JPH04295455A - Cyanation of nucleophilic reaction accepting compound and catalyst for asymmetric synthesis - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION The present invention relates to a method for cyanating carbonyl compounds such as aldehydes and ketones, and compounds receptive to nucleophilic reactions such as imine compounds and nitroolefin compounds.

0002

BACKGROUND OF THE INVENTION In order to synthesize a cyano compound, a method in which a nucleophilic reaction-accepting compound is reacted with a cyanating agent as a nucleophilic reaction reagent is widely known. In this case, hydrogen cyanide has so far been used as the cyanating agent, but since this is highly toxic and dangerous, it has become common to use trisubstituted silyl cyanides instead. (J.Chem
．． Soc. Chem. Commun. 1973, 55)
. In the cyanation reaction using trisubstituted silyl cyanides, Lewis acid catalysts such as ZnI2 and AlCl3 have conventionally been used as catalysts, but in the case of this Lewis acid catalyst,
After the reaction, separation and removal of the catalyst is accompanied by great difficulty, and a part of the silyl group is detached from the obtained cyanated product (trisubstituted silyl ether of cyanohydrin).

On the other hand, in the cyanation reaction, an optically active cyano compound has also been synthesized by using an asymmetric synthesis catalyst. In this case, the asymmetric synthesis catalyst is a Lewis acid (Bull.Chem.Soc.Jp) derived from titanium tetrachloride and an optically active alcohol.
m. 1988, 61, 4379), dipeptide (L-
Phenylalanyl-L-histidine) (J.Org.C
hem. , 1990, 55, 181), Sharple
ss Catafyst (Asymmetric synthesis catalyst derived from Ti(OPri)4 and diisopropyl tartrate) (
J. Chem. Soc. Commun. , 1990, 3
64) etc. are known. However, in all of these asymmetric synthesis catalysts, the optically active compounds used as catalyst components are difficult to obtain, and they have not been applicable as industrial catalysts.

0004

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned problems by using a novel catalyst in the cyanation reaction of a nucleophilic reaction-accepting compound.

[0005]

[Means for Solving the Problems] The present inventors have conducted extensive research to solve the above problems, and as a result, have completed the present invention.

That is, according to the present invention, in cyanating a nucleophilic reaction-receptive compound using a trisubstituted silyl cyanide, a Lewis base is used as a catalyst for the cyanation reaction. A method of cyanating a chemical compound is provided.

According to the present invention, the structural formula

0008
]

Provided is an asymmetric synthesis catalyst for cyanation of a nucleophilic reaction-accepting compound using a trisubstituted silyl cyanide, which is a cinchonine derivative represented by the following formula.

The raw material used in the present invention is a nucleophilic reaction-accepting compound, and conventionally well-known compounds can be used. Such compounds include carbonyl compounds such as aldehydes and ketones, imine compounds, nitroolefins, and the like. Aldehydes include aliphatic, aromatic and heterocyclic aldehydes. The aldehyde preferably used in the present invention is represented by the following general formula. RCHO

In the formula (1), examples of R include hydrocarbon groups such as alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aralkenyl, and cycloalkyl. Examples of the alkyl group and alkenyl group include those having 2 or more carbon atoms, preferably 3 to 30 carbon atoms. Cycloalkyl includes cyclohexyl. Aryl includes phenyl, tolyl, and the like. Examples of aralkyl include benzyl and phenethyl, and examples of aralkenyl include styryl. These hydrocarbon groups may have a substituent that is inert to the cyanation reaction.

[0010] In addition, as ketone compounds, aliphatic,
Various types of alicyclic, aromatic, and heterocyclic types may be mentioned, such as diisopropyl ketone, chalcone, cyclohexanone, acetophenone, and benzoquinone. Examples of imine compounds include aliphatic, alicyclic, aromatic, and heterocyclic compounds, such as Ph=
Examples include NCH2Ph. The nitroolefin compound has the general formula (R1R2)C=C(R3)(NO2
) (wherein R1, R2, R3 represent an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, a heterocyclic group, etc.), such as styryl nitroolefin.

