N-Cyanomethylation

Benzylamine, o-chloro-N-(cyanomethyl)-N-methyl-isoindole synthesis from, 4, 323 Benzylisoquinoline alkaloids synthesis, 1, 446 Benzynes... 

Treatment of 4 with glycinonitrile (aminoacetonitrile) affords50,a) (N-cyanomethyl-D-glucofuranosylamine)urono-6,3-lactone. Its negative optical rotation is an indication of the /3-d configuration of this compound. 

Ethylcyanomethylamine and derivs 6 E224 N-trinitroethyl-N-cyanomethyl nitramine 6E224... 

Cyanobenziodoxoles 36-38 are used as efficient cyanating reagents toward N,N-dialkylarylamines. In a typical example, reagent 38 reacts with N,N-dimethylanilines 39 in 1,2-dichloroethane at reflux to afford the respective N-cyanomethyl-N-methylanilines 40 in good yield (Scheme 17) [34]. 

In a recent paper, cyanobenziodoxole 38 was applied to the synthesis of N-cyanomethyl-AT-cyclopropylamine, which is an important metabolite of the cyclopropylamine derived drugs [37]. 

A three-step reaction sequence starting from /3-amino alcohol 212 has been utilized in the synthesis of 2-cyanoazetidine (Scheme 42) <2002TA297, 2006SL78>. The A-benzyl-substituted /3-amino alcohol was first N-cyanomethylated to give the corresponding A-benzyl-A-cyanomethyl /3-amino alcohol 213. The latter compound was stereoselectively transformed into chlorinated amine 214 using thionyl chloride. An intramolecular alkylation of... 

A stirred mixture of cyanobenziodoxole (225 mg, 0.824 mmol) in dry 1,2-dichloroethane (20 ml) was treated with A,iV-dimethylaniline (0.824 mmol) under nitrogen. After 1 h reflux, the reaction mixture was washed with aqueous potassium hydroxide (0.5 M, 2 x 20 ml) and water (20 ml), dried and evaporated to give N-cyanomethyl-N-methylanilines as oils, in 80-96% yield. 

Monoalkylation of primary amines. A two-step sequence for this reaction involves conversion of the amine to the N-(cyanomethyl)amine (2) by reaction with chloroaceto-nitrile or with formaldehyde and KCN. Reaction of 2 with an organolithium or a Grignard reagent generates an unstable formaldehyde imint (a) that reacts with a second equivalent of the organometallic reagent to form a secondary amine (3). 

CYANOLIT see MIQ075 CYANOMETHANE see ABE500 CYANOMETHANOL see HIM500 (CYANOMETHYL)BENZENE see PEA750 N-(CYANOMETHYL)DIMETHYLAMINE see DOS200 S-N-(l-CYANO-l-... 

In a similar manner, the 2-cyano-6-oxazolopiperidine synthon is useful for the chiral synthesis of in-dolizidine (monomerine piperidine [(+)- and (-)-coniine and dihydropinidine] and quinolizidine alkaloids.2-Hydroxymethyl-1-amino-1-cyclopropanecarboxylic acid (-)-(2I )-hydroxy-(3S)-nonylamine and a-substituted phenylethylamines are obtained in optically active form from (-)-N-cyanomethyl-4-phenyloxazolidine. 

Lactams. This N-(cyanomethyl)amine reacts with lithium ester enolates to afford 4-unsubstituted p-lactams in 60-75% yield (equation I). This reaction is generally applicable to N-(cyanomethyl)amines. 3-Amino-p-lactams can be ob-... 

Amino-N-cyanomethyl-3-thiophenecarboxamide (216), easy accessible according to the Gewald method,21 cyclizes in the presence of sodium methoxide to give 2-amino-3,4-dihydrothieno[2,3-/]-l,4-diazepine-5-one (217), which is converted with acetylhydrazine to a thieno[3,2-/][l,2,4]-triazolo[4,3-a][l,4]diazepine-6-one (218).129 These compounds are of interest because of their hypnogenic and anxiolytic properties (Scheme 56). By a one-step procedure, 2-aminothiophene-3-carboxylates 219 are transformed with cyclohexanone by heating with HMPT and catalytic amounts of PPA to 4-dimethylamino-2-methyl-5,6,7,8-tetrahydrothieno[2,3-b]quino-lines such as 220.130... 

Treatment of the linker with diazomethane or bromoacetonitrile gives base-labile N-alkylsul-fone amide. The N-cyanomethyl-sulfone amide linker is also cleaved by sterically hindered amines. 

An in situ method for the preparation of N-methyleneamines has been devised by Overman and Osawa for use in condensation reactions with enolates and organometallic reagents. These species, with the exception of very hindered N-methyleneamines, cannot be isolated in the condensed phase because they rapidly trimerize to hexahydro-l,3,5-triazines. In this in situ method, A -methyleneamines (230) are generated from N-(cyanomethyl)amines (228) by deprotonation with an equivalent of enolate to give an intermediate amide (229) which loses LiCN (equation 22). When two equivalents of enolate are present, addition to the N-methyleneamine occurs and 3-lactams (233) are obtained in 60-70% yield upon warming the reaction mixture to 25 C (Scheme 48 Table 26). Uncyclized 3-amino esters can be isolated if the reaction is quenched at lower temperature a possible cycloaddition mechanism is thus ruled out. It is not clear to what extent, if any, the reaction is limited to a,a-disubstituted enolates. N-Methyleneamines, like oxime ethers, are useful for the synthesis of 4-unsubstituted 3-lactams and should also have important applications in the synthesis of monobactam antibiotics. 

Entry R Ester (231) B N-(Cyanomethyl)amine (232) Lactam (233) Yield i%)... 

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