CN117185975A - Disulfide She Li German compound, and preparation method and application thereof - Google Patents

Disulfide She Li German compound, and preparation method and application thereof Download PDF

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CN117185975A
CN117185975A CN202210603040.XA CN202210603040A CN117185975A CN 117185975 A CN117185975 A CN 117185975A CN 202210603040 A CN202210603040 A CN 202210603040A CN 117185975 A CN117185975 A CN 117185975A
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reaction
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沈其龙
吕龙
凌熠晶
高枫
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Shanghai Institute of Organic Chemistry of CAS
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Shanghai Institute of Organic Chemistry of CAS
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Abstract

The invention discloses a disulfide She Li German compound, a preparation method and application thereof. The invention discloses a compound shown as a formula I: wherein m and n are independently 0,1, 2, 3, 4 or 5; r is R 7 And R is 8 Independently C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, nitro or halogen; e is CO 2 R 9 ；R 9 Is C 1 ～C 6 An alkyl group. The disulfide She Li compound can be used as a photoinitiated difluoro carbene precursor, can release difluoro carbene under the condition of blue light at room temperature and neutrality, can realize geminal difluoro cyclopropanation reaction of olefin and difluoro methylation reaction of alcohol under photocatalysis, and provides important methodological support for the later modification of functional molecules in the fields of medicine, materials and the like.

Description

Disulfide She Li German compound, and preparation method and application thereof
Technical Field
The invention relates to a disulfide She Li German compound, a preparation method and application thereof.
Background
The introduction of fluorine-containing functional groups can enhance the lipophilicity of molecules, promote the transmembrane transport of the molecules, and effectively improve the metabolic stability and bioavailability of the molecules along with the pseudo-effect and blocking effect of fluorine, so that the introduction of fluorine atoms into bioactive molecules becomes an important strategy in drug design (chem. Rev.2005,105, 827). Of the numerous fluorine-containing groups, difluoromethyl as a hydroxyl isostere (J.org.chem.1995, 60,1626), difluoromethylene as an ether oxygen isostere (J.Chem.Soc., chem.Commun.1981,930), and geminal difluorovinyl as a carbonyl isostere (J.Chem.Soc., chem.Commun.1989,1437) are also favored. The following formula shows one proton pump inhibitor and one ITK signal pathway inhibitor in sequence (Drugs 2003,63,101; J.Med. Chem.2015,58, 3806), and it can be seen that the introduction of difluoromethylene blocks into drug molecules plays an important role in improving the biological activity of the molecules.
Difluoro carbenes are active singlet electrophilic carbenes and are common intermediates in fluorine chemistry. The introduction of difluoromethylene blocks into various molecules with difluorocarbenes is the most direct and efficient way to build difluoromethyl, difluoromethylene and other functional groups at present, and therefore scientists have developed a wide variety of difluorocarbene precursor reagents for many years and have utilized them to complete a variety of reactions (Tetrahedron lett.2018,59,1301;Synthesis 2014,46,842). However, the existing difluoro carbene precursor reagent has a single activation mode, and needs to be initiated by strong alkali or high temperature, so that the problems of limited substrate range and the like exist in application, and the development of a milder and efficient difluoro methylene block introduction method still has very important significance.
Disclosure of Invention
The invention aims to overcome the defects of single activation mode, harsh initiation conditions, narrow substrate application range and the like of the existing difluoro carbene precursor reagent. Therefore, the invention provides a disulfide She Li German compound, a preparation method and application thereof. The disulfide She Li compound can be used as a photoinitiated difluoro carbene precursor, can release difluoro carbene under the condition of blue light at room temperature and neutrality, can realize geminal difluoro cyclopropanation reaction of olefin and difluoro methylation reaction of alcohol under photocatalysis, and provides important methodological support for the later modification of functional molecules in the fields of medicine, materials and the like.
The invention provides a compound shown as a formula I:
wherein m and n are independently 0, 1, 2, 3, 4 or 5;
R 7 and R is 8 Independently C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, nitro or halogen;
e is CO 2 R 9 ；
R 9 Is C 1 ～C 6 An alkyl group.
In one embodiment, n and m are independently 0, 1 or 2, for example 0 or 1.
In one embodiment, R is 7 And R is 8 The same or different.
In one embodiment, R 7 And R is 8 Wherein said halogen may independently be F, cl, br or I, preferably Cl.
In one embodiment, R 7 And R is 8 independently-CH 3 、-OCH 3 、-NO 2 or-Cl.
In one embodiment, R 9 Is methyl.
In one embodiment, the compound of formula I is:
the invention provides a preparation method of a compound shown as a formula I, which comprises the following steps:
step (1) is method 1 or method 2:
method 1: in an organic solvent, in the presence of (trifluoromethyl) trimethylsilane and alkali, carrying out the following reaction on the compound shown in the formula II to obtain a compound shown in the formula III;
method 2: in an organic solvent, in the presence of (triphenylphosphine) difluoroacetic acid inner salt, carrying out the following reaction on the compound shown in the formula II to obtain a compound shown in the formula III;
Step (2): in an organic solvent, in the presence of a catalyst, carrying out the following reaction on a compound shown in a formula III and a compound shown in a formula IV to obtain a compound shown in a formula I;
wherein R is 7 、R 8 M, n, E and R 9 Is defined as set forth in any one of the preceding claims.
In one embodiment, in method 1, the organic solvent may be an amide-based solvent (e.g., N-dimethylformamide and/or N, N-dimethylacetamide), preferably N, N-dimethylformamide.
In one embodiment, in method 1, the base may be one or more of lithium t-butoxide, potassium t-butoxide, and sodium t-butoxide, preferably lithium t-butoxide.
In certain embodiments, in process 1, the molar ratio of the base to the compound of formula II can be a molar ratio conventional in the art, preferably 1.5:1 to 5:1, more preferably 2:1 to 4:1 (e.g., 3:1).
In certain embodiments, in process 1, the molar ratio of the (trifluoromethyl) trimethylsilane to the compound of formula II can be a molar ratio conventional in the art, preferably 1.5:1 to 3:1, more preferably 1.5:1 to 2.5:1 (e.g., 2:1).
In one embodiment, in method 1, the molar concentration of the compound of formula II in the organic solvent may be conventional in the art, preferably 0.2 to 1.2mol/L, more preferably 0.5 to 1mol/L (e.g., 0.8 mol/L).
In one embodiment, the temperature of the reaction in process 1 may be a temperature of the reaction conventional in the art, preferably 0-40 ℃, more preferably 20-30 ℃.
In one embodiment, the organic solvent in method 2 may be an ether solvent (e.g., dioxane), preferably 1, 4-dioxane.
In certain embodiments, in process 2, the molar ratio of the (triphenylphosphine) internal salt of difluoroacetic acid to the compound of formula II can be a molar ratio conventional in the art, preferably 1.2:1-3:1, more preferably 1.2:1-2.5:1 (e.g., 2:1 or 1.4:1).
In one embodiment, in method 2, the molar concentration of the compound of formula II in the organic solvent may be conventional in the art, preferably 0.1 to 1.2mol/L, more preferably 0.1 to 1mol/L (e.g., 0.125 mol/L).
In one embodiment, the temperature of the reaction in method 2 may be a temperature of a reaction conventional in the art, preferably 0-80 ℃, more preferably 55-65 ℃.
In one embodiment, the reaction in process 1 or process 2 may be carried out under a nitrogen or inert gas atmosphere, preferably under an argon atmosphere.
In an embodiment, in step (2), the organic solvent may be an organic solvent conventional in the art, and may be a halogenated hydrocarbon solvent (e.g., one or more of dichloromethane, chloroform and 1, 2-dichloroethane) and/or an aromatic solvent (e.g., one or more of toluene, xylene, chlorobenzene and benzotrifluoride), preferably dichloromethane and/or toluene, more preferably dichloromethane.
In one embodiment, in step (2), the catalyst may be Rh 2 (esp) 2 、Rh 2 (OAc) 4 And Rh 2 (C 7 H 15 CO 2 ) 4 One or more of (a)Preferably Rh 2 (esp) 2 Or Rh 2 (C 7 H 15 CO 2 ) 4 。
In one embodiment, the molar ratio of the catalyst to the compound of formula III in step (2) may be conventional in the art, preferably (0.5-2): 100, more preferably (0.8-1.5): 100 (e.g., 1:100).
In one embodiment, in step (2), the molar ratio of the compound of formula IV to the compound of formula III may be a molar ratio conventional in the art, preferably 1.5:1 to 5:1, more preferably 2:1 to 4:1 (e.g. 3:1 or 4:1).
In one embodiment, in step (2), the molar concentration of the compound of formula III in the organic solvent may be conventional in the art, preferably 0.02 to 0.2mol/L, more preferably 0.05 to 0.15mol/L (e.g., 0.1 mol/L).
In one embodiment, the temperature of the reaction in step (2) may be a temperature of a reaction conventional in the art, preferably 0-40 ℃, more preferably 20-30 ℃.
In one embodiment, in step (2), the reaction may be carried out under a nitrogen or inert gas atmosphere, preferably under an argon atmosphere.
In one embodiment, in step (2), the compound of formula IV is slowly added dropwise to a solution of the compound of formula III and the organic solvent.
The application also provides any one of the following compounds:
the application also provides application of the compound shown in the formula I in an organic synthesis reaction, wherein the organic synthesis reaction is a geminal difluoro cyclopropanation reaction of olefin or a difluoro methylation reaction of alcohol.
In one embodiment, the geminal difluorocyclopropanation of olefins comprises the steps of:
in an organic solvent, under the existence of a catalyst and a compound shown as a formula I, carrying out geminal difluorocyclopropanation reaction on the compound containing the fragment shown as a formula V under the irradiation of blue light to obtain a compound containing the fragment shown as a formula Va;
E、m、n、R 7 and R is 8 Is defined as in any one of the present applications.