The cyanating agent used in the present invention is a trisubstituted silylanide, which is a well-known compound represented by the following general formula. (R1)(R2)(R3)Si-CN
(2
) In the formula, R1, R2, and R3 are hydrocarbon groups that may be the same or different. Examples of the hydrocarbon group include alkyl, cycloalkyl, aryl, aralkyl, and the like. These hydrocarbon groups may have substituents that are inert to the reaction.

The catalyst used in the present invention is a Lewis base. The Lewis base includes organic amine compounds, organic phosphorus compounds, organic arsenic compounds, and organic antimony compounds. As the organic amine, secondary amines and tertiary amines are preferably used. As these amines, those represented by the following general formula are preferable. (R1) (R2)NR3

(3) In the formula, R1 and R2 are an alkyl group, R
3 is an alkyl group or a hydrogen atom. As the alkyl group, a lower alkyl group having 1 to 6 carbon atoms is preferable. (R1) (R2) N-R-N (R3) (R4)
(4) In the formula, R1, R2, R3 and R4 are alkyl groups, and R is an alkylene group. The alkyl group has 1 to 1 carbon atoms.
The lower alkyl group and alkylene group of 6 have a carbon number of 1
~6 lower alkylene groups are preferred. Other amines preferably used in the present invention include cyclic amines. The cyclic amine includes cinchonine, pyridine, piperazine, N-substituted products and ring-substituted products thereof, and the like.

[0013] As organic phosphorus compounds, secondary and tertiary
Class phosphines are preferably used, and these organophosphorus compounds can be linear or cyclic compounds. Preferred phosphines used in the present invention include, for example, triarylphosphines, trialalkylphosphines,
Examples include alkylphosphine, tricyclohexylphosphine, and the like.

As organic arsenic compounds, secondary and tertiary
Class arsine is preferably used, and these organic arsenic compounds can be linear or cyclic compounds. Preferred arsines for use in the present invention include, for example, triarylalysine, trialalkylarsine, trialkylarsine, tricycloalkylarsine, and the like. As the organic antimony compound, secondary and tertiary stibine are preferably used, and such an organic antimony compound can be a chain or cyclic compound. Preferred skevins used in the present invention include triarylstivines, trialkylstivines, trialkylstivines, tricycloalkylstivines, and the like.

The organic phosphorus compound, organic arsenic compound and organic antimony compound can generally have the same structure as the organic amine compound. The cyanation reaction of the present invention itself is known, and the present invention is characterized in that the aforementioned Lewis base is used as the catalyst. The reaction temperature is preferably -78°C to room temperature. As the reaction solvent, hydrocarbons such as methylene chloride, toluene, methanol, and pentane, halogenated hydrocarbons, and organic solvents such as alcohols are used. Among them, methylene chloride is most preferably used. The amount of the Lewis base catalyst used is 0.01 to 1 mol, preferably 0.1 to 0.3 mol, per 1 mol of the nucleophilic reaction-accepting compound as a reaction raw material.

In the cyanation reaction of the present invention, a compound having a structure in which a trisubstituted silyl cyanide is added to a nucleophilic reaction-accepting compound is obtained. The reaction formula between benzaldehyde and trimethylsilyl cyanide is as follows.

PhCHO+(CH3)3SiCN→PhC[
OSi(CH3)3].CN According to the present invention, a new asymmetric synthesis catalyst for use in the cyanation reaction is provided. The asymmetric synthesis catalyst of the present invention has the structural formula

This is an optically active amino catalyst represented by the following formula. In the above formula, Tf is a trifluoromethanesulfonic acid residue and is represented by the formula CF3SO2--. This catalyst is made by adding trifluoromethanesulfonic acid and (+)-cinchonine to 1,1'-dimethylstanocene, which is obtained by reacting tin dichloride and 1,1'-dimethylcyclopentadiene, to about 0.0% in dichloromethane. It is easily produced by reacting at ℃.

