One-pot synthesis of pyrroles using a titanium-catalyzed multicomponent coupling procedure

Abstract

A simple one-pot procedure for the production of 2-carboxylpyrroles with 4-alkyl, 5-alkyl, 4aryl, 4-aryl-5-alkyl, or 3,4-diaryl substitution patterns is presented. The procedure involves the titanium-catalyzed multicomponent coupling of alkynes, primary amines and isonitriles to give 1,3-diimines in situ; the multicomponent product is then treated with the ethyl ester of glycine hydrochloride to give the NH-pyrrole. The reaction can be carried out with the neutralized glycine ester or with the hydrochloride salt using DBU as a base. Yields of pyrrole based on starting alkyne varied from 25-65% over the one pot procedure, and in most cases only one regioisomer of the product is observed. Further, it is proposed that the regioselectivities of the reactions are a result of rate-determining ring closure after relatively fast transimination with glycine ethyl ester.

Synthesis of pentasubstituted 2-aryl pyrroles from boryl and stannyl alkynes via one-pot sequential Ti-catalyzed [2 + 2 + 1] pyrrole synthesis/cross coupling reactions

“…Other oxygenated substrates such as 6d and 6e were poor cross coupling partners. Although nitro groups and esters are commonly tolerated in Suzuki reactions, 11 B NMR spectroscopic evidence indicates that deleterious chemistry with the 9-BBN group may be taking place (Fig. S150 †).…”

“…A series of pioneering studies has been reported by Odom on Ti-catalyzed multicomponent pyrrole synthesis based on hydroamination and iminoamination. [9][10][11] Following a slightly different strategy, we recently developed a multicomponent [2 + 2 + 1] Ti-catalyzed pyrrole forming reaction that yields the heterocycle in a single step. 12 Chemo-and regioselective intermolecular reactions can be achieved via the heterocoupling of trialkylsilyl-protected alkynes, which selectively engage in migratory insertion into a key azatitanacyclobutene [2 + 2] cycloadduct intermediate.…”

“…11 B NMR study demonstrating pyridine-bound 1a-BBN-py (bottom) reacts more slowly than 1a-BBN (top).…”

An Efficient Synthesis of Aryl-Substituted Pyrroles by the Suzuki–Miyaura Coupling Reaction of SEM-Protected Pyrroles

“…Aryl pyrroles bearing an ester functional group are commonly used in organic synthesis and medicinal chemistry as synthetic intermediates [2,3,4,5,6]. There are a great deal of methods for the preparation of aryl-substituted pyrroles with this pendant ester group, and generally, the pyrrole core is formed from functionalized precursors with complex structures employing various catalysts and ligands [7,8,9,10,11,12,13,14]. As our aim was to construct a small library of aryl-substituted pyrroles for biological activity assays, we found that it was inefficient to build these required pyrrole structures from some non-commercial starting materials.…”

Synthesis of Highly Substituted Pyrrole and Dihydro‐1H‐Pyrrole Containing Barbituric Acids via Catalyst‐Free One‐Pot Four‐Component Reactions

“…There are other methodologies for the construction of pyrroles by using metal or base-catalyzed MCRs. Examples include gold [21], titanium [22], ruthenium [23], AgSbF 6 [24], silver [25], and n-BuLi [26] catalyzed reactions. Nonetheless, most of the synthetic approaches toward pyrrole synthesis suffer from disadvantages such as using either expensive toxic metal catalyst and base or harsh reaction conditions.…”