Carboxyl group reactions with ammonia derivatives

Protected primary allylic amines were generated from allylic carbonates and ammonia equivalents. Iridium-catalyzed allylic substitution has now been reported with sulfonamides [90, 91], imides [89, 91-93], and trifluoroacetamide [89] to form branched, protected, primary allylic amines (Table 5). When tested, yields and selectivities were highest from reactions catalyzed by complexes derived from L2. Reactions of potassium trifluoroacetamide and lithium di-tert-butyhminodi-carboxylate were conducted with catalysts derived from the simplified ligand L7. Reactions of nosylamide and trifluoroacetamide form singly-protected amine products. The other ammonia equivalents lead to the formation of doubly protected allylic amine products, but one protecting group can be removed selectively, except when the product is derived from phthalimide. 

Reaction of the imidazole (7-4) with the benzofuran derivative (6-7) leads to the displacement of the benzylic halogen and the formation of the alkylation product (8-1). Treatment of that intermediate with trifluoroacetic acid breaks open the urethane to afford the corresponding free amine. This is allowed to react with ttiflic anhydride to afford the trifluoromethyl sulfonamide (8-2). The ester group on the imdidazole is then saponified, and the newly formed acid is reacted with carbonyl diimidazole. Reaction with ammonia converts the activated carboxyl group to the amide. There is thus obtained the angiotensin antagonist saprisartan (8-3) [6]. 

Selective oxidation of polymethylpyrimidines. 2,4-Di- and 2,4,6-trimethyl-pyrimidines are selectively oxidized to 4-carboxylic acids by a slight excess of Se02 in pyridine. Yields are about 40-65%. This increased reactivity of a 4-methyl group of polymethylpyrimidines is also observed in reaction with ethyl nitrite in liquid ammonia to form 4-aldoximcs and with ethyl benzoate in the presence of KOC2H to form phenacyl derivatives. 

Due to the extremely low nucleophilicity of the imino group, 187,188 acylation of thiazolidine-4-carboxylic acid (11) is not a trivial procedure. In fact, N-protected Thz derivatives can be prepared by standard procedures, but strong acylating conditions are required. The related N-Boc derivative is obtained only by prolonged reaction times with Boc-N3 U2,189 or with Boc20. 113 For preparation of the N-Z derivative, silylation of Thz with, for example, chlorotrimethylsilane is recommended prior to the reaction benzyl chloroformate. 200 Due to the stability of thiazolidine-4-carboxylic acid to acids its methyl ester is obtained by HC1 catalyzed reaction with methanol, 190 whereas the amide is formed by reacting Thz N-carboxyanhydride with ammonia.1 89 Derivatives of thiazolidine-4-carboxylic acid are listed in Table 8. 

The methyl group in ethyl 5-methylpyridazine-4-carboxylate can be converted by reaction with dimethylformamide dimethyl acetal to the 2-(dimethylamino)vinyl group (see Houben-Weyl, Vol. E9a, p 649), which may serve as a C-C unit for the annulation of a pyridine ring. Thus, ethyl 5-[2-(dimethylamino)-l-phenylvinyl]pyridazine-4-carboxylate reacts with ammonia or benzylamine in acetic acid/ethanol at elevated temperatures to give 8-phenylpyrido[3,4-r/]-pyridazin-5(6//)-one (4a) or the 6-benzyl derivative 4b.67 Similar condensations have been carried out with ethyl 5-[2-(dimethylamino)vinyl]pyridazine-4-carboxylate and ammonia or butylamine.131... 

Pyrimido[5.4-r/]pyrimidines 5 and 6 are readily prepared by the condensation of 5-amino-2,6-dihydroxypyrimidine-4-carboxylic acid ( orotic acid ) with formamidc or urea. Reaction of the starting pyrimidine with formamide gives pyrimido[5,4-c/]pyrimidine-2,4,8-triol (5), which can also be prepared from ethyl 5-aminoorotate in 72% yield. In this case, the 5-amino group is first converted into the (ethoxymethylene)amino derivative and then treated with ammonia.207 The corresponding tetrol 6 results from reaction of the starting pyrimidine with urea.152,203... 

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