CN111217731B - Ortho-imine ester or cyano-substituted aryl thioether derivative, preparation and application thereof - Google Patents

Ortho-imine ester or cyano-substituted aryl thioether derivative, preparation and application thereof Download PDF

Info

Publication number
CN111217731B
CN111217731B CN202010101631.8A CN202010101631A CN111217731B CN 111217731 B CN111217731 B CN 111217731B CN 202010101631 A CN202010101631 A CN 202010101631A CN 111217731 B CN111217731 B CN 111217731B
Authority
CN
China
Prior art keywords
cyano
ortho
formula
substituted aryl
imidate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202010101631.8A
Other languages
Chinese (zh)
Other versions
CN111217731A (en
Inventor
李先纬
欧阳文森
王杰
蔡晓清
李韵捷
霍延平
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong University of Technology
Original Assignee
Guangdong University of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangdong University of Technology filed Critical Guangdong University of Technology
Priority to CN202010101631.8A priority Critical patent/CN111217731B/en
Publication of CN111217731A publication Critical patent/CN111217731A/en
Application granted granted Critical
Publication of CN111217731B publication Critical patent/CN111217731B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to an ortho-imidate or cyano-substituted aryl thioether derivative, and preparation and application thereof. The structural formula of the ortho-imine ester or cyano-substituted aryl thioether derivative is shown as a formula (I) or a formula (I'). According to the invention, through selection of an imine ester substrate and different substituted disulfide coupling reagents, the reactants are mixed with a catalyst, an oxidant and a halogen ion capture agent under the air atmosphere and alkaline conditions, and the ortho-position imine ester or cyano-substituted aryl thioether derivative is obtained through activation reaction of an aromatic ring ortho-position carbon-hydrogen bond; the method has the advantages of simple and easily obtained substrate and simple operation, and can realize the high-efficiency synthesis of the aryl thioether derivative of the ortho-imine ester or the cyano group through the regulation and control of a catalytic system; the product can be applied to the later derivatization reaction of drug molecules such as probenecid, and provides synthesis potential for the rapid construction of the thioether derivatives in a molecule library with biological activity.
Figure DDA0002387047850000011