In one embodiment, the difluoromethylation reaction of an alcohol comprises the steps of:
in a solvent, under the existence of a catalyst and a compound shown as a formula I, carrying out difluoromethylation reaction on the compound containing a fragment shown as a formula VI under the irradiation of blue light to obtain a compound containing a fragment shown as a formula VIb;
In one embodiment, the geminal difluorocyclopropanation of olefins comprises the steps of:
in an organic solvent, under the existence of a catalyst and a compound shown as a formula I, carrying out geminal difluoro cyclopropanation reaction on the compound shown as a formula VII under the irradiation of blue light to obtain a compound shown as a formula VIIa;
wherein R is 1 Is that
R 3 Is hydrogen or C 1 ～C 6 An alkyl group;
alternatively, R 3 And R is 1 Together with the atoms to which they are attached, form a 9-18 membered aromatic ring;
ring A is a 6-20 membered aromatic ring;
R 5 independently C 1 ～C 6 Alkyl, substituted by one or more R 5-1 Substituted C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, -COOC 1 ～C 6 Alkyl, 6-10 membered aryl, -NR b R c Halogen, cyano, oxo or thioxo;
R 5-1 independently is one or more R 5-1-1 Substituted 5-10 membered heteroaryl, C 1 ～C 6 Alkoxy, -NR b R c Halogen or cyano; in the 5-10 membered heteroaryl, the heteroatom is selected from 1, 2 or 3 in N, O and S, and the heteroatom number is 1, 2 or 3;
R 5-1-1 independently oxo;
R b and R is c Independently C 1 ～C 6 An alkyl group;
k is 0, 1 or 2;
R 2 is hydrogen, C 1 ～C 6 Alkyl or-OC (O) -C 1 ～C 6 An alkyl group;
R 4 is hydrogen or C 1 ～C 6 An alkyl group.
In one embodiment, the difluoromethylation reaction of an alcohol comprises the steps of:
in a solvent, under the existence of a catalyst and a compound shown as a formula I, carrying out difluoromethylation reaction on the compound shown as a formula VIII under the irradiation of blue light to obtain a compound shown as a formula VIIIb;
Wherein L is C 1 ～C 6 Alkylene or * -COOC 1 ～C 6 Alkylene-, connected to ring B via the terminal;
ring B is a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; in the 5-10 membered heteroaromatic ring, the heteroatom is selected from 1, 2 or 3 in N, O and S, and the heteroatom number is 1, 2 or 3;
R 6 independently C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, halogen or cyano;
t is 0, 1, 2 or 3.
In one embodiment, the ring A may be a benzene ring or
In one embodiment, R 2 、R 3 、R 4 、R 5 、R b And R is c In the above, the C 1 ～C 6 Alkyl groups can independently be C 1 ～C 4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
In one embodiment, R 5 And R is 5-1 In the above, the C 1 ～C 6 Alkoxy groups can independently be C 1 ～C 4 Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
In one embodiment, R 5 And R is 5-1 In (2), the halogen may be F, cl, br or I, preferably Br.
In one embodiment, R 5 In the above, the 6-to 10-membered aryl group may be phenyl.
In one embodiment, when R 3 And R is 1 When forming a 9-18 membered aromatic ring together with the atoms to which they are attached, the 9-18 membered aromatic ring may be a 9-12 membered aromatic ring, preferably
In one embodiment, k is 0 or 1.
At a certain positionIn an embodiment, the compound of formula VII is
In some embodiments, the catalyst may be Ir (ppy) in the geminal difluorocyclopropanation of the olefin 3 、Ir(p- t Bu-ppy) 3 、Ru(bpy) 3 (PF 6 ) 2 And rhodamine 6G, preferably Ir (ppy) 3 And/or Ir (p- t Bu-ppy) 3 。
In some embodiments, the molar ratio of the catalyst to the compound of formula VII in the geminal difluorocyclopropanation of the olefin may be (0.05-2): 100 (e.g., 0.05:100, 0.2:100, 0.5:100, 1:100 or 2:100), preferably (0.5-2): 100.
In one embodiment, the molar ratio of the compound of formula I to the compound of formula VII in the geminal difluorocyclopropanation of the olefin is (1-2.5): 1 (e.g., 1:1, 1.5:1, 2:1, or 2.5:1); preferably (1.5-2.5): 1.
In one embodiment, the organic solvent is one or more of nitrile solvents (e.g., acetonitrile), ketone solvents (e.g., acetone), halogenated hydrocarbon solvents (e.g., dichloromethane), ether solvents (e.g., tetrahydrofuran), and aromatic solvents (e.g., toluene), preferably aromatic solvents.
In one embodiment, the volume molar ratio of the organic solvent to the compound of formula VII in the geminal difluorocyclopropanation of the olefin is from 5mL/mmol to 20mL/mmol (e.g., 10 mL/mmol); preferably 5-15mL/mmol.
In one embodiment, the temperature of the gem-difluorocyclopropanation reaction of the olefin is 10-40 ℃; preferably 20-30 ℃.
In one embodiment, the wavelength of the blue light in the gem-difluorocyclopropanation reaction of the olefin is 463-475nm, for example, a blue LED.
In one embodiment, L is C 1 ～C 6 The alkylene group may be C 1 ～C 4 Alkylene radicals, e.g. -CH 2 -、-CH 2 CH 2 -、-CH(CH 3 )-、-CH 2 CH 2 CH 2 -、-CH(CH 3 )CH 2 -、-C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 CH 2 -、-CH(CH 3 )CH 2 CH 2 -、-CH 2 CH(CH 3 )CH 2 -or-CH 2 C(CH 3 ) 2 -, preferably-CH 2 -、-CH 2 CH 2 -、-CH(CH 3 ) -or-CH 2 CH 2 CH 2 -。
In one embodiment, L, said * -COOC 1 ～C 6 The alkylene group may be * -COOC 1 ～C 4 Alkylene groups, e.g. * -COO-CH 2 -、 * -COO-CH 2 CH 2 -、 * -COO-CH(CH 3 )-、 * -COO-CH 2 CH 2 CH 2 -、 * -COO-CH(CH 3 )CH 2 -、 * -COO-C(CH 3 ) 2 -、 * -COO-CH 2 CH 2 CH 2 CH 2 -、 * -COO-CH(CH 3 )CH 2 CH 2 -、 * -COO-CH 2 CH 2 CH(CH 3 )-、 * -COO-CH 2 CH(CH 3 )CH 2 -or * -COO-CH 2 C(CH 3 ) 2 -, preferably * -COO-CH 2 CH 2 CH(CH 3 )-。
In one embodiment, in ring B, the 6-18 membered aromatic ring may be a 6-10 membered aromatic ring, preferably a benzene ring or naphthalene ring.
In one embodiment, in ring B, the 5-10 membered heteroaromatic ring may be a 5-6 membered heteroaromatic ring, preferably
In one embodiment, R 6 In the above, the C 1 ～C 6 Alkyl groups can independently be C 1 ～C 4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
In one embodiment, R 6 In the above, the C 1 ～C 6 Alkoxy groups can independently be C 1 ～C 4 Alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy.
In one embodiment, R 6 In (2), the halogen may be F, cl, br or I, preferably Br.
In one embodiment, t is 0, 1 or 2.
In one embodiment, the compound of formula VIII
In some embodiments, the catalyst is fac-Ir (ppy) in the difluoromethylation of the alcohol 3 。
In some embodiments, the molar ratio of the catalyst to the compound of formula VIII in the difluoromethylation reaction of the alcohol may be (0.05 to 0.5): 100 (e.g., 0.05:100, 0.1:100, 0.3:100, or 0.5:100), preferably (0.1 to 0.5): 100.
In one embodiment, the molar ratio of the compound of formula I to the compound of formula VIII in the difluoromethylation reaction of the alcohol is (1-2): 1 (e.g., 1:1, 1.5:1, or 2:1); preferably (1.5-2): 1.
In one embodiment, the difluoromethylation of the alcohol may be carried out in the presence of water in a molar ratio of (0-4): 1 (e.g., 0.5:1, 1:1, 2:1 or 4:1) to the compound of formula VIII; preferably (1-4): 1.
In one embodiment, the solvent is one or more of nitrile solvent (e.g., acetonitrile), halogenated hydrocarbon solvent (e.g., dichloromethane), ether solvent (e.g., tetrahydrofuran), amide solvent (e.g., N-dimethylformamide) and aromatic solvent (e.g., toluene), preferably aromatic solvent.
In one embodiment, the volume molar ratio of the solvent to the compound of formula VIII in the difluoromethylation reaction of the alcohol is from 5mL/mmol to 20mL/mmol (e.g., 10 mL/mmol); preferably 5-15mL/mmol.
In one embodiment, the temperature of the difluoromethylation reaction of the alcohol is 10-40 ℃; preferably 20-30 ℃.
In one embodiment, the wavelength of blue light in the difluoromethylation reaction of the alcohol is 463-475nm, for example, blue light LED.
The invention also provides any one of the following compounds:
unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In this specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds. When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left.
The section headings used herein are for purposes of organizing articles only and should not be construed as limiting the subject matter. All documents or portions of documents cited in this disclosure, including but not limited to patents, patent applications, articles, books, operating manuals, and treatises, are hereby incorporated by reference in their entirety.
Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C 1 -C 6 Alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the reduced notation does not include carbon that may be present in a substituent of the group.
In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below, unless otherwise specified.
In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
In the present application, as part of a group or other groups (e.g., as used in halogen-substituted alkyl groups and the like), the term "alkyl" is meant to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the indicated number of carbon atoms; for example, C 1 ～C 6 . As in "C 1 ～C 6 Alkyl "is defined to include groups having 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched chain structure. For example, in the present application, the C 1 ～C 6 Alkyl is each independently methyl, ethyl, propyl, butyl, pentyl or hexyl; wherein propyl is C 3 Alkyl (including isomers such as n-propyl or isopropyl); butyl is C 4 Alkyl (including isomers such as n-butyl, sec-butyl, isobutyl, or tert-butyl); pentyl is C 5 Alkyl (including isomers such as n-pentyl, 1-methyl-butyl, 1-ethyl-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, isopentyl, tertiary pentyl or neopentyl); hexyl is C 6 Alkyl (including isomers such as n-hexyl or isohexyl).
The term "alkoxy" refers to the group R X -O-，R X Is defined as the term "alkyl".
In the present application, the term "aryl" as part of a group or other group refers to a group ("C") having 6-10 ring atoms and zero heteroatoms provided in the aromatic ring system, either monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 shared p-electrons in a cyclic array) 6 -C 14 Aryl "). Examples of the above aryl unit include phenyl or naphthyl.
