Chloromethyl p-Tolyl Sulfide1

[34125-84-3]  · C8H9ClS  · Chloromethyl p-Tolyl Sulfide  · (MW 172.68)

(source of the p-tolylthio carbanion2 and reactive electrophiles;1 starting material for the synthesis of 1-halomethyl p-tolyl sulfoxide3)

Physical Data: bp 125-126 °C/15 mmHg.

Solubility: sol most organic solvents; insol H2O.

Preparative Methods: several methods are available.4 The most commonly used and convenient method is the chlorination of methyl p-tolyl sulfide with Sulfuryl Chloride in methylene chloride.4a,b

Handling, Storage, and Precautions: use in a fume hood.

Chloromethyl p-Tolyl Sulfide Carbanion.

The reaction of p-tolylthiochloromethylpotassium, generated by the reaction of chloromethyl p-tolyl sulfide with Potassium t-Butoxide in t-butanol in the presence of 1,4-Diazabicyclo[2.2.2]octane (DABCO), with benzaldehyde gives the corresponding a,b-epoxy sulfide as a mixture of isomers, the cis isomer being the predominant product. When Pivalaldehyde is used as the carbonyl component, only the cis isomer of the corresponding a,b-epoxy sulfide is formed. The cis isomers upon treatment with Boron Trifluoride Etherate rearrange to a-tolylthio aldehydes with the exclusive migration of the p-tolylthio group (eq 1).2a This type of rearrangement is analogous to the reaction of a,b-epoxy sulfoxides5 (see also Chloromethyl Phenyl Sulfoxide).

Attempts to generate p-tolylthiochloromethylpotassium with t-butoxide in t-butanol without DABCO in the presence of the carbonyl compounds gave only trans-1,2-bis(p-tolylthio)ethylene as a byproduct, presumably by a displacement-elimination reaction involving the p-tolylthiochloromethyl carbanion (eq 2).2a

A low yield of b-hydroxy-a-chloro sulfide is obtained from the reaction of p-tolylthiochloromethyllithium with benzaldehyde, presumably due to the inefficient generation of the carbanion with n-butyllithium. The phenylthio analog of the a,b-epoxy sulfide is prepared by the reaction of bis(phenylthio)methyllithium with carbonyl compounds. The adducts, a-hydroxybis(phenylthio) acetals, on reaction with Copper(I) Trifluoromethanesulfonate (6 equiv) in benzene containing Diisopropylethylamine (4 equiv), give a,b-epoxy sulfides which are thermally labile and undergo thermal rearrangement to a-phenylthio ketones (eq 3).6

A high yield of a Grignard reagent, p-tolylthiomethylmagnesium chloride, is obtained by the reaction of chloromethyl p-tolyl sulfide with Magnesium in THF at 10-20 °C. The temperature is the crucial factor, and small amounts of Iodine and 1,2-Dibromoethane are used to initiate the Grignard reaction. (+)-(S)-p-Tolyl p-tolylthiomethyl sulfoxide is formed in 81% yield with 88% optical purity upon reacting an equimolar amount of the Grignard reagent with (-)-(S)-menthyl p-toluenesulfinate (see (-)-(1R,2S,5R)-Menthyl (S)-p-Toluenesulfinate) (eq 4).2b This method is used for preparation of the chiral thioacetal monosulfoxide with a higher chemical yield but lower optical purity than the method reported earlier, which utilizes p-tolylthiomethyllithium as the carbanion partner.7 The chiral thioacetal monosulfoxide is useful as a chiral synthon for the synthesis of chiral a-substituted aldehyde s (eq 5).8

N-Alkylation.

2H-1,3-Benzothiazine derivatives, a group of compounds with significant pharmacological activities, are synthesized by N-alkylation followed by cyclization of aryl and alkyl nitriles using Antimony(V) Chloride as a Lewis acid (eq 6).9

P-Alkylation.

The Michael-Arbuzov reaction of chloromethyl p-tolyl sulfide with Trimethyl Phosphite10 or Triethyl Phosphite11 yields dimethyl- or diethylphosphonylmethyl p-tolyl sulfides, which are important intermediates for the synthesis of vinyl sulfides and sulfoxides,12 as well as for optically active derivatives of dimethylphosphonylmethyl p-tolyl sulfoxide (eq 7). This method of preparation of the chiral p-tolylthio monosulfoxide is complementary to the reaction using dimethylphosphonylmethyllithium and (-)-(S)-menthyl p-toluenesulfinate in which the (+)-(R) isomer is obtained in high yield and high optical purity (eq 8). The lithio dimethylphosphonylmethyl p-tolyl sulfoxide reacts with aldehydes and ketones to give the corresponding vinyl sulfoxides, which can be converted into optically active allylic alcohols (eq 9).10,13

Self-Condensation.

Bis(p-tolylthio)methane, an important dithioacetal for nucleophilic alkylation,14 is formed by self-alkylation of chloromethyl p-tolyl sulfide using neutral Alumina as a catalyst (eq 10).15

Oxidation.

Fluoromethyl p-tolyl sulfide, which can be oxidized to fluoromethyl p-tolyl sulfoxide with N-Bromosuccinimide in methanol, is synthesized by the reaction of chloromethyl p-tolyl sulfide with Potassium Fluoride in the presence of 18-Crown-6 (eq 11).3b Chloromethyl p-tolyl sulfoxide can be synthesized by a one-pot operation from methyl p-tolyl sulfide with Silver(I) Nitrate and Sulfuryl Chloride via the intermediacy of chloromethyl p-tolyl sulfide (eq 12).3b,c


1. (a) Dilworth, B. M.; McKervey, M. A. T 1986, 42, 3731. (b) Barrett, G. C. In Comprehensive Organic Chemistry; Barton, D. H. R., Ed.; Pergamon: Oxford, 1979; Vol. 3, Chapter 11.4. (c) Nudelman, A. The Chemistry of Optically Active Sulfur Compounds; Gordon & Breach: New York, 1984.
2. (a) Tavares, D. F.; Estep, R. E. TL 1973, 1229. (b) Ogura, K.; Fujita, M.; Takahashi, M.; Takahashi, K.; Iida, H. TL 1982, 1679.
3. (a) Hojo, M.; Masuda, R. TL 1976, 613. (b) More, K. M.; Wemple, J. S 1977, 791. (c) Kim, Y. H.; Shin, H. H.; Park, Y. J. S 1993, 209.
4. (a) Bordwell, F. G.; Cooper, G. D.; Morita, H. JACS 1957, 79, 376. (b) Trost, B. M.; Kunz, R. A. JOC 1974, 39, 2648. (c) Goralski, C. T.; Burk, G. A. JOC 1977, 42, 3094. (d) Ono, N.; Miyake, H.; Saito, T.; Kaji, A. S 1980, 952.
5. (a) Tavares, D. F.; Estep, R. E.; Blezard, M. TL 1970, 2373. (b) Durst, T.; Tin, K.-C. TL 1970, 2369.
6. Cohen, T.; Kuhn, D.; Falck, J. R. JACS 1975, 97, 4749.
7. Colombo, L.; Gennari, C.; Narisano, E. TL 1978, 3861.
8. Guanti, G.; Narisano, E.; Banfi, L.; Scolastico, C. TL 1983, 24, 817.
9. Thakur, D. K.; Vankar, Y. D. S 1983, 223.
10. Mikolajczyk, M.; Midura, W.; Grzejszczak, S.; Zatorski, A.; Chefczