CN109912456B - Preparation method of gamma-carboxylation alkyl nitrile compound - Google Patents

Preparation method of gamma-carboxylation alkyl nitrile compound Download PDF

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CN109912456B
CN109912456B CN201910336514.7A CN201910336514A CN109912456B CN 109912456 B CN109912456 B CN 109912456B CN 201910336514 A CN201910336514 A CN 201910336514A CN 109912456 B CN109912456 B CN 109912456B
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宋仁杰
姜帅帅
李金恒
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Nanchang Hangkong University
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Abstract

The invention discloses a preparation method of gamma-carboxylation alkyl nitrile compounds, which comprises the step of carrying out olefin bifunctional reaction on an olefin compound shown in a formula II, a carboxylic acid compound shown in a formula III and an alkyl nitrile compound shown in a formula IV under the conditions of a nickel catalyst and a silver oxidant to prepare a series of gamma-carboxylation alkyl nitrile compounds with different structures. The synthetic route of the gamma-carboxylation alkyl nitrile compound has the advantages of easily obtained raw material sources, low price of a catalytic system, wide application range of reaction substrates and high yield of target products.

Description

Preparation method of gamma-carboxylation alkyl nitrile compound
Technical Field
The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a gamma-carboxylation alkyl nitrile compound.
Background
The rapid increase in molecular complexity from readily available chemicals (especially feedstocks derived from the petroleum industry, such as olefins, alkanes and aromatics) through a mild, economical and practical selective catalytic pathway is one of the main goals of academia and industry. In this field, the functionalization of molecules by conversion of olefins and/or C-H bonds is an attractive and challenging goal, which has attracted great interest to researchers. Typical strategies include two-carbon functionalization of olefins by introducing two ortho functional groups to extend the carbon chain, resulting in compounds with complex structures. However, most olefin two-carbon functionalization processes are often limited to classical cross-coupling reactions, which in turn often require the use of expensive nucleophilic and/or electrophilic reagents (e.g., organometallic compounds and organic halides) and catalytic systems. The inventors have previously reported a process for the intermolecular 1, 2-dialkylation of olefinic compounds (CN108640839A, 20181012) which achieves the dialkylation of olefins under photo-redox/iron (II) concerted catalysis.
Gamma-carboxylated alkyl nitrile compounds are an important class of organic compounds which are widely used in pharmaceutical and organic synthesis (Org. biomol. chem., 2014, 12, 5407-5426; Journal of Organometallic Chemistry 177(1979) 211-220; US3932159, 19760113; US401121, 19770308; Zeitschrift fur Nature project, Teil B: Anorgansise Chemie, Organische Chemie (1982), 37B (7), 923-9.). However, the prior art methods for synthesizing such compounds are relatively inefficient, require multiple reactions and/or require the prior design of reaction substrates with complex synthetic structures. For example, Wenying Ai et al report a method for synthesizing gamma-or delta-carboxylated alkyl nitrile compounds, which uses cyclobutanone or cyclopentanone oxime ester as a reaction raw material and performs ring opening under the catalysis of copper to obtain gamma-or 6-carboxylated alkyl nitrile compounds (see formula one).
Figure BDA0002038148030000021
The present inventors have made extensive studies and, in the present invention, have proposed a novel method for directly producing a γ -carboxylated alkylnitrile compound from readily available reaction raw materials (simple olefins, carboxylic acids, and alkylnitrile compounds).
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a novel method for directly preparing gamma-carboxylated alkyl nitrile compounds from easily obtained reaction raw materials (simple olefin, carboxylic acid and alkyl nitrile compounds). The method has the advantages of easily available raw material sources, low cost of a catalytic system, wide application range of reaction substrates and high yield of target products.
The invention provides a preparation method of gamma-carboxylation alkyl nitrile compounds, which comprises the following steps:
an olefin compound shown in a formula II, a carboxylic acid compound shown in a formula III, a nickel catalyst, a silver oxidant and an alkyl nitrile compound shown in a formula IV are sequentially added into a reactor, and the mixture reacts for 12-36 h at 100-140 ℃ under the protection of inert atmosphere. After the reaction is completed, the reaction solution is concentrated in vacuum, and the residue is separated by silica gel column chromatography to obtain the gamma-carboxylation alkyl nitrile compound shown in the formula I.
Figure BDA0002038148030000022
In the formula II and the formula I, R is selected from substituted or unsubstituted C6-C20Aryl, substituted or unsubstituted C3-C20Heteroaryl, substituted or unsubstituted C6-C20An arylvinyl group of (a);
R1selected from hydrogen, C1-C20Alkyl of (C)6-C20Aryl of (a);