In the present application, as part of a group or other group, the term "heteroaryl" refers to a group ("5-10 membered heteroaryl") of a 4n+2 aromatic ring system having ring carbon atoms and 1-3 ring heteroatoms (each heteroatom independently selected from nitrogen, oxygen and sulfur) provided in the aromatic ring system, either 5-7 membered monocyclic or 8-10 polycyclic (e.g., bicyclic or tricyclic). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Thus, it is included that a heteroaryl ring is fused to one or more of the aryl groups as defined above, where the linkage is either on the aryl or on the heteroaryl ring, and in such cases the number of ring members is the number of ring members in the fused (aryl/heteroaryl) ring system. The point of attachment in a bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) where one ring does not include a heteroatom may be on one of the rings, i.e., either the ring carries a heteroatom (e.g., 2-indolyl) or the ring does not contain a heteroatom (e.g., 5-indolyl). The nitrogen, carbon or sulfur atom in the "heteroaryl" group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Heteroaryl groups within the scope of this definition, exemplary 5-membered heteroaryl groups include, but are not limited to: pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, furazanyl, oxazolyl. Exemplary 6-membered heteroaryl groups include, but are not limited to: pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl or tetrazinyl. Exemplary 5, 5-bicyclic heteroaryl groups include, but are not limited to, thienothioyl, thienofuranyl, thienopyrrolyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, imidazothiazolyl, or pyrazolooxazolyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoxazolyl, indazolyl, isoindazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, indolizinyl, pyrrolopyridinyl, pyridoxazolyl, pyridothiazolyl, imidazopyridazinyl, imidazopyrazinyl, pyridoimidazolyl, triazolopyridazinyl, triazolopyrazinyl, triazolopyridinyl, pyridopyridinyl, tetrazolopyridinyl, or purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to: quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, quinazolinyl, naphthyridinyl, pyridopyrimidine, pyrazinopyridazine or pteridinyl. Exemplary tricyclic heteroaryl groups include, but are not limited to: carbazolyl, dibenzofuranyl, carbolinyl, acridinyl, phenanthridinyl, phenanthroline, phenazinyl, bipyridine or bitrithiophene.
The term "halogen" as used herein means fluorine, chlorine, bromine, iodine, or astatine.
The term "cyano" as used herein means-CN.
The term "nitro" as used herein means-NO 2 。
The term "oxo" as used herein means =o.
The term "thio" as used herein means =s.
The term "aromatic ring" as used herein refers to any stable mono-or bi-cyclic carbocycle of up to 7 atoms in each ring, wherein at least one ring is an aromatic ring. Examples of the above aromatic ring unit include a benzene ring, a naphthalene ring, a tetrahydronaphthalene ring, a 2, 3-indane ring, a biphenyl ring, a phenanthrene ring, an anthracene ring, or an acenaphthene ring (acenaphthy). It will be appreciated that where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is through an "aromatic ring".
The term "heteroaryl" as used herein is intended to mean a stable single or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains 1-4 heteroatoms selected from O, N, and S. Heteroaryl rings within the scope of this definition include, but are not limited to: acridine, carbazole, cinnoline, carboline, quinoxaline, imidazole, pyrazole, pyrrole, indole, indoline, benzotriazole, benzimidazole, furan, thiophene, isothiazole, benzothiophene, dihydrobenzothiophene, benzofuran, isobenzofuran, benzoxazole, benzofurazan, benzopyrazole, quinoline, isoindoline, isoquinoline, oxazole, oxadiazole, isoxazole, indole, pyrazine, pyridopyridine, tetrazolopyridine, pyridazine, pyridine, naphthyridine, pyrimidine, pyrrole, tetrazole, thiadiazole, thiazole, thiophene, triazole, quinazoline, tetrahydroquinoline, dihydrobenzimidazole, dihydrobenzofuran, dihydrobenzoxazole, dihydroquinoline. As defined for the heterocycle below, a "heteroaryl ring" is also understood to include N-oxide derivatives of any nitrogen-containing heteroaryl ring. In the case where the heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or contains no heteroatoms, it is understood that the linkage occurs through the aromatic ring or through the heteroatom containing ring, respectively.
The terms "structural fragment", "group" as used herein refer to a particular fragment or functional group in a molecule.
Unless otherwise specified, all technical and scientific terms used herein have the standard meaning of the art to which the claimed subject matter belongs. In case there are multiple definitions for a term, the definitions herein control.
As used herein, the singular forms "a", "an", and "the" are understood to include plural referents unless the context clearly dictates otherwise.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the difluoro methylene reagent shown in the formula I can realize the gem difluoro cyclopropanation reaction of olefin and the difluoro methylation reaction of alcohol under photocatalysis, can be used as a photoinitiated difluoro carbene precursor, can release difluoro carbene under the condition of blue light at room temperature and neutrality, and provides important methodological support for the later modification of functional molecules in the fields of medicine, materials and the like.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
EXAMPLE 1 Synthesis of Dithioylide difluoromethylene reagent (reagent 1)
Diphenyl disulfide (21.8 g,100 mmol) was weighed into a 350mL Schlenk flask with stirrer, argon was exchanged three times, lithium t-butoxide (24.0 g,300 mmol) was weighed into the system in a glove box, and after addition of ultra-dry DMF (120 mL), the reaction was stirred at room temperature for 5min. Under the protection of argon, TMSCF is added into the system drop by drop 3 (29.6 mL,200 mmol) and the system was stirred at room temperature for 1h. At the end of the reaction, the reaction was quenched by addition of an appropriate amount of hydrochloric acid (1M), extracted with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and flash column chromatography (petroleum ether) to give the product as a colorless transparent liquid (17.1 g, 64%).
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.61(d,J＝7.1Hz,4H),7.45(t,J＝7.3Hz,2H),7.38(t,J＝7.9Hz,4H)； 19 F NMR(376MHz,CDCl 3 )δ-49.04(s,2F)； 13 C NMR(151MHz,CDCl 3 ,293K,TMS)δ136.15,132.24(t,J＝314.1Hz),130.17,129.09,127.30ppm.IR(KBr):ν max ＝3062,1475,1441,1042,1023,888,748,689,517,503cm -1 MS (EI): 159 (100), 268.HRMS (EI): calculated value C 13 H 10 F 2 S 2 268.0186, found 268.0190.
Weighing Rh 2 (esp) 2 (191 mg,0.250 mmol) in a 350mL Schlenk flask equipped with a stirrer, argon was purged three times, and the thioether prepared in the previous step (6.71 g,25.0 mmol) was added under argon protection, dissolved in ultra-dry dichloromethane (250 mL), and then the diazonium ester (11.9 g,75.0 mmol) was slowly added dropwise to the system, which was then allowed to react at room temperature under stirring for 24h. After the reaction, the solvent was removed by rotary evaporation, and the crude product was obtained by flash column chromatography (petroleum ether: ethyl acetate=1:5), dissolved in a small amount of dichloromethane, poured into a large amount of diethyl ether for recrystallization, and suction filtered to obtain the product as a pale yellow solid (11.3 g,85%, dr=2:1).
Mp:110-112℃. 1 H NMR(400MHz,CDCl 3 Tms, 293 k) delta 7.85 (d, j=8.1 hz, 2H), 7.76 (d, j=7.7 hz, 4H), 7.63-7.59 (m, 3H), 7.56-7.50 (m, 6H), 3.70 (s, 6H, minor isomer), 3.69 (s, 12H, major isomer); 19 F NMR(376MHz,CDCl 3 ) Delta-55.60 (d, j=128.1 hz,1F, major isomer), -61.19 (s, 1F, minor isomer), -64.30 (d, j=128.1 hz,1F, major isomer); 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ165.69,165.61,133.23,133.02,131.62(dd,J＝372.4,367.9Hz),130.25,130.19,130.14,129.48,127.80(t,J＝373.4Hz),126.46,126.20,56.04,55.73,51.67ppm.IR(KBr):ν max ＝3072,2946,1729,1697,1667,1438,1323,1242,1085,766,525cm -1 .MS(ESI):551.1(M + +Na). HRMS (ESI) calculated C 23 H 22 O 8 F 2 NaS 2 :551.06164(M + +Na), found 551.06108.
EXAMPLE 2 Synthesis of methoxy-substituted dithiol ylide reagent
Disulfide (4.18 g,15.0 mmol) was weighed into a 100mL Schlenk flask with a stirrer, argon was purged three times, lithium t-butoxide (3.60 g,45.0 mmol) was weighed into the system in a glove box, and after addition of ultra-dry DMF (18.0 mL), the reaction was stirred at room temperature for 5min. Under the protection of argon, TMSCF is added into the system drop by drop 3 (4.43 mL,30.0 mmol) and after the addition, the system was left to stir at room temperature for 1h. At the end of the reaction, the reaction was quenched by addition of an appropriate amount of hydrochloric acid (1M), extracted with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, and flash column chromatography (petroleum ether: ethyl acetate=50:1) to give the product as a pale yellow transparent liquid (1.9 g, 38%).
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.50(d,J＝8.7Hz,4H),6.88(d,J＝8.7Hz,4H),3.81(s,6H)； 19 F NMR(376MHz,CDCl 3 )δ-51.00(s,2F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ161.31,138.12,132.21(t,J＝313.9Hz),117.88,114.57,55.33ppm.IR(KBr):ν max ＝3006,2838,1592,1495,1293,1174,1030,889,828,529cm -1 MS (EI): 189 (100), 328.HRMS (EI): calculated value C 15 H 14 O 2 F 2 S 2 328.0398, found 328.0403.
Weighing Rh 2 (esp) 2 (31.0 mg,0.0400 mmol) in a 100mL Schlenk flask with a stirrer, argon was purged three times, and the thioether prepared in the previous step (1.31 g,4.00 mmol) was added under argon to dissolve in ultra-dry dichloromethane (40.0 mL), and then the diazonium ester (1.90 g,12.0 mmol) was slowly added dropwise to the system, which was then allowed to react at room temperature with stirring for 24h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography (petroleum ether: ethyl acetate=1:5) gave a crude product, which was dissolved in a small amount of dichloromethane and poured into The large amount of diethyl ether was recrystallized and filtered off with suction to give the product as a white solid (1.9 g,80%, dr=2:1).
Mp:84-86℃. 1 H NMR(500MHz,CDCl 3 Tms, 293 k) delta 7.81 (d, j=9.0 hz, 2H), 7.74 (d, j=9.0 hz, 4H), 6.95-6.90 (m, 6H), 3.78 (s, 6H), 3.77 (s, 3H), 3.62 (s, 12H, major isomer), 3.62 (s, 6H, minor isomer); 19 F NMR(376MHz,CDCl 3 ) Delta-58.59 (d, j=132.1 hz,1F, major isomer), -62.43 (s, 1F, minor isomer), -65.55 (d, j=132.1 hz,1F, major isomer); 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ165.57,165.52,163.48,163.41,133.10,132.58,130.47(dd,J＝368.4,364.0Hz),127.37(t,J＝369.7Hz),116.42,115.96,115.37,115.28,57.77,57.34,55.50,51.25ppm.IR(KBr):ν max ＝2950,2842,1728,1698,1663,1590,1435,1313,1181,1087,770,733,530cm -1 .MS(ESI):611.1(M + +Na). HRMS (ESI) calculated C 25 H 26 O 10 F 2 NaS 2 :611.08277(M + +Na), found 611.08250.
