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In this paper we describe the preparation of a series of 2-acyl-4-aminopyridines, and their use as catalysts for the hydroxyl-directed methanolysis of alpha-hydroxy esters in preference to alpha-methoxy esters. Hydroxyl-direction with these catalysts, which contain ketones at the 2-position of the pyridine, is achieved by reversible addition of the alcohol of the hydroxy ester to the ketone to provide the corresponding hemiketal. Their activity is compared to that of the previously described catalyst 2-formyl-4-pyrrolidinopyridine (FPP), which contains an aldehyde at the 2-position of the pyridine. The catalysts which contain ketones at the 2-position range in reactivity from 10 times slower to slightly faster than FPP, and certain of these are much more selective for the methanolysis of hydroxy esters than FPP. This increase in selectivity is ascribed to a decrease in the rate of the nondirected methanolysis reaction with the ketone-derived catalysts. The evidence suggests that the nondirected reaction does not proceed by an intermolecular general base mechanism, but rather via a nucleophilic catalysis mechanism in which the hydroxyl group of the hemiacetal formed upon addition of methanol to the aldehyde of FPP acts as the nucleophile. Since the hydroxyl group derived from a hemiketal is more hindered and less nucleophilic than that derived from a hemiacetal, the nondirected reaction is much slower for the catalysts containing ketones as binding sites.

Aliphatic amines react with phosphoimidazolide-activated derivatives of guanosine and cytidine (ImpN) by replacing the imidazole group. The kinetics of reaction of guanosine 5'-phospho-2-methylimidazolide (2-MeImpG) with glycine ethyl ester, glycinamide, 2-methoxyethylamine, n-butylamine, morpholine, dimethylamine (Me2NH), ethylmethylamine (EtNHMe), diethylamine (Et2NH), pyrrolidine, and piperidine were determined in water at 37 degrees C. With primary amines, a plot of the logarithm of the rate constant for attack by the amine on the protonated substrate, log kSH(A), versus the pKa of the amine exhibits a good linear correlation with a Bronsted slope, beta nuc = 0.48. Most of the secondary amines tested react with slightly higher reactivity than primary amines of similar pKa. Interestingly, some secondary amines show substantially lower reactivity than might be expected: EtNHMe reacts about eight times, and Et2NH at least 100 times, more slowly than Me2NH although all three amines are of similar basicity. For comparison, the kinetics of reaction of guanosine 5'-phosphoimidazolide (ImpG) and cytidine 5'-phosphoimidazolide (ImpC) were determined with Me2NH, EtNHMe, and Et2NH, and similar results were obtained. These results establish that the increased steric hindrance observed with the successive addition of ethyl groups are not due to any special steric requirements imposed by the guanosine or the methyl on the 2-methylimidazole leaving group of 2-MeImpG. It is concluded that addition of ethyl and, perhaps, groups larger than ethyl dramatically increases the kinetic barrier for addition of aliphatic secondary amines to the P-N bond of ImpN. This study supports the observation that the primary amino groups on the natural polyamines are at least 2 orders of magnitude more reactive than the secondary amino groups in the reaction with ImpN.