Aminonitrile formation

Aminonitrile formation on 125 with potassium cyanide and piperidine hydrochloride affords the derivative, 135. Hydrolysis as above gives the corresponding amide (136). Debenzylation is accomplished by catalytic reduction. Alkylation of the secondary amine with the side chain (96) used in the preparation of diphenoxylate affords pirintramide (138) This compound, interest-... 

Allylic amine is a less reactive leaving group[7], but the allylic ammonium salts 214 (quaternary ammonium salts) can be used for allylalion(l30,131]. Allylic sulfonium salts are also used for the allylation[130]. The allylic nitrile in the cyclic aminonitrile 215 can be displaced probably via x-allylic complex formation. The possibility of the formation of the dihydropyridinium salts 216 and subsequent conjugate addition are less likelyfl 32],... 

The reaction of a-aminonitriles and carbon disulphide was stated by Cook and Heilbron to give 5-amino-2-mercaptothiazoles however, they later found that the same reaction with aminoacetonitrile was more complex. When aminoacetonitrile sulphate in ethanolic solution was treated with carbon disulphide, the dithiodicarbamate 9 was formed. Benzylation was then carried out treatment of the resulting ester 10 with phosphorus tribromide with subsequent loss of water gave 5-amino-2-benzylthiothiazole 11 in a quantitative fashion. The rapid reaction was thought to be the first example of the formation of a 5-aminothiazole from an a-aminoamide. 

Reaction of the carbonyl group of pi perl done with cyanide and aniline leads to formation of a cyanohydrin-like function known as an oc-aminonitrile (37) hydrolysis under... 

A very efficient and universal method has been developed for the production of optically pue L- and D-amino adds. The prindple is based on the enantioselective hydrolysis of D,L-amino add amides. The stable D,L-amino add amides are effidently prepared under mild reaction conditions starting from simple raw materials (Figure A8.2). Thus reaction of an aldehyde with hydrogen cyanide in ammonia (Strecker reaction) gives rise to the formation of the amino nitrile. The aminonitrile is converted in a high yield to the D,L-amino add amide under alkaline conditions in the presence of a catalytic amount of acetone. The resolution step is accomplished with permeabilised whole cells of Pseudomonas putida ATCC 12633. A nearly 100% stereoselectivity in hydrolysing only the L-amino add amide is combined with a very broad substrate spedfidty. 

Some covalent compounds, such as a-aminonitriles D (formation of an iminium ion by solvolysis) or TV-substituted 1,3-oxazolidincs E can be regarded as masked iminium salts because there is evidence that in reactions of these species with organometallic reagents iminium intermediates are involved101214-17. 

Optically pure a-amino acids can be converted to 1,2-diamines by a route that involves the preliminary formation of N-protected a-aminonitriles through the intermediate amides. The addition of organometallic reagents to these a-aminonitriles gives a-amino ketimines, which are then reduced in situ to 1,2-diamines. However, this route has been scarcely applied to acychc a-aminonitriles. As a matter of fact, the sequential addition of methylmag-... 

Thiazolopyridopyrimidines such as 259-263 are prepared by formation of the pyrimidine ring as the final step either from an o-aminonitrile (Equation 80) <2002PS( 177)293, 2004PS( 179) 1279, 2005PS(180)19,... 

The five-membered ring can also be formed by intramolecular nucleophilic attack of an alkoxide on a carbamate such as for the formation of 196 from 195 <1997T9553>, by dehydration of fV-carbamate-pipecolic acid derivatives <2002EJO3936>, by treatment of amino-amides under Eschweiler-Clarke conditions <1999TA3371>, or by treatment of hydroxyl aminonitriles with silver trifluoroacetate <2002JA2951> (Scheme 57). 

The ease of the Strecker synthesis from aldehydes makes a-aminonitriles an attractive and important route to a-amino acids. Fortunately, the microbial world offers a number of enzymes for carrying out the necessary conversions, some of them highly stereoselective. Nitrilases catalyze a direct conversion of nitrile into carboxylic acid (Equation (11)), whereas nitrile hydratases catalyze formation of the amide, which can then be hydrolyzed to the carboxylic acid in a second step (Equation (12)). In a recent survey, with a view to bioremediation and synthesis, Brady et al have surveyed the ability of a wide range of bacteria and yeasts to grow on diverse nitriles and amides as sole nitrogen source. This provides a rich source of information on enzymes for future application. 

