Reakcje tia-Dielsa-Aldera z wykorzystaniem tioketonów oraz tiochalkonów jako aktywnych heterodienofili lub heterodienów

Abstract

Considering the growing importance of thiocarbonyl compounds in modern organic synthesis and continuing interest in studies focused on the mechanisms of organic reactions, a research project based on the exploration of aryl and hetaryl thioketones, as well as structurally related thiochalcones has been implemented. Firstly, the [4+2]-cycloaddition reactions of hetaryl thioketones with non-activated dienes (thia-Diels-Alder reactions) were investigated and the obtained results confirmed extremely high reactivity of thiocarbonyl dienophiles against 1,3-dienes. Thus, hetaryl thioketones have to be considered as reagents which belong to the class of ‘superdienophiles’. Moreover, results obtained in reactions with isomeric 2,4-hexadienes have shown that they follow a non-conventional, stepwise mechanism, involving an intermediate, delocalized diradical. The presence of a hetaryl ring (preferably thiophen-2-yl or selenophen-2-yl) is essential for the appearance of these intermediates. In the next step of the study, aryl/hetaryl and dihetaryl thioketones were investigated as 1-thia-1,3-dienes in reactions with activated acetylenic dienophiles. It has been found that these cycloadditions occurred efficiently when the reaction mixtures were heated in THF solution with catalytic amounts LiClO4 as a catalyst. Derivatives of 2H-thiopyran were formed as sole product in a completely chemo- and regioselective manner. Attempts to perform the same reactions under high pressure (5 kbar) have resulted in a slight improvement of yields without the influence on the reaction times. To the best of our knowledge this was the first attempt to apply the high pressure technique in cycloaddition reactions performed with thioketones. In the extension of the study focused on thia-Diels-Alder reactions, a series of reactions of acetylenic dienophiles with thiochalcones containing aryl and hetaryl substituent have been tested. Along with dimethyl acetylenedicarboxylate also methyl propionate was used as a dienophile. Both dienophiles reacted readily with thiochalcones yielding the expected 4H-thiopyran derivatives. In the case of methyl propionate, thia-Diels-Alder reactions proceeded in a completely regioselective manner. These results point out that in the transition state, the sulfur atom of the C=S bond attacks the β carbon atom exclusively. Substantial progress was achieved by performing these reactions under microwave irradiation. Significant reduction of the reaction times and high yields have been observed. Moreover, microwave irradiation did not affect regioselectivity observed in reactions with methyl propiolate. In the next step, diaryl and aryl/hetaryl thiochalcones were reacted with in situ generated, reactive nitrile imines derived from trifluoroacetonitrile to give regioselectively 1,3,4-thiadiazole derivatives as the expected [3+2]-cycloadducts. To date these results have to be considered as first cases of an efficient applications of thiochalcones as C=S dipolarophiles in 1,3-dipolar cycloaddition reactions. Reaction of chalcones with thiocarbonyl S-methanides used as electron rich 1,3-dipoles were also studied. The obtained results showed that thiocarbonyl S-methanides react effectively only with enones activated with electron withdrawing –CF3 group. Furthermore, it has been established that [3+2]-cycloadditions occurred chemoselectively and the type of the products formed depended on the location of the activating –CF3 group. Enones with the CF3–C=O fragment were less reactive and in addition to the observed 1,3-oxathiole derivatives some amounts of corresponding thiiranes were also formed as products of competitive 1,3-dipolar electrocyclization of the intermediate thiocarbonyl S-methanide.