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

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.

Key words

thionation - pomalidomides - dithionation - aminophthalimides - regioselectivity

Publication History

Received: 22 December 2020

Accepted after revision: 13 March 2021

Article published online:
28 April 2021

• References and Notes

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