Hetero-Diels-Alder Reactions of In Situ-Generated Azoalkenes with Thioketones; Experimental and Theoretical Studies.

Grzegorz Mlostoń,Dieter Lentz,Heinz Heimgartner,Malwina Sobiecka,Katarzyna Urbaniak,Ernst-Ulrich Würthwein,Reinhold Zimmer,Hans-Ulrich Reissig

doi:10.3390/molecules26092544

Abstract

The hetero-Diels-Alder reactions of in situ-generated azoalkenes with thioketones were shown to offer a straightforward method for an efficient and regioselective synthesis of scarcely known N-substituted 1,3,4-thiadiazine derivatives. The scope of the method was fairly broad, allowing the use of a series of aryl-, ferrocenyl-, and alkyl-substituted thioketones. However, in the case of N-tosyl-substituted cycloadducts derived from 1-thioxo-2,2,4,4-tetramethylcyclobutan-3-one and the structurally analogous 1,3-dithione, a more complicated pathway was observed. By elimination of toluene sulfinic acid, the initially formed cycloadducts afforded 2H-1,3,4-thiadiazines as final products. Advanced DFT calculations revealed that the observed high regioselectivity was due to kinetic reaction control and that the (4 + 2)-cycloadditions of sterically less unhindered thiones occurred via highly unsymmetric transition states with shorter C..S-distances (2.27–2.58 Å) and longer N..C-distances (3.02–3.57 Å). In the extreme case of the sterically very hindered 2,2,4,4-tetramethylcyclobutan-1,3-dione-derived thioketones, a zwitterionic intermediate with a fully formed C‒S bond was detected, which underwent ring closure to the 1,3,4-thiadiazine derivative in a second step. For the hypothetical formation of the regioisomeric 1,2,3-thiadiazine derivatives, the DFT calculations proposed more symmetric transition states with considerably higher energies.

Highlights

IntroductionThiochalcones, considered α,β-unsaturated analogues of thioketones, e.g., Figure 1 (1l), were demonstrated to act as active C=S dieno- and dipolarophiles [2,3,4]
In our very recent publications, diverse thioketones were demonstrated to act as reactive building blocks yielding five-membered Sheterocycles with typical 1,3-dipoles such as thiocarbonyl S-methanides [7,8], diazo alkanes [9,10,11], nitrile imines [12,13], nitrile oxides [14], etc., and with donor-acceptor cyclopropanes in the presence of an activating Lewis acid [15]
The presented study showed important mechanistic aspects and demonstrated that scarcely known 3,6-dihydro2H-1,3,4-thiadiazines can efficiently be prepared by regioselective hetero-Diels-Alder reactions of thioketones with in situ-generated azoalkenes, bearing an electron-withdrawing substituent at the terminal N-atom

Summary

Introduction

Thiochalcones, considered α,β-unsaturated analogues of thioketones, e.g., Figure 1 (1l), were demonstrated to act as active C=S dieno- and dipolarophiles [2,3,4]. Mechanistic studies demonstrated that both (3 + 2)- as well as (4 + 2)-cycloadditions with aromatic and ferrocenyl thioketones do not follow the Molecules 2021, 26, x FOR PEER REVIEW standard concerted pathways [17,18] but they occur via step-wise mechanisms involving diradicaloid or zwitterionic intermediates [7,9,19,20,21]

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