To perform a cyanation reaction for asymmetric synthesis using this optically active amino catalyst, a nucleophilic reaction-accepting compound and a trisubstituted silyl cyanide as starting materials are heated at -45°C to -45°C in the presence of the amine catalyst. The reaction is carried out at a temperature in the range -100°C. The reaction time is about 1 to 2 days. As the reaction solvent, methylene chloride is most suitable, but any aprotic polar solvent such as tetrahydrofuran can generally be used. The amount of catalyst used is per mole of raw material compound,
The proportion is from 0.01 to 1 mol, preferably from 0.3 to 1 mol. Furthermore, by performing this reaction in the presence of zeolite, the product yield and optical yield can be improved. It is preferable to use Linde's Molecular Sieve 4A, etc., and the amount added is 1 to 500 parts by weight, preferably 100 to 200 parts by weight, based on 100 parts by weight of the raw material compound.
It is a proportion of parts by weight. In the cyanation reaction using the amine catalyst of the present invention, a cyanation product can be obtained with a high optical yield.

[0019]

According to the present invention, cyanated products can be obtained in high yield. The catalyst used in the present invention is a sauce that is a Lewis base, and the catalyst can be easily separated and removed after the reaction, and the removal of the silyl group from the obtained product is also prevented. The cyanated products obtained according to the invention are advantageously used as raw materials for the production of many compounds, in particular pharmaceuticals, agricultural chemicals, liquid-crystalline substances. The cyanated carbonyl compound obtained by the present invention can be converted into cyanohydrin by removing its silyl group. This cyanohydrin is advantageously used as a raw material for producing pyrethroid compounds and liquid crystalline substances. Moreover, this cyanohydrin can be made into an α-hydroxycarboxylic acid by hydrolyzing it, and on the other hand, it can be made into a β-hydroxyamine by reducing it. Therefore, by using these reactions, various compounds can be synthesized from cyanohydrin. Cyanation of imine compounds yields aminonitrile, which is advantageously used as a raw material for amino acid synthesis by the Strecker method. The photoactive amine catalyst of the present invention is advantageously used as a catalyst for asymmetric synthesis in cyanation reactions and provides high optical yields. Furthermore, since this catalyst is cinchonine, which is optically active and is easily available, it has the advantage that it can be supplied stably and at low cost compared to conventional asymmetric synthesis catalysts. By using this amine catalyst, various optically active cyanohydrins and their derivatives can be synthesized.

[0020]

EXAMPLES Next, the present invention will be explained in more detail with reference to examples.

Example 1 Cyclohexylaldehyde 44.9 mg (0.4 mmo
1) was dissolved in 1 ml of methylene chloride, 1 ml of a methylene chloride solution of 47.6 mg (0.48 mmol) of trimethylsilyl cyanide was added thereto, and the mixture was cooled to 0°C. A solution of 4.1 mg (0.04 mmol) of trimethylamine in 1 ml of methylene chloride is slowly added thereto, followed by stirring for 2 hours. Thereafter, the reaction solution was distilled off under reduced pressure using an aspirator to obtain a cyanated product. The yield was 80.0 mg (99% yield), and the product was identified by 1H-nmr and IR. 1H-nmr (CDC13): δ=0.2 (s, 9H)
, 1.2-1.8 (m,
11H), 4.1-4.
4(brd,1H)IR(CH2C12):2930,
2860, 1450, 1040

Example 2 42.4 mg (0.4 mmol) of benzaldehyde is dissolved in 1 ml of methylene chloride, 79.4 mg (0.8 mmol) of trimethylsilyl cyanide and 1 ml of methylene chloride solution are added thereto, and the mixture is cooled to 0°C. To this, 1 ml of a methylene chloride solution containing 4.1 mg (0.04 mmol) of trimethylamine was slowly added, and then for 15 hours (overnight).
Stir. Thereafter, the reaction solution was distilled off under reduced pressure using an aspirator to obtain a cyanated product. The yield was 78.8 mg (yield 96%), and the product was identified in the same manner as cyanohydrin derived from cyclohexylaldehyde. 1H-nmr (CDC13): δ=0.2 (S, 9H)
, 5.4 (s, 1H), 7.2-7.6 (m, 5H) I
R(CH2C12): 2930, 1750, 1490,
1015

