.78(m,1.12H,mixture),2.38–2.26(m,2H,mixture),1.66–1.54(m,6H),1.41–1.32(m,6H),1.09–1.05(m,12H),0.80–0.72(m,3H).
13C NMR(151MHz,CDCl3):δ146.3(minor),146.0(major)135.7(major),135.4(minor),134.2(major),130.2(minor),129.6(major),127.9(major),127.8(minor),127.7(major),126.9(minor),124.9(major),120.8(minor),120.4(major),107.8(major),107.0(minor),63.99(minor),63.93(major),50.3(minor),49.9(major),45.0(major),43.5(minor),37.19(major),37.10(minor),33.6(minor),32.7(major),32.6(minor),32.5(major),32.3(minor),32.0(major),29.1(major),28.9(minor),28.3(major),28.1(minor),27.6(minor),27.0(major),26.1(major),25.74(minor),25.66(major),25.5(minor),19.4(major),15.9(minor),11.9(minor),11.8(major),9.0(major),8.44(minor).
IR(neat):3330,3069,2930,2857,2236,1734,1461,1427,1111,823,702,504.
HRMS analysis was also carried out at TOF-MS instrument with ESI and APCI sources under both positive and negative model,however the expected MS was not found.
example 16
Figure GDA0002227626850000201
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate and 7-cyano-7- (tributylstannyl) heptylthiophene-2-carboxylate was substituted for 2- (tributylstannyl) acetonitrile. The resulting residue was separated by column chromatography to give the two diastereomeric products (80/20dr) in 63% and 16% yields, respectively, as light yellow oily liquids. The target product was characterized as follows:
(major) pale yellow oily liquid, 64.8mg, 63% (Rf ═ 0.32, eluent: PE/EtOAc ═ 10/1).
1H NMR(600MHz,CDCl3):δ7.80(dd,J＝3.7,1.3Hz,1H),7.54(dd,J＝5.0,1.2Hz,1H),7.10(dd,J＝5.0,3.8Hz,1H),6.02–5.96(m,1H),5.33–5.28(m,1H),4.29(t,J＝6.6Hz,2H),3.04–2.88(m,2H),2.82–2.74(m,1H),2.31(q,J＝7.5Hz,2H),1.78–1.73(m,2H),1.69–1.63(m,2H),1.60–1.55(m,2H),1.48–1.35(m,6H),1.04(t,J＝7.6Hz,3H),0.74(t,J＝7.3Hz,3H).
13C NMR(151MHz,CDCl3):δ162.4,146.1,134.1,133.4,132.4,128.0,127.9,124.9,120.4,107.7,65.2,49.9,45.0,37.2,32.7,32.0,28.9,28.7,28.2,26.1,25.9,11.8,9.0.
IR(neat):2964,2930,2863,2237,1706,1418,1258,1092,751,722.
HRMS(ESI-TOF):calculated for[C23H30INO2SNa(M+Na+)]:534.0934,found:534.0938.
(minor) light yellow oily liquid, 16.2mg, 16% (Rf ═ 0.31, eluent: PE/EtOAc ═ 10/1).
1H NMR(600MHz,CDCl3):δ7.79(dd,J＝3.7,1.3Hz,1H),7.55(dd,J＝5.0,1.2Hz,1H),7.10(dd,J＝4.9,3.7Hz,1H),5.97–5.92(m,1H),5.58–5.52(m,1H),4.28(t,J＝6.7Hz,2H),2.92(dd,J＝10.7,4.8Hz,1H),2.82–2.77(m,2H),2.35–2.19(m,2H),1.78–1.95(m,4H),1.45–1.34(m,6H),1.01(t,J＝7.5Hz,3H),0.71(t,J＝7.3Hz,3H).
13C NMR(151MHz,CDCl3):δ162.5,146.4,134.2,133.4,132.3,127.9,127.0,124.9,120.8,107.0,65.3,50.3,43.5,37.1,33.6,32.8,28.8,28.7,28.1,27.5,25.9,11.9,8.5.
IR(neat):2963,2930,2860,2234,1708,1419,1259,1093,751,722.
HRMS(ESI-TOF):calculated for[C23H30INO2SNa(M+Na+)]:534.0934,found:534.0936.
Example 17
Figure GDA0002227626850000211
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate and benzothiophene was substituted for Et3SiH. The residue obtained is separated by column chromatography (Rf 0.38, developing solvent: petroleum ether/ethyl acetate 10/1, v/v) to give a mixture of the two diastereomers ((90/10dr) and as a white solid, with a yield of 78% (determined on a single crystal, 90% of which correspond to the main product having the structure given above)The method comprises the following steps: 2- ((1S,4S) -4- (benzob [ b ]]thiophen-3-yl) -1,3-diethyl-2-iodocyclohexa-2,5-dien-1-yl) acetonitrile, the remaining 10% being the corresponding diastereomer).