Description

Ortho-imine ester or cyano-substituted aryl thioether derivative, preparation and application thereof
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an ortho-imidate or cyano-substituted aryl thioether derivative, and preparation and application thereof.
Background
Sulfur-containing compounds such as sulfides, sulfoxides, sulfones, and sulfur-containing heterocycles such as thiophene and dibenzothiophene are widely used in bioactive drug molecules, pesticides, and functional materials such as polymer materials. In addition, sulfur-containing compounds play an important role in modifying the physical and biological properties of molecules.
In the last decades, thioetherification reactions have been recognized as a very important platform in the field of synthetic organic chemistry. One of the most effective methods is the Ullmann coupling of aryl or alkenyl halides with thiols or thioesters catalyzed by transition metal catalysts such as palladium, copper, and the like. In recent years, transition metal catalyzed carbon-hydrogen bond thioetherification reactions are attracting attention, mainly because the reactions omit extra steps of introducing halogen-containing or pseudohalogen functional groups into substrates in advance and the like, and the post-derivatization reaction of complex molecules is easy to realize, thereby providing convenience for quickly constructing related thioether bioactive molecule libraries.
However, past work has focused primarily on metal-catalyzed aromatic ring carbon-hydrogen bond thioetherification reactions with rigid, strongly coordinating nitrogen-containing heterocyclic directing groups. Stoichiometric copper salt-promoted 2-phenylpyridine derivative-mediated aryl ring ortho carbon hydrogen bond thioetherification reaction is reported as the script research institute's residual right. The Daugulis group utilizes 8-aminoquinoline derived benzamide derivatives as bidentate ligands to promote aromatic ring carbon hydrogen bond thioetherification reactions.
In general, although these reactions exhibit good activity in economically achieving aromatic ring ortho-selective thioetherification reactions in atom and step, they have limited utility. This is mainly due to the fact that the pre-installed directing groups in the substrate are difficult to remove or require subsequent conversion.
Inspired by the above work, carbon-hydrogen bond sulfide reactions promoted with a weakly convertible ligand guide are highly desirable. However, the main challenge of such reactions is the strong coordination of the sulfur functional group to the metal center, resulting in competitive coordination of the weakly coordinating substrate with the thioetherification reagent and the metal catalyst center, making such reactions difficult to achieve high conversion efficiencies.
It is noted that, to date, the carbon-hydrogen bond thioetherification reactions facilitated by the facile conversion of weak coordination-directing strategies have remained very rare.
Disclosure of Invention
In order to overcome the disadvantages and drawbacks of the prior art, it is a primary object of the present invention to provide an ortho-imidate or cyano-substituted aryl thioether derivative.
The invention also aims to provide a preparation method of the ortho-imidate or cyano-substituted aryl thioether derivative, which effectively overcomes the technical defects of poor synthesis area selectivity, difficult subsequent conversion of a product and weak synthesis potential in the selective aromatic ring carbon-hydrogen bond thioetherification reaction in the prior art by effectively designing a catalytic system and a readily convertible guide group.
It is a further object of the present invention to provide the use of the above-mentioned ortho-imidate or cyano-substituted aryl thioether derivatives.
The purpose of the invention is realized by the following technical scheme:
an ortho-imine ester or cyano-substituted aryl thioether derivative, the structural formula of which is shown as formula (I) or formula (I');
Figure BDA0002387047830000021
wherein, R is1Hydrogen, alkyl, benzene ring, halogen, ester group, carbonyl, nitro, cyano, sulfone group, acyl or benzyl chloride; said R2Is C1-C12 alkyl or aryl; r is alkyl or aryl; ar is benzene ring, thiophene, naphthalene, indole, furan, pyridine, quinoline or isoquinoline;
said R2When aryl, it is preferably phenyl, thienyl or furyl;
when R is alkyl, methyl, ethyl or isopropyl are preferred;
the invention provides ortho-imidate or cyano-substituted aryl thioether derivatives of formula (I) or formula (I'), wherein the imidate or cyano can be conveniently converted into functional groups such as carboxylic acid, benzylamine, ketone, amide and the like, and further illustrates the universality of the invention of the application.
The preparation method of the ortho-imine ester or cyano-substituted aryl thioether derivative comprises the following steps:
dissolving a compound shown as a formula (II) and a compound shown as a formula (III) in an inert solvent, mixing the system with a metal catalyst, an oxidant and a halogen ion seizing agent under the air atmosphere and alkaline conditions, and reacting to obtain ortho-imine ester or cyano-substituted aryl thioether derivative;
the structural formulas of the compound shown in the formula (II) and the compound shown in the formula (III) are respectively shown as follows:
Figure BDA0002387047830000022
wherein, R is1Hydrogen, alkyl, benzene ring, halogen, ester group, carbonyl, nitro, cyano, sulfone group, acyl or benzyl chloride; said R2Is C1-C12 alkyl or aryl; r is alkyl or aryl; ar is benzene ring, thiophene, naphthalene, indole, furan, pyridine, quinoline or isoquinoline;
said R2When aryl, it is preferably phenyl, thienyl or furyl;
when R is alkyl, methyl, ethyl or isopropyl are preferred;
the reaction temperature is 40-150 ℃; the reaction time is 8-48 h;
the temperature of the reaction is preferably 100 ℃; the reaction time is preferably 8-36 h;
the alkali for adjusting the alkaline condition is at least one of sodium acetate, cesium acetate, potassium acetate, sodium carbonate and potassium phosphate;
the alkali for adjusting the alkaline condition is preferably sodium acetate;
the metal catalyst is palladium metal catalyst, ruthenium metal catalyst or trivalent rhodium metal catalyst;
the metal catalyst is preferably palladium acetate, palladium chloride, ruthenium trichloride, dichloro (p-methyl isopropylphenyl) ruthenium (II) dimer, pentamethylcyclopentadienyl rhodium chloride dimer or pentamethylcyclopentadienyl trisacetonitrile-bis (hexafluoroantimonate) rhodium;
the oxidant is at least one of silver acetate, silver carbonate, silver trifluoromethanesulfonate, silver trifluoroacetate, silver oxide, silver nitrate, copper acetate, cuprous halide, copper halide, ferric trihalide and ferric nitrate;
the oxidant is preferably copper acetate or silver acetate;
the halide ion gripping agent is monovalent silver salt;
the halide ion seizing agent is preferably silver hexafluoroantimonate or bis (trifluoromethyl) sulfonyl imide silver salt;
the inert solvent is at least one of toluene, tetrahydrofuran, 1,4-dioxane, N '-dimethylformamide, N' -dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, acetonitrile, 1, 2-dichloroethane, ethanol and acetone;
the inert solvent is preferably 1, 2-dichloroethane;
the molar ratio of the compound shown in the formula (II) to the compound shown in the formula (III) is (1:1) - (1: 4);
the mol ratio of the compound shown in the formula (II) to the compound shown in the formula (III) is preferably 1: 1;
the dosage of the alkali is 5-200% of the molar dosage of the compound shown in the formula (II), and preferably 30%;
the dosage of the metal catalyst is 0.5-5% of the molar dosage of the compound shown in the formula (II);
the dosage of the metal catalyst is preferably 1 percent of the molar dosage of the compound shown in the formula (II);
the dosage of the oxidant is 10-300% of the molar dosage of the compound shown in the formula (II), and preferably 30%;
the dosage of the halide ion gripping agent is 1-12% of the molar dosage of the compound shown in the formula (II), and is preferably 3%;
the concentration of the compound shown in the formula (II) in the inert solvent is 0.1-3.0 mol/L, preferably 0.2 mol/L;
the application of the ortho-imine ester or cyano-substituted aryl thioether derivative in the field of biological medicine preparation;
the use of said ortho-imidate or cyano-substituted aryl thioether derivative, preferably for the preparation of a carboxylic acid, ketone, benzylamine or amide-substituted thioether compound;
