Me3SBr was prepared by the reaction of bromine with dimethylsulfoxide (DMSO) by a simplification of a published method [3]. Other methods from DMSO are also known (e.g., by the reaction with benzyl bromide or ethyl bromoacetate [1]). Reaction of DMSO with hydrogen bromide might also lead to Me3SBr, but I could find no literature support for this. Trimethylsulfonium chloride (Me3SCl) analogously forms from the reaction of DMSO with Cl2,[4] but I could find no specific information on the selectivity and no preparative example.
Trimethylsulfonium bromide (Me3SBr):
Into a 20 mL dimethylsulfoxide (DMSO) was slowly and very carefully added 2 mL bromine (39 mmol) dropwise from a micropipette, while stirring in a cooling bath (note 1), at such a rate to maintain the temperature of the reaction mixture at about 40 °C. The reaction is very exothermic and each drop of Br2 makes a hissing noise upon contact with DMSO. The clear yellow solution was left stirring for 3 days at room temperature. It formed a thick yellow slurry which was then diluted with 60 mL acetone. The insoluble product was vacuum filtered, washed with 3×15 mL acetone and left drying under vacuum in a desiccator. There was thus obtained 7.72 g (63%) of a light yellow crystalline powder having a faint “sulfide stench” (note 2): mp 194–198 °C, subl. (lit.[3] 198–200 °C, from EtOH); IR (KBr):
Note 1: The oxidation of DMSO with Br2 is extremely exothermic! Each drop of Br2 would violently react with DMSO (similarly as adding TCCA to DMSO). Adding all the bromine at once can result in accidents and serious injuries! Cooling and good stirring is advised. Do not use an ice bath (mp of DMSO!), but a water bath at about 15 °C will do. Do not upscale the reaction without all the necessary precautions!
Note 2: During the reaction there were no gasses evolved. During the work up some dimethyl sulfide smell was present but not up to any annoying level.
Use of Me3SBr
I looked on the shelves for a phenolic substrate to O-methylate which would be less reactive (e.g., having a hydroxy orto to a carbonyl group) and giving a product that would be solid at room temperature (so that no chromatography would be needed in the reaction work up). I found some old 2-hydroxy-5-methylbenzophenone from Aldrich picking dust on the shelves, which looked like nobody will ever use or miss. I decided to sacrifice it in the name of amateur chemistry.
Not being sure about the reaction temperature required, or best solvent to use, I decided not to waste time reinventing the wheel and used the conditions previously reported to work for tetramethylammonium chloride as a reagent for the methylation of phenols [6]. Since sulfonium salts are more electrophilic than the ammonium counterparts, I used a lower reaction temperature (100 °C instead of 150 °C). It worked just fine.
Methylation of 2-hydroxy-5-methylbenzophenone with trimethylsulfonium bromide:
A mixture of 1.90 g Me3SBr (12 mmol), 2.12 g 2-hydroxy-5-methylbenzophenone (10 mmol), 1.66 g K2CO3 (12 mmol) and 6 mL polyethyleneglycol (PEG400) was stirred for 6 h at 100 °C (note 1). The reaction was checked with TLC at 3 h and there was only one spot for a new product being formed, while the spot of the starting phenol was already faint. The reaction mixture was then worked up by diluting in 100 mL water and extraction into 40 mL diisopropyl ether, which was then washed with 3×40 mL 1M NaOH(aq), 100 mL water and rotavaped to give 2.08 g (92%) of a TLC pure colorless viscous oil. This was crystallized by dissolving it in 30 mL methanol, precipitating the oily product with 10 mL water and leaving this mixture overnight at -16 °C. The solidified product was vacuum filtered and dried under vacuum in a desiccators to give 1.93 g (85%) of 2-methoxy-5-methylbenzophenone as chunks of solids with part of it having crystallized nicely in needles: mp 37–38 °C (lit.[5] 37–38 °C); NMR (300 MHz, CDCl3):
Note 1: During the course of the reaction there was dimethyl sulfide forming as perceived by its smell. But since this was done in a fume hood this represented no problem. On such a small reaction scale and such a slow reaction rate, this is no problem even out of the fume hood as long as your neighbors don’t mind, but on a larger scale I suggest to recover the dimethyl sulfide by absorption in acetone.