EXAMPLE 3 Synthesis of chloro-substituted dithiol ylide reagent
Disulfide (4.31 g,15.0 mmol) was weighed into a 100mL Schlenk flask with a stirrer, argon was purged three times, lithium t-butoxide (3.60 g,45.0 mmol) was weighed into the system in a glove box, and after addition of ultra-dry DMF (18.0 mL), the reaction was stirred at room temperature for 5min. Under the protection of argon, TMSCF is added into the system drop by drop 3 (4.43 mL,30.0 mmol) and after the addition, the system was left to stir at room temperature for 1h. At the end of the reaction, the reaction was quenched by addition of an appropriate amount of hydrochloric acid (1M), extracted with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated by rotary evaporation, redissolved with a small amount of ethyl acetate, poured into a large amount of petroleum ether, and recrystallized to give the product as a white needle-like solid (3.1 g, 61%).
Mp:132-134℃. 1 H NMR(500MHz,CDCl 3 ,293K,TMS)δ7.55-7.52(m,4H),7.40-7.38(m,4H)； 19 F NMR(376MHz,CDCl 3 )δ-49.43(s,2F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ137.46,137.07,131.82(t,J＝315.3Hz),129.50,125.49ppm.IR(KBr):ν max ＝3087,1571,1475,1389,1092,1045,1023,873,823,504cm -1 MS (EI) 193 (100), 336.HRMS (EI) calculated value C 13 H 8 Cl 2 F 2 S 2 335.9407, found 335.9406.
Weighing Rh 2 (esp) 2 (31.0 mg,0.0400 mmol) in a 100mL Schlenk flask with stirrer, argon was purged three times, and the thioether prepared in the previous step (1.35 g,4.00 mmol) was added under argon to dissolve in ultra-dry dichloromethane (40.0 mL), and then the diazonium ester (1.90 g,12.0 mmol) was slowly added dropwise to the system, which was then allowed to react at room temperature with stirring for 24h. After the reaction, the solvent was removed by rotary evaporation, and the crude product was obtained by flash column chromatography (petroleum ether: ethyl acetate=1:5), dissolved in a small amount of dichloromethane, poured into a large amount of diethyl ether for recrystallization, and suction filtered to obtain the product as a pale yellow solid (1.4 g,57%, dr=2:1).
Mp:121-123℃. 1 H NMR(500MHz,CDCl 3 Tms, 293 k) delta 7.77 (d, j=8.5 hz, 2H), 7.70 (d, j=8.5 hz, 4H), 7.49-7.45 (m, 6H), 3.66 (s, 6H, minor isomer), 3.65 (s, 12H, major isomer); 19 F NMR(376MHz,CDCl 3 ) Delta-55.96 (d, j=129.7 hz,1F, major isomer), -60.08 (s, 1F, minor isomer), -63.58 (d, j=129.6 hz,1F, major isomer); 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ165.50,165.42,140.29,140.05,131.65,131.28(dd,J＝370.4,371.7Hz),131.09,130.50,130.45,127.98(t,J＝374.2Hz),124.56,124.35,56.22,56.06,51.77ppm.IR(KBr):ν max ＝3412,2949,1702,1671,1645,1432,1325,1294,1088,822,766,503cm -1 .MS(ESI):619.0(M + +Na). HRMS (ESI) calculated C 23 H 20 O 8 F 2 NaS 2 Cl 2 :618.98369(M + +Na), found 618.98378.
EXAMPLE 4 Synthesis of methyl and nitro substituted dithioylide reagents
Into a dry 250mL round bottom flask equipped with a stirrer were added p-nitrophenol (4.70 g,30.0 mmol), p-toluenesulfonyl chloride (17.2 g,90.0 mmol) and 120mL acetonitrile, triphenylphosphine (47.2 g,180 mmol) was slowly added, and the round bottom flask was then placed in an oil bath at 80℃and stirred for 3h. After the reaction was completed, the reaction mixture was cooled to room temperature, the magnetons were removed, the solvent was removed by spin-drying under reduced pressure, and then 500mL of petroleum ether/diethyl ether (1:1) was used to extract the spin-dried solid, which was filtered, the filtrate was concentrated, and flash column chromatography (petroleum ether: ethyl acetate=20:1) was performed to obtain 6.5g of a yellow solid in 79% yield.
1 H NMR(500MHz,CDCl 3 ,293K,TMS)δ8.16(d,J＝8.9Hz,2H),7.65(d,J＝8.8Hz,2H),7.37(d,J＝8.1Hz,2H),7.13(d,J＝8.0Hz,2H),2.33(s,3H)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS):δ146.60,146.51,138.58,132.04,130.27,128.80,126.26,124.23,21.22ppm。
1- (4-nitrophenyl) -2- (p-tolyl) disulfane (2.80 g,10.0 mmol), PDFA (7.10 g,20.0 mmol), 80.0mL of 1, 4-dioxane were placed in a dry 250mL Schlenk flask equipped with a stirrer in an argon atmosphere, and stirred for 12h in an oil bath at 60 ℃. After the reaction was completed, after cooling to room temperature, 200mL of water was added for dilution, ethyl acetate (100 mL of x 3) was extracted and separated, and after the organic phases were combined, 100mL of water was used for backwashing, and the separated organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Flash column chromatography (petroleum ether: ethyl acetate=20:1) afforded 1.1g of yellow solid in 36% yield.
1 H NMR(500MHz,CDCl 3 ,293K,TMS)δ8.21(d,J＝8.8Hz,2H),7.73(d,J＝8.8Hz,2H),7.48(d,J＝7.9Hz,2H),7.22(d,J＝7.9Hz,2H),2.39(s,3H)； 19 F NMR(376MHz,CDCl 3 ,293K,TMS)δ-48.57ppm(s,2F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS):δ148.56,141.34,136.47,136.34,135.40,132.18(t,J＝315.5Hz),130.24,124.05,123.14,21.50ppm.IR(KBr):v max ＝3096,1600,1523,1347,1045,885,852,809cm -1 .MS(DART):328.0(M + +H). HRMS (DART) calculated value C 14 H 12 O 2 NF 2 S 2 :328.0272(M + +H), found 328.0273.
Rhodium (II) octanoate dimer (15.0 mg,0.0200 mmol) was weighed into a 50mL Schlenk flask with stirrer, argon was exchanged three times, under the protection of argon, (difluoro ((4-nitrophenyl) thio) methyl) (p-tolyl) sulfane (0.254 g,2.00 mmol) was added to dissolve in ultra-dry dichloromethane (20.0 mL), and then diazo acid ester (1.26 g,8.00 mmol) was slowly dropped into the system, which was then left to stir at room temperature for 12h. After the reaction, the solvent was removed by rotary evaporation, and the crude product was obtained by flash column chromatography (petroleum ether: acetone=3:1), dissolved in a small amount of dichloromethane, poured into a large amount of diethyl ether for recrystallization, and suction filtered to obtain the product as a yellow solid (0.7 g,61%, dr=2:1).
1 H NMR(400MHz,CDCl 3 Tms) δ8.39 (d, j=9.0 hz,2H, major isomer), 7.98 (d, j=9.0 hz,2H, major isomer), 7.66 (d, j=8.2 hz,2H, major isomer), 7.37 (d, j=8.2 hz,2H, major isomer), 3.72 (s, 6H, major isomer), 2.44 (s, 3H, major isomer), 8.35 (d, j=9.2 hz,2H, minor isomer), 8.03 (d, j=8.2 hz,2H, minor isomer), 7.76 (d, j=8.1 hz,2H, minor isomer), 7.35 (d, j=8.0 hz,2H, minor isomer), 3.74 (s, 6H, minor isomer), 3.72 (s, 6H, minor isomer), 2.43 (s, 3H, minor isomer); 19 F NMRδ(376MHz,CDCl 3 delta-55.2 ppm (d, j=128.2 Hz, major isomer), -63.2 (d, j=128.3 Hz, major isomer), -59.75ppm (d, j=126.0 Hz, minor isomer), -60.52ppm (d, j=126.5 Hz, minor isomer); 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ165.92,165.87,165.51,165.34,150.22,150.12,145.17,144.89,133.60,133.50,131.81(t,J＝371.7Hz),131.26,131.18,130.88,130.60,130.52,129.75,125.02,124.98,122.60,122.31,57.02,55.05,54.98,52.05,51.99,21.70.IR(KBr):v max ＝3105,1735,1530,1434,1310,1084,761cm -1 .MS(ESI):610.1(M + +Na). HRMS (ESI) calculated C 24 H 23 O 10 NF 2 NaS 2 :610.0624(M + +Na), found 610.0623.
EXAMPLE 5 Synthesis of nitro-substituted dithioylide reagent
1, 2-bis (4-nitrophenyl) disulfane (9.30 g,30.0 mmol), PDFA (15.0 g,42.0 mmol), 240mL of 1, 4-dioxane were placed in a dry 500mL Schlenk flask equipped with a stirrer and stirred in an oil bath at 60℃for 12h under an argon atmosphere in a glove box. After the reaction was completed, after cooling to room temperature, 200mL of water was added for dilution, ethyl acetate (200 mL of x 3) was extracted and separated, the organic phases were combined and backwashed with 20mL of water, separated, the organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. Flash column chromatography (petroleum ether: ethyl acetate=20:1) afforded 10.4g of yellow solid in 97% yield.
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ8.25(d,J＝8.4Hz,4H),7.76(d,J＝8.3Hz,4H)； 19 F NMR(376MHz,CDCl 3 ,293K,TMS)δ-47.37ppm(s,2F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ148.99,136.01,135.04,131.66(t,J＝317.5Hz),124.31.IR(KBr):v max ＝3101,1605,1547,1437,1348,1045,849,741cm -1 .LRMS(DART):359.0(M + +H). HRMS (DART) calculated value C 13 H 9 O 4 N 2 F 2 S 2 :359.9966(M + +H), found 358.9967.
Rhodium (II) octanoate dimer (78.0 mg,0.100 mmol) was weighed into a 250mL Schlenk flask equipped with a stirrer, argon was exchanged three times, difluoro bis ((4-nitrophenyl) thio) methane (3.58 g,10.0 mmol) was added under argon protection, dissolved in ultra-dry dichloromethane (100 mL), and then azoate (6.32 g,40.0 mmol) was slowly added dropwise to the system, and the system was stirred at room temperature for 12h after the dropwise addition. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography (petroleum ether: acetone=3:1) gave a crude product, which was dissolved in a small amount of dichloromethane, poured into a large amount of diethyl ether for recrystallization, and suction filtered to give the product as a yellow solid (3.0 g, 48%).