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ7.96–7.78(m,2H,mixture),7.50(s,0.80H,major),7.45–7.34(m,2H,mixture),7.10(s,0.16H,minor),6.03(dd,J＝9.8,3.2Hz,0.15H,minor),5.99(dd,J＝9.8,3.2Hz,0.85H,major),5.52–5.44(m,1H,mixture),4.73–4.68(m,0.15H,minor),4.61–4.57(m,0.85H,major),2.96(d,J＝16.6Hz,0.85H,major),2.86(d,J＝16.5Hz,0.15H,minor),2.52(d,J＝16.6Hz,0.85H,major),2.42–2.34(m,1.15H,mixture),2.06–2.00(m,1H,mixture),1.89–1.81(m,1H,mixture),1.40–1.32(m,1H,mixture),0.99–0.93(m,3.40H,mixture),0.82(t,J＝7.3Hz,2.60H,major).
13C NMR(151MHz,CDCl3):δ148.6(minor),148.1(major),140.8(major),140.7(minor),138.3(major),138.2(minor),136.2(major),130.7(minor),130.4(major),126.0(major),125.0(minor),124.73(major),124.68(minor),124.5(major),124.4(minor),124.30(major),124.27(minor),123.25(major),123.20(minor),121.5(minor),121.2(major),117.9(major),117.2(minor),108.9(minor),108.7(major),47.9(minor),47.8(major),40.1(major),35.4(minor),35.3(major),35.2(major),33.5(minor),32.7(major),29.8(minor),12.52(minor),12,48(major),10.0(minor),8.6(major).
IR(neat):2964,2929,2871,2248,1677,1457,905,762,731.
HRMS(ESI-TOF):calculated for[C20H20INSNa(M+Na+)]:456.0253,found:456.0261.
example 18
Figure GDA0002227626850000221
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate instead of (2, 6-dimethylphenyl) iododiacetate and 4-methylbenzenesulfonamide instead of Et3SiH. The residue was separated by column chromatography (Rf ═ 0.1)The developing solvent petroleum ether/ethyl acetate 5/1, v/v) gave a mixture of the two diastereomers ((75/25dr) and as a white solid, in 80% yield (75% of the main product having the structure given above, i.e., N- ((1R,4S) -4- (cyanomethyl) -2,4-diethyl-3-iodocyclohexa-2,5-dien-1-yl) -4-methylbenezenesulfonimide, the remaining 25% being its corresponding diastereomer). The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ7.86–7.70(m,2H,mixture),7.36–7.28(m,2H,mixture),5.61–5.57(m,0.75H,major),5.56–5.51(m,0.50H,mixture),5.50–5.46(m,0.75H,major),4.91(d,J＝10.4Hz,0.75H,major),4.47–4.37(m,1.25H,mixture),2.79(d,J＝16.7Hz,0.76H,major),2.70(d,J＝16.7Hz,0.24H,minor),2.46–2.43(m,3H,mixture),2.42–2.29(m,2.21H,mixture),2.24(d,J＝16.7Hz,0.79H,major),1.83–1.75(m,1H,mixture),1.31–1.21(m,1H,mixture),1.02–0.96(m,3H,mixture),0.68–0.60(m,3H,mixture).
13C NMR(151MHz,CDCl3):δ147.0(major),146.5(minor),144.1(minor),143.7(major),138.7(major),137.8(minor),130.1(minor),130.0(major),129.9(major),129.5(minor),128.4(major),128.0(minor),127.2(minor),127.1(major),118.4(major),116.5(minor),111.5(minor),111.4(major),50.4(major),48.0(major),47.6(minor),35.5(major),33.5(major),33.4(minor),33.2(minor),32.5(minor),31.3(major),21.70(minor),21.68(major),12.24(minor),12.21(major),9.1(minor),8.78(major).
IR(neat):2964,2929,2871,2248,1677,1457,1424,905,761,731.
HRMS(ESI-TOF):calculated for[C19H23IN2O2SNa(M+Na+)]:493.0417,found:493.0421.
Example 19
Figure GDA0002227626850000231
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate instead of (2, 6-dimethylphenyl)) Iodinated diacetate, 1-BOC-indole instead of Et3SiH. The residue was separated by column chromatography (Rf 0.26, developing solvent: petroleum ether/ethyl acetate 20/1, v/v) to give the single polysubstituted alicyclic compound: (a)>20/1dr) and as a white solid, in 81% yield, (the product structure is shown above, i.e.: the characterization of the 3- ((1S,4S) -4- (cyanomethyl) -2,4-diethyl-3-iodocyclohexa-2,5-dien-1-yl) -1H-indole-1-carboxylate) target product is as follows:
1H NMR(600MHz,CDCl3):δ8.17(s,1H),7.66(s,1H),7.62(d,J＝7.8Hz,1H),7.36–7.32(m,1H),7.29–7.24(m,1H),5.98(dd,J＝9.7,3.2Hz,1H),5.51(d,J＝9.8Hz,1H),4.40–4.36(m,1H),2.92(d,J＝16.6Hz,1H),2.55(d,J＝16.6Hz,1H),2.44–2.35(m,1H),2.17–2.07(m,1H),1.88–1.79(m,1H),1.66(s,9H),1.42–1.32(m,1H),0.99(t,J＝7.5Hz,3H),0.81(t,J＝7.3Hz,3H).