In addition, stereoselective synthesis of solenopsin A has been reported by four research groups. An approach utilizing the stereoselective reductive de-cyanation (596) starts with aminonitrile 229, prepared from 2-picoline. It was selectively hydrogenated in the presence of Pd-C, followed by alkylation with undecyl bromide, affording 231. Reductive decyanation of 231 with NaBH4 in MeOH led to predominant (8 2) formation of the trans isomer (232) which was then debenzylated to ( )-solenopsin A (Id). The cis product (Ic) was in turn prepared by treatment of 231 with sodium in liquid ammonia followed by de-benzylation (Scheme 10). 

Tsuge et al. (14) outlined the use of A-silylmethyl thioureas as azomethine ylide precursors. Treatment of [2-methyl-3-(trimethylsilyl)]thiouronium triflates (59, R = H, R =Ph) with CsF in 1,2-dimethoxyethane (DME) and A-methyhnaleimide led to the formation of a cycloadduct in 90% yield. The initial adduct 60, however, could never be isolated and underwent in situ loss of MeSH to furnish the adducts shown, which represent formal aminonitrile ylide cycloadducts (Scheme 3.15). 

Thus, the N,N-dibenzyl-protected aminonitrile 55 was prepared via Swern oxidation of N,N-dibenzylaminoethanol 54 followed by treatment with the enantio-pure amine auxiliary (S,S)-53 and HCN, resulting in the formation of a 3 2 epimeric mixture of the aminonitriles 55 in 55% yield, from which the single dia-stereomers could be isolated by chromatography. After lithiation with LDA, addition to the requisite (E)-a, P-unsaturated esters and hydrolysis of the aminonitrile moiety with silver nitrate, the desired a-amino keto esters R)-S6 were obtained with yields of 65-81% and enantiomeric excesses ee of 78-98%, which could be improved to ee > 98% by a simple recrystallization. Since the amino ketone functionality can be cleaved oxidatively, the 5-amino-4-oxo-esters 56 could be transformed to the corresponding succinic half-esters 57 with hydrogen peroxide in methanol in good to excellent yields (68-90%) (Scheme 1.1.15). 

One of the first so-called potassium sparing, nonthiazide diuretic agents contains a pterdine nucleus. This is reflected in the use of the pterdine staring material tetra-aminopyrimidine (38-2) in the synthesis. Thus, reaction of benzaldehyde with that polyamine and potassium cyanide leads to the formation of the cyanohydrinlike a-aminonitrile (63-2) from reaction of the most basic amino group. Treatment of the intermediate with a base leads to the addition of the amine to the nitrile to give the dihydropteridine (63-3). Simple exposure to air leads to dehydrogenation and the formation of triamterine (63-4) [65]. 

The excess of ammonia is necessary to cause the formation of the aminonitrile from the acetone cyanohydrin formed in the first stage of the process. 

Osteolathyrism is a disease characterized by lameness, skeletal deformities, aortic aneurysms, and slowing or cessation of body growth. Certain aminonitriles are known to cause osteolathyrism in several animal species aminoacetonitrile, 3-aminopropionitrile, and 3-amino-2-methylpropionitrile are potent inducers of this disease. It is believed that the basis of their ability to cause osteolathyrism is due to their ability to inhibit lysine oxidase, an enzyme important in cross-linking of collagen and formation of connective tissue. While no reports of these substances causing osteolathyrism in humans have appeared, it seems plausible that these substances could cause this disease in humans because they are known to cause it in a variety of experimental animals. 

Four mechanisms have been advanced for the prebiotic formation of amino acids. The first involves a cyanohydrin (reaction 2) and a related route (reaction 3) can be invoked to account for the presence of hydroxy acids. These particular reactions have been studied in considerable detail both kinetically and in terms of thermodynamic quantities.347 An alternative route (4) involves the hydrolysis of a-aminonitriles, which are themselves formed directly in anhydrous CH4/NH3 mixtures.344 Cyanoacetylene, formed in CH4/N2 irradiations,349 yields significant amounts of asparagine and aspartic acids (reaction 5). Finally, a number of workers336,350"354 have proposed that HCN oligomers, especially the trimer aminoacetonitrile and the tetramer diaminomaleonitrile, could have been important precursors for amino acid synthesis. Reaction mixtures involving such species have yielded up to 12 amino acids. Table 11 indicates the range of amino acids produced in these kinds of sparking syntheses. Of some interest is the fact that close parallels between these kinds of experiments and amino acid contents of carbonaceous chondrite meteorites exist.331,355,356... 

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