Aminomalononitrile tosylate

Another efficient 1,2-diamine for synthesis of cyanopyrazines is 2,3-diamino-3-phenylthioacrylonitrile 135, an adduct of thiophenol to aminomalononitrile tosylate (Scheme 37). The condensation with phenylglyoxal diethyl acetal affords a mixture of two possible isomers 136 and 137, whose regioselectivity is improved by addition of trifluoroacetic acid finally, the isomer 136 is isolated in 86% yield <2001SC725>. 

The above problems of concomitant formation of regioisomers (as well as products resulting from disproportionation of various dihydro intermediates) have been successfully surmounted by an unequivocal synthesis of 2-amino-3-cyano-5-halomethylpyrazines (16a,b) and their corresponding 1-oxides (28a,b), which can then be utilized for the construction of isomer-free 6-substituted pteridines and pterins (Scheme 3.3a). Thus, condensation of / -chloropyruval-doxime or / -bromopyruvaldoxime, derived from diketene by chlorination or bromination, respectively, with aminomalononitrile tosylate in 2-propanol gives the 2-amino-3-cyano-5-halomethylpyrazine 1-oxides (28a) and (28b). Deoxygenation to (16a) and (16b) is readily accomplished with phosphorus trichloride [47]. 

A. Rosowsky and K. K. N. Chen, J. Med. Chem., 1974,17, 1308 describe the preparation of 2-amino-5-chloromethyl-3oxide from aminomalononitrile tosylate and l-chloro-3-hydroxyimino-2-butanone using a method similar to that described (529) for an analogue. 

Amino-3-cyano-5-(benzylthiomethyl)pyrazine 1-oxide has been prepared from j3-bromopyruvaldoxime, benzylmercaptan, and aminomalononitrile tosylate in propan-2-ol (542). 

A-Substituted aminoacetonitrile hydrochlorides (156), which are easily prepared by the Strecker reaction from the corresponding aldehyde, condense with oxalyl chloride in 1,2-dichlorobenzene to give 3,5-dichloro-l-substituted-2(l//)-pyrazinones (157) <83JHC919, 86JHC113>. A plausible pathway is illustrated in Scheme 39. Aminomalononitrile tosylate (153) reacts with benzaldehyde in methanol... 

A-Oxides are also prepared by primary construction from oximes, as exemplified by the synthesis of 2-aminopyrazine 1-oxides from aminomalononitrile tosylate and a-oximinoketones (Scheme 37). Some other syntheses of A-oxides from a-functionalized oxime derivatives are available . Analogues of aspergillic acid, l-hydroxy-2(li7)-pyrazinones, are prepared by condensation of a-aminohydroxamic acids with 1,2-dicarbonyl compounds <49JCS2707> or alternatively of a-oxohydroxamic acids with a-aminoketones <50JCS3409> (Scheme 47). 

Formation of heterocycles. Five membered heterocycles Phenacylmalononitrile underwent cyclization in acidic media to yield substituted furans 136164 and 137166. Cyclization with anilines afforded pyrroles 138166. Benzylmalononitriles have been cyclized with hydrazine or hydroxylamine to yield 3,5-diaminopyrazoles or isoxazoles, respectively 6. Aminomalononitrile tosylate can be reacted with aliphatic or aromatic isothiocyanates to yield 2,5-diaminothiazole-4-carbonitrilesi6. ... 

Freeman s group ° prepared a series of 5-amino-4-cyano-2-substituted oxazoles 517 from carboxylic acids and aminomalononitrile tosylate (AMNT) (Scheme 1.140). Presumably, AMNT is acylated by a carboxylic acid using DCC, which produces an intermediate A-acylamino nitrile 516 that is cyclized under the reaction conditions to yield 517. The yields of 517 are fair to excellent, and the reaction tolerates a wide variety of functional groups. This further extended the scope of their earlier work. ° Representative examples are shown in Table 1.35. 

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