Liquid-assisted grinding and ion pairing regulates percentage conversion and diastereoselectivity of the Wittig reaction under mechanochemical conditions

Abstract

Mechanochemistry is maturing as a discipline and continuing to grow, so it is important to continue understanding the rules governing the system. In a mechanochemical reaction, the reactants are added into a vessel along with one or more grinding balls and the vessel is shaken at high speeds to facilitate a chemical reaction. The dielectric constant of the solvent used in liquid-assisted grinding (LAG) and properly chosen counter-ion pairing increases the percentage conversion of stilbenes in a mechanochemical Wittig reaction. Utilizing stepwise addition/evaporation of ethanol in liquid-assisted grinding also allows for the tuning of the diastereoselectivity in the Wittig reaction.

Catalyst‐free one‐pot three‐component rapid synthesis of polysubstituted pyrroles by liquid‐assisted grinding

“…Inspired by the great progress in LAG [32][33][34], we then investigated the effect of different liquids on the Reaction conditions: methyl acetoacetate 1a (0.5 mmol), benzylamine 2a (0.5 mmol), β-nitrostyrene 3a (0.5 mmol), liquid additive, and grinding auxiliary were placed in a 25 ml stainless steel grinding jar along with stainless steel grinding balls and milled at the specified grinding frequency. b η = V (liquid; μL)/m (reagents; mg).…”

“…Inspired by the great progress in LAG [32–34], we then investigated the effect of different liquids on the reaction, and methanol was identified as the best LAG additive among the tested solvents (Table, entry 16). The volume/mass ratio of liquid additive used to solid reagents (μL/mg), denoted as η , is an important parameter in LAG experiments.…”

Solvent-Free Mechanochemical Diaza-Cope Rearrangement

“…DCR, proposed to go through a six-membered chair-like transition state, is poised to be more favored within a well-ordered lattice. 85,86 We hypothesize that mechanochemical reactions preorganize 6 into a "TS-like" structure within a solid-state matrix and minimize the formation of unproductive conformational isomers 69 (axial−axial and equatorial−axial) or a fused-bicyclic intermediate 8 34 of 6 prior to DCR. To test this idea, we intentionally paused a reaction between 1 and 2a after 40 min of ball milling and we found that simply storing the milled reaction mixture at rt increases the yield of 3a from 6% (immediately after ball milling) to 18% (after aging for 10 h, Scheme 4A).…”

Mechanochemical Asymmetric Cross‐Dehydrogenative Coupling Reaction: Liquid‐Assisted Grinding Enables Reaction Acceleration and Enantioselectivity Control

“…Considering the importance of mechanical parameters of the milling process, some of the parameters were next investigated to give the results that the milling frequency, the number and diameters of milling balls had some influences on both yields and enantioselectivities (see Table S3 in SI for details).…”