13C NMR(151MHz,CDCl3):δ149.8,148.2,130.6,130.5,129.9,125.4,124.8,124.6,122.7,121.2,118.6,117.8,115.5,108.4,84.0,47.6,37.4,35.2,35.1,32.6,28.3,12.4,8.6.
IR(neat):2967,2931,2872,2247,1729,1450,1359,1263,1151,1077,733.
HRMS(ESI-TOF):calculated for[C25H29IN2O2Na(M+Na+)]:539.1166,found:539.1166.
example 20
Figure GDA0002227626850000241
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate instead of (2, 6-dimethylphenyl) iododiacetate and 4-methyl-N-phenylbenzenesulfonamide instead of Et3SiH. The residue was separated by column chromatography (Rf 0.40, developing solvent: petroleum ether/ethyl acetate 5/1, v/v) to give the single polysubstituted alicyclic compound: (a)>20/1dr) and as a white solid, in 60% yield (wherein the product has the structure shown above, i.e.: n- ((1R,4S) -4- (cyanomethyl) -2, 4-diethyl-3-iodocyc)lohexa-2,5-dien-1-yl) -4-methyl-N-phenylbenzizenesulfonamide). The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ7.62(d,J＝8.2Hz,2H),7.36–7.27(m,5H),6.86–6.79(m,2H),5.82(dd,J＝9.9,4.1Hz,1H),5.75(d,J＝9.9Hz,1H),5.49(d,J＝4.0Hz,1H),2.68–2.59(m,1H),2.48–2.41(m,4H),2.20(d,J＝16.3Hz,1H),1.61–1.54(m,1H),1.52–1.43(m,1H),1.09(t,J＝7.5Hz,3H),0.55(t,J＝7.3Hz,3H),0.16(d,J＝16.2Hz,1H).
13C NMR(151MHz,CDCl3):δ144.7,143.8,138.0,135.0,132.6,132.5,129.8,129.3,128.7,127.5,126.1,116.6,114.3,56.7,45.0,34.1,33.5,29.3,21.7,12.1,8.2.
IR(neat):2965,2930,2873,2252,1489,1158,902,706,578,542.
HRMS(ESI-TOF):calculated for[C25H27IN2O2SNa(M+Na+)]:569.6730,found:569.0735.
Example 21
Figure GDA0002227626850000242
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate instead of (2, 6-dimethylphenyl) iododiacetate and 2-ethyl-1-butene instead of Et3SiH. The resulting residue was separated by column chromatography (Rf 0.30, developing solvent: petroleum ether/ethyl acetate 20/1, v/v) to give a mixture of two diastereomers ((73/27dr) and a 52% yield of this mixture as a pale yellow oily liquid, (73% of the main product having the structure shown above, i.e.: 2- ((1S,4S) -1,3-diethyl-4- (2-ethylbout-1-en-1-yl) -2-iodocyclohexa-2,5-dien-1-yl) acetonitrile, and the remaining 27% being their corresponding diastereomers) the target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ5.93–5.86(m,1H,mixture),5.41–5.34(m,1.7H,mixture),5.28–5.22(m,0.3H,mixture),3.02–2.92(m,1H,mixture),2.73(d,J＝16.6Hz,0.7H,major),2.67(d,J＝16.6Hz,0.3H,minor),2.57–2.42(m,1.40H,mixture),2.41–2.33(m,1.64H,mixture),2.32–2.23(m,0.94H,mixture),2.08–1.92(m,1.5H,mixture),1.98–1.93(m,0.5H,mixture),1.84–1.76(m,1H,mixture),1.64–1.56(m,4H,mixture),1.31–1.27(m,1H,mixture),1.11–1.05(m,3H,mixture),1.05–0.96(m,3H,mixture),0.71(t,J＝7.3Hz,3H,mixture).
13C NMR(151MHz,CDCl3):δ150.3(major),150.2(minor),138.40(major),138.35(minor),131.9(minor),131.8(major),125.3(major),125.2(minor),121.5(minor),120.6(major),117.6(major),108.5(major),108.4(minor),47.8(major),47.6(minor),43.4(minor),39.9(minor),39.8(major),36.8(major),35.6(major),35.5(minor),34.79(major),34.75(minor),32.2(major),32.1(minor),29.7(major),22.8(minor),14.0(major),13.2(minor),13.01(major),12.95(minor),12.7(major),12.6(minor),8.75(major).
IR(neat):2964,2930,2872,2250,1681,1458,1417,1377,906,731,649.
HRMS(ESI-TOF):calculated for[C18H26INNa(M+Na+)]:406.1002,found:406.1026.
example 22
Figure GDA0002227626850000251
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate and TMSCN was substituted for Et3SiH. The resulting residue was separated by column chromatography (Rf 0.30, developing solvent: petroleum ether/ethyl acetate 5/1, v/v) to give a mixture of the two diastereomers (62/38dr) in 83% yield as a pale yellow oily liquid (62% of the main product having the structure shown above, i.e., (1R,4S) -4- (cyanomethyl) -2,4-diethyl-3-iodocyclohexa-2,5-dienecarbonitrile, the remaining 38% being the corresponding diastereomer).
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ6.03–5.97(m,1H,mixture),5.79(dd,J＝9.8,2.0Hz,0.25H,minor),5.70(dd,J＝9.8,2.0Hz,0.75H,major),4.15–4.11(m,0.77H,major),4.07–4.03(m,0.23H,minor),2.81(d,J＝16.8Hz,0.79H,major),2.69(d,J＝16.7Hz,0.26H,minor),2.65–2.59(m,1.31H,mixture),2.55–2.48(m,1.13H,mixture),2.38(d,J＝16.8Hz,0.79H,major),1.86–1.77(m,1.20H,mixture),1.49–1.43(m,0.26H,minor),1.39–1.34(m,0.78H,major),1.20–1.13(m,3.15H,mixture),0.79(t,J＝7.4Hz,2.34H,major),0.66(t,J＝7.4Hz,0.71H,minor).
13C NMR(151MHz,CDCl3):δ139.2(major),138.9(minor),130.3(minor),130.1(major),122.1(major),121.6(minor),117.2(major),117.0(minor),116.5(major),116.3(minor),111.1(minor),110.7(major),48.0(major),47.2(minor),35.49(major),35.45(minor),34.4(minor),33.7(major),33.1(major),32.42(minor),32.39(major),31.9(minor),11.84(major),11.81(minor),8.90(major),8.60(minor).
IR(neat):2967,2932,2875,2248,2221,1457,1418,903,725,649.
HRMS(ESI-TOF):calculated for[C13H15IN2Na(M+Na+)]:349.0172,found:349.0171.
example 23
Figure GDA0002227626850000261
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate was substituted for (2, 6-dimethylphenyl) iododiacetate and allyltrimethylsilane was substituted for Et3SiH. The resulting residue was separated by column chromatography (Rf 0.31, developing solvent: Petroleum ether/Ethyl acetate 10/1, v/v) to give a mixture of the two diastereomers (85/15dr) in 73% yield (85% of the main product structure being shown above, i.e., 2- ((1S,4R) -4-allyl-1, 3-diethyl-2-iodocyclohexoxa-2, 5-dien-1-yl) acetotriole, the remaining 15% being its corresponding diastereomer) as a pale yellow oily liquid. The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ5.90(dd,J＝9.9,3.6Hz,1.00H,mixture),5.81–5.65(m,0.98H,mixture),5.50–5.40(m,1H,mixture),5.11–5.01(m,2H,mixture),3.09–3.04(m,0.13H,minor),2.99–2.95(m,0.87H,major),2.80–2.70(m,0.50H,mixture),2.64(d,J＝16.6Hz,0.93H,major),2.50–2.44(m,2.52H,mixture),2.35–2.22(m,2.08H,mixture),1.84–1.72(m,1.08H,mixture),1.39–1.31(m,1.05H,mixture),1.09(t,J＝7.5Hz,0.42H,minor),1.05(t,J＝7.5Hz,2.66H,major),0.76(t,J＝7.4Hz,0.39H,minor),0.70(t,J＝7.3Hz,2.66H,major).
13C NMR(151MHz,CDCl3):δ148.97(minor),148.91(major),142.8(minor),135.2(major),131.3(minor),131.1(major),126.0(major),125.9(minor),117.53(major),117.47(major),117.3(minor),109.1(minor),109.0(major),47.9(minor),47.3(major),40.9(major),40.4(minor),39.4(major),39.2(minor),35.1(major),34.6(minor),34.5(major),33.8(minor),32.7(minor),32.4(major),15.0(minor),12.4(major),9.6(minor),8.6(major).
IR(neat):3076,2965,2930,2873,2246,1638,1456,954,912,783,756.
