Multicomponent Synthesis of Biologically Relevant S‐Diarylmethane Dithiocarbamates Using p‐Quinone Methides

Abstract

A metal and base-free, operationally simple, and scalable multicomponent approach towards the synthesis of S-diarylmethane dithiocarbamates is reported. A range of structurally and electronically diverse p-quinone methides are shown to react with a variety of amines, and carbon disulfide to furnish corresponding dithiocarbamates in good to excellent yields under mild conditions. Furthermore, p-QMs embedded with aliphatic substituents are well accommodated. Importantly, these readily accessible compounds demonstrated promising anti-proliferative activity in the low micromolar ranges in lung adenocarcinoma cells, reiterating the importance of the developed methodology.

Base-Promoted 1,6-Aza-Michael Addition of Azauracils to para-Quinone Methides

“…Considering the implications of N-substituents on the biological activities of azauracil derivatives and the scarcity of methods for the installation of secondary alkyl groups on azauracil derivatives, we envisioned the coupling of p-QMs with azauracils through 1,6-conjugate addition under met- We recently reported a transition-metal-free multicomponent reaction between p-QMs, carbon disulfide and amines to access S-diarylmethane dithiocarbamates. 12 In continuation of our interest in metal-free synthetic techniques, 9,12,13 we herein report an organic-base-promoted 1,6-conjugate addition of azauracils with p-QMs to furnish biologically relevant N 4 -diarylmethane azauracils (Scheme 1c).…”

“…We recently reported a transition-metal-free multicomponent reaction between p -QMs, carbon disulfide and amines to access S -diarylmethane dithiocarbamates. 12 In continuation of our interest in metal-free synthetic techniques, 9 12 13 we herein report an organic-base-promoted 1,6-conjugate addition of azauracils with p -QMs to furnish biologically relevant N 4 -diarylmethane azauracils (Scheme 1c ).…”

“…We recently reported a transition-metal-free multicomponent reaction between p-QMs, carbon disulfide and amines to access S-diarylmethane dithiocarbamates. 12 In continuation to our interest in metal-free synthetic To assess feasibility of the envisaged approach, we reacted 2,6-di-tert-butyl-p-QM 1a (0.1 mmol, 1 equiv) with 2-benzyl-1,2,4-triazine-3,5(2H,4H)-dione 2a (1.02 equiv) in the presence of additives in CH2Cl2 at room temperature (Table 1). Initially, we opted for a LUMO lowering strategy (activation of electrophile) and screened different Brønsted (1 equiv) and Lewis (5 mol%) acids as additives (entries 1-4).…”

Multicomponent Approaches Involving Carbon Disulfide

“…In 2022, Murarka et al developed an operationally simple and attractive multicomponent strategy for the synthesis of Sdiarylmethane dithiocarbamates from amines, p-quinone methides, and carbon disulfide (Scheme 52). [83] The preliminary reaction was performed using piperidine (1.2 equiv. ), p-QM (1 equiv.…”

A Decade of Advances of CS2/Amines in Three-Component Reactions

“…p -Quinone methides ( p -QMs) are able to undergo 1,6-conjugate addition with a range of nucleophiles. Sing, Murarka­, and co-workers 8a reported the reaction of p -QMs, aliphatic amines, and CS 2 under mild conditions to give S -aryl(4-hydroxyphenyl)methyl dithiocarbamates 6.1 (Scheme 6 ). Both dichloromethane and water were suitable reaction solvents for these transformations.…”