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 13C NMR or
after D2O quenching by 2H 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 (1bI). The kinetics of epimerization for the menthyl/neomenthylmagnesium
system was analyzed (ΔH⧧ =
98.5 kJ/mol, ΔS⧧ = −113
J/mol·K for 1bI → 1aI). Reactions of 1 with
phosphorus electrophiles proceed stereoconvergently at C-1 of 1a/b to give predominantly menthyl-configured substitution
products: PCl3 and 2 equiv of 1 give Men2PCl (6), which hydrolyzes to dimenthylphosphine P-oxide (7), whereas Ph2PCl with
1 equiv of 1 gave P-menthyldiphenylphosphine
oxide (27) after workup in air.