EXAMPLE 1 Production of 2-methoxy-5-methyl-benzophenonehttp://www.google.com/patents/US6809225
5.00 g (23.5 mmole) 2-hydroxy-5-methyl-benzophenone
6.67 g (47.1 mmole) methyliodide
4.50 g (32.6 mmole) potassium carbonate
50 ml abs. acetone
Method:
To a solution of 5.00 g (23.5 mmole) 2-hydroxy-5-methyl-benzophenone and 6.67 g (47.1 mmole) methyliodide in 50 ml abs. acetone 4.50 g (32.6 mmole) potassium carbonate are added. The reaction mixture is then heated for 5 hours with recycling. Following cooling, 50 ml water and 50 ml petroleum ether (30/60) are added to the suspension. The organic phase is separated off, the aqueous phase is extracted twice with 75 ml petroleum ether (30/60) and the purified organic phase is washed twice with 50 ml 10% NaOH solution. The organic phase is then dried through magnesium sulphate and the solvent is removed. 3.80 g (16.8 mmole, 71%) 2-methoxy-5-methyl-benzophenone are obtained.
Yield: 3.80 g (16.8 mmole, 71%) 2-methoxy-5-methyl-benzophenone 1H-NMR (400 MHz, CDCl3): δ [ppm]=2.21 (s, 3H, CH3), 3.56 (s, 3H, OCH3), 6.77 (d, 3J=8.4 Hz, 1H, PhH), 7.06 (d, 4J=1.9 Hz, 1H, PhH), 7.15 (m, 1H, PhH), 7.31 (t, 3J=7.7 Hz, 2H, PhH), 7.43 (m, 1H, PhH), 7.71 (dd, 3J=8.3 Hz, 2J=1.2 Hz, 2H, PhH). 13C-NMR (100 MHz, CDCl3): δ [ppm]=20.3 (CH3), 55.6 (OCH3), 111.4 (CHarom), 128.1 (2×CHarom), 128.5 (Cqarom), 129.7 (2×CHarom), 129.8 (Cqarom), 129.9 (CHarom), 132.2 (CHarom), 132.8 (CHarom), 137.8 (Cqarom), 155.2 (Cqarom), 196.6 (C═O).
References
[1] http://www.google.com/patents/US6809225
[2] (a) K. Yamauchi, T. Tanabe, M. Kinoshita, J. Org. Chem., 44, 1979, 638–639, DOI: 10.1021/jo01318a037 (b) M. Kobayashi, K.Umemura, N. Watanabe, H. Matsuyama, Chemistry Letters, 1985, 1067–1070. (c) M. Kobayashi, K.Umemura, H. Matsuyama, Chemistry Letters, 1987, 327–328. (d) K. Umemura, H. Matsuyama, N. Watanabe, M. Kobayashi, N. Kamigata, J. Org. Chem., 54, 1989, 2374–2383, DOI: 10.1021/jo00271a025 (e) K. Umemura, H. Matsuyama, N. Kamigata, Bull. Chem. Soc. Jpn. 63, 1990, 2593–2600 (f) N. Shibata, A. Matsnev, D. Cahard, Beilstein J. Org. Chem., 6, 2010, 65, DOI: 10.3762/bjoc.6.65
(these are not a result of a full literature review, but see also the references therein)
[3] D. Martin, A. Berger, Journal für Praktische Chemie, 312, 1970, 683–689, DOI: 10.1002/prac.19703120418
[4] J. R. Gauvreau, S. Poignant, G. J. Martin Tetrahedron Letters, 21, 1980, 1319–1322.
[5] G. Stadnikoff, A. Baryschewa, Ber., 61, 1928, 1996–1999, DOI: 10.1002/cber.19280610869
[6]
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