Overcoming Product Inhibition in Catalysis of the Intramolecular Schmidt Reaction

Abstract

A method for carrying out the intramolecular Schmidt reaction of alkyl azides and ketones using a substoichiometric amount of catalyst is reported. Following extensive screening, the use of the strong hydrogen bond donating solvent hexafluoro-2-propanol was found to be consistent with low catalyst loadings, which range from 2.5 mol% for favorable substrates to 25 mol% for more difficult cases. Reaction optimization, broad substrate scope, and preliminary mechanistic studies of this improved version of the reaction are described.

Synthesis of novel N-cyclopentenyl-lactams using the Aubé reaction

“…We were able to achieve a moderate yield of cyclic lactam (±)- 6 with excess ketone, Lewis acid and longer reaction times. While this research was underway, Aubé et al proposed that an unfavorable catalyst–product interaction results in product inhibition, thus deterring the progress of the reaction under catalytic conditions, which leads to the use of excess Lewis acid in super stoichiometric amounts [37–38]. They reported that the use of hexafluoroisopropanol (HFIP) can reduce the Lewis acid requirement.…”

“…Upon careful examination of the spectral data and on the basis of the recent results from the Aubé group [37–38], the initially anticipated 1,3-substituted structure was revised to 1,2-substituted cyclopentenoid lactams (±)- 6 , as drawn in Scheme 3.…”

Temperature dependence of turnover in a Sc(OTf) 3 -catalyzed intramolecular Schmidt reaction

“…(C) Overcoming product inhibition through proton shuffling with hexafluoroisopropanol (HFIP) solvent. 5 …”

“…1,5 However, the observation that turnover frequency and number were strongly correlated with temperature supports the idea that heat may be underexplored in overcoming product inhibition in catalysis.…”

“…The phenyl chromophore of 1b allowed analysis by ultra-high performance liquid chromatography (UPLC). In addition, we used the cis isomer of the 4-substituted cyclohexanone 1b to avoid complicating the analysis by possible trans -to- cis epimerization 5 under the reaction conditions. Conversions were estimated using NMR or UPLC.…”