1 H NMR(500MHz,CDCl 3 δ8.39 (d, j=9.1 hz,4H, major isomer), 7.95 (d, j=8.6 hz,4H, major isomer), 3.70 (s, 12H, major isomer), δ8.37 (d, j= 8.7,4H, minor isomer), 8.02 (d, j=8.7 hz,4H, minor isomer), 3.74 (s, 12H, minor isomer). 19 F NMR(376MHz,CDCl 3 Delta-53.66 ppm (d, j=127.3 hz,1F, major isomer), -61.31 (d, j=127.2 hz,1F, major isomer), -57.95ppm (s, 2F, minor isomer); 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ165.46,165.28,150.39,150.26,132.91,132.81,132.11(t,J＝376.7Hz)130.87,130.37,125.19,125.16,55.81,55.27,52.24.IR(KBr):v max ＝3105,2953,1737,1530,1435,1346,1088,853,769cm -1 ；LRMS(ESI):641.0(M + +Na). HRMS (ESI) calculated C 23 H 20 O 12 N 2 F 2 NaS 2 :641.0318(M + +Na), found 641.0330.
Application example 1 application of dithiol ylide difluoromethylene reagent Using 1-photo-catalytic olefin geminal difluorocyclopropanation reaction
General operation steps: ir (ppy) is weighed 3 (0.002 mmol) and dithioylide difluoromethylene reagent (0.8 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, and under the protection of argon, an olefin substrate (0.4 mmol) and ultra-dry toluene (4 mL) were added, and the system was placed under irradiation of LED blue light and stirred at room temperature for 3 hours. And after the reaction is finished, removing the solvent by rotary evaporation, and performing flash column chromatography to obtain a product.
The conditions were explored as follows:
reaction conditions in solvent (1 mL), 4-vinylbiphenyl (0.1 mmol), ylide testReacting t h the agent (x equivalent) and the catalyst (y mol%) under blue LED irradiation; by passing through 19 F NMR (1-fluoronaphthalene as an internal standard) gave the yield.
The chemical formula shown below shows that no product is produced for the reaction under dark conditions, blue light is used to excite the photocatalyst Ir (ppy) 3 To an excited state, thereby completing the photocatalytic cycle.
Next we examined the substrates of the reaction. The reaction is applicable to monosubstituted or polysubstituted styrene substrates, the reaction is compatible with both electron donating group substitution and electron withdrawing group substitution on the aromatic ring, and in addition, the reaction is successfully applied to derivatization of estrone molecules (application examples a1-a 10).
Application example 2 application of dithioylide difluoromethylene reagent 2- -Difluoromethylation of photocatalytic alcohol
General operation steps: ir (ppy) is weighed 3 (0.0004 mmol) and dithioylide difluoromethylene reagent (0.6 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were added under the protection of argon, and the system was placed under LED blue light and stirred at room temperature for 3h. And after the reaction is finished, removing the solvent by rotary evaporation, and performing flash column chromatography to obtain a product.
The conditions were explored as follows:
reaction conditions in solvent (1 mL), phenethyl alcohol (0.1 mmol), ylide reagent (y equivalent) and fac-Ir (ppy) 3 (z mol%) and water (x equivalents) under blue LED irradiation t h; by passing through 19 F NMR (1-fluoronaphthalene as an internal standard) gave the yield.
Next we extended the substrates. The reaction is suitable for primary or secondary alcohol, the functional group compatibility is good, methoxy, halogen, cyano, ester groups and other groups are compatible, and corresponding products (application examples b1-b 10) can be obtained in good yield for thiophene heterocyclic substrates.
Application example a1
The operation steps are as follows: ir (ppy) is weighed 3 (0.002 mmol), dithioylide difluoromethylene reagent (0.8 mmol) and olefin substrate (0.4 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, ultra-dry toluene (4 mL) was added under the protection of argon, and the system was placed under the irradiation of LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a white solid (74 mg,80%, nuclear magnetic purity) >95％)。
Mp:66-68℃. 1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.62(t,J＝8.2Hz,4H),7.49(t,J＝7.6Hz,2H),7.40(t,J＝7.3Hz,1H),7.34(d,J＝8.1Hz,2H),2.87-2.79(m,1H),1.93-1.84(m,1H),1.74-1.66(m,1H)； 19 F NMR(376MHz,CDCl 3 )δ-125.71(dtd,J＝153.8,12.9,3.9Hz,1F),-142.18(ddd,J＝153.8,12.7,4.9Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ140.57,140.07,132.70,128.77,128.38,127.32,127.15,127.00,112.60(dd,J＝287.1,283.9Hz),26.91(t,J＝11.7Hz),17.09(t,J＝10.3Hz)ppm.IR(KBr):ν max ＝3080,3031,1467,1245,1190,1048,937,839,764,731,687,496cm -1 MS (EI) 230 (100), 230.HRMS (EI) calculated value C 15 H 12 F 2 230.0902, found 230.0903.
Application instance a2
The operation steps are as follows: ir (ppy) is weighed 3 (0.002 mmol) and dithioylide difluoromethylene reagent (0.8 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, and under the protection of argon, an olefin substrate (0.4 mmol) and ultra-dry toluene (4 mL) were added, and the system was placed under irradiation of LED blue light and stirred at room temperature for 3 hours. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a brown transparent liquid (52 mg,66%, nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.13(d,J＝8.7Hz,2H),6.75(d,J＝8.7Hz,2H),2.96(s,6H),2.74-2.66(m,1H),1.80-1.71(m,1H),1.55(dtd,J＝11.8,7.9,3.8Hz,1H)； 19 F NMR(376MHz,CDCl 3 )δ-126.20(dtd,J＝152.6,13.2,3.8Hz,1F),-142.37(ddd,J＝152.5,12.7,4.7Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ148.52,127.81,120.53,111.99(dd,J＝286.8,283.9Hz),111.74,39.72,25.41(t,J＝11.6Hz),15.71(t,J＝10.5Hz)ppm.IR(KBr):ν max ＝2889,1619,1529,1470,1361,1236,1200,1048,931,818,735,516cm -1 MS (EI) 196 (100), 197.HRMS (EI) calculated value C 11 H 13 NF 2 197.1011, found 197.1009.
Application example a3
The operation steps are as follows: ir (ppy) is weighed 3 (0.002 mmol), dithioylide difluoromethylene reagent (0.8 mmol) and olefin substrate (0.4 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, ultra-dry toluene (4 mL) was added under the protection of argon, and the system was placed under the irradiation of LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a white solid (51 mg,41% nuclear magnetic purity)>95％)。
Mp:108-110℃. 1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.83(dd,J＝5.4,3.1Hz,2H),7.70(dd,J＝5.4,3.0Hz,2H),7.40(d,J＝8.1Hz,2H),7.17(d,J＝8.0Hz,2H),4.83(s,2H),2.70(td,J＝12.4,8.2Hz,1H),1.79(tdd,J＝12.4,7.9,4.9Hz,1H),1.58(dtd,J＝12.1,8.0,3.9Hz,1H)； 19 F NMR(376MHz,CDCl 3 )δ-125.90(dtt,J＝154.0,12.9,3.8Hz,1F),-142.30(ddd,J＝154.0,12.7,4.7Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ167.96,135.28,133.97,133.30,132.01,128.76,128.29,123.30,112.42(dd,J＝286.6,284.4Hz),41.15,26.83(t,J＝11.4Hz),17.02(t,J＝10.3Hz)ppm.IR(KBr):ν max ＝3109,1770,1708,1467,1400,1295,1227,1032,940,733,532cm -1 MS (EI) 160 (100), 313.HRMS (EI) calculated value C 18 H 13 O 2 NF 2 313.0909, found 313.0915.
Application example a4
The operation steps are as follows: ir (ppy) is weighed 3 (0.002 mmol) and dithioylide difluoromethylene reagent (0.8 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, and under the protection of argon, an olefin substrate (0.4 mmol) and ultra-dry toluene (4 mL) were added, and the system was placed under irradiation of LED blue light and stirred at room temperature for 3 hours. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (89 mg,92% nuclear magnetic purity) >95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.50(d,J＝8.6Hz,2H),6.90(d,J＝8.7Hz,2H),3.80(s,3H),2.09-2.01(m,4H),1.91(ddd,J＝15.0,9.8,5.2Hz,1H)； 19 F NMR(376MHz,CDCl 3 )δ-133.54(ddd,J＝160.5,13.3,5.2Hz,1F),-139.30(ddd,J＝160.5,15.0,6.6Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ169.46,160.06,131.23,124.58,113.70,110.29(t,J＝291.6Hz),61.56(dd,J＝12.7,9.5Hz),55.18,23.03(t,J＝10.1Hz),20.72ppm.IR(KBr):ν max ＝2939,1766,1519,1466,1232,1134,1024,896,837,549cm -1 MS (FI) 242.HRMS (FI) calculated C 12 H 12 O 3 F 2 242.0749, found 242.0751.
Application example a5
The operation steps are as follows: ir (ppy) is weighed 3 (0.002 mmol) and dithioylide difluoromethylene reagent (0.8 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, and under the protection of argon, an olefin substrate (0.4 mmol) and ultra-dry toluene (4 mL) were added, and the system was placed under irradiation of LED blue light and stirred at room temperature for 3 hours. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (99 mg,85%, nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.51(d,J＝8.5Hz,2H),7.40(d,J＝8.4Hz,2H),2.11-2.04(m,4H),1.94(ddd,J＝15.4,10.0,5.6Hz,1H)； 19 F NMR(376MHz,CDCl 3 )δ-133.91(ddd,J＝161.8,13.5,5.5Hz,1F),-139.04(ddd,J＝161.9,14.6,6.6Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ169.38,131.65,131.61,130.99,123.41,109.86(t,J＝293.0Hz),61.21(dd,J＝12.6,10.0Hz),23.10(t,J＝10.1Hz),20.66ppm.IR(KBr):ν max ＝3108,2925,1774,1758,1459,1370,1231,1210,1145,991,836,769,549cm -1 MS (FI) 290.HRMS (FI) calculated C 11 H 9 O 2 F 2 Br 289.9749, found 289.9755.
Application example a6
The operation steps are as follows: ir (ppy) is weighed 3 (0.002 mmol) and dithioylide difluoromethylene reagent (0.8 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, and under the protection of argon, an olefin substrate (0.4 mmol) and ultra-dry toluene (4 mL) were added, and the system was placed under irradiation of LED blue light and stirred at room temperature for 3 hours. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (60 mg,78%, nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.63(d,J＝8.4Hz,2H),7.42(d,J＝8.3Hz,2H),1.70(ddd,J＝13.7,7.8,3.6Hz,1H),1.53-1.46(m,4H)； 19 F NMR(471MHz,CDCl 3 )δ-132.24(d,J＝151.8Hz,1F),-137.29(d,J＝151.8Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ144.31,132.36,129.19,118.56,113.66(dd,J＝290.5,287.1Hz),111.16,30.95(t,J＝10.2Hz),22.65(t,J＝9.9Hz),20.75(d,J＝5.4Hz)ppm.IR(KBr):ν max ＝2985,2230,1610,1509,1472,1216,1005,906,841,741,580cm -1 MS (EI) 178 (100), 193.HRMS (EI) calculated value C 11 H 9 NF 2 193.0698, found 193.0697.
