Experimental and Computational Exploration of Indolizinyl Carbene Generation. A Route to Biindolizines

Abstract

In previous work, (E)-2-enynyl pyridines were reported to yield indolizinyl singlet carbenes through base-catalyzed E/Z isomerization followed by a 5-exo-dig pseudocoarctate cyclization. We report herein that in the presence of ethyl acrylate these carbenes undergo stereoselective cis-cyclopropanation due mainly to electrostatic interactions in the transition state. The scope of this carbene generation scheme has been further explored through the preparation of a symmetric bis(pyridylenyl)alkyne which spontaneously furnished the biindolizine core in a one-pot reaction. Computational characterization of this transformation suggests a highly asynchronous double cyclization.

Hydrohalogenation of Ethynylpyridines Involving Nucleophilic Attack of a Halide Ion

“…Instead, 3,3′-bis­(indolizine) 16 was isolated as a result of double coupling and tandem cyclization (Scheme ). Modification of the 3,3′-positions of the bis­(indolizine) framework was easily achieved by changing the starting 2-(bromoethenyl)­pyridines 4 .…”

Heteroarylcarbenes

“…Cyclizations of a variety of aza analogs of ene-ene-yne systems to produce 2-heteroarylcarbenes have been explored . For example, Lahoz et al offered evidence that Z -2-enynylpyridines ring close readily to indolizinyl carbenes (Scheme ) . Hence, in preliminary studies, they showed that 218 provided 219 in MeOH at 25 °C .…”

Reaction mechanisms: pericyclic reactions

“…Experiments revealed that in situ generated indolizinyl carbene from enynyl pyridine could be trapped by ethyl acrylate to yield a single product, cis-cyclopropylindolizine (top reaction, Scheme 2). 10 Calculations at M06/6-31+G(d,p) provided insight into the subsequent indolizinyl carbine reactions, predicting a highly asynchronous transition structure for reaction with ethyl acrylate leading to a ciscyclopropylindolizine. The asynchronicity was attributed to the electrostatic effects between reacting species.…”