An Unexpected [1,5]-H Shift in the Synthesis of Nitroanilines

Abstract

An Unexpected [1,5]-H Shift in the Synthesis of Nitroanilines.Page 439. The outcome of the reaction of methyl acetoacetate and nitrovinamidinium salts (1a-d) to give substituted anilines (2a-c) was rationalized as proceeding through a [1,5]-H shift. After publication of this work, we began to investigate the mechanistic pathway by computational methods in collaboration with Prof. Ken Houk (UCLA). All 1,5hydrogen shifts have barriers of greater than 45 kcal/mol according to B3LYP/6-31G* calculations for both neutral and anionic intermediates. Since we were unable to locate a thermally accessible transition state, these computational studies prompted us to revisit the structural assignment of the anilines. The regiochemistry was previously determined by an HMBC NMR experiment. Extensive NOE studies and preparation of the authentic alternative regioisomers have led us to revise the aniline 2a to 2-(dimethylamino)-5nitrobenzoic acid methyl ester. Additional support for the revision is based on X-ray crystallographic analysis of an analogue. The mechanisitic implication of this revision is a formal 1,5-dimethylamine shift.

Demonstrating the Synergy of Synthetic, Mechanistic, and Computational Studies in a Regioselective Aniline Synthesis

“…On the basis of the compelling mechanistic and theoretical studies, the assignment of structure was revisited. 20 The regioisomeric aniline product 4 was demonstrated to be the unambiguous product in the reaction by authentic synthesis, NOE studies, and X-ray crystallographic analysis of an analogue. In this paper we provide full details of the synthetic, mechanistic and computational aspects of our program.…”

Computational Studies on the Electrocyclizations of 1-Amino-1,3,5-hexatrienes

“…However, we have demonstrated that ring closure to provide aromatic products occurs in the case of nitro-, phenylsulfonyl-, and dimethylaminomethylene substitution. 6,7 The major reaction pathway has been formalized as (1) enamine or enol formation, (2) electrocyclization, and (3) elimination of dimethylamine to provide the aromatic product (Scheme 1). 8 The electrocyclization of 1,3,5-hexatrienes having a 1-dimethylamino latent leaving group has been previously observed 9 and similarly occurs for the 1-SMe 10 and 1-Cl 11 hexatrienes.…”