Mechanistic Investigation of Castagnoli-Cushman Multicomponent Reactions Leading to a Three-Component Synthesis of Dihydroisoquinolones.

The mechanisms for the three- and four-component variants of the Castagnoli-Cushman reaction (CCR) have been investigated. A series of crossover experiments were conducted to probe the structure and reactivity of known amide-acid intermediates for the three- and four-component variants of the CCR (3CR and 4CR, respectively). Control experiments paired with in situ reaction monitoring with infrared spectroscopy for the 4CR align with a mechanism in which amide-acids derived from maleic anhydride can reversibly form free amine and cyclic anhydride. Although this equilibrium is unfavorable, the aldehyde present can trap the primary amine through imine formation and react with the enol form of the anhydride through a Mannich-like mechanism. This detailed mechanistic investigation coupled with additional crossover experiments supports an analogous mechanism for the 3CR and has led to the elucidation of new 3CR conditions with homophthalic anhydride, amines, and aldehydes for the formation of dihydroisoquinolones in good yields and excellent diastereoselectivity. This work represents the culmination of more than a decade of mechanistic speculation for the 3- and 4CR, enabling the design of new multicomponent reactions that exploit this novel mechanism.

Organocatalytic Mukaiyama Mannich Reactions of 2,5-Bis(trimethylsilyloxy)furan.

The organocatalytic synthesis of densely substituted mono- and bis-γ-lactams involving the Mukaiyama Mannich addition of 2,5-bis(trimethylsilyloxy)furan to imines is described. Use of a ditoluenesulfonylimide catalyst produces γ-lactams from monoaddition, whereas a more acidic catalyst (triflic acid) produces fused bis-lactams from double addition. Optimized organocatalytic conditions allow for the selective synthesis of either desired core as well as the one-pot, multicomponent assembly of the trisubstituted monolactams from aldehydes, amines, and bis-trimethylsilyloxyfuran. An examination of chiral acids found these organocatalysts to be highly active and diastereoselective in the monoaddition reaction, albeit with no enantioselectivity.

Formal [4 + 2] Cycloadditions of Anhydrides and α,ß-Unsaturated N-Tosyl Ketimines.

A method for the diastereoselective synthesis of highly substituted ß-enamino ketones from anhydrides and ketone-derived imines is reported. Cyclic, enolizable anhydrides undergo a base-promoted conjugate addition reaction with α,ß-unsaturated N-tosyl ketimines, followed by an intramolecular acylation to give formal [4 + 2] cycloaddition products. The carboxylic acid-containing products are formed with modest selectivity for the cis-diastereomer and can be fully epimerized to the trans-diastereomer upon esterification.