Example 3 78.1 mg (0.4 mg) of N-benzylidenebenzylamine
mmol) was dissolved in 1 ml of methylene chloride, and 47.6 mg (0.48 mmol) of trimethylsilyl cyanide was dissolved therein.
1 ml of methylene chloride solution of ) is added and cooled to 0°C. There, 4.1 mg of trimethylamine (0.04 mmo
Slowly add 1 ml of methylene chloride solution of 1), and then stir for 2 hours. Thereafter, the reaction solution was distilled off under reduced pressure using an aspirator to obtain a cyanated product. Yield is 35.6m
g (yield 40%). Confirm the structure by 1H-nmr
I went there. 1H-nmr (CDC13): 3.5-3.6 (bds
, 1H), 6.3 (s, 1H), 7.2-7.5 (m,
10H)

Example 4 A cyanation reaction was carried out in the same manner as in Example 1, except that 3-phenylpropanal was used instead of cyclohexylaldehyde and various amines shown in Table 1 were used as amines. The results are shown in Table 1.

[0025]

[Table 1]

Example 5 An experiment was conducted in the same manner as in Example 1, except that various aldehydes shown in Table 2 were used instead of cyclohexyl aldehyde. The results are shown in Table 2.

[0027]

[Table 2]

Example 6 A cyanation reaction was carried out in the same manner as in Example 1, except that 3-phenylpropanal was used instead of cyclohexylaldehyde and various catalysts shown in Table 3 were used as catalysts. The results are shown in Table 3.

[0029]

[Table 3]

Example 7 An experiment was carried out in the same manner as in Example 1 except that (+)-cinchonine was used as the catalyst and -78°C was used as the reaction temperature. As a result, a cyanide yield of 94% and an optical yield of 25% were obtained.

Example 8 Stanocene derived from tin dichloride and 1,1'-dimethyldicyclocyclopentadiene (33.2 mg, 0.5 mg).
After cooling 12 mmol) to 0°C, a methylene chloride solution of 16.2 mg (0.36 mmol) of commercially available trifluorosulfonic acid was slowly added dropwise and stirred for 10 minutes, followed by commercially available cinchonine (42.4 mg, 0.14 mmol). Add and stir for an additional 30 minutes. After cooling this to -78°C, 79.4 mg (0.8 mg) of trimethylsilyl cyanide was added.
mmol) and cyclohexylaldehyde 44.9 mg (
0.4 mmol) was slowly added and stirred for 40 hours. After the reaction was completed, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution, the precipitate was filtered, the product was extracted with ether, the extracted solution was dried over anhydrous sodium sulfate, and the solvent was distilled off using an evaporator under reduced pressure. The resulting crude product was separated and purified by silica gel chromatography to obtain 53.3 mg (0.25 m
mol) was obtained in a yield of 63%. The optical purity of the product is determined by deprotecting the silyl protecting group of the product with a 1N hydrochloric acid-THF solution and reacting the generated free hydroxyl group with MTPA-Cl (methyl trifluoromethylphenylacetic acid chloride). Determined by liquid chromatography analysis. The optical yield was 96%. The optical rotation of the product (trimethylsilylcyclohexylcyanohydrin) is [α]D25=-49.1° (C=2, CHC13)
Met. Product identification was performed by 1H-nmr.

Claims (5)

[Claims] 1. A method for cyanating a nucleophilic reaction-receptive compound, which comprises using a Lewis base as a catalyst for the cyanation reaction in cyanating the nucleophilic reaction-receptive compound using a trisubstituted silyl cyanide. . 2. The method according to claim 1, wherein the catalyst is an organic amine compound, an organic phosphorus compound, an organic arsenic compound, or an organic antimony compound. 3. The method of claim 1, wherein the catalyst is cinchonine or a derivative thereof. 4. The method according to claim 1, wherein the nucleophilic reaction-accepting compound is an aldehyde compound. 5. An asymmetric synthesis catalyst for the cyanation of a nucleophilic reaction-receptive compound using a trisubstituted silyl cyanide, which is a cinchonine derivative represented by the structural formula: [Claim 5]