R2selected from hydrogen, C1-C20Alkyl groups of (a);
in the formulae III and I, R3Selected from substituted or unsubstituted C1-C20Alkyl, substituted or unsubstituted C6-20Aryl, substituted or unsubstituted C3-C20Cycloalkyl, substituted or unsubstituted C3-C20A heterocyclic group of (a);
in the formulae IV and I, R4Selected from hydrogen, C1-C20Alkyl of (C)6-C20Aryl of (a), -COOR5Wherein R is5Is selected from C1-C6Alkyl group of (1).
Preferably, in formula II and formula I, R is selected from substituted or unsubstituted C6-C14Aryl, substituted or unsubstituted C3-C12Heteroaryl, substituted or unsubstituted C6-C14An arylvinyl group of (a);
R1selected from hydrogen, C1-C12Alkyl of (C)6-C14Aryl of (a);
R2selected from hydrogen, C1-C12Alkyl groups of (a);
in the formula III and the formula I,R3selected from substituted or unsubstituted C1-C12Alkyl, substituted or unsubstituted C6-C14Aryl, substituted or unsubstituted C3-C12Cycloalkyl, substituted or unsubstituted C3-C12A heterocyclic group of (a);
in the formulae IV and I, R4Selected from hydrogen, C1-C12Alkyl of (C)6-C14Aryl of (a), -COOR5Wherein R is5Is selected from C1-C6Alkyl group of (1).
In any of the definitions of the present invention for substituent R: said substituted or unsubstituted C6-C20Aryl, substituted or unsubstituted C6-C14The substituents in the aryl group of (A) are selected from halogen, C1-C6Alkyl of (C)1-C6Alkoxy group of (C)1-C6Alkylthio group of-NO2、C1-C6Any one or more of the alkylcarbonyl groups of (a). Wherein "C" is6-C20Aryl of (2), "" C6-C14The aryl group of (1) is preferably selected from, for example, phenyl, naphthyl, anthryl, phenanthryl.
Said "substituted or unsubstituted C3-C20Heteroaryl of (a), (a) substituted or unsubstituted C3-C12In the heteroaryl group of (1), "the substituents are selected from halogen and C1-C6Alkyl of (C)1-C6Any one or more of the alkoxy groups of (a). The heteroatom species may be selected from O, S, N and the like, and specific heteroaryl groups may be selected from, for example, thienyl, furyl, pyridyl, indolyl, benzofuryl, quinolyl, benzopyranyl and the like.
Said substituted or unsubstituted C6-C20Aryl vinyl group of (A), substituted or unsubstituted C6-C14The substituents in the arylethenyl group of (A) are selected from halogen, C1-C6Alkyl of (C)1-C6Any one or more of the alkoxy groups of (a). Wherein "C" is6-C20Aryl vinyl group of "," C6-C14Aryl of (2)Alkenyl "may be selected from, for example, styryl, naphthylvinyl.
For R in any part of the invention1，R2And R4In the group definitions of (1), the "C" is1-C20Alkyl of (2), "" C1-C12Alkyl of (2), "" C1-C6Practical examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, 3-heptyl, n-octyl, undecyl, and the like. Said C is6-C20Aryl group of6-C14Aryl of (b) may be selected, for example, from preferably selected, for example, from phenyl, naphthyl, anthryl, phenanthryl.
For R in any part of the invention3In the definition of the group (1), the "substituted or unsubstituted C1-C20Alkyl of "," substituted or unsubstituted C1-C12In the "alkyl group", the substituent is selected from one or more of halogen, NHBoc, N (Me) (Boc), N (et) (Boc), phenyl and benzyloxy. Wherein "C" is1-C20Alkyl of (2), "" C1-C12Alkyl groups "having R as defined above1，R2And R4The same definition as in the group definitions of (a).
Said "substituted or unsubstituted C6-20Aryl of (2), "substituted or unsubstituted C6-C14Aryl of (a) has "substituted or unsubstituted C" as in the definition of R substituents hereinbefore6-20Aryl of (2), "substituted or unsubstituted C6-C14The same definition as in the above.
Said "substituted or unsubstituted C3-C20Cycloalkyl group of (1), "" substituted or unsubstituted C3-C12In the cycloalkyl group, the substituents are selected from halogen and C1-C6Alkyl of (C)1-C6Any one or more of the alkoxy groups of (a). Wherein "C" is3-C20Cycloalkyl of (A), "" C3-C12Cycloalkyl groups "are preferably selected from monocyclic, e.g. cyclopropylCyclobutyl, cyclopentyl, cyclohexyl, etc.; bicyclic, e.g. bicyclo [2.2.2]Octyl, bicyclo [2, 2, 1 ]]Heptadecyl, decalinyl; polycyclic such as adamantyl and the like.
Said "substituted or unsubstituted C3-C20Heterocyclic group of (1), "" substituted or unsubstituted C3-C12In the heterocyclic group of (1), "the substituent is selected from the group consisting of halogen and C1-C6Alkyl of (C)1-C6And (3) alkoxy and/or Boc. The heteroatom species may be selected from O, S, N, etc., wherein "C" is3-C20Heterocyclic group of (2), "" C3-C12The "heterocyclic group" of (a) may be selected from, for example, furyl, thienyl, pyridyl, tetrahydrothienyl, tetrahydrofuryl, tetrahydropyranyl, piperidyl, piperazinyl, tetrahydropyranyl, dioxane, morpholinyl and the like; preferably selected from the group consisting of furyl, tetrahydropyranyl, piperidinyl.
Most preferably, the compound of formula II is selected from compounds having the following structure:
Figure BDA0002038148030000051
the compound of formula III is selected from compounds having the following structures:
Figure BDA0002038148030000061
the compound of formula IV is selected from compounds having the following structure:
Figure BDA0002038148030000062
according to the preparation method of the gamma-carboxylation alkyl nitrile compound, the nickel catalyst is selected from NiI2、Ni(acac)2、NiBr2、Ni(OAc)2And Ni (PPh)3)4Any one of them. Preferably, theThe nickel catalyst is selected from NiI2。
