A-Aminonitrile

The thiazole ring can be obtained directly by other methods, but they have limited application. An example is the synthesis of Cook and Heilbron using a-aminonitriles or a-aminoamides and carbon disulfide (or thioacid derivatives) as reactants of type II. 

By condensing the salts or the esters of either dithioformic (207) or dithiophenacetic acids with a-aminonitriles (206) 5-aminothiazoles (209), in which R] = hydrogen, benzyl and Rj = phenyl, carbethoxy, or car-bophenoxy, were obtained in fairly good yields (Scheme 108) (271). These reactions were carried out in aqueous ethereal solution at room temperature. Acyclic thioamides as intermediates in this reaction have been isolated in some cases (208). 

Carbon disulfide readily reacts with a-aminonitriles giving 2-mercapto-5-aminothiazoles (213), (271, 293) which can be converted to 5-aminothiazoles unsubstituted in the 2-position (Scheme 110 and Table II-34a). If this reaction is carried out in the presence of benzyl chloride in phosphorus tribromide, a 2-S-substituted thiazole derivative (214) is obtained in quantitative yield (Scheme 111), with R = hydrogen or phenyl (68, 304). 

When benzaldehyde or its substituted derivatives are added to carbon disulfide and a-aminonitrile, the corresponding 2-mercapto-5-(p-R-benzylideneamino)thiazoles (215), R = hydrogen atom or a propenyl or phenyl group and Ar = aryl, are obtained (Scheme 112) (393, 442, 694). Yields ranged from 40 to 60% (Table II-34b). 

Reactions were carried out by condensing a-aminonitriles [NCCHiRiiNHJ with carbon disulfide in the presence of aldehydes (R CHO) or ketones [Pg.287]

Isothiocyanates of general formula 221 condensed with a-aminonitriles lead to 2-substituted 5-aminothiazoles (223) (Table 11-36) through an acyclic intermediate (222) (Scheme 116). 

Monooximes of a-diketones have found applicability in the synthesis of 2-aminopyrazine 1-oxides by condensation with a-aminonitriles, and this reaction was used by White and coworkers in an approach to the synthesis of Cypridina etioluciferamine (Scheme 66 R = 3-indoloyl) (73T3761). In this instance, the use of TiCU as a catalyst was essential, since the carbonyl group in 3-acylindoles is normally deactivated and the required amine/carbonyl condensation is impractically slow. Under normal circumstances the carbonyl group in simple alkyl-substituted monoximes of a-diketones is the more reactive site and the reaction is rapid, requiring no catalysis (69LA(726)loo). 

The stereospecific generation of enamines by -elimination reactions (187) and a vinylogous elimination, which leads to a dienamine (188), have been reported. The loss of an a substituent from a tertiary amine is seen in the generation of enamines by elimination of hydrogen cyanide from benzylic a-aminonitriles (189,190). 

The Cook-Heilbron reaction involves the reaction of a-aminonitriles with salts and esters of dithioacids, carbon disulfide, carbon oxysulfide, and isothiocyanates under extremely mild conditions to form 5-aminothiazoles. 

The mechanism of the Cook-Heilbron reaction between a-aminonitriles and dithioformic ester 6 proceeds via an acyclic intermediate 7, as proven by its isolation in several cases. Nucleophilic attack of the amine function on the sulfur-bearing carbon leads to the elimination of hydrogen sulphide. Cyclization of the acyclic thiacetoamide results in a five membered ring which aromatises favourably to give 5-amino-2-benzylthiazole 8. 

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. 

The reaction of carbon oxysulphide with a-aminonitriles results in 5-amino-2-hydroxy thiazoles these are structurally similar to the 2-mercaptothiazoles but are found to be less stable, readily undergoing cleavage or rearrangement to give 4-thiohydantoins. Thus the reaction between ethyl aminocyanoacetate and carbon oxysulphide 31 in ether afforded 5-amino-2-hydroxy-4-carbethoxythiazole 32, which in the presence of aqueous ammonia was converted into 5-carbethoxy-4-thiohydantoin 33. When using sodium... 