1) the imino ester or cyano compound can be converted into corresponding carboxylic acid, ketone, benzylamine and amide in one step, so that the aryl thioether derivative containing ortho imino ester or cyano substituent provided by the invention can be directly converted into the thioether compound substituted by carboxylic acid, ketone, benzylamine and amide, namely, the invention provides a strategy for quickly constructing a thioether compound library; 2) the ortho-functionalized aryl thioether is an important skeleton of a plurality of important medicine and pesticide molecules, and the invention also realizes the efficient construction of a plurality of important bioactive molecules; 3) the thioether and cyano functional group substituted compound is widely present in biological and physiologically active molecules, so that the development of the method for quickly introducing thioether or cyano functional groups into drug molecules provides important inspiration for the discovery and application of novel drug molecules.
The principle of the invention is as follows:
the invention realizes the synthesis of ortho-position selective imine ester or cyano-substituted aryl thioether derivatives under the catalysis of transition metal by selecting an imine ester substrate (II) and various substituted disulfide coupling reagents (formula (III)). Different from the traditional carbon-hydrogen bond thioetherification reaction promoted by a guide group which is relatively complex in application and difficult to convert, the conversion utilizes a catalytic system of trivalent rhodium, divalent ruthenium, trivalent ruthenium, divalent palladium and the like which is always developed in the subject group and promoted by an easily-converted imidate guide group, realizes the simple synthesis of the polysubstituted thioether with good functional group universality, and is suitable for the later derivatization of complex bioactive molecules.
The core of the invention is, besides the catalytic system of trivalent rhodium or divalent ruthenium, trivalent ruthenium, divalent palladium and the like for imidate, the selection of disulfide which is simple and easy to obtain and has certain oxidizability as a thioetherification reagent plays an important role in the conversion. Specifically, in the catalytic reaction process, under the assistance of acetate and the like, a high-valence metal catalyst performs ligand exchange on an imine ester substrate, and further realizes hydrocarbon activation of an aromatic ring through a coordinated metallization-deprotonation (CMD) process to obtain a five-membered metal cyclic intermediate; then, disulfide is used as an oxidative thioetherification reagent, and the oxidation of divalent copper salt or monovalent silver salt in a catalytic system is added, so that the further oxidation of five-membered cyclic metal species can be realized in the single electron oxidation process, a higher-valence intermediate which is easy to reduce and eliminate is obtained, and finally, the target ortho-imidate or cyano-substituted thioether derivative is obtained through reduction and elimination.
Preliminary mechanistic studies have now shown that the oxidative nature of copper or silver salts (cupric to cuprous or zero-valent copper, and silver to have different oxidation potentials) promotes the selective formation of imidate or cyano (i.e., imidate with elimination of the alcohol moiety) substituted thioether products.
In view of the wide universality of the chemical transformation of the invention, the chemical transformation comprises different heterocycles, condensed ring type imidates and various functional groups (such as nitro and iodine) which are not easily compatible in the common carbon-hydrogen bond activation reaction, and can also be applied to the later modification of drugs and natural products with biological activity.
In conclusion, the invention has better practical potential, such as being applicable to regioselective modification of multi-functionalization aromatic ring and being applicable to later derivatization of complex drug molecules, through the synthetic advantages of the easily-converted guide group of the imine ester in the guide carbon-hydrogen bond activation reaction, including the characteristics of moderate guide capability, easy obtaining, easy conversion and the like. The method solves the problems of selectivity, practicability and the like in the prior regioselective carbon-hydrogen bond thioetherification reaction promoted by the easily-convertible functional group, and provides important synthesis guidance for the high-added-value conversion of the widely-existing thioether derivatives.
Compared with the prior art, the invention has the following advantages and effects:
according to the research interests and results of the inventor (chem. Eur.J.2014,20, 7911-7915; ACS Catal.2019,9, 8749-8756.), the inventor selects easily available and convertible imidates as effective guiding groups to promote the ortho-carbon hydrogen sulfide reaction of the metal-catalyzed aromatic ring. The selectivity of the directing group is based primarily on the following considerations:
(1) the imidate is a guide group with medium guide capability, and can realize effective carbon-hydrogen bond activation reaction of aromatic rings under the catalytic action of metal;
(2) the imidate can be synthesized from corresponding aryl nitrile in one step, so that the source of the imidate is wide, and the imidate is expected to realize the later modification of a plurality of molecules with biological activity and functional material molecules.
(3) More importantly, the imidate is a functional group capable of performing rapid conversion, and can be conveniently converted into a cyano group, an amide group, a carboxylic acid and the like, thereby providing important support for the later application of the imidate-guided regioselective carbon-hydrogen bond activation reaction.
On the basis, the simple synthesis of the adjustable thioether-substituted imidate and thioether-substituted aromatic nitrile is realized by regulating and controlling a catalytic system. The transformation in the present invention is mainly characterized in that:
(1) the carbon-hydrogen bond thioetherification reaction of the aromatic ring is promoted by utilizing the easily-converted imidate guiding group, and the reaction can be regulated and controlled by a catalytic system, for example, when cupric salt or monovalent silver salt in the catalytic system is used as an oxidant, the selective synthesis of two different products is realized.
It is noted that the present invention represents very few examples of readily convertible directing group promoted regioselective carbon-hydrogen thioetherification reactions. This is mainly because, when a relatively weakly coordinating functional group which is easily convertible is used, the thioether functional group has a strong coordinating effect on the metal catalyst, resulting in deactivation of the catalyst, thereby greatly affecting the efficiency of the catalytic reaction.
(2) Because the prior aromatic ring carbon-hydrogen bond thioetherification reaction based on metal catalysis mainly focuses on guide groups which are not easy to obtain and difficult to convert, the reaction is not easy to carry out later modification on complex molecules with biological activity. In the invention, the inventor realizes the carbon-hydrogen bond thioetherification reaction with the region selectivity promoted by the easily obtained and easily converted guide group, the converted functional group has good universality, and the method is suitable for the later modification of complex drug molecules such as ibuprofen, probenecid and the like, and provides a basis for quickly constructing a related thioethereal compound molecular library with potential biological activity.
It is to be noted that, at present, the direct use of aryl nitriles as directing groups to achieve metal-catalyzed activation of carbon-hydrogen bonds at ortho positions of aromatic rings has not been reported. In the invention, the imidate can be used as a guiding group to assist the selective carbon-hydrogen bond activation of the ortho-position of the aromatic ring, and can also be used as a precursor of cyano group, and the imidate is converted into the cyano group in situ after the reaction to obtain the ortho-position cyano-substituted thioether derivative.
In conclusion, the invention provides a simple, high-efficiency and high-practicability catalytic aromatic ring carbon-hydrogen bond thioetherification reaction, and further, the aromatic ring ortho-imidate or cyano-substituted thioether derivative with adjustable selectivity is realized; more importantly, the strategy is also applied to realize the later modification of drug molecules such as ibuprofen, probenecid and the like, and a new idea is provided for the development of related new drugs and the like.