HRMS(ESI-TOF):calculated for[C15H20INNa(M+Na+)]:364.0533,found:364.0546.
example 24
Figure GDA0002227626850000271
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate instead of (2, 6-dimethylphenyl) iododiacetate and 1-phenyl-1-trimethylsiloxyethylene instead of Et3SiH. The resulting residue was separated by column chromatography to give a mixture of two diastereomers (56/44dr) in 45% and 26% yields, respectively, of the two compounds as pale yellow oily liquids (56% of the main product having the structure shown above: 2- ((1S,4R) -1,3-diethyl-2-iodo-4- (2-oxo-2-phenylethyl) cyclohexa-2,5-dien-1-yl) acetonitrile, and the remaining 44% being the corresponding diastereomer). The target product was characterized as follows:
(major):light yellow oil,37.7mg,45％yield.(Rf＝0.25,eluent:PE/EtOAc＝10/1).
1H NMR(600MHz,CDCl3):δ7.98(d,J＝7.3Hz,2H),7.58–7.52(m,1H),7.48–7.41(m,2H),6.03(dd,J＝9.8,3.9Hz,1H),5.34(d,J＝9.9Hz,1H),3.73–3.66(m,1H),3.42–3.20(m,2H),2.84(d,J＝16.6Hz,1H),2.58–2.48(m,1H),2.31–2.15(m,2H),1.87–1.77(m,1H),1.29–1.17(m,1H),1.09(t,J＝7.5Hz,3H),0.74(t,J＝7.3Hz,3H).
13C NMR(151MHz,CDCl3):δ198.6,149.4,136.9,133.4,131.7,128.8,128.3,126.0,118.1,108.5,48.2,45.5,36.7,36.0,34.7,31.7,12.6,8.8.
IR(neat):2964,2930,2872,2246,1680,1447,1206,749,688.
HRMS(ESI-TOF):calculated for[C20H22INONa(M+Na+)]:442.0638,found:442.0640.
(minor):light yellow oil,21.8mg,26％yield.(Rf＝0.24,eluent:PE/EtOAc＝10/1).
1H NMR(600MHz,CDCl3):δ7.97–7.90(m,2H),7.61–7.56(m,1H),7.51–7.45(m,2H),6.00(dd,J＝9.9,3.7Hz,1H),5.42(dd,J＝9.9,1.1Hz,1H),3.76–3.70(m,1H),3.33–3.27(m,1H),2.94–2.87(m,1H),2.78(d,J＝16.6Hz,1H),2.56–2.47(m,1H),2.43(d,J＝16.6Hz,1H),2.28–2.18(m,1H),1.81–1.72(m,1H),1.36–1.27(m,1H),1.13(t,J＝7.5Hz,3H),0.80(t,J＝7.3Hz,3H).
13C NMR(151MHz,CDCl3):δ197.7,148.8,136.9,133.6,131.0,128.9,128.2,125.8,117.1,108.9,47.9,44.6,36.6,34.8,34.2,32.8,12.6,9.5.
IR(neat):2966,2930,2872,2250,1684,1448,1207,906,730,689.
HRMS(ESI-TOF):calculated for[C20H22INONa(M+Na+)]:442.0638,found:442.0639.
Example 25
Figure GDA0002227626850000281
Following the procedure of example 1, diethyl (2, 6-diethylphenyl) iodide instead of diethyl (2, 6-dimethylphenyl) iodide, TMSN3Substitute Et3SiH. The resulting residue was isolated by column chromatography (Rf 0.30, developing solvent: petroleum ether/ethyl acetate 10/1, v/v) to give a compound in 34% yield as a pale yellow oily liquid (wherein the product structure is shown above, i.e., 2- ((1S,4R) -4-azido-1, 3-diethyl-2-iodocyclohexoxa-2, 5-dien-1-yl) acetonitrile).
The target product was characterized as follows:
1H NMR(600MHz,CDCl3):δ6.09(dd,J＝9.9,3.3Hz,1H),5.84(dd,J＝9.9,1.3Hz,1H),4.21(d,J＝2.3Hz,1H),2.78(d,J＝16.7Hz,1H),2.59–2.44(m,2H),2.39(d,J＝16.7Hz,1H),1.86–1.78(m,1H),1.46–1.37(m,1H),1.13(t,J＝7.5Hz,3H),0.79(t,J＝7.4Hz,3H).
13C NMR(151MHz,CDCl3):δ145.1,131.5,125.8,116.4,112.5,57.5,47.9,34.3,33.0,32.9,12.0,9.2.
IR(neat):2968,2932,2875,2091,1458,1312,1188,855,793,762.
