An Improvement of the Synthesis of (1R,2S,5R)-(–)-Menthyl (S)-p-Toluenesulfinate

Key words

synthesis - p-tolyl menthyl sulfinate - enantiopure - thionyl chloride - p-tolyl - sulfinic acid

Publication History

Received: 26 January 2021

Accepted after revision: 10 February 2021

Accepted Manuscript online:
17 February 2021

Article published online:
04 March 2021

• References and Notes

• 1a Carreño MC. Chem. Rev. 1995; 95: 1717
• 1b Carreño MC, Hernández-Torres G, Ribagorda M, Urbano A. Chem. Commun. 2009; 6129
• 2a Sipos G, Drinkel EE, Dorta R. Chem. Soc. Rev. 2015; 44: 3834
• 2b Trost BM, Rao M. Angew. Chem. Int. Ed. 2015; 54: 5026
• 3a Hazra CK, Dherbassy Q, Wencel-Delord J, Colobert F. Angew. Chem. Int. Ed. 2014; 53: 13871
• 3b Dherbassy Q, Schwertz G, Chessé M, Hazra CK, Wencel-Delord J, Colobert F. Chem. Eur. J. 2016; 22: 1735
• 3c Jerhaoui S, Chahdoura F, Rose C, Djukic J.-P, Wencel-Delord J, Colobert F. Chem. Eur. J. 2016; 22: 17397
• 3d Jerhaoui S, Djukic J.-P, Wencel-Delord J, Colobert F. Chem. Eur. J. 2017; 23: 15594
• 3e Rae J, Frey J, Jerhaoui S, Choppin S, Wencel-Delord J, Colobert F. ACS Catal. 2018; 8: 2805
• 4 Andersen KK. Tetrahedron Lett. 1962; 3: 93
• 5 Phillips H. J. Chem. Soc. Trans. 1925; 127: 2552
• 6a Mioskowski C, Solladié G. Tetrahedron 1980; 36: 227
• 6b Solladié G, Hutt J, Girardin A. Synthesis 1987; 173
• 7 Herbrandson HF, Dickerson RT. J. Am. Chem. Soc. 1959; 81: 4102
• 8 Mislow K, Simmons T, Melillo JT, Ternay AL. J. Am. Chem. Soc. 1964; 86: 1452
• 9 Klunder JM, Sharpless KB. J. Org. Chem. 1987; 52: 2598
• 10 Trost BM, Rao M, Dieskau AP. J. Am. Chem. Soc. 2013; 135: 18697
• 11a Hajipour AR, Mallakpour SE, Afrousheh A. Tetrahedron 1999; 55: 2311
• 11b Hajipour AM, Mallakpour SE, Afrousheh A. Phosphorus, Sulfur Silicon Relat. Elem. 2000; 160: 67
• 12 Hajipour AR, Falahati AR, Ruoho AE. Tetrahedron Lett. 2006; 47: 2717
• 13 Gafur SH, Waggoner SL, Jacobsen E, Hamaker CG, Hitchcock SR. Synthesis 2018; 50: 4855
• 14 Blakemore PR, Marsden SP, Vater HD. Org. Lett. 2006; 8: 773
• 15 Dherbassy Q, Djukic J.-P, Wencel-Delord J, Colobert F. Angew. Chem. Int. Ed. 2018; 57: 4668
• 16 The costings were evaluated for the synthesis of 1 mmol of product according to the yields reported based on the price of starting materials and reagents available from Sigma-Aldrich (12/2020).
• 17 In a 250 mL flask, equipped with either a large stirrer bar or mechanical stirring, neat SOCl₂ (1.47 equiv., 49.2 g, 30 mL, 0.414 mol) was added and then cooled to 0 °C. Dried solid sodium 4-methylbenzene-1-sulfinate (1 equiv., 50 g, 0.281 mol) was then added portionwise as quickly as possible to avoid blow back of the powder by the evolving sulfur dioxide (addition generally takes around 5–10 min and should not be longer than 20 min). NOTE: After about two-thirds of the addition, depending on the speed of the addition, a solid paste can form that will impede the stirrer bar. If this happens, the addition should be continued nonetheless, and the mixture should recover its initial appearance after a few minutes. After addition was complete, DMF (1 mol%, 0.21 g, 0.222 mL, 0.00287 mol) was then added, the cold bath removed, and the solution stirred for 1 h at 80 °C with a drying tube fitted containing a desiccant such as Na₂SO₄. At this point toluene (100 mL) was added and the flask fitted for reduced pressure distillation to remove the excess SOCl₂ as a toluene azeotrope. In so doing, the pressure was slowly reduced so that the thick solution would not bump. At the end of the distillation the reaction mixture was bright straw yellow, with very little residual toluene. The SOCl₂-free solution was then cooled to 0 °C in an ice-water bath and the flask fitted with an addition funnel charged with a solution of (–)-menthol (0.958 equiv., 42 g, 47.2 mL, 0.269 mol) in triethylamine (44 mL). The menthol solution was slowly added dropwise at 0 °C. After addition was complete, the resulting mixture was stirred at 0 °C for 1 h and at rt for 2 h. It was then poured into a mixture of brine (50 mL) and aqueous HCl (1 M, 50 mL) along with Et₂O (50 mL) to reach pH ca. 1–2. Then the minimum of Et₂O was added to achieve a homogeneous biphasic mixture. The phases were separated, and the organic phase washed with 1 M HCl (2 × 50 mL) followed by saturated NaHCO₃ (2 × 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was dissolved in acetone (100 mL) to which was added 3–5 drops of 37% HCl and the whole mixture put into a freezer. The resultant crystals were filtered and washed once with cold acetone (–18 °C); the mother liquor was then concentrated to half its volume, 1–2 drops of concentrated HCl were added, and the process repeated as long as appreciable amounts of crystals could be recovered (6–8 iterations). The combined batches were recrystallized from acetone (reflux to rt to –18 °C), affording large rectangular colorless crystals of (–)-menthyl (S)-p-toluenesulfinate (57.3 g, 0.194 mol, 72.4%).