Drawings
FIG. 1 shows NMR of 4-fluoro-2- (phenylthio) benzonitrile (1a) provided in example 11And H, spectrum.
FIG. 2 shows NMR of 4-fluoro-2- (phenylthio) benzonitrile (1a) provided in example 113And C, spectrum.
FIG. 3 shows NMR of 4-fluoro-2- (phenylthio) benzonitrile (1a) provided in example 119And F, spectrum.
FIG. 4 shows NMR of 4- (chloromethylene) -2- (phenylthio) benzonitrile (1b) provided in example 21And H, spectrum.
FIG. 5 shows NMR of 4- (chloromethylene) -2- (phenylthio) benzonitrile (1b) provided in example 213And C, spectrum.
FIG. 6 is a NMR of methyl 4-cyano-3- (phenylthio) benzoate (1c) provided in example 31And H, spectrum.
FIG. 7 is a NMR of methyl 4-cyano-3- (phenylthio) benzoate (1c) provided in example 313And C, spectrum.
FIG. 8 shows NMR of 3- (phenylthio) -2-naphthonitrile (1d) provided in example 41And H, spectrum.
FIG. 9 shows NMR of 3- (phenylthio) -2-naphthonitrile (1d) provided in example 413And C, spectrum.
FIG. 10 shows NMR of 3- (phenylthio) thiophene-2-carbonitrile (1e) provided in example 51And H, spectrum.
FIG. 11 is a NMR of 3- (phenylthio) thiophene-2-carbonitrile (1e) provided in example 513And C, spectrum.
FIG. 12 is a NMR of 2- ((4-methoxyphenyl) thio) benzonitrile (1f) provided in example 61And H, spectrum.
FIG. 13 shows NMR of 2- ((4-methoxyphenyl) thio) benzonitrile (1f) provided in example 613And C, spectrum.
FIG. 14 NMR of 2- (pentylthio) benzonitrile (1g) provided in example 71And H, spectrum.
FIG. 15 is a NMR of 2- (pentylthio) benzonitrile (1g) provided in example 713And C, spectrum.
FIG. 16 is a nuclear magnetism of propyl 3- (4-cyano-3- (phenylthio) phenoxy) -4- (N, N-diisopropylsulfonamide) benzoate (1h) provided in example 8Resonance of1And (4) an H spectrogram.
FIG. 17 is a NMR of propyl 3- (4-cyano-3- (phenylthio) phenoxy) -4- (N, N-diisopropylsulfonamide) benzoate (1h) provided in example 813And C, spectrum.
FIG. 18 is a NMR of 2- ((4-phenyl) thio) benzonitrile (1i) provided in example 91And H, spectrum.
FIG. 19 is a NMR of 2- ((4-phenyl) thio) benzonitrile (1i) provided in example 913And C, spectrum.
FIG. 20 is a NMR of 2- ((4-bromophenyl) thio) benzonitrile (1j) provided in example 101And H, spectrum.
FIG. 21 is a NMR of 2- ((4-bromophenyl) thio) benzonitrile (1j) provided in example 1013And C, spectrum.
FIG. 22 is a nuclear magnetic resonance of ethyl 2- (phenylmercapto) phenyliminate (1k) provided in example 111And H, spectrum.
FIG. 23 shows NMR for ethyl 2- (benzenethiol) phenyliminecarboxylate (1k) provided in example 1113And C, spectrum.
FIG. 24 shows NMR of (2- (phenylthio) phenyl) methyleneamine (1 i') provided in application example1And H, spectrum.
FIG. 25 shows NMR of (2- (phenylthio) phenyl) methyleneamine (1 i') provided in application example13And C, spectrum.
FIG. 26 shows 4- (benzo [ b ] is provided by the application example]Nuclear magnetic resonance of thiophen-2-yl) -2- (phenylthio) benzonitrile (1j1And H, spectrum.
FIG. 27 shows 4- (benzo [ b ] is provided in the application example]Nuclear magnetic resonance of thiophen-2-yl) -2- (phenylthio) benzonitrile (1j13And C, spectrum.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
The application provides an ortho-imidate or cyano-substituted thioether derivative, and a preparation method and application thereof, which effectively overcome the technical defects of reactivity, selectivity and practicability in a regioselective carbon-hydrogen bond thioetherification reaction promoted by an easily-converted functional group in the prior art.
According to the method, easily obtained and easily converted imine ester is taken as a substrate, and the selective thioetherification reaction of the aromatic ring ortho-position C-H bond region is realized through the metal catalysis, so that different types of ortho-position thioetherified thioether derivatives can be obtained by selecting oxidative disulfide and regulating and controlling an oxidant in a catalytic system. The invention promotes the simple, high-efficiency and high-selectivity synthesis of polysubstituted thioether derivatives with wide application value in the fields of pesticides, medicaments, polymer materials and the like by using an easily-converted guide group and combining disulfide as a coupling reagent under the catalysis of metal, and provides certain theoretical guidance for the rapid construction of materials, medicaments and the like with high added values.
In the present invention, the preparation method preferably comprises the steps of: charging an imido ester compound II (0.1 to 0.20mmol), a disulfide compound III (0.1 to 0.20mmol) and a trivalent rhodium catalyst [ Cp RhCl ] into a 15mL Schlenk reaction tube in this order under an air atmosphere2]2(0.6-2.4 mg), bis (trifluoromethanesulfonimide) silver salt (2.3-6.9 mg), sodium acetate (2.5-4.9 mg), copper acetate or silver acetate (12.0-33.4 mg), and 1, 2-dichloroethane (DCE,1mL), after the reaction is determined to be finished by thin-layer chromatography, the reaction solution is filtered by diatomite, dried powder is prepared by rotary evaporation and concentration of 400-mesh silica gel, then a reaction product is separated by column chromatography, 5 g of 400-mesh silica gel is obtained, and a developing agent is petroleum ether and ethyl acetate with the volume ratio of 50: 1-5: 1, so as to obtain the ortho-imino ester or cyano-thiother compound I.
Wherein, the imido ester raw material II is synthesized according to the following method: nitrile (10mmol), alcohol (12mmol) were added sequentially to a round bottom flask in an ice-water bath and stirred, and acetyl chloride (80mmol) was added dropwise to the solution with injection. After the dropwise addition, the reaction was stopped with a rubber stopper, the ice-water bath was removed, the mixture was stirred at room temperature for 12 hours, the volatile compound was rotary evaporated after the reaction, and the hydrochloride of the target compound was obtained by atmospheric distillation. The hydrochloride is washed by aqueous solution of sodium bicarbonate, and then the organic phase is extracted by ether, dried by anhydrous sodium sulfate and evaporated by rotation to obtain the target compound II. The method is carried out according to the prior literature: yadav, v.k.; babu, K.G.ARemarkable Efficient Markovnikov Hydrochlorination of Olefins and Transformation of Nitriles intos Imidates by Use of AcCl and an alcohol Eur.J.Org.chem.2005,452.
Figure BDA0002387047830000071
The disulfide is synthesized according to the following method: a commercially available thiol compound (10mmol) was dissolved in acetonitrile (20mL), and potassium carbonate (10mmol) was added, and the solution was stirred at room temperature for one hour, after which the resulting solution was filtered, further rotary-distilled, and separated by column chromatography.
Figure BDA0002387047830000072
The method is carried out according to the prior literature: q.chen, g.yu, x.wang, y.huang, y.yana, y.huo.cs2CO3-promoted methylene insertion into disulfide bonds using acetone as a methylene source.Org.Biomol.Chem.,2018,16,4086–4089.
Example 1
This example carries out the preparation of 4-fluoro-2- (phenylthio) benzonitrile (1a), which is represented by the following reaction scheme:
Figure BDA0002387047830000073
to a 15mL Schlenk reaction tube under an atmospheric air atmosphere were added in the order imidate compound 2a (33.4mg,0.20mmol), disulfide 3a (43.6mg,0.20mmol), trivalent rhodium catalyst [ Cp. RhCl ]2]2(1.2mg), silver bistrifluoromethanesulfonylimide (2.3mg), sodium acetate (2.5mg), copper acetate (12.0mg), 1, 2-dichloroethane (DCE,1mL) was reacted at 100 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. The crude product is chromatographed on prepared silica gel plates, whereuponSelecting a developing solvent or an eluent with the volume ratio of 50:1, the product 4-fluoro-2- (phenylthio) benzonitrile (1a), 35.7mg, 78% yield, was isolated.
4-fluoro-2- (phenylthio) benzonitrile (1a) is subjected to nuclear magnetic resonance detection,1h spectrogram,13C spectrum and19the F spectrogram is shown in figures 1 to 3, and the result is as follows:1H NMR(400MHz,CDCl3)δ7.62(dd,J＝5.2Hz,8.4Hz,1H),7.55-7.53(m,2H),7.48-7.46(m,3H),6.90(td,J＝2.8Hz,8.0Hz,1H),6.63(dd,J＝2.4Hz,9.2Hz,1H).13C NMR(100MHz,CDCl3)δ165.1(d,J＝258Hz),147.2(d,J＝9Hz),135.7(d,J＝10Hz),134.8,130.2,130.0,129.8,116.2,115.5(d,J＝26Hz),113.7(d,J＝23Hz),107.3.19F NMR(300MHz,CDCl3)δ-101.9。
