Pyrrole Syntheses Based on Titanium-Catalyzed Hydroamination of Diynes

Abstract

Titanium-catalyzed hydroamination of 1,4-and 1,5-diynes by primary amines leads to imino-alkynes that undergo in situ 5-endo dig and 5-exo dig cyclization reactions, respectively. The products are 1,2,5-trisubsituted pyrroles accessed directly from readily available diyne starting materials.New synthetic strategies for the generation of substituted pyrroles are of continuous interest due to the ubiquity of this heterocycle in natural products and pharmaceuticals. 1 We have been exploring new reactions based on titaniumcatalyzed intermolecular hydroamination 2,3 using a selection of pyrrolyl-based ancillary ligands. In the course of previous studies, new protocols for the synthesis of hydrazones, indoles, 4,5 and R, -unsaturated iminoamines 6 have been discovered. In this paper, it is reported that the readily prepared, inexpensive titanium catalysts Ti(NMe 2 ) 2 (dpma) (A) and Ti(NMe 2 ) 2 (dmpm) (B) (Scheme 1) can be used in the monohydroamination of 1,4-and 1,5-diynes, which then undergo cyclization to the corresponding pyrroles. These pyrrole syntheses are an expansion of CuCl-catalyzed 1,3-diyne reactions with primary amines to generate similar products. 7 The pyrrolyl-based catalyst Ti(NMe 2 ) 2 (dpma) (A), 8,9 which has an X 2 L ancillary ligand 10 set (Scheme 1), has been examined for a variety of hydroamination applications by our group. The H 2 dpma ligand is prepared in a single step by a Mannich reaction between 2 equiv of pyrrole, 2 equiv of formaldehyde, and methylamine hydrochloride. 11 The most active catalyst known to date is the dipyrrolylmethane (1) For reviews see: (a) Gilchrist, T. L.

Modular N,O‐Chelating Ligands: Group‐4 Amidate Complexes for Catalytic Hydroamination

“…[65][66][67][68] Following an initial report of titanium catalyzed hydroamination by Rothwell and coworkers, [69] research into hydroamination catalysis has also followed the trend of focusing on Cp-based ligand systems and then moving onto non-Cp-based catalysts. A variety of systems have been developed for hydroamination reactions including work from the groups of Bergman, [15,64,[70][71][72][73] Livinghouse, [74,75] Odom, [67,[76][77][78][79][80][81] Beller, [65,[82][83][84][85][86] Doye, [87][88][89][90][91][92][93][94] ourselves, [59,61,62,95,96] and others. [11,[97][98][99][100][101][102][103][104]…”

Homogeneous Catalytic Hydroamination of Alkynes and Allenes with Ammonia

“…Both products result from the Markovnikov addition of NH 3 , followed by ring-closing hydroamination. [22,23] The treatment of the 1,4-diyne 1 f with NH 3 under similar conditions led to a 3:2 mixture of the fiveand six-membered heterocycles 5 f and 6 f in 88 % yield. The six-membered ring 6 f arises from two consecutive Markovnikov hydroamination reactions, whereas the formation of 5 f involves an anti-Markovnikov addition of NH 3 or ring-closing step.…”

Metal-mediated synthesis of furans and pyrroles

“…39 Titanium-catalyzed hydroamination of 1,4-diynes 131a and 1,5-diynes 131b by primary amines leads to imino-alkynes that undergo in situ 5-endo dig and 5-exodig cyclization reactions, to afford pyrroles 132a and 132b, respectively. It should be noted that the products 1,2,5-trisubsituted pyrroles are accessed directly from readily available diyne starting materials.…”