Application instance a7
The operation steps are as follows: ir (ppy) is weighed 3 (0.002 mmol) and dithioylide difluoromethylene reagent (0.8 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, and under the protection of argon, an olefin substrate (0.4 mmol) and ultra-dry toluene (4 mL) were added, and the system was placed under irradiation of LED blue light and stirred at room temperature for 3 hours. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a pale yellow transparent liquid (42 mg,47%, nuclear magnetic purity) >95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.96(d,J＝8.3Hz,2H),7.23(d,J＝8.3Hz,2H),3.89(s,3H),2.30(dd,J＝13.4,7.6Hz,1H),1.93-1.83(m,1H),1.34(dd,J＝6.2,1.2Hz,3H)； 19 F NMR(376MHz,CDCl 3 )δ-136.97(dd,J＝153.5,13.5Hz,1F),-138.12(ddd,J＝153.6,14.4,1.8Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ166.77,139.66,129.64,128.67,127.66,114.36(dd,J＝291.5,289.6Hz),52.06,34.08(t,J＝11.0Hz),24.97(t,J＝9.8Hz),11.36(d,J＝4.9Hz)ppm.IR(KBr):ν max ＝2953,1724,1612,1477,1437,1281,1186,1111,1024,987,868,711cm -1 MS (EI): 195 (100), 226.HRMS (EI): calculated value C 12 H 12 O 2 F 2 226.0800, found 226.0803.
Application example a8
The operation steps are as follows: ir (ppy) is weighed 3 (0.002 mmol), dithioylide difluoromethylene reagent (0.8 mmol) and olefin substrate (0.4 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, ultra-dry toluene (4 mL) was added under the protection of argon, and the system was placed under the irradiation of LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave colorless transparent liquid (67 mg,71%, nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.39-7.37(m,1H),7.24-7.22(m,2H),7.15-7.13(m,1H),2.91-2.87(m,1H),2.67-2.58(m,1H),2.23-2.03(m,6H)； 19 F NMR(376MHz,CDCl 3 )δ-129.84(dd,J＝159.6,16.6Hz,1F),-142.42(d,J＝159.5Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ169.62,135.46,128.72,128.37,127.76,126.52,125.51,111.68(dd,J＝301.2,299.1Hz),59.34(dd,J＝15.3,10.5Hz),30.35(dd,J＝10.8,8.2Hz),26.27(d,J＝5.2Hz),20.88,15.33ppm.IR(KBr):ν max ＝2945,1770,1471,1371,1212,1150,1022,917,792,551cm -1 MS (EI): 168 (100), 238.HRMS (EI): calculated value C 13 H 12 O 2 F 2 238.0800, found 238.0801.
Application example a9
The operation steps are as follows: ir (ppy) is weighed 3 (0.002 mmol) and dithioylide difluoromethylene reagent (0.8 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, and under the protection of argon, an olefin substrate (0.4 mmol) and ultra-dry toluene (4 mL) were added, and the system was placed under irradiation of LED blue light and stirred at room temperature for 3 hours. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (80 mg,88% nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.14(d,J＝8.1Hz,2H),6.87(d,J＝8.7Hz,2H),3.80(s,3H),1.38-1.37(m,3H),1.30(d,J＝2.4Hz,3H),0.91(s,3H)； 19 F NMR(376MHz,CDCl 3 )δ-140.69(d,J＝146.3Hz,1F),-143.58(d,J＝147.0Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ158.16,131.54,130.36,117.53(dd,J＝299.5,294.3Hz),113.74,55.14,33.54(t,J＝10.1Hz),27.38(t,J＝9.7Hz),18.22-18.18(m),14.96(d,J＝5.7Hz)ppm.IR(KBr):ν max ＝2958,1612,1516,1296,1248,1155,1099,1035,989,833,607,560cm -1 MS (EI): 211 (100), 226.HRMS (EI): calculated value C 13 H 16 OF 2 226.1164, found 226.1159.
Application example a10
The operation steps are as follows: ir (ppy) is weighed 3 (0.002 mmol), dithioylide difluoromethylene reagent (0.8 mmol) and olefin substrate (0.4 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, ultra-dry toluene (4 mL) was added under the protection of argon, and the system was placed under the irradiation of LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a white solid (98 mg,74% nuclear magnetic purity) >95％)。
Mp:107-109℃. 1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.25(d,J＝8.0Hz,1H),7.01(d,J＝8.2Hz,1H),6.97(s,1H),2.91(dd,J＝8.7,3.8Hz,2H),2.69(td,J＝12.5,8.3Hz,1H),2.50(dd,J＝18.8,8.7Hz,1H),2.44-2.40(m,1H),2.28(dd,J＝13.6,6.9Hz,1H),2.19-1.95(m,4H),1.78(tdd,J＝12.3,7.8,4.8Hz,1H),1.68-1.38(m,7H),0.90(s,3H)； 19 F NMR(376MHz,CDCl 3 )δ-125.94(dtt,J＝153.4,13.1,3.9Hz,1F),-142.30(ddd,J＝153.4,12.7,4.8Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ220.79,138.70,136.59,130.97,128.59,125.46,125.29,112.62(t,J＝287.0Hz),50.38,47.90,44.20,38.00,35.78,31.49,29.28,26.71(t,J＝11.4Hz),26.37,25.60,21.51,16.79(td,J＝10.5,3.6Hz),13.76ppm.IR(KBr):ν max ＝2943,1739,1504,1470,1375,1245,1209,1046,841,824cm -1 MS (FI) 330.HRMS (FI) calculated C 21 H 24 OF 2 330.1790, found 330.1784.
Application example b1
The operation steps are as follows: ir (ppy) is weighed 3 (0.0004 mmol) and dithioylide difluoromethylene reagent (0.6 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were added under the protection of argon, and the system was placed under LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (51 mg,74% nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.33-7.30(m,2H),7.26-7.22(m,3H),6.18(t,J＝74.8Hz,1H),4.06(t,J＝7.1Hz,2H),2.96(t,J＝7.1Hz,2H)； 19 F NMR(376MHz,CDCl 3 )δ-84.20(d,J＝74.8Hz,2F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ137.49,128.92,128.57,126.71,116.03(t,J＝260.8Hz),64.02(t,J＝5.6Hz),35.72ppm.IR(KBr):ν max ＝2964,1498,1456,1363,1190,1016,750,700,492cm -1 MS (EI) 172 (100), 172.HRMS (EI) calculated value C 9 H 10 OF 2 172.0694, found 172.0698.
Application instance b2
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The operation steps are as follows: ir (ppy) is weighed 3 (0.0004 mmol) and dithioylide difluoromethylene reagent (0.6 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were added under the protection of argon, and the system was placed under LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (65 mg,80%, nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.16(d,J＝8.4Hz,2H),6.87(d,J＝8.5Hz,2H),6.19(t,J＝74.9Hz,1H),4.03(t,J＝7.1Hz,2H),3.80(s,3H),2.91(t,J＝7.1Hz,2H)； 19 F NMR(376MHz,CDCl 3 )δ-84.08(d,J＝74.9Hz,2F)； 13 C NMR(151MHz,CDCl 3 ,293K,TMS)δ158.37,129.83,129.43,116.02(t,J＝260.2Hz),113.93,64.27(t,J＝5.0Hz),55.20,34.80ppm.IR(KBr):ν max ＝2962,1614,1515,1302,1250,1179,1035,830cm -1 MS (EI) 121 (100), 202.HRMS (EI) calculated value C 10 H 12 O 2 F 2 202.0800, found 202.0795.
Application example b3
The operation steps are as follows: ir (ppy) is weighed 3 (0.0004 mmol) and dithioylide difluoromethylene reagent (0.6 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were added under the protection of argon, and the system was placed under LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (70 mg,85%, nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.15(dd,J＝8.3,5.6Hz,2H),6.99(t,J＝8.7Hz,2H),6.22(t,J＝75.0Hz,1H),3.85(t,J＝6.3Hz,2H),2.71(t,J＝7.6Hz,2H),1.98-1.91(m,J＝13.7,2H)； 19 F NMR(376MHz,CDCl 3 )δ-83.92(d,J＝75.0Hz,2F),-117.47--117.54(m,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ161.40(d,J＝243.9Hz),136.72(d,J＝3.3Hz),129.84(d,J＝7.8Hz),116.15(t,J＝259.6Hz),115.21(d,J＝21.2Hz),62.52(t,J＝5.5Hz),30.95(d,J＝19.5Hz)ppm.IR(KBr):ν max ＝2968,1490,1403,1363,1189,1135,1074,1012,808,512cm -1 MS (FI) 204.HRMS (FI) calculated C 10 H 11 OF 3 204.0757, found 204.0760.
Application example b4
The operation steps are as follows: ir (ppy) is weighed 3 (0.0004 mmol) and dithioylide difluoromethylene reagent (0.6 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were added under the protection of argon, and the system was placed under LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (84 mg,84% nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.44(d,J＝8.3Hz,2H),7.11(d,J＝8.3Hz,2H),6.18(t,J＝74.6Hz,1H),4.05(t,J＝6.9Hz,2H),2.91(t,J＝6.9Hz,2H)； 19 F NMR(376MHz,CDCl 3 )δ-84.33(d,J＝74.6Hz,2F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ136.51,131.56,130.60,120.52,115.86(t,J＝261.4Hz),63.44(t,J＝5.6Hz),35.01ppm.IR(KBr):ν max ＝2967,1602,1511,1159,1132,1016,822,755,531cm -1 MS (FI) 250.HRMS (FI) calculated C 9 H 9 OBrF 2 249.9799, found 249.9806.
Application instance b5
The operation steps are as follows: ir (ppy) is weighed 3 (0.0004 mmol) and dithioylide difluoromethylene reagent (0.6 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were added under the protection of argon, and the system was placed under LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a pale yellow transparent liquid (45 mg,49% nuclear magnetic purity) >95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.45(d,J＝8.6Hz,2H),7.19(dd,J＝8.2,1.7Hz,1H),6.32(t,J＝73.7Hz,1H),4.85(s,2H)； 19 F NMR(376MHz,CDCl 3 )δ-84.61(d,J＝73.6Hz,2F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ135.65,132.74,132.41,130.58,129.60,126.87,115.63(t,J＝262.3Hz),63.50(t,J＝6.3Hz)ppm.IR(KBr):ν max ＝2963,1567,1471,1440,1359,1211,1185,1135,1086,1016,750cm -1 MS (FI) 226.HRMS (FI) calculated C 8 H 6 OCl 2 F 2 225.9758, found 225.9757.
