LAUSR

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 via TiCl4-catalyzed extrusion of SO2 from menthyl chlorosulfite (3). The products from 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 via the catalytic rearrangement of chlorosulfite 3 is reported.