Journal
TETRAHEDRON
Volume 70, Issue 44, Pages 8267-8279Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tet.2014.09.020
Keywords
Pyrazolo[1,5-a]pyrimidines; Heterocycles; Cyclization; Regioselective alkylation; Amidation
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Funding
- Boehringer-Ingelheim Pharma (Biberach, Germany)
- Slovenian Research Agency [P1-0179]
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The synthesis of 7-substituted pyrazolo[1,5-a]pyrimidine-3-carboxamides was studied. First, methyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (5) was prepared in three steps from methyl 5-amino-1H-pyrazole-4-carboxylate (3). Treatment of 5 with POCI3 gave the highly reactive 7-chloro derivative 10, which was reacted with amines, benzyl alcohol, and phenylboronic acid in the presence of Pd-catalyst to give the corresponding 7-substituted derivatives 11. Hydrolysis of the esters 5 and 11 followed by amidation gave the corresponding carboxamides 16a-h and 15. Regioselectivity of N-alkylation of 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives 5 and 16 was tunable by the carboxy function. Alkylation of the secondary amides 16a-f furnished the 1-alkyl derivatives 17a-f, whereas the ester 5 and the tertiary amides 16g,h gave the 4-alkyl derivatives 14a-d and 16m,n, selectively. (C) 2014 Elsevier Ltd. All rights reserved.
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