Highly Stereoselective Formal [3 + 3] Cycloaddition of Enals and Azomethine Imines Catalyzed by N-Heterocyclic Carbenes

Link: JACS ASAP

Audrey Chan and Karl A. Scheidt*

Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208

A method for polarity reversal (umpolung) applied to alpha,beta-unsaturated aldehydes (1) using NHC catalyst and reaction of the resulting intermediate with azomethine imines (2) in a formal [3+3] cycloaddition to form pyridazinones (3). NHC catalyst effectively generated homoenolate species in the process.The mechanism was proposed to involve addition of NHC to aldehyde to form the extended Breslow intermediate I, followed by reaction of this intemediate with azomethine imine to give intermediate II. This intermediate then tautomerized to give III which intramolecularly acylated to give product 3.

Initial studies were conducted between aldehyde 1a and imine 2a to give bicycle 4. Three NHC precursors, A, B, and C, were screened and results are in the table below.

From the table, one could conclude that catalyst C containing a single mesitylene group worked best (entry 8). In all cases, products were obtained in high diastereoselectivity having all syn substituents.

Having identified optimal reaction parameters, scope of the reaction was explored with various aldehydes and azomethine imines. The results are summarized below.The reaction tolerated various R groups on aldehyde including aliphatic (entry 6) and extended olefin (entry 7). However, when R group was eletron-withdrawing group-substituted phenyl ring, the reaction did not yield any product (entry 8).

In term of variation in R1 groups, the reaction tolerated well with both electron-donating and electron-withdrawing aryl groups (entries 9-14), although yield was lower in a more electron-rich system (entry 14). When R1 contained an enolizable alpha-carbon such as entry 15, the reaction was shut down.

The nature of an all-syn selectivity was proposed to be a hydrogen-bond-directed addition of 'homoenolate' to the imine away from phenyl group as shown in the scheme below.Further transformations of pyridazinone 4 were found to be facile both with MeOH and BnNH2 to give the corresponding ester 19 and amide 20 in almost quantitative yields.