Application example b6
The operation steps are as follows: ir (ppy) is weighed 3 (0.0004 mmol) and dithioylide difluoromethylene reagent (0.6 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were added under the protection of argon, and the system was placed under LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (52 mg,46%, nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.86(d,J＝7.9Hz,1H),7.45(d,J＝7.4Hz,1H),7.38(t,J＝7.5Hz,1H),7.04(t,J＝7.6Hz,1H),6.38(t,J＝74.2Hz,1H),4.92(s,2H)； 19 F NMR(376MHz,CDCl 3 )δ-84.32(d,J＝74.1Hz,2F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ139.41,137.87,129.90,128.88,128.49,115.97(t,J＝261.9Hz),97.44,69.19(t,J＝5.8Hz)ppm.IR(KBr):ν max ＝2963,1475,1385,1354,1186,1133,1089,1033,818,687cm -1 MS (FI) 284.HRMS (FI) calculated C 8 H 7 OF 2 283.9504, 283.9511.
Application instance b7
The operation steps are as follows: ir (ppy) is weighed 3 (0.0004 mmol), dithioylide difluoromethylene testAgent (0.6 mmol) in a 25mL Schlenk tube, argon was purged three times, under argon protection, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were added and the system was placed under LED blue light with stirring at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (47 mg,59% nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.60(d,J＝8.1Hz,2H),7.34(d,J＝8.1Hz,2H),6.18(t,J＝74.2Hz,1H),4.09(t,J＝6.6Hz,2H),3.01(t,J＝6.6Hz,2H)； 19 F NMR(376MHz,CDCl 3 )δ-84.68(d,J＝74.2Hz,2F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ143.25,132.27,129.69,118.81,115.70(t,J＝262.1Hz),110.63,62.73(t,J＝5.7Hz),35.61ppm.IR(KBr):ν max ＝2970,2229,1610,1507,1364,1185,1131,1086,1015,841,570cm -1 MS (FI) 197.HRMS (FI) calculated C 10 H 9 ONF 2 197.0647, found 197.0648.
Application instance b8
The operation steps are as follows: ir (ppy) is weighed 3 (0.0004 mmol) and dithioylide difluoromethylene reagent (0.6 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were added under the protection of argon, and the system was placed under LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (60 mg,85%, nuclear magnetic purity) >95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.29(dd,J＝4.8,3.0Hz,1H),7.07-7.06(m,1H),7.00(d,J＝4.9Hz,1H),6.22(t,J＝74.7Hz,1H),4.08(t,J＝6.9Hz,2H),3.01(t,J＝6.9Hz,2H)； 19 F NMR(376MHz,CDCl 3 )δ-84.20(d,J＝74.8Hz,2F)； 13 C NMR(151MHz,CDCl 3 ,293K,TMS)δ137.70,128.15,125.65,121.65,116.00(t,J＝260.5Hz),63.36(t,J＝5.3Hz),30.14ppm.IR(KBr):ν max ＝2967,1402,1362,1189,1135,1085,1012,777,634cm -1 MS (FI) 178.HRMS (FI) calculated C 7 H 8 OF 2 S178.0258, found 178.0255.
Application example b9
The operation steps are as follows: ir (ppy) is weighed 3 (0.0004 mmol) and dithioylide difluoromethylene reagent (0.6 mmol) were placed in a 25mL Schlenk tube, argon was exchanged three times, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were added under the protection of argon, and the system was placed under LED blue light and stirred at room temperature for 3h. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (26 mg,29% nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.89-7.80(m,4H),7.53-7.48(m,3H),6.21(dd,J＝77.9,73.5Hz,1H),5.35(q,J＝6.5Hz,1H),1.67(d,J＝6.5Hz,3H)； 19 F NMR(376MHz,CDCl 3 )δ-81.56(dd,J＝163.5,77.9Hz,1F),-83.11(dd,J＝163.5,73.5Hz,1F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ138.60,133.13,133.10,128.65,127.98,127.71,126.39,126.25,124.95,123.64,116.26(dd,J＝262.1,255.8Hz),74.26(t,J＝4.2Hz),23.66ppm.IR(KBr):ν max ＝2985,1509,1455,1379,1201,1130,1071,1020,897,820,749cm - 1 MS (EI): 207 (100), 222.HRMS (EI): calculated value C 13 H 12 OF 2 222.0851, found 222.0857.
Application instance b10
The operation steps are as follows: ir (ppy) is weighed 3 (0.0004 mmol), dithioylide difluoromethylene reagent (0.6 mmol) in a 25mL Schlenk tube, argon was purged three times, under argon protection, alcohol (0.4 mmol), deionized water (0.8 mmol) and ultra-dry toluene (4 mL) were addedThe system is placed under the blue light of an LED and stirred at room temperature for reaction for 3 hours. After the reaction, the solvent was removed by rotary evaporation, and flash column chromatography gave a colorless transparent liquid (57 mg,51%, nuclear magnetic purity)>95％)。
1 H NMR(400MHz,CDCl 3 ,293K,TMS)δ7.96(d,J＝8.3Hz,2H),7.41(d,J＝8.3Hz,2H),6.24(t,J＝74.9Hz,1H),4.52-4.35(m,3H),2.00(q,J＝6.4Hz,2H),1.36(d,J＝6.2Hz,3H)； 19 F NMR(376MHz,CDCl 3 )δ-80.67--81.87(m,2F)； 13 C NMR(126MHz,CDCl 3 ,293K,TMS)δ165.55,139.39,130.89,128.70,128.53,117.12(t,J＝260.2Hz),68.85(t,J＝4.3Hz),61.34,35.74,21.55ppm.IR(KBr):ν max ＝2982,1717,1596,1489,1402,1274,1209,1105,1016,851,760,686cm -1 MS (FI) 278.HRMS (FI) calculated C 12 H 13 O 3 ClF 2 278.0516, found 278.0517.
HPLC (IB, 0.46×25cm,5 μm, n-hexane/isopropanol=96/4 (ν/ν%), flow rate 0.7mL/min, uv detection wavelength 214 nm), retention time=6.87 min (minor) and 7.38min (major) [ α ] D 25 ＝-21.3(c 1.0,CHCl 3 ,93％ee)。

Claims (12)

1. A compound of formula I:
wherein m and n are independently 0, 1, 2, 3, 4 or 5;
R 7 and R is 8 Independently C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, nitro or halogen;
e is CO 2 R 9 ；
R 9 Is C 1 ～C 6 An alkyl group.
2. A compound of formula I according to claim 1, which satisfies one or more of the following conditions:
(1) n and m are independently 0, 1 or 2, for example 0 or 1;
(2)R 7 and R is as described 8 The same or different;
(3) Said R is 7 And R is as described 8 Wherein said halogen is independently F, cl, br or I, preferably Cl;
(4) Said R is 7 And R is as described 8 independently-CH 3 、-OCH 3 、-NO 2 or-Cl;
(5) Said R is 9 Is methyl.
3. The compound shown in the formula I as claimed in claim 2, wherein the compound shown in the formula I is any one of the following compounds,
4. a process for the preparation of a compound of formula I comprising the steps of:
step (1) is method 1 or method 2:
method 1: in an organic solvent, in the presence of (trifluoromethyl) trimethylsilane and alkali, carrying out the following reaction on the compound shown in the formula II to obtain a compound shown in the formula III;
method 2: in an organic solvent, in the presence of (triphenylphosphine) difluoroacetic acid inner salt, carrying out the following reaction on the compound shown in the formula II to obtain a compound shown in the formula III;
Step (2): in an organic solvent, in the presence of a catalyst, carrying out the following reaction on a compound shown in a formula III and a compound shown in a formula IV to obtain a compound shown in a formula I;
wherein R is 7 、R 8 M, n, E and R 9 Is as defined in any one of claims 1 to 3.
5. The method of preparing a compound of formula I according to claim 4, wherein the method of preparing meets one or more of the following conditions:
(1) In the method 1, the organic solvent is an amide solvent, such as N, N-dimethylformamide and/or N, N-dimethylacetamide, preferably N, N-dimethylformamide;
(2) In the method 1, the alkali is one or more of lithium tert-butoxide, potassium tert-butoxide and sodium tert-butoxide, preferably lithium tert-butoxide;
(3) In process 1, the molar ratio of the base to the compound of formula II is from 1.5:1 to 5:1, preferably from 2:1 to 4:1, for example 3:1;
(4) In process 1, the molar ratio of (trifluoromethyl) trimethylsilane to the compound of formula II is from 1.5:1 to 3:1, preferably from 1.5:1 to 2.5:1, for example 2:1;
(5) In process 1, the molar concentration of the compound of formula II in the organic solvent is from 0.2 to 1.2mol/L, preferably from 0.5 to 1mol/L, for example 0.8mol/L;
(6) In method 1, the temperature of the reaction is 0-60 ℃, preferably 20-30 ℃;
(7) In method 2, the organic solvent is an ether solvent, such as dioxane, preferably 1, 4-dioxane;
(8) In process 2, the molar ratio of the (triphenylphosphine) internal salt of difluoroacetic acid to the compound of formula II is from 1.2:1 to 3:1, preferably from 1.2:1 to 2.5:1, for example 2:1 or 1.4:1;
(9) In method 2, the molar concentration of the compound of formula II in the organic solvent is 0.1 to 1.2mol/L, preferably 0.1 to 1mol/L, for example 0.125mol/L;
(10) In method 2, the temperature of the reaction is 0-80 ℃, preferably 55-65 ℃;
(11) In process 1 or process 2, the reaction is carried out under nitrogen or under an inert gas atmosphere, preferably under nitrogen atmosphere;
(12) In the step (2), the organic solvent is a halogenated hydrocarbon solvent and/or an aromatic solvent; the halogenated hydrocarbon solvent is preferably one or more of dichloromethane, chloroform and 1, 2-dichloroethane; the aromatic solvent is preferably one or more of toluene, xylene, chlorobenzene and benzotrifluoride; the organic solvent is preferably dichloromethane and/or toluene, more preferably dichloromethane;
(13) In the step (2), the catalyst is Rh 2 (esp) 2 、Rh 2 (OAc) 4 And Rh 2 (C 7 H 15 CO 2 ) 4 Preferably Rh 2 (esp) 2 Or Rh 2 (C 7 H 15 CO 2 ) 4 ；
(14) In the step (2), the molar ratio of the catalyst to the compound shown as the formula III is (0.5-2): 100, preferably (0.8-1.5): 100, for example 1:100;
(15) In step (2), the molar ratio of the compound of formula IV to the compound of formula III is 1.5:1 to 5:1, preferably 2:1 to 4:1, for example 3:1 or 4:1, a step of;
(16) In the step (2), the molar concentration of the compound represented by the formula III in the organic solvent is 0.05 to 0.2mol/L, preferably 0.02 to 0.15mol/L, for example 0.1mol/L;
(17) In step (2), the temperature of the reaction is 0-40 ℃, preferably 20-30 ℃;
(18) In step (2), the reaction is carried out under the protection of nitrogen or inert gas, preferably under the protection of argon;
(19) In the step (2), the compound shown in the formula IV is slowly dripped into a solution of the compound shown in the formula III and the organic solvent.