in the embodiment, the imido ester is used as a planar guide group which is easy to convert, so that the simple synthesis of the o-cyano aryl thioether is realized.
Example 2
This example carries out the preparation of 4- (chloromethylene) -2- (phenylthio) benzonitrile (1b) according to the formula:
Figure BDA0002387047830000081
to a 15mL Schlenk reaction tube under an atmospheric air atmosphere were added in the order of imidate compound 2b (39.2mg,0.20mmol), disulfide 3a (43.6mg,0.20mmol), and trivalent rhodium catalyst [ Cp. RhCl ]2]2(1.2mg), silver bistrifluoromethanesulfonylimide salt (4.6mg), sodium acetate (2.5mg), copper acetate (20.0mg), 1, 2-dichloroethane (DCE,1mL) were reacted at 100 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 50:1, the product 4- (chloromethylene) -2- (phenylthio) benzonitrile (1b), 25.9mg, 85% yield, is isolated.
4- (Chloromethylene) -2- (phenylthio) benzonitrile (1b) for NMR detection1H spectrum and13the spectrum C is shown in figures 4-5, and the result is:1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.0Hz,1H),7.52-7.48(m,2H),7.43-7.41(m,3H),7.28(dd,J＝1.6Hz,8.0Hz,1H),7.10(d,J＝1.2Hz,1H),4.43(s,2H).13C NMR(100MHz,CDCl3)δ143.2,142.7,133.9,133.7,132.5,131.1,129.9,129.2,129.1,126.4,116.5,112.3,44.7。
the embodiment can be compatible with benzyl chloride functional groups with oxidability and easy conversion, and provides a basis for further modifying products.
Example 3
This example carries out the preparation of methyl 4-cyano-3- (phenylthio) benzoate (1c) having the formula:
Figure BDA0002387047830000082
to a 15mL Schlenk reaction tube under an atmospheric air atmosphere were added in the order imidate compound 2c (41.4mg,0.20mmol), disulfide 3a (43.6mg,0.20mmol), trivalent rhodium catalyst [ Cp. RhCl ]2]2(1.8mg), silver bistrifluoromethanesulfonylimide salt (6.9mg), sodium acetate (2.5mg), copper acetate (12.0mg), 1, 2-dichloroethane (DCE,1mL) were reacted at 100 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration through diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 50:1, the product methyl 4-cyano-3- (phenylthio) benzoate (1c), 41.9mg, 78% yield, was isolated.
Detecting 4-cyano-3- (phenylthio) methyl benzoate (1c) by nuclear magnetic resonance,1h spectrum and13the spectrum C is shown in FIGS. 6-7, and the results are:1H NMR(400MHz,CDCl3)δ8.59(d,J＝3.6Hz,1H),8.12(d,J＝7.6Hz,1H),7.80(d,J＝7.6Hz,1H),7.56(d,J＝7.2Hz,1H),7.48-7.39(m,2H),7.17(dd,J＝6.8Hz,5.2Hz,1H),3.86(s,2H).13C NMR(100MHz,CDCl3)δ160.4,148.2,143.6,140.8,136.7,132.4,128.7,127.3,125.2,121.1,120.9,34.5。
this embodiment allows for the regioselective carbon-hydrogen thioetherification of polyfunctional aromatic rings, such as aromatic rings containing both ester and imino groups.
Example 4
This example carries out the preparation of 3- (phenylthio) -2-naphthonitrile (1d), whose reaction scheme is shown below:
Figure BDA0002387047830000091
to a 15mL Schlenk reaction tube under an atmospheric air atmosphere were added in the order Imidate compound 2d (40.0mg,0.20mmol), disulfide 3a (43.6mg,0.20mmol), trivalent rhodium catalyst [ Cp. RhCl ]2]2(0.6mg), silver bistrifluoromethanesulfonylimide salt (2.3mg), sodium acetate (2.5mg), copper acetate (12.0mg), 1, 2-dichloroethane (DCE,1mL) were reacted at 100 ℃ for 16 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 50:1, the product, 3- (phenylthio) -2-naphthonitrile (1d), was isolated in 39.1mg, 75% yield.
Detecting the nuclear magnetic resonance of the 3- (phenylthio) -2-naphthacenitrile (1d),1h spectrum and13the spectrum C is shown in figures 8-9, and the results are:1H NMR(400MHz,CDCl3)δ8.25(s,1H),7.85(d,J＝8.0Hz,1H),7.76(s,1H),7.71(d,J＝8.0Hz,1H),7.63-7.54(m,2H),7.45(d,J＝2.4Hz,8.0Hz,2H),7.40-7.34(m,3H).13C NMR(100MHz,CDCl3)δ136.1,134.9,134.1,133.4,132.2,131.2,131.0,129.6,128.2,128.16,127.6,127.5,117.2,112.3。
this example can be applied to the modification of fused rings including naphthalene rings and regioselectively to C2-imidate substituted naphthalenes to give C3-thioetherified naphthalene carbonitrile products.
Example 5
This example carries out the preparation of 3- (phenylthio) thiophene-2-carbonitrile (1e), which has the formula:
Figure BDA0002387047830000101
to a 15mL Schlenk reaction tube under an atmospheric air atmosphere were added in the order imidate compound 2e (31.0mg,0.20mmol), disulfide 3a (43.6mg,0.20mmol), trivalent rhodium catalyst [ Cp. RhCl ]2]2(0.6mg), silver bistrifluoromethanesulfonylimide (2.3mg), sodium acetate (2.5mg), copper acetate (12.0mg), 1, 2-dichloroethane (DCE,1mL) was reacted at 100 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 50:1, the product, 3- (phenylthio) thiophene-2-carbonitrile (1e), was isolated in 31.2mg, 72% yield.
Detecting the nuclear magnetic resonance of the 3- (thiophenyl) thiophene-2-carbonitrile (1e),1h spectrum and13the spectrum C is shown in fig. 10-11, and the result is:1H NMR(400MHz,CDCl3)δ7.48(d,J＝5.2Hz,1H),7.46-7.43(m,2H),7.38-7.35(m,3H),6.80(d,J＝5.2Hz,1H).13C NMR(100MHz,CDCl3)δ145.1,132.7,132.3,131.9,129.9,129.6,128.6,113.0,106.9。
this embodiment can be applied to regioselective modification of heterocycles such as thiophene and can overcome electrophilic substitution type reactions at the C2 or C5 positions electrically controlled by electron-rich heteroaromatic rings such as thiophene itself.
Example 6
This example carries out the preparation of 2- ((4-methoxyphenyl) thio) benzonitrile (1f), which is represented by the formula:
Figure BDA0002387047830000102
to a 15mL Schlenk reaction tube, an imidate compound 2f (30.0mg,0.20mmol), a disulfide 3b (83.4mg,0.30mmol), and a trivalent rhodium catalyst [ Cp. rhCl ] were sequentially added under an atmospheric air atmosphere2]2(2.4mg), bistrifluoromethaneMethanesulfonylimide silver salt (4.6mg), sodium acetate (4.9mg), copper acetate (12.0mg), 1, 2-dichloroethane (DCE,1mL) were reacted at 110 ℃ for 18 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 50:1 the product, 2- ((4-methoxyphenyl) thio) benzonitrile (1f), 38.6mg, was isolated in 80% yield.
The nuclear magnetic resonance detection of 2- ((4-methoxyphenyl) thio) benzonitrile (1f) is shown in fig. 12 to 13, and the results are:1H NMR(400MHz,CDCl3)δ7.59(d,J＝7.2Hz,1H),7.48(d,J＝8.4Hz,2H),7.35(td,J＝1.2Hz,8.0Hz,1H),7.17(t,J＝7.6Hz,1H),6.97-6.92(m,3H).13C NMR(100MHz,CDCl3)δ160.8,144.6,136.8,133.4,132.8,127.8,125.4,120.9,117.0,115.4,110.9,55.4。
this example is compatible with different substituted disulfide reagents to give different aromatic ring substituted thioether products.
Example 7
This example carries out the preparation of 2- (pentylthio) benzonitrile (1g) of the formula:
Figure BDA0002387047830000111
to a 15mL Schlenk reaction tube, an imidate compound 2f (30.0mg,0.20mmol), a disulfide 3c (41.2mg,0.20mmol), and a trivalent rhodium catalyst [ Cp. rhCl ] were sequentially added under an atmospheric air atmosphere2]2(1.2mg), silver bistrifluoromethanesulfonylimide (2.3mg), sodium acetate (4.6mg), copper acetate (20.0mg), 1, 2-dichloroethane (DCE,1mL) was reacted at 100 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 50:1, the product 2- (pentylthio) benzonitrile (1g), 33.6mg, 82% yield, was isolated.
2- (pentylthio) benzenesThe nitrile (1g) was subjected to nuclear magnetic resonance detection,1h spectrum and13the spectrum C is shown in FIGS. 14-15, and the results are:1H NMR(400MHz,CDCl3)δ7.60(d,J＝7.6Hz,1H),7.49(t,J＝8.0Hz,1H),7.40(d,J＝8.0Hz,1H),7.23(t,J＝7.6Hz,1H),3.01(t,J＝7.2Hz,2H),1.72-1.65(m,2H),1.47-1.40(m,2H),1.36-1.31(m,2H),0.90(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ142.2,133.6,132.7,129.1,128.6,125.7,117.2,113.3,33.5,30.9,28.4,22.2,13.9。
this example is compatible with different substituted disulfide reagents to give different alkyl substituted thioether products.
Example 8
This example illustrates the preparation of propyl 3- (4-cyano-3- (phenylthio) phenoxy) -4- (N, N-diisopropylsulfonamide) benzoate (1h), having the following reaction scheme:
Figure BDA0002387047830000112
to a 15mL Schlenk reaction tube under an atmospheric air atmosphere were added 2g (49.0mg,0.10mmol) of the imidate compound, 3a disulfide (43.6mg,0.20mmol), and a trivalent rhodium catalyst [ Cp. RhCl ] in that order2]2(1.2mg), silver bistrifluoromethanesulfonylimide (4.6mg), sodium acetate (2.5mg), copper acetate (20.0mg), 1, 2-dichloroethane (DCE,1mL) was reacted at 110 ℃ for 18 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 5:1, the product, propyl 3- (4-cyano-3- (phenylthio) phenoxy) -4- (N, N-diisopropylsulfonamide) benzoate, was isolated (1h), 46.9mg, 85% yield.
