Timmis reaction

The Timmis reaction makes use of the regioselective condensations of 6-amino-5-nitroso-pyrimidines with aldehydes, ketones, esters, and nitriles under base catalysis. An extension of this principle is seen in the condensation reaction of 6-amino-5-nitroso-(320) and 6-amino-5-phenylazo-1,3-dimethyluracils (321) with dimethyl alkenedicarboxylate and propiolamide, respectively, leading by a Michael addition mechanism to 6,7-bis(methoxycarbonyl)- (322) and 6-carbamoyl-l,3-dimethyllumazine (323) (Scheme 52) <82JHC949>. 

The reaction of 6-amino-5-(l,2-diethoxycarbonylhydrazino)pyrimidines with enamines represents another convenient method for the preparation of pteridines. Fusion of 5-(l,2-diethoxycarbonylhydrazino)-2,4,6-triaminopyrimidine (281) with an excess of mor-pholinocyclohexene leads to 2,4-diaminotetrahydrobenzo[g]pteridine, and with the morpholinoenamine (282) from 17/3-hydroxy-5a-androstan-3-one regioselective condensation to the fused pteridine (283) takes place in almost quantitative yield (equation 101) (71CC83). 6-Amino-5-nitroso- and 6-amino-5-phenylazo-pyrimidines react similarly, imitating the Timmis-type reaction (72CPB1428). 

Pyman and Timmis investigated azo coupling reactions of imidazoles as long ago as 1922. Ridd and coworkers suggested in another relatively early publication (Brown et al., 1953) that reaction of imidazole occurs not via the neutral molecule but via the anion, despite the fact that imidazole is a very weak acid (pK = 14.5). Butler s group (Anderson et al., 1989) confirmed this suggestion by kinetic experiments in the pH range 6.52-7.48, supported by informative MNDO calculations. 

The versatility of 5-nitrosopyrimidines in pteridine syntheses was noticed by Pachter (64MI21603) during modification of the Timmis condensation between (262) and benzyl methyl ketone simple condensation leads to 4-amino-7-methyl-2,6-diphenylpteridine (264) but in the presence of cyanide ion 4,7-diamino-2,6-diphenylpteridine (265) is formed (equation 90). The mechanism of this reaction is still uncertain (63JOC1187) it may involve an oxidation of an intermediate hydroxylamine derivative, nitrone formation similar to the Krohnke reaction, or nucleophilic addition of the cyanide ion to the Schiff s base function (266) followed by cyclization to a 7-amino-5,6-dihydropteridine derivative (267), oxidation to a quinonoid-type product (268) and loss of the acyl group (equation 91). Extension of these principles to a-aryl- and a-alkyl-acetoacetonitriles omits the oxidation step and gives higher yields, and forms 6-alkyl-7-aminopteridines, which cannot be obtained directly from simple aliphatic ketones. 

In the second sequence, degradation is mediated by a 2,3-dioxygenase reaction with the methyl group intact (Figure 6.27b), and this pathway is followed in the metabolism of alkylated benzenes such as ethylbenzene and isopropylbenzene (Eaton and Timmis 1986). 

The Timmis synthesis is a versatile reaction and a range of 2,6-substituted 5-nitrosopyrim-idin-4-amines can be condensed with a variety of a-oxomethylene compounds as well as a-methylenenitriles. Generally, the products have unambiguous structures as it is the nitroso group which condenses with the methylene group, and the amine with the carbonyl group. However, the yields which are obtained are often rather poor. 

The Pachter modification of the Timmis synthesis is performed in the presence of cyanide ion,129 products other than those expected being obtained. For example, the condensation of phenylacetonitrile with 5-nitroso-2-phenylpyrimidine-4,6-diamine in the presence of cyanide ion gives, not 7-methyl-2,6-diphenylpteridin-4-amine but 2,6-diphenylpteridine-4,7-diamine (5).121 The mechanism of the reaction is still uncertain, but it may involve nucleophilic addition of cyanide ion to the Schiff base formed by condensation between the nitroso group and the active methylene, cyclization to yield a dihydropteridine, and subsequent elimination. 

There is a competing side reaction, and that reaction is hydrolysis of the amide LSD to lysergic acid. In the Smith and Timmis works cited, they found that very little hydrolysis was done to complex lysergic amides like ergotamine or ergometrine within one hour of boiling with one molar KOH, but they got the steric inversion they wanted. 

A clinically valuable alkylating agent of quite another kind is busulphan 13.46) (1,4-dimethanesulfonyloxobutane), discovered by G. Timmis. It is highly effective in, and almost specific for, chronic myelocytic leukaemia, and has few side effects (Haddow and Timmis, 1953). Its mode of action is apparently the alkylation of, and eventual stripping of sulfur from, cysteine residues of proteins and peptides (Roberts and Warwick, 1961). Busulphan acts, without prior ionization, by an S 2 reaction, i.e. one whose rate depends on the concentrations of both the alkylating agent and the nucleophilic site on the biopolymer. 

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