Synthetic Studies Directed towards Agelasine Analogs – Synthesis, Tautomerism, and Alkylation of 2‐Substituted N‐Methoxy‐9‐methyl‐9H‐purin‐6‐amines

Abstract

N-Methoxy-9-methyl-9H-purin-6-amines, carrying various substituents in the 2 positions, were synthesized by the Nmethylation of known 6-chloropurines, followed by a displacement of the chlorine. Great variations in the amino/ imino tautomer ratio among the compounds studied were observed. The tautomers were identified by NMR methods. Treatment of N-methoxy-9-methyl-9H-purin-6-amines carrying alkyl, alkoxy, or amino substituents in the 2 position with

2-Substituted agelasine analogs: Synthesis and biological activity, and structure and reactivity of synthetic intermediates

“…The reactions resulted in the expected N-7-and N 6 -alkylated products in most cases, with the former as the major product, but also revealed a significant variation in reactivity for the nine analogs. Benzylation of the methoxy compound 2f resulted in the formation of a range of products; the O 2 -methyl group appeared to be unstable under the reaction conditions either in starting material 2f and/or product 3f [7]. Demethylation of other methoxypurines has previously been observed in the Gundersen research group at the University of Oslo [15].…”

“…A comparison of the field/inductive withdrawing ability (Hammett F values were employed) of the 2-substituents with the reactivity of the compounds was then conducted. Compounds 2 with substituents with Hammett F values lower than approximately 0.3 displayed good reactivity toward N-7-alkylation, whereas Hammett F values higher than this resulted in very low or no formation of the desired compounds 3 [7]. To determine the atomic charges on N-7 (which should function as the nucleophile in the alkylation of compounds 2), a partial natural bond orbital (NBO) analysis [17] was performed (Table 1) as a part of a computation study of the compounds 2 [9].…”

“…Nine N-methoxy-9-methyl-9H-purin-6amines (2) were then prepared as intermediates for the synthesis of a series of 2-substituted agelasine analogs (3) (Scheme 1). Preparation of these synthetic intermediates was achieved either by introduc- tion of a methoxyamino group on C-6 from corresponding 2-substituted 6-chloro-9-methyl-9H-purines (1) or by nucleophilic aromatic substitution on C-2 of the 2-chloro-N-methoxy-9-methyl-9H-purin-6amines (2h) [7].…”

“…2 [18]. During the synthesis of 2-substituted N-methoxy-9-methyl-9H-purin-6-amines 2, we discovered that these synthetic intermediates showed great diversity in tautomeric ratios depending on the substituent in the 2-position (Table 1) [7].…”

“…We would now like to give a short review on our recently reported work related to 2-substituted agelasine analogs, and the structure and reactivity of certain interesting synthetic intermediates [7][8][9].…”