Synlett 2021; 32(09): 917-922
DOI: 10.1055/s-0040-1720460
letter

Thionation of Aminophthalimide Hindered Carbonyl Groups and Application to the Synthesis of 3,6′-Dithionated Pomalidomides

Michael T. Scerba
a  Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA
,
b  Small Molecule X-ray Facility, Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, USA
,
Nigel H. Greig
a  Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD 21224, USA
› Author Affiliations
This research was supported by the Intramural Research Program of the NIH, National Institute on Aging (#AG000311).


Abstract

Herein, we present a new one-pot procedure for the 3,6′-dithionation of pomalidomide derivatives in which the key 3-position sulfur atom is preferentially installed at the desired (but sterically congested) carbonyl of the aminophthalimide system and with regiochemistry distinct from Lawesson’s Reagent thionation methods. When heated in 1,4-dioxane with P4S10–pyridine complex, pomalidomides are smoothly and reproducibly converted into their 3,6′-dithionated analogues in roughly 30% isolated yield and at various scales. While detrimental to the desired 3,6′-type outcome when employing Lawesson’s Reagent, we hypothesize that the pomalidomide aniline group instead facilitates P4S10-type thionation at the otherwise hindered 3-position carbonyl, contributing to the selectivity observed. When paired with classical methods of thionation, this approach offers an interesting and appealing addition to the synthetic toolbox, permitting facile late-stage access to complementary thionated pomalidomides in direct single-flask procedures.

Supporting Information



Publication History

Received: 22 December 2020

Accepted after revision: 13 March 2021

Publication Date:
28 April 2021 (online)

© 2021. Thieme. All rights reserved

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