Detecting the propyl 3- (4-cyano-3- (phenylthio) phenoxy) -4- (N, N-diisopropyl sulfonamide) benzoate (1h) by nuclear magnetic resonance,1h spectrum and13the spectrum C is shown in FIGS. 16-17, and the results are:1H NMR(400MHz,CDCl3)δ8.15-8.10(m,2H),7.88-7.86(m,2H),7.59-7.54(m,1H),7.49-7.46(m,2H),7.41-7.39(m,2H),6.95(d,J＝8.8Hz,1H),6.75(dd,J＝2.4Hz,8.4Hz,1H),6.58(d,J＝5.6Hz,1H),4.48(t,J＝6.0Hz,2H),4.02(d,J＝6.0Hz,2H),3.10(t,J＝7.6Hz,4H),2.24-2.18(m,2H),1.55(dd,J＝7.2Hz,6.8Hz,4H),0.87(t,J＝7.2Hz,6H).13C NMR(100MHz,CDCl3)δ165.1,161.9,144.5,144.3,135.2,134.0,133.6,133.2,130.1,129.7,129.0,127.0,119.0,117.1,115.7,115.1,112.7,104.8,64.7,62.1,49.9,28.3,21.9,11.1。
this example demonstrates that this transformation can be applied to the late modification of drug molecules such as probenecid, and also provides a basis for the rapid establishment of libraries of related biologically active molecules.
Example 9
This example proceeds to the preparation of 2- ((4-phenyl) thio) benzonitrile (1i), which is represented by the reaction formula:
Figure BDA0002387047830000121
to a 15mL Schlenk reaction tube, an imidate compound 2f (30.0mg,0.20mmol), a disulfide 3a (43.6mg,0.20mmol), and a trivalent rhodium catalyst [ Cp. rhCl ] were sequentially added under an atmospheric air atmosphere2]2(0.6mg), silver bistrifluoromethanesulfonylimide (2.3mg), sodium acetate (2.5mg), copper acetate (12.0mg), 1, 2-dichloroethane (DCE,1mL) was reacted at 100 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 20: 1 the product, 2- ((4-phenyl) thio) benzonitrile (1i), 36.3mg, was isolated in 86% yield.
Performing nuclear magnetic resonance detection on the 2- ((4-phenyl) sulfenyl) benzonitrile (1i),1h spectrum and13the spectrum C is shown in FIGS. 18-19, and the results are:1H NMR(400MHz,CDCl3)δ7.40(dd,J＝1.2Hz,7.6Hz,1H),7.49-7.46(m,2H),7.43-7.38(m,4H),7.28-7.25(m,1H),7.13(dd,J＝0.4Hz,8.0Hz,1H).13C NMR(100MHz,CDCl3)δ142.3,133.6,133.5,132.9,131.8,129.9,129.7,128.9,126.4,116.9,112.9。
example 10
This example carries out the preparation of 2- ((4-bromophenyl) thio) benzonitrile (1j) according to the formula:
Figure BDA0002387047830000122
to a 15mL Schlenk reaction tube under an atmosphere of atmospheric air were added the imidate compound 2h (45.4mg,0.20mmol), disulfide 3a (43.6mg,0.20mmol), and the trivalent rhodium catalyst [ Cp. RhCl ]2]2(0.6mg), silver bistrifluoromethanesulfonylimide (2.3mg), sodium acetate (2.5mg), copper acetate (12.0mg), 1, 2-dichloroethane (DCE,1mL) was reacted at 120 ℃ for 16 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 30: 1, the product, 2- ((4-bromophenyl) thio) benzonitrile (1j), 47.4mg, 82% yield was isolated.
Performing nuclear magnetic resonance detection on 2- ((4-bromophenyl) sulfenyl) benzonitrile (1j),1h spectrum and13the spectrum C is shown in fig. 20-21, and the result is:1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.0Hz,1H),7.58-7.53(m,4H),7.47-7.43(m,5H),7.37-7.34(m,2H),7.11(s,1H).13C NMR(100MHz,CDCl3)δ145.1,143.1,141.2,140.1,139.9,138.9,134.1,133.6,129.9,129.4,129.1,127.3,125.4,124.9,124.2,123.9,122.3,122.0,116.8。
example 11
This example carries out the preparation of ethyl 2- (benzenemercapto) phenylimine (1k) having the formula:
Figure BDA0002387047830000131
to a 15mL Schlenk reaction tube was added an imidate compound 2f (30.0mg,0.20mmol), and disulfide 3a (43.6mg, 0) in this order under an atmospheric air atmosphere.20mmol), trivalent rhodium catalyst [ Cp RhCl2]2(1.2mg), bis (trifluoromethanesulfonimide) silver salt (2.3mg), sodium acetate (2.5mg), silver acetate (33.4mg), 1, 2-dichloroethane (DCE,1mL) was reacted at 100 ℃ for 12 hours. After the reaction is finished, cooling to room temperature, carrying out suction filtration by using diatomite, and concentrating to obtain a crude product. And (3) carrying out chromatographic separation on the crude product by using a prepared silica gel plate, wherein the volume ratio of the selected developing agent or eluent to the petroleum ether to the ethyl acetate is 50:1 the product, ethyl 2- (p-toluenesulfonyl) phenylimine (1k), was isolated in 37.5mg, 73% yield.
Detecting 2- (p-toluene mercapto) phenyl imine ethyl ester (1k) by nuclear magnetic resonance,1h spectrum and13the spectrum C is shown in FIGS. 22-23, and the results are:1H NMR(400MHz,CDCl3)δ7.73(d,J＝3.6Hz,2H),7.51-7.48(m,4H),7.35(t,J＝8.0Hz,2H),7.14(t,J＝7.2Hz,1H),4.45(q,J＝6.8Hz,2H),1.45(t,J＝6.8Hz,3H).13C NMR(100MHz,CDCl3)δ157.2,137.4,132.5,130.4,128.7,128.3,127.9,127.5,125.5,125.0,123.2,62.5,14.3。
the embodiment can realize the imine ester substituted thioether derivative through the regulation and control of a catalytic system, and the retention of the guide group is used for subsequent conversion, so that the construction of the polysubstituted thioether derivative is facilitated.
Application examples
It is noted that, in view of the wide application value of thioethers and aromatic nitriles in synthetic chemistry, as well as in bioactive molecules, the claimed invention realizes the following applications of thioethers compounds:
1) the invention realizes the late modification of the probenecid drug molecule (example 8), and simultaneously introduces two functional groups of thioether and cyano into the molecule, and the conversion provides a novel molecule library of probenecid drug derivatives and is expected to provide a new idea for the development of the novel drug in the type considering that aryl thioether and cyano are not only important skeletons of bioactive molecules, and the two functional groups can be efficiently converted into corresponding sulfone, carboxylic acid and benzyl amine functional groups in one step.
2) The ortho-cyano or imino ester substituted aryl thioether compound provided by the invention is an important framework or precursor of a plurality of bioactive molecules, so that the applicant further performs rapid conversion on the product to thioether substituted by other functional groups or bioactive molecule precursors:
i) the cyano-substituted thioether compound is converted to a benzylamine-substituted thioether compound according to the following reaction formula:
Figure BDA0002387047830000141
a25 mL round-bottom flask was charged with the thioether product 1i (21.1mg,0.1mmol) from example 9, anhydrous ether (0.5mL), stirred in an ice-water bath, slowly added with lithium aluminum hydride (0.4mmol), reacted for one hour, added dropwise with a dilute hydrochloric acid solution (0.1M, 2mL), the organic phase extracted with ether and dried over anhydrous sodium sulfate, and the product separated by column chromatography after rotary evaporation (volume ratio of petroleum ether to ethyl acetate as developing solvent: 5: 1). The objective product (2- (phenylthio) phenyl) methyleneamine (1 i') was isolated in 19.1mg, 89% yield.
The (2- (phenylthio) phenyl) methyleneamine (1 i') was subjected to nuclear magnetic resonance detection,1h spectrum and13the spectrum C is shown in FIGS. 24-25, and the results are:1H NMR(400MHz,CDCl3)δ7.42(d,J＝7.2Hz,1H),7.33(t,J＝6.8Hz,2H),7.30-7.23(m,3H),7.21-7.20(m,3H),3.95(s,2H).13C NMR(100MHz,CDCl3)δ144.6,136.2,133.9,132.9,129.6,129.2,128.7,128.5,127.9,126.5,45.0。
ii) the biaryl cyano compound is an important framework of a plurality of liquid crystal molecules, and in view of good functional group compatibility shown by the invention, the product obtained by the reaction can be further subjected to coupling reaction to obtain a heterocyclic substituted biaryl ring nitrile compound, and the product is expected to be applied in the fields of novel liquid crystal molecules and the like. Conversion of the thioether product to an organic light-emitting material, the reaction formula of which is as follows:
Figure BDA0002387047830000142
atmosphere of nitrogenNext, to a 25mL round-bottomed flask were added the thioether compound 1j (28.9mg,0.1mmol) obtained in example 10, the heterocycle-substituted boronic acid compound 4(0.1mmol), and Pd (PPh) in that order3)4(0.005mmol), aqueous sodium bicarbonate (0.4mmol,1M), 1,4-dioxane (1mL), and the reaction refluxed for one hour. After the reaction is finished, extracting an organic phase by using ethyl acetate, drying by using anhydrous sodium sulfate, and separating a product by column chromatography after rotary evaporation (a developing solvent is petroleum ether and ethyl acetate in a volume ratio of 50: 1). Separating to obtain the target product 4- (benzo [ b ]]Thiophen-2-yl) -2- (phenylthio) benzonitrile (1 j'), 28.1mg, 82% yield.
4- (benzo [ b ]]Detecting the thiophene-2-yl) -2- (thiophenyl) benzonitrile (1 j') by nuclear magnetic resonance,1h spectrum and13the spectrum C is shown in FIGS. 26-27, and the results are:1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.0Hz,1H),7.58-7.53(m,4H),7.47-7.43(m,5H),7.37-7.34(m,2H),7.11(s,1H).13C NMR(100MHz,CDCl3)δ145.1,143.1,141.2,140.1,139.9,138.9,134.1,133.6,129.9,129.4,129.1,127.3,125.4,124.9,124.2,123.9,122.3,122.0,116.8.
the above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (5)

