Abstract
Substituted aminopyrimidines are an important class of compounds, in part because they frequently show biological activity. Facile synthesis of polysubstituted aminopyrimidines is highly desirable for the synthesis of screening libraries. We describe a route to 4,6‐diamino‐5‐alkoxypyrimidines via a SNAr‐alkylation‐SNAr sequence from readily available 4,6‐dichloro‐5‐methoxypyrimidine, which allows the synthesis of such compounds with regiochemical control. The extension of this approach to alkylating agents bearing amino substituents led to unexpected and, in some cases, unprecedented products resulting from intramolecular SNAr cyclization and subsequent fragmentation.
Highlights
Pyrimidines can be regarded as privileged scaffolds that occur frequently in pharmaceuticals owing to their low lipophilicity and stability in vivo.[1]
Introduction of the first amino-substituent was achieved by the reaction of 4,6-dichloro-5-methoxypyrimidine 1 with an amine, for example, cyclopentylamine, affording the monoamino derivative 2 in high yield (Scheme 1)
Two minor products were isolated from the reaction, which were assigned from mass and NMR spectra to the 6-chloro-1-vinylpyrimidinium-5-olate and the 6-dimethyl amino-5-(vinyloxy)pyrimidine
Summary
Pyrimidines can be regarded as privileged scaffolds that occur frequently in pharmaceuticals owing to their low lipophilicity and stability in vivo.[1]. Introduction of the first amino-substituent was achieved by the reaction of 4,6-dichloro-5-methoxypyrimidine 1 with an amine, for example, cyclopentylamine, affording the monoamino derivative 2 in high yield (Scheme 1).
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