According to the preparation method of the gamma-carboxylation alkyl nitrile compound, the silver oxidant is selected from Ag2CO3、Ag2Any one of O, AgOAc and AgF, preferably, the silver oxidant is selected from Ag2CO3。
According to the preparation method of the gamma-carboxylated alkyl nitrile compound, the inert atmosphere is inert to the reaction and is not considered to be inert gas mechanically. It will be appreciated by those skilled in the art that the inert atmosphere commonly used for organic reactions may be selected from an argon atmosphere or a nitrogen atmosphere. An argon atmosphere is preferred.
According to the preparation method of the gamma-carboxylated alkyl nitrile compound, the reaction temperature is preferably 120 ℃, and the reaction time is preferably 24 hours.
According to the preparation method of the gamma-carboxylation alkyl nitrile compound, the olefin compound shown in the formula II, the carboxylic acid compound shown in the formula III, the nickel catalyst and the silver oxidant are fed in a molar ratio of 1: 1-3: 0.05-0.2: 1-3; preferably 1:2: O.01: 2. The alkyl nitrile of formula IV serves as a reactant and also as a reaction medium (solvent), and the amount added can be determined by routine selection by those skilled in the art, so that the material is uniformly dispersed and easily stirred.
The invention has the following beneficial effects:
1. the invention firstly reports a synthetic route for preparing a series of gamma-carboxylation alkyl nitrile compounds with different structures by carrying out olefin dual-functionalization reaction on an olefin compound shown in a formula II, a carboxylic acid compound shown in a formula III and an alkyl nitrile compound shown in a formula IV under the conditions of a nickel catalyst and a silver oxidant.
2. The synthetic route of the gamma-carboxylation alkyl nitrile compound has the advantages of easily obtained raw material sources, low price of a catalytic system, wide application range of reaction substrates and high yield of target products.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Examples 1-17 optimization of reaction conditions
P-methoxystyrene shown in a formula II-1, BOC-N-ethylglycine shown in a formula III-1 and acetonitrile are used as raw materials, influences of different reaction conditions on process optimization results are discussed, representative examples 1-17 are selected, and the results are shown in a table I:
Figure BDA0002038148030000071
a typical experimental procedure for example 1 is as follows:
into a dry, closed Schlenk reactor was added 4-methoxystyrene of formula II-1 (0.2mmol), BOC-N-ethylglycine of formula III-1 (2equiv), NiI in that order2(10mol％)， Ag2CO3(2equiv) and CH3CN (1mL) was reacted at 120 ℃ for 24h under argon as a protective gas. After completion of the reaction, the reaction solution was concentrated in vacuo, and the residue was separated by silica gel column chromatography (n-hexane/ethyl acetate 10: 1, volume ratio) to give the objective product of formula I-1 (67.7mg, 90%). A yellow oily liquid;1H NMR(500 MHz，CDCl3)δ∶7.28-7.24(m，2H)，6.90-6.88(m，2H)，5.85-5.82 (m，1H)，4.00-3.89(m，2H)，3.80(s，3H)，3.36-3.25(m，2H)，2.39-2.25(m，3H)， 2.17-2.10(m，1H)，1.47(s，5H)，1.32(s，4H)，1.11-1.07(m，3H)；13C NMR(125 MHz，CDCl3)δ：169.4，159.9，159.7，155.6，154.8，130.2，130.0，127.9，127.7， 118.9，118.7，114.2，114.1，80.1，77.3，77.2，77.0，76.8，74.5，74.4，55.3，48.9，48.8， 43.5，42.9，32.0，31.6，28.3，28.1，13.8，13.6，13.6，13.2；HRMS m/z(ESI)calcd for C20H29N2O5([M+H]+)377.2071，found 377.2080。
table one:
Figure BDA0002038148030000081
Figure BDA0002038148030000091
the specific operations and parameters of examples 2-17 were the same as in example 1, except that the variables listed in Table one above were different from those of example 1.
As can be seen from representative examples 1-17 in Table I, the optimum process conditions for the present invention are those of example 1. On the basis of obtaining the optimal process conditions, the inventors further selected the reaction raw materials of formula II, formula III and formula IV of different substituents to react under the optimal process conditions (example 1) to prepare various target compounds of formula I. The results are shown in Table two, wherein the starting compounds II-1 to II-11, III-1 to III-30, IV-1 to IV-4 referred to in Table two have the same structures as defined herein before, and the structures of these starting compounds are not shown here for the sake of brevity.
Table two:
Figure BDA0002038148030000092
Figure BDA0002038148030000101
Figure BDA0002038148030000111
Figure BDA0002038148030000121
Figure BDA0002038148030000131
Figure BDA0002038148030000141
Figure BDA0002038148030000151
Figure BDA0002038148030000161
Figure BDA0002038148030000171
Figure BDA0002038148030000181
Figure BDA0002038148030000191
Figure BDA0002038148030000201
Figure BDA0002038148030000211
Figure BDA0002038148030000221
the embodiments described above are only preferred embodiments of the invention and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the above would be obvious to those of ordinary skill in the art, but would not bring the invention so modified beyond the spirit and scope of the present invention.

