Synthesis 2019; 51(23): 4434-4442
DOI: 10.1055/s-0039-1690677
paper
© Georg Thieme Verlag Stuttgart · New York

Base-Mediated 1,6-Aza-Michael Addition of Heterocyclic Amines and Amides to para-Quinone Methides Leading to Meclizine-, Hydroxyzine- and Cetirizine-like Architectures

Deblina Roy
,
Gautam Panda
Lab No. CSS 106, Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road, Jankipuram Extension, Lucknow 226031, UP, India   Email: [email protected]   Email: [email protected]
› Author Affiliations
This work was supported by the Ministry of Earth Sciences (MoES, 09-DS/3/201P5C-IV), New Delhi, India.
Further Information

Publication History

Received: 23 July 2019

Accepted after revision: 22 August 2019

Publication Date:
13 September 2019 (online)


Abstract

An expeditious, cost-effective synthetic methodology for a wide range of nitrogen-containing unsymmetrical trisubstituted methanes (TRSMs) is reported. The synthesis involves base-mediated 1,6-conjugate addition of heterocyclic amines and amides to substituted para-quinone methides, giving the unsymmetrical TRSMs in moderate to very good yields (up to 83%) in one pot. The low cost, mild temperature, high atom economy and yields, easy scale-up and broad substrate scope are some of the salient features of this protocol. Further, the methodology could be extended for the synthesis of meclizine-, ­hydroxyzine- and cetirizine-like molecules. The structure of one such compound, 2,6-di-tert-butyl-4-((4-chlorophenyl)(4-methylpiperazin-1-yl)methyl)phenol, was determined by single crystal X-ray analysis.

Supporting Information

 
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