1. A process for the preparation of ortho-imidate or cyano-substituted aryl thioether derivatives, characterized in that it comprises the steps of:
dissolving the compound shown in the formula (II) and the compound shown in the formula (III) in an inert solvent, and reacting the system with a metal catalyst [ Cp & RhCl ] under the air atmosphere and the basic condition2]2Mixing an oxidant copper acetate and a halide ion seizing agent bis (trifluoromethanesulfonyl) imide silver salt, and reacting to obtain a cyano-substituted aryl thioether derivative;
or dissolving the compound shown in the formula (II) and the compound shown in the formula (III) in an inert solvent in the airMixing the above system with metal catalyst [ Cp + RhCl ] in gas atmosphere and alkaline condition2]2Mixing an oxidant silver acetate and a halide ion seizing agent bis (trifluoromethanesulfonyl) imide silver salt, and reacting to obtain an ortho-imidate substituted aryl thioether derivative;
the structural formulas of the compound shown in the formula (II) and the compound shown in the formula (III) are respectively shown as follows:
Figure FDA0003333758830000011
the structural formula of the ortho-imine ester or cyano-substituted aryl thioether derivative is shown as a formula (I) or a formula (I');
Figure FDA0003333758830000012
wherein, R is1Hydrogen, alkyl, benzene ring, halogen, ester group, carbonyl, nitro, cyano, sulfone group, acyl or benzyl chloride; r is as described2Is C1-C12 alkyl, aryl, thienyl or furyl; r is alkyl or aryl; ar is benzene ring, thiophene, naphthalene, indole, furan, pyridine, quinoline or isoquinoline.
2. The process for the preparation of ortho-imidate or cyano-substituted aryl thioether derivatives according to claim 1, wherein:
said R2When aryl, it is phenyl.
3. The process for the preparation of ortho-imidate or cyano-substituted aryl thioether derivatives according to claim 1, wherein:
and when R is alkyl, the R is methyl, ethyl or isopropyl.
4. The process for the preparation of ortho-imidate or cyano-substituted aryl thioether derivatives according to claim 1, wherein:
the reaction temperature is 40-150 ℃; the reaction time is 8-48 h.
5. The process for the preparation of ortho-imidate or cyano-substituted aryl thioether derivatives according to claim 1, wherein:
the alkali for adjusting the alkaline condition is at least one of sodium acetate, cesium acetate, potassium acetate, sodium carbonate and potassium phosphate.
CN202010101631.8A 2020-02-19 2020-02-19 Ortho-imine ester or cyano-substituted aryl thioether derivative, preparation and application thereof Active CN111217731B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010101631.8A CN111217731B (en) 2020-02-19 2020-02-19 Ortho-imine ester or cyano-substituted aryl thioether derivative, preparation and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010101631.8A CN111217731B (en) 2020-02-19 2020-02-19 Ortho-imine ester or cyano-substituted aryl thioether derivative, preparation and application thereof

