Synthesis of N-alkoxycarbonyl Pyrroles from O-Substituted Carbamates: A Synthetically Enabling Pyrrole Protection Strategy

Abstract

The condensation of readily available O-substituted carbamates with 2,5-dimethoxytetrahydrofuran gives N-alkoxycarbonyl pyrroles in a single step and in good yield. By this method, several common amine protecting groups can be introduced on the pyrrole nitrogen. With the exception of N-Boc, N-alkoxycarbonyl groups have seen only minimal use for protection of the pyrrole nitrogen to date. Here, we show that N-alkoxycarbonyl protection can endow pyrrole with distinct reactivity in comparison with N-sulfonyl protection, for example, in a pyrrole acylation protocol employing carboxylic acids with a sulfonic acid anhydride activator.

Scheme 1. Pyrrole Synthesis Employing 2,5-Dimethoxytetrahydrofuran 1

Scheme 2. Synthesis of N-alkoxycarbonyl Pyrroles 8–13^,

ORTEP representation of the X-ray structure of 13 (CCDC #2241194) shows ellipsoids at 50% probability. Hydrogens are shown as spheres of arbitrary radius. Only one of two independent molecules in the unit cell is shown for clarity. Crystals of 13 were formed upon cooling to 0 °C for a prolonged period. 1.0 equiv of 1 used, as 11 was unstable upon prolonged drying.

Scheme 3. Acetylation of N-alkoxycarbonyl Pyrroles 8–13

(a) 3.0 equiv AcOH, 10 equiv TFAA, CH₂Cl₂, rt. (b) 1.0 equiv AcOH, 10 equiv Tf₂O, CH₂Cl₂, 0 °C to rt.

Scheme 4. N-Troc-pyrrole Acylation and Deprotection

ORTEP representations of the X-ray structures of 25 (CCDC #2241195) and 27 (CCDC #2241193) show ellipsoids at 50% probability. Hydrogens are shown as spheres of arbitrary radius. Disorder in the CCl₃ group and a phenyl ring of 25, and in the isobutyl group of 27, is omitted for clarity. Crystals 25 formed upon prolonged standing of a solution of 25 in CDCl₃ and crystals 27 formed by diffusion of hexane vapor into a CH₂Cl₂ solution of 27.

Scheme 5. Overacetylation of N-Fmoc Pyrrole

Scheme 6. N-Ts-pyrrole Acylation and Deprotection

ORTEP representation of the X-ray structure of 31 (CCDC #2241194) shows ellipsoids at 50% probability. Hydrogens are shown as spheres of arbitrary radius. Crystals of 31 were formed by diffusion of hexane vapor into a CH₂Cl₂ solution of 31.