R] Taylor, E. C. McKillop, A. The Chemistry of Cyclic Enaminonitriles and a-Aminonitriles, Interseience New York, 1970. 

Antispasmodic activity, interestingly, is maintained even in the face of the deletion of the ethanolamine ester side chain. Reaction of anisaldehyde with potassium cyanide and dibutylamine hydrochloride affords the corresponding a-aminonitrile (72) (a functionality analogous to a cyanohydrin). Treatment with sulfuric acid hydrolyzes the nitrile to the amide to yield ambucet-amide (73). ... 

Triamterene (31) is a diuretic that has found acceptance because it results in enhanced sodium ion excretion without serious loss of potassium ion or significant uric acid retention. Tautomerism of aminopyrimidines (e.g., 27a and 27b) serves to make the "nonenolized" amine at the 5 position more basic than the remaining amines. Thus, condensation of 27 with benzaldehyde goes at the most basic nitrogen to form 28. Addition of hydrogen cyanide gives the a-aminonitrile (29). Treatment of that intermediate with base leads to the eyelized dihydropirazine compound (30). This undergoes spontaneous air oxidation to afford triamterene (31). ... 

Hie bioconversion of a-aminonitriles, although up until now not used on an industrial scale, is of practical interest in the production of optical active a-amino adds. This, however, will only be the case if one can select a nitrilase that enantioselectively hydrolyses die aminonitrile. 

Figure A8.3 Preparation of optically active a-amino acids via bioconversion of the corresponding a-aminonitriles.

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. 

The method can be used to prepare a number of a-aminonitriles from aliphatic or aromatic aldehydes and ketones and secondary aliphatic amines.4... 

A versatile synthesis of the 2(lH)-pyrazinone scaffold was developed starting from a suitable amine, an aldehyde and cyanide to give an a-aminonitrile. 

The solid-phase synthesis of the 2(lff)-pyrazinone scaffold is based on a Strecker reaction of commercially available Wang amide linker with appropriate aldehyde and tetramethylsilyl (TMS) cyanide, followed by cyclization of a-aminonitrile with oxalyl chloride resulting in the resin linked pyrazinones. This approach allows a wide diversity at the C-6-position of pyrazinone scaffold (Scheme 35, Table 1). As it has been shown for the solution phase, the sensitive imidoyl chloride moiety can easily undergo an addition/elimination reaction with in situ-generated sodium methoxide affording the resin-linked... 

The synthesis of a-amino acids by reaction of aldehydes or ketones with ammonia and hydrogen cyanide followed by hydrolysis of the resulting a-aminonitrile is called the Strecker synthesis. Enzymatic hydrolysis has been applied to the kinetic resolution of intermediate a-aminonitriles [90,91]. The hydrolysis of (rac)-phenylglycine nitrile... 

To date most of the nitriles studied have been simple alkyl or aromatic derivatives with little other functionality. We recently attempted to extend the reaction to iV-protected a-aminonitriles, derived by dehydration of a-aminoacid amides (Path A, Scheme 25), but this proved unsatisfactory, and therefore we investigated an alternative diazocarbonyl based route in which the order of steps was reversed, i.e. a rhodium catalysed N-H insertion reaction on the amide followed by cyclodehydration to the oxazole (Path B, Scheme 25). 

Like the nitronate ion, the cyanide ion is synthetically equivalent to the aminomethyl carbanion (CH2NH2) , because of the possible reduction of - CN to the - CH2NH2 group. Consequently, the addition of cyanide ion to imines to give a-aminonitriles (Strecker-type reaction) is a viable route to 1,2-diamines. As a matter of fact, a number of diastereoselective and catalytic... 

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-... 

Scheme 37 Asymmetric synthesis of 1,2-diamines from chiral a-aminonitriles derived from diastereoselective aldolization...

The psychotropic (stimulant) action of amphetaminil (57) may be intrinsic or due to in vivo hydrolysis of the a-aminonitrile function—akin to a cyanohydrin—to liberate amphetamine itself. It is synthesized by forming the Schiff s base of amphetamine with benzaldehyde to give 56, and then nucleophilic attack on the latter with cyanide anion to... 

---