Computation-Guided Scope Exploration of a Conjugate Addition/Truce-Smiles Cascade Reaction for Scaffold Diversification

Based on the successful application of a nitroaryl transfer cascade reaction in the total synthesis of various monoterpene indole alkaloids proceeding via fused bicyclic intermediate, we investigated analogous cascade reactions involving spiro, bridged, and alternatively fused bicyclic intermediates. Unfortunately, none of these was found to afford the desired nitroaryl transfer product. DFT studies of the original cascade process revealed that the Truce-Smiles rearrangement is the rate-determining step. In addition, we found that the subsequent SO2 extrusion is accompanied by retro-Mannich ring opening, resulting in a stabilized enolate that only recyclizes after activation of the cyclic imine moiety. Computation of the reaction profiles of the proposed alternative cascade reactions showed that the barrier for the Truce-Smiles rearrangement is unreasonably high for the bridged and alternatively fused systems, but only moderately higher for the five-membered spiro system. Reasoning that even more electron-deficient arenesulfonamides should have a lower barrier for the Truce-Smiles rearrangement, we synthesized the corresponding 2,4-dinitrobenzenesulfonamide precursor and found that it indeed smoothly undergoes the nitroaryl transfer cascade at room temperature. In this case, however, the cascade reaction produces a cyclic imine product, as the intermediate 2,4-dinitrophenyl-substituted enolate is insufficiently nucleophilic to undergo the Mannich cyclization.