Publications (2)

Publication Number Publication Date
CN111217731A CN111217731A (en) 2020-06-02
CN111217731B true CN111217731B (en) 2022-06-03

Family

ID=70811711

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010101631.8A Active CN111217731B (en) 2020-02-19 2020-02-19 Ortho-imine ester or cyano-substituted aryl thioether derivative, preparation and application thereof

Country Status (1)

Country Link
CN (1) CN111217731B (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3951952A (en) * 1972-08-02 1976-04-20 Pfizer Inc. Broad spectrum antibiotics
CN102066327A (en) * 2008-04-23 2011-05-18 武田药品工业株式会社 Iminopyridine derivatives and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3951952A (en) * 1972-08-02 1976-04-20 Pfizer Inc. Broad spectrum antibiotics
CN102066327A (en) * 2008-04-23 2011-05-18 武田药品工业株式会社 Iminopyridine derivatives and use thereof

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Activation of Aryl Thiocyanates Followed by Aryne Insertion: Access to 1,2-Thiobenzonitriles;Martin Pawliczek et al.;《Org. Lett.》;20150316;第17卷;第1716-1719页 *
Ligand-Promoted RhIII-Catalyzed Thiolation of Benzamides with a Broad Disulfide Scope;Yan-Shang Kang et al.;《Angew.Chem.Int.Ed.》;20190524;第58卷;第9099-9103页 *
Martin Pawliczek et al..Activation of Aryl Thiocyanates Followed by Aryne Insertion: Access to 1,2-Thiobenzonitriles.《Org. Lett.》.2015,第17卷第1716-1719页. *
Rhodium(III)-catalyzed carboxylate-directed ortho-selective thiolation of benzoic acids;Dongjie Wang et al.;《Org.Chem.Front.》;20200918;第7卷;第3229-3233页 *
Sequential C−H and C−C Bond Cleavage: Divergent Constructions of Fused N‑Heterocycles via Tunable Cascade;Xianwei Li et al.;《ACS Catal.》;20190822;第9卷;第8749-8756页 *

Also Published As

Publication number Publication date
CN111217731A (en) 2020-06-02

Similar Documents

Publication Publication Date Title
Amos et al. Metal-free electrophilic alkynylation of sulfenate anions with ethynylbenziodoxolone reagents
Zhang et al. Pd (II)-catalyzed selective sulfenylation of arene C–H bonds using N-arylthiobenzamides as thiolation reagent and oxidant
Xia et al. Regioselective addition of thiophenol to α, β-unsaturated N-acylbenzotriazoles
Liu et al. Non-directed copper-catalyzed regioselective C–H sulfonylation of phenothiazines
CN113416161B (en) Polysubstituted thioether compound and preparation method thereof
CN114181122A (en) Benzyl thioether compound and preparation method thereof
Beukeaw et al. Iodine/persulfate-promoted site-selective direct thiolation of quinolones and uracils
Marchese et al. A Simplified Protocol for the Stereospecific Nickel-Catalyzed C–S Vinylation Using NiX2 Salts and Alkyl Phosphites
CN111217731B (en) Ortho-imine ester or cyano-substituted aryl thioether derivative, preparation and application thereof
CN114835625A (en) Synthesis method of axial chiral indole derivative containing 2-thiocyano-3-aryl
Llamas et al. Copper (I)-catalyzed enantioselective 1, 3-dipolar cycloaddition of azomethine ylides with vinyl sulfones
Filipan-Litvić et al. A highly efficient biomimetic aromatization of Hantzsch-1, 4-dihydropyridines with t-butylhydroperoxide, catalysed by iron (III) phthalocyanine chloride
CN110294730B (en) Difluoromethyl sulfuration flavonoid compound and preparation method thereof
CN110317172B (en) Azafluorenone derivative and preparation method and application thereof
CN112812084B (en) Synthetic method of benzofuran compound
CN110845363B (en) O-alkenyl aromatic nitrile compound and preparation method thereof
Kissane et al. Investigation of the chemoselective and enantioselective oxidation of α-thio-β-chloroacrylamides
CN110305157B (en) Conjugated eneyne amide derivatives, and preparation method and application thereof
Zhu et al. Access to 2-pyridinones comprising enaminonitriles via AgOAc promoted cascade reactions of thioesters with aminomethylene malononitriles
Fu et al. Tf2O/2-Chloropyridine-Triggered Synthesis of Benzo [b] thiophene 1, 1-Dioxides from Sulfonium α-Acyl Sulfonylmethylides
CN109369645A (en) A kind of green synthesis method of the 3- arylthio -7- azaindole compounds of base catalysis
CN114790179B (en) Sulfur-containing 2,4, 5-trisubstituted oxazole compound and preparation method and application thereof
CN109485587B (en) Method for preparing sulfoxide compound by one-step reaction of benzyl chloride compound and thiophenol under metal-free condition
CN111925308B (en) Method for synthesizing N-substituted sulfone diimine by photocatalysis
CN112125843B (en) Preparation method of 3-hydroxymethyl-4-phenyl-3, 4-dihydroquinolinone compound

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant