Stereochemistry of the Menthyl Grignard Reagent: Generation, Composition, Dynamics, and Reactions with Electrophiles

Menthyl Grignard reagent 1 from either menthyl chloride (2) or neomenthyl chloride (3) consists of menthylmagnesium chloride (1a), neomenthylmagnesium chloride (1b), trans-p-menthane (4), 2-menthene (8), 3-menthene (9), and Wurtz coupling products including symmetrical bimenthyl 13. The diastereomeric ratio 1a/1b was determined in situ by ¹³ C NMR or after D ₂ O quenching by ² H NMR analysis. Hydrolysis of the C-Mg bond proceeds with retention of configuration at C-1. The kinetic ratio 1a/1b from Grignard reagent generation (dr 59:41 at 50 °C in THF) is close to the thermodynamic ratio (56:44 at 50 °C in THF). Carboxylation of 1 at -78 °C separates diastereomers 1a/b to give the anion of menthanecarboxylic acid (19) from 1a, which combines with unreactive 1b to give neomenthylmagnesium menthanecarboxylate (1b ^I ). The kinetics of epimerization for the menthyl/neomenthylmagnesium system was analyzed (ΔH ^† = 98.5 kJ/mol, ΔS ^† = -113 J/mol·K for 1b ^I → 1a ^I ). Reactions of 1 with phosphorus electrophiles proceed stereoconvergently at C-1 of 1a/b to give predominantly menthyl-configured substitution products: PCl ₃ and 2 equiv of 1 give Men ₂ PCl (6), which hydrolyzes to dimenthylphosphine P-oxide (7), whereas Ph ₂ PCl with 1 equiv of 1 gave P-menthyldiphenylphosphine oxide (27) after workup in air.