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 (–)-(1R)-menthol (1) with Lucas' reagent (ZnCl₂ 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 TiCl₄-catalyzed extrusion of SO₂ from menthyl chlorosulfite (3). The products of both syntheses have now been analyzed by quantitative ¹H and ¹³C 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.