6. A compound of any one of:
7. use of a compound of formula I according to any one of claims 1 to 3 in an organic synthesis reaction, which is a geminal difluorocyclopropanation reaction of an olefin or a difluoromethylation reaction of an alcohol.
8. The use of claim 7, wherein the use satisfies one or more of the following conditions:
(1) The geminal difluorocyclopropanation reaction of the olefin comprises the following steps: in an organic solvent, under the existence of a catalyst and a compound shown as a formula I, carrying out geminal difluorocyclopropanation reaction on the compound containing the fragment shown as a formula V under the irradiation of blue light to obtain a compound containing the fragment shown as a formula Va;
(2) The difluoromethylation reaction of the alcohol comprises the following steps: in a solvent, under the existence of a catalyst and a compound shown as a formula I, carrying out difluoromethylation reaction on the compound containing a fragment shown as a formula VI under the irradiation of blue light to obtain a compound containing a fragment shown as a formula VIb;
E、m、n、R 7 and R is 8 Is as defined in any one of claims 1 to 3.
9. The use of claim 8, wherein the use satisfies one or more of the following conditions:
(1) The geminal difluorocyclopropanation reaction of the olefin comprises the following steps: in an organic solvent, under the existence of a catalyst and a compound shown as a formula I, carrying out geminal difluoro cyclopropanation reaction on the compound shown as a formula VII under the irradiation of blue light to obtain a compound shown as a formula VIIa;
Wherein R is 1 Is that
R 3 Is hydrogen or C 1 ～C 6 An alkyl group;
alternatively, R 3 And R is 1 Together with the atoms to which they are attached, form a 9-18 membered aromatic ring;
ring A is a 6-20 membered aromatic ring;
R 5 independently C 1 ～C 6 Alkyl, substituted by one or more R 5-1 Substituted C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, -COOC 1 ～C 6 Alkyl, 6-10 membered aryl, -NR b R c Halogen, cyano, oxo or thioxo;
R 5-1 independently is one or more R 5-1-1 Substituted 5-10 membered heteroaryl, C 1 ～C 6 Alkoxy, -NR b R c Halogen or cyano; in the 5-10 membered heteroaryl, the heteroatom is selected from 1, 2 or 3 in N, O and S, and the heteroatom number is 1, 2 or 3;
R 5-1-1 independently oxo;
R b and R is c Independently C 1 ～C 6 An alkyl group;
k is 0, 1 or 2;
R 2 is hydrogen, C 1 ～C 6 Alkyl or-OC (O) -C 1 ～C 6 An alkyl group;
R 4 is hydrogen or C 1 ～C 6 An alkyl group;
(2) The difluoromethylation reaction of the alcohol comprises the following steps:
in a solvent, under the existence of a catalyst and a compound shown as a formula I, carrying out difluoromethylation reaction on the compound shown as a formula VIII under the irradiation of blue light to obtain a compound shown as a formula VIIIb;
wherein L is C 1 ～C 6 Alkylene or-COOC 1 ～C 6 Alkylene-, connected to ring B via the terminal;
ring B is a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring; in the 5-10 membered heteroaromatic ring, the heteroatom is selected from 1, 2 or 3 in N, O and S, and the heteroatom number is 1, 2 or 3;
R 6 Independently C 1 ～C 6 Alkyl, C 1 ～C 6 Alkoxy, halogen or cyano;
t is 0, 1, 2 or 3;
(3) In the geminal difluorocyclopropanation of olefins, the catalyst is Ir (ppy) 3 、Ir(p- t Bu-ppy) 3 、Ru(bpy) 3 (PF 6 ) 2 And rhodamine 6G, preferably Ir (ppy) 3 And/or Ir (p- t Bu-ppy) 3 ；
(4) In the geminal difluorocyclopropanation of the olefin, the molar ratio of the catalyst to the compound shown as the formula VII is (0.05-2) 100 (for example, 0.05:100, 0.2:100, 0.5:100, 1:100 or 2:100), preferably (0.5-2) 100;
(5) In the geminal difluorocyclopropanation reaction of the olefin, the molar ratio of the compound shown in the formula I to the compound shown in the formula VII is (1-2.5): 1 (for example, 1:1, 1.5:1, 2:1 or 2.5:1); preferably (1.5-2.5): 1;
(6) In the geminal difluorocyclopropanation reaction of the olefin, the organic solvent is one or more of nitrile solvents (such as acetonitrile), ketone solvents (such as acetone), halogenated hydrocarbon solvents (such as dichloromethane), ether solvents (such as tetrahydrofuran) and aromatic solvents (such as toluene), preferably aromatic solvents;
(7) In the geminal difluorocyclopropanation reaction of the olefin, the volume molar ratio of the organic solvent to the compound shown as the formula VII is 5mL/mmol-20mL/mmol (for example, 10 mL/mmol); preferably 5-15mL/mmol;
(8) In the gem-difluoro cyclopropanation reaction of the olefin, the temperature of the gem-difluoro cyclopropanation reaction of the olefin is 10-40 ℃; preferably 20-30 ℃;
(9) In the gem-difluoro cyclopropanation reaction of the olefin, the wavelength of the blue light is 463-475nm, for example, blue light LED;
(10) In the difluoromethylation reaction of the alcohol, the catalyst is fac-Ir (ppy) 3 ；
(11) In the difluoromethylation of the alcohol, the molar ratio of the catalyst to the compound of formula VIII is (0.05-0.5): 100 (e.g. 0.05:100, 0.1:100, 0.3:100 or 0.5:100), preferably (0.1-0.5): 100;
(12) In the difluoromethylation reaction of the alcohol, the molar ratio of the compound shown in the formula I to the compound shown in the formula VIII is (1-2): 1 (for example, 1:1, 1.5:1 or 2:1); preferably (1.5-2): 1;
(13) In the difluoromethylation of the alcohol, the difluoromethylation is carried out in the presence of water in a molar ratio of (0-4): 1 (e.g., 0.5:1, 1:1, 2:1 or 4:1) to the compound of formula VIII; preferably (1-4): 1;
(14) In the difluoromethylation reaction of the alcohol, the solvent is one or more of nitrile solvents (such as acetonitrile), halogenated hydrocarbon solvents (such as dichloromethane), ether solvents (such as tetrahydrofuran), amide solvents (such as N, N-dimethylformamide) and aromatic solvents (such as toluene), preferably aromatic solvents;
(15) In the difluoromethylation reaction of the alcohol, the volume molar ratio of the solvent to the compound shown in the formula VIII is 5mL/mmol-20mL/mmol (for example, 10 mL/mmol); preferably 5-15mL/mmol;
(16) In the difluoromethylation reaction of the alcohol, the temperature of the difluoromethylation reaction is 10-40 ℃; preferably 20-30 ℃;
(17) In the difluoromethylation reaction of the alcohol, the wavelength of the blue light is 463-475nm, for example, a blue light LED.
10. The use according to claim 9, wherein said use satisfies any of the following conditions:
(1) The ring A is benzene ring or benzene ring
(2)R 2 、R 3 、R 4 、R 5 、R b And R is c In the above, the C 1 ～C 6 Alkyl is independently C 1 ～C 4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl;
(3)R 5 and R is 5-1 In the above, the C 1 ～C 6 Alkoxy is independently C 1 ～C 4 Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy;
(4)R 5 and R is 5-1 Wherein the halogen is F, cl, br or I, preferably Br;
(5)R 5 wherein the 6-10 membered aryl is phenyl;
(6) When R is 3 And R is 1 When taken together with the atoms to which they are attached form a 9-18 membered aromatic ring, the 9-18 membered aromatic ring is a 9-12 membered aromatic ring, preferably
(7) k is 0 or 1;
(8) In L, said C 1 ～C 6 Alkylene is C 1 ～C 4 Alkylene radicals, e.g. -CH 2 -、-CH 2 CH 2 -、-CH(CH 3 )-、-CH 2 CH 2 CH 2 -、-CH(CH 3 )CH 2 -、-C(CH 3 ) 2 -、-CH 2 CH 2 CH 2 CH 2 -、-CH(CH 3 )CH 2 CH 2 -、-CH 2 CH(CH 3 )CH 2 -or-CH 2 C(CH 3 ) 2 -, preferably-CH 2 -、-CH 2 CH 2 -、-CH(CH 3 ) -or-CH 2 CH 2 CH 2 -；
(9) In L, said: -COOC 1 ～C 6 Alkylene is-COOC 1 ～C 4 Alkylene radicals, e.g. -COO-CH 2 -、*-COO-CH 2 CH 2 -、*-COO-CH(CH 3 )-、*-COO-CH 2 CH 2 CH 2 -、*-COO-CH(CH 3 )CH 2 -、*-COO-C(CH 3 ) 2 -、*-COO-CH 2 CH 2 CH 2 CH 2 -、*-COO-CH(CH 3 )CH 2 CH 2 -、*-COO-CH 2 CH 2 CH(CH 3 )-、*-COO-CH 2 CH(CH 3 )CH 2 -or-COO-CH 2 C(CH 3 ) 2 -, preferably, -COO-CH 2 CH 2 CH(CH 3 )-；
(10) In the ring B, the 6-18 membered aromatic ring is a 6-10 membered aromatic ring, preferably a benzene ring or naphthalene ring;
(11) In ring B, the 5-10 membered heteroaromatic ring is a 5-6 membered heteroaromatic ring, preferably
(12)R 6 In the above, the C 1 ～C 6 Alkyl is independently C 1 ～C 4 Alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl;
(13)R 6 in the above, the C 1 ～C 6 Alkoxy is independently C 1 ～C 4 Alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, preferably methoxy;
(14)R 6 wherein the halogen is F, cl, br or I, preferably Br;
(15) t is 0, 1 or 2.
11. The use according to claim 10, wherein said use satisfies any of the following conditions:
(1) The compound shown in the formula VII is
(2) The compound shown in the formula VIII is
12. A compound of any one of:
CN202210603040.XA 2022-05-30 2022-05-30 Disulfide She Li German compound, and preparation method and application thereof Pending CN117185975A (en)

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