Synthesis of 1,4-Disubstituted Pyrazolo[3,4-d]pyrimidines from 4,6-Dichloropyrimidine-5-carboxaldehyde: Insights into Selectivity and Reactivity

Christie Morrill; Suresh Babu; Neil G. Almstead; Young-Choon Moon

doi:10.1055/s-0033-1338862

Synthesis, Table of Contents

Synthesis 2013; 45(13): 1791-1806
DOI: 10.1055/s-0033-1338862

paper

Synthesis of 1,4-Disubstituted Pyrazolo[3,4-d]pyrimidines from 4,6-Dichloropyrimidine-5-carboxaldehyde: Insights into Selectivity and Reactivity

Christie Morrill*

PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA Fax: +1(908)2220567 Email: cmorrill@ptcbio.com Email: ymoon@ptcbio.com

,

Suresh Babu

PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA Fax: +1(908)2220567 Email: cmorrill@ptcbio.com Email: ymoon@ptcbio.com

,

Neil G. Almstead

PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA Fax: +1(908)2220567 Email: cmorrill@ptcbio.com Email: ymoon@ptcbio.com

,

Young-Choon Moon*

PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, NJ 07080, USA Fax: +1(908)2220567 Email: cmorrill@ptcbio.com Email: ymoon@ptcbio.com

› Author Affiliations

Abstract

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Dedicated to Prof. Scott E. Denmark on the occasion of his 60^th birthday

Abstract

Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5-carboxaldehyde with both aromatic and aliphatic hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective, high-yielding, and operationally simple manner are presented. For aromatic hydrazines, the reaction is performed at a high temperature in the absence of an external base. For aliphatic hydrazines, the reaction proceeds at room temperature in the presence of an external base. The observed selectivity and reactivity trends are rationalized through consideration of the proposed reaction mechanism. The 1-substituted 4-chloropyrazolo[3,4-d]pyrimidine products serve as versatile synthetic intermediates, through further functionalization of the 4-chloride moiety, enabling the rapid generation of a structurally diverse array of 1,4-disubstituted pyrazolo[3,4-d]pyrimidines.

Key words

condensation - hydrazines - hydrazones - nucleophilic aromatic substitution - pyrazolo[3,4-d]pyrimidines

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References

References

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