Rearrangement in Stereoretentive Syntheses of Menthyl Chloride from Menthol: Insight into Competing Reaction Pathways through Component Quantification Analysis

The enantiopure reagent menthyl chloride ( 2 ) is generally prepared from (–)‐(1 R )‐menthol ( 1 ) with Lucas' reagent (ZnCl 2 in conc. aqueous HCl) in a stereoretentive reaction that appeared to be free from accompanying rearrangements. The same was assumed for a recent synthesis of 2 through TiCl 4 ‐catalyzed extrusion of SO 2 from menthyl chlorosulfite ( 3 ). The products of both syntheses have now been analyzed by quantitative 1 H and 13 C NMR methods, and all reaction components have been identified down to the ≤ 0.5 mol‐% level. Either reaction is accompanied by cationic rearrangement to the considerable extent of 18–25 mol‐%. Besides the expected 2 , neomenthylchloride ( 4 ) and five rearrangement products have been identified, among them three regioisomeric tertiary chloromenthanes ( 9 , 10 , 11 ), and both a secondary ( 12 ) and tertiary chloride ( 16 ) derived from ψ‐menthane (1‐isobutyl‐3‐methylcyclopentane). A scheme of rearrangement pathways starting from a common menthyl carbenium ion pair is derived. The effect of purification protocols on crude 2 has been studied quantitatively. Either selective solvolysis of tertiary sideproducts (98 mol‐% purity) or low‐temperature crystallization (≥ 97 mol‐% purity) was successful. An improved, scalable synthesis of 2 through the catalytic rearrangement of chlorosulfite 3 is reported.