Claims (4)

1. A method for preparing gamma-carboxylated alkyl nitrile compounds shown as formula I comprises the following steps:
adding an olefin compound shown in a formula II, a carboxylic acid compound shown in a formula III, a nickel catalyst, a silver oxidant and an alkyl nitrile compound shown in a formula IV into a reactor in sequence, reacting for 24 hours at 120 ℃ under the protection of inert atmosphere, concentrating the reaction liquid in vacuum after the reaction is completed, and separating the residue by silica gel column chromatography to obtain a gamma-carboxylated alkyl nitrile compound shown in the formula I;
Figure FDA0003195062100000011
wherein the nickel catalyst is selected from NiI2；
The silver oxidant is selected from Ag2CO3；
The olefinic compound of formula II is selected from compounds having the following structure:
Figure FDA0003195062100000012
the carboxylic acid compounds shown in the formula III are selected from compounds with the following structures:
Figure FDA0003195062100000021
the alkyl nitrile compound of formula IV is selected from compounds having the following structure:
Figure FDA0003195062100000022
the feeding molar ratio of the olefin compound shown in the formula II, the carboxylic acid compound shown in the formula III, the nickel catalyst and the silver oxidant is 1:2:0.01: 2.
2. The method of claim 1, wherein: the inert atmosphere is selected from argon atmosphere or nitrogen atmosphere.
3. The method of claim 2, wherein the inert atmosphere is selected from argon atmosphere.
4. The production method according to any one of claims 1 to 3, characterized in that: the elution solvent separated by the silica gel column chromatography is a mixed solvent of n-hexane and ethyl acetate.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108640839A (en) * 2018-06-21 2018-10-12 南昌航空大学 The intermolecular 1,2- dialkylations reaction method of alkenes compounds under a kind of photoredox/iron (II) catalyst system and catalyzing
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CN108640839A (en) * 2018-06-21 2018-10-12 南昌航空大学 The intermolecular 1,2- dialkylations reaction method of alkenes compounds under a kind of photoredox/iron (II) catalyst system and catalyzing
CN108707081A (en) * 2018-07-09 2018-10-26 南昌航空大学 A kind of alkene 1,2- difunctionalities dough reaction method
CN108912036A (en) * 2018-08-24 2018-11-30 南昌航空大学 A kind of method that the dough reaction of alkene 1,4- difunctionality prepares allyl Benzazole compounds

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