HRMS(ESI-TOF):calculated for[C12H15IN4Na(M+Na+)]:365.0234,found:365.0239.
example 26
Figure GDA0002227626850000291
Following the procedure of example 1, (2, 6-diethylphenyl) iododiacetate instead of (2, 6-dimethylphenyl) iododiacetate, 4-chlorobenzenethiol instead of Et3SiH. The resulting residue was separated by column chromatography to give two diastereomeric compounds (74/26dr) in 75% yield (74% of which the main product has the structure shown above, i.e., 2- ((1S,4R) -4- ((4-chlorophenyl) thio) -1,3-diethyl-2-iodocyclohexa-2,5-dien-1-yl) acetonitrile, the remaining 26% being their corresponding diastereomers). The target product was characterized as follows:
(major): white solid, melting point: 92-93 deg.C, 44.3mg, 50% (Rf: 0.33, eluent: PE/EtOAc: 20/1).
1H NMR(600MHz,CDCl3):δ7.33(d,J＝8.4Hz,2H),7.23(d,J＝8.4Hz,2H),6.01(dd,J＝9.8,4.0Hz,1H),5.62(d,J＝9.8Hz,1H),4.12(d,J＝3.9Hz,1H),2.9–2.81(m,1H),2.60–2.50(m,1H),2.36(d,J＝16.4Hz,1H),1.65–1.57(m,1H),1.50–1.41(m,1H),1.09(t,J＝7.5Hz,3H),0.58(t,J＝7.3Hz,3H),0.44(d,J＝16.4Hz,1H).
13C NMR(151MHz,CDCl3):δ144.6,138.7,136.2,129.0,128.8,128.4,127.3,116.8,112.2,49.9,45.8,35.0,34.2,31.0,12.5,8.4.
IR(neat):2963,2929,2872,2245,1570,1473,1092,1013,820,794,496.
HRMS(ESI-TOF):calculated for[C18H19ClINSNa(M+Na+)]:465.9864,found:465.9869.
(minor) pale yellow oily liquid, 22.2mg, 25% (Rf ═ 0.3, eluent: PE/EtOAc ═ 20/1).
1H NMR(600MHz,CDCl3):δ7.32–7.24(m,4H,overlap with CDCl3),6.08(dd,J＝9.8,3.6Hz,1H),5.45(d,J＝9.8Hz,1H),4.26(d,J＝3.5Hz,1H),2.94–2.85(m,1H),2.70(d,J＝16.7Hz,1H),2.64–2.53(m,1H),2.28(d,J＝16.7Hz,1H),1.34–1.20(m,2H),1.14(t,J＝7.5Hz,3H),0.38(t,J＝7.4Hz,3H).
13C NMR(151MHz,CDCl3):δ145.7,136.3,135.1,130.8,129.3,128.8,127.4,116.9,111.9,49.3,47.8,35.3,33.6,33.5,12.6,8.5.
IR(neat):2966,2930,2872,2246,1571,1474,1093,1013,821,792,496.
HRMS(ESI-TOF):calculated for[C18H19ClINSNa(M+Na+)]:465.9864,found:465.9869.
Application example 1:
Figure GDA0002227626850000301
at 25 deg.CTo a stirred solution of cyanomethyl-substituted cycloaliphatic compound (60.2mg, 0.2mmol) in DMSO (0.5mL) was added H in sequence2O2(30% aq, 60. mu.L, 2.5equiv) and K2CO3Solid (5.5mg, 0.5 equiv). After stirring for 24 hours, the mixture is washed with H2Dilute O and extract with DCM. Then passing through Na2SO4Dried and concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel to give the title compound as a white solid with a melting point of 83-84 ℃ (Rf 0.20, developing solvent PE/EtOAc 1/1). Yield 95% (60.6 mg).
1H NMR(600MHz,CDCl3):δ5.89–5.83(m,1H),5.69(s,1H),5.58–5.39(m,2H),2.88–2.71(m,3H),2.34–2.24(m,2H),2.14(d,J＝14.1Hz,1H),1.78–1.68(m,1H),1.25–1.18(m,1H),1.02(t,J＝7.5Hz,3H),0.71(t,J＝7.4Hz,3H).
Application example 2
Figure GDA0002227626850000302
DIBAL-H (1.5M in toluene, 0.2mL, 1.5equiv) was added dropwise to a stirred solution of cyanomethyl-substituted cycloaliphatic compound (60.2mg, 0.2mmol) in dry toluene (1.0mL) at-78 ℃. After stirring for 1 hour, the mixture was quenched with MeOH (0.5mL), warmed to room temperature, and poured into rochelle salt solution (5 mL). The mixture was then extracted with EtOAc and over Na2SO4Dried and concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel to give the aldehyde methyl substituted cycloaliphatic compound as a yellow oil in 91% yield. (Rf 0.27, eluent: PE/EtOAc 10/1).
1H NMR(600MHz,CDCl3):δ9.54(dd,J＝3.7,2.4Hz,1H),5.88–5.83(m,1H),5.41–5.35(m,1H),2.89–2.77(m,3H),2.33–2.24(m,2H),2.10(dd,J＝15.6,3.7Hz,1H),1.83–1.73(m,1H),1.24–1.17(m,1H),1.01(t,J＝7.6Hz,3H),0.72(t,J＝7.4Hz,3H).
Application example 3
Figure GDA0002227626850000311
To a stirred solution of cyanomethyl-substituted cycloaliphatic compound (60.2mg, 0.2mmol) in MeCN (2mL) was added ethyl acrylate (26. mu.L, 1.2equiv), Et in a sealed tube3N (335. mu.L, 1.2equiv) and Pd (PPh)3)4(23mg, 10 mol%) and then stirred at 80 ℃ for 12 hours. The mixture was cooled to room temperature and saturated NaHCO was added3(2mL) and extracted with DCM and Na2SO4Dried and concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel to give the title compound as a yellow oil in 65% yield. (Rf 0.22, eluent: PE/EtOAc 10/1).
1H NMR(600MHz,CDCl3):δ7.30–7.24(m,1H),6.02-5.93(m,2H),5.36–5.32(m,1H),4.22(q,J＝7.1Hz,2H),2.80(dd,J＝89.9,22.1Hz,2H),2.51(d,J＝16.6Hz,1H),2.31(d,J＝16.6Hz,1H),2.23(q,J＝7.5Hz,2H),1.69–1.62(m,1H),1.39–1.32(m,1H),1.32(t,J＝7.1Hz,3H),1.04(t,J＝7.6Hz,3H),0.75(t,J＝7.4Hz,3H).
Application example 4
Figure GDA0002227626850000312
To a stirred cyanomethyl-substituted cycloaliphatic compound (60.2mg, 0.2mmol) in i-Pr in a sealed tube2NEt2To a solution of/DMF ═ 1/1(2mL) were added ethynylbenzene (40.9mg, 2.0equiv), CuI (2.0mg, 5 mol%) and Pd (PPh)3)Cl2(7.2mg, 5 mol%) and then stirred at 100 ℃ for 12 hours. The mixture was cooled to room temperature and saturated NaHCO was added3(2mL) and extracted with DCM and Na2SO4Dried and concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel to give the title compound as a yellow oil in 83% yield. (Rf 0.35, eluent: PE/EtOAc 10/1).
1H NMR(600MHz,CDCl3):δ7.47–7.41(m,2H),7.38–7.28(m,3H),6.07–5.96(m,1H),5.51–5.45(m,1H),2.93–2.76(m,2H),2.73(d,J＝16.5Hz,1H),2.56–2.38(m,3H),1.95–1.86(m,1H),1.50–1.42(m,1H),1.12(t,J＝7.6Hz,3H),0.80(t,J＝7.4Hz,3H).
Application example 5
Figure GDA0002227626850000321
To a stirred solution of cyanomethyl-substituted cycloaliphatic compound (60.2mg, 0.2mmol) in toluene (0.5mL) was added phenylboronic acid (24.4mg, 1.0equiv), K in a sealed tube2CO3(41.5mg, 1.5equiv) and Pd (PPh)3)4(23.1mg,10 mol%) and then stirred at 80 ℃ for 12 hours. The mixture was cooled to room temperature and saturated NaHCO was added3(1mL) and extracted with DCM and Na2SO4Dried and concentrated under vacuum. The resulting residue was purified by flash chromatography on silica gel to give the title compound as a yellow oil in 50% yield. (Rf 0.39, eluent: PE/EtOAc 10/1).
1H NMR(600MHz,CDCl3):δ7.38–7.32(m,2H),7.31–7.27(m,1H),7.23(d,J＝7.5Hz,1H),7.06(d,J＝7.5Hz,1H),6.12–6.06(m,1H),5.47–5.42(m,1H),2.93–2.66(m,2H),2.19(dd,J＝97.5,16.6Hz,2H),1.83–1.68(m,2H),1.51–1.43(m,1H),1.26–1.17(m,1H),0.93(t,J＝7.3Hz,3H),0.87(t,J＝7.6Hz,3H).
Application example 6
Figure GDA0002227626850000322
To a stirred solution of cyanomethyl-substituted cycloaliphatic compound (60.2mg, 0.2mmol) in toluene (0.5mL) was added Ac in sequence at 0 deg.C2O (180. mu.L), AcOH (350. mu.L) and CrO3(86mg, 4.25equiv), stirred for 12 hours. Adding saturated NaHCO3Solution and extracted with EtOAc. The organic layer was washed with brine, washed with Na2SO4Dried and concentrated under vacuum. The obtained residuePurification by flash chromatography on silica gel afforded the title compound as a yellow oil in 80% yield. (Rf: 0.21, eluent: PE/EtOAc: 5/1).
1H NMR(600MHz,CDCl3):δ6.99(d,J＝9.8Hz,1H),6.52(d,J＝9.8Hz,1H),2.79(dd,J＝53.3,16.7Hz,2H),2.72–2.63(m,2H),2.02–1.94(m,1H),1.76–1.68(m,1H),1.03(t,J＝7.5Hz,3H),0.65(t,J＝7.4Hz,3H).
The compounds obtained in the application examples 1 to 6 are important intermediates, and can be used for synthesis of various intermediates or medicines.

Claims (5)

1. A method for preparing polysubstituted alicyclic compound, characterized by, aryl hypervalent iodide compound is activated by activating reagent, carry on the rearrangement reaction with nitrile compound substituted by alpha-tin or silicon at-70-100 duC, get electrophilic dearomatization midbody, this midbody reacts with nucleophilic reagent, get said polysubstituted alicyclic compound;
the aryl hypervalent iodine compound has the structure shown as the following formula:
Figure FDA0003496146130000011
x is selected from C1-C4 alkanoyloxy, substituted C1-C4 alkanoyloxy or two X are one O atom, i.e. with I, I ═ O;
the structure of the nitrile compound is shown as the following formula:
Figure FDA0003496146130000012
m is selected from 3L-substituted Sn or Si;
the structure of the polysubstituted alicyclic compound is shown as the following formula:
Figure FDA0003496146130000013
nu is a nucleophilic group moiety in a nucleophile;
R1selected from halogen, C1-C2 alkyl, chlorobenzyl, halogenated C1-C2 alkyl, C1-C2 alkoxy substituted C1-C2 alkyl, C1-C2 alkanoyloxy substituted C1-C2 alkyl, halogen substituted thienyl acyloxy substituted C1-C2 alkyl, styrene acyloxy substituted C1-C2 alkyl, halogen substituted C1-C3 alkanoyloxy substituted C1-C2 alkyl, ester substituted C1-C2 alkanoyloxy substituted C1-C2 alkyl, cyano or cyanomethyl;
R2Selected from C1-C2 alkyl;
R3selected from hydrogen, halogen, methyl alkyl, chlorobenzyl, phenyl, chloromethyl, chloroethyl, phenyl acyloxy substituted C1-C2 alkyl;
r is selected from H, C1-C3 alkyl, halogenated C1-C3 alkyl, aryl substituted C1-C2 alkyl, alkenyl substituted C1-C4 alkyl, thienyl acyloxy substituted C1-C6 alkyl, styryloxy substituted C1-C6 alkyl, substituted phenyl acyloxy substituted C1-C6 alkyl, propionaldehyde ethylene acetal substituted C1-C2 alkyl, TBDPS-OR4-，R4Selected from C1-C6 alkyl;
3L are respectively and independently selected from C1-C5 alkyl and phenyl;
the nucleophilic reagent is selected from dimethyl phenyl silane, diphenyl methyl silane, triphenyl silane, triisopropyl silane, trimethoxy silane, chloro dimethyl silane, triethyl silane, 9-boron bicyclo [3.3.1 ]]Nonane, benzothiophene, benzofuran, N-Boc protected indole, 4-methylbenzenesulfonamide, 4-methyl-N-phenylbenzenesulfonamide, 2-ethyl-1-butene, TMSCN, allyltrimethylsilane, 1-phenyl-1-trimethylsiloxyethylene, TMSN3And 4-chlorobenzenethiol.
2. The method of claim 1, wherein the activating reagent comprises boron trifluoride etherate, trimethylsilyl trifluoromethanesulfonate, trifluoromethanesulfonic anhydride, tert-butyldimethylsilyl trifluoromethanesulfonate, triethylsilyltrifluoromethanesulfonate, TMSOCOCF 3And other higher iodine capable of activating aryl groupsOne or more of the activators (c).
3. The method of claim 1, wherein the reaction solvent comprises: one or more of dichloromethane, trichloromethane, acetonitrile, Tetrahydrofuran (THF), N-dimethylformamide, dibromomethane, 1, 2-dimethoxyethane and 1, 4-dioxane.
4. The method according to claim 1, wherein the molar ratio of the compound represented by aryl higher iodine to the α -tin or silicon substituted nitrile compound is 1: 1-2; the molar ratio of the compound shown by aryl hypervalent iodine to the activating reagent is 1: 1-3; the molar ratio of the compound shown by aryl hypervalent iodine to the nucleophilic reagent is 1: 1 to 3.
5. The method for producing a polysubstituted alicyclic compound according to claim 1, wherein the activation temperature of the activating agent is-70 to-90 ℃ and the activation time is 5 to 60 minutes; the rearrangement reaction temperature is-70 to-90 ℃, and the reaction time is 5 to 60 minutes; the temperature for reaction with the nucleophilic reagent is-70 to-90 ℃, and the reaction time is 1 to 20 hours.
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