Pyrrole-2-carbaldehydes, 5-substituted synthesis

An efficient synthesis of rigid tricyclic (5 5 5) nitrogen heterocycles 64 has been achieved via sequential and tandem Ugi/intramolecular Diels-Alder (IMDA) cycloaddition of pyrrole derivatives <2004JOC1207> and the trienes 477 were prepared by the acylaton of amines 475 with the anhydride 476. The amines 475 were in turn prepared starting from pyrrole-2-carbaldehyde. The triene 477 on heating in toluene at 80 °C for 15 h underwent the IMDA to afford the tricyclic compound 64 as a single diastereomer in quantitative yield. The sterically bulky N-substitutent on the triene 477 promoted cycloaddition under milder condition at 65 °C in toluene to provide the tricyclic compound 64 in quantitative yield (Scheme 108). 

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-c]pyrrole ring system 99 [27] and its derivatives was accomplished using the same synthetic sequence (Scheme 16). Starting with 2-mcthyl benzolb thiophcnc-3-carbaldehyde 100, an intermediate 101 was obtained. Treatment of bromo compound 101 with sodium azide in ethanol led to the stable triazoline 102.1,3-Dipolar cycloreversion of 102 was induced by a catalytic amount of p-TsOH to give the parent 27/-benzo [4,5]thieno[2,3-c]pyrrole 99. Alternatively, direct treatment of bromo compound 101 with excess ammonia furnished 99 in one step. Compound 99 was treated with Boc20 and DMAP to give the /V-Boc derivative 103. Reaction of 101 with alkyl- and arylamines, respectively, afforded the N-substituted benzo[4,5]thieno[2,3-c]pyrroles 105 via a retro-malonate addition from intermediate 104. 

Iodo-li/-pyrrole-2-carbaldehyde, used in the synthesis of nucleoside derivatives, was prepared via protection of the aldehyde group in l//-pyrrole-2-carbaldehyde with an iminium salt for the efficient w f -directed electrophilic substitution of the starting pyrrole followed by a treatment of the iminium salt with N-iodosuccinimide in acetonitrile then with sodium bicarbonate (57% two-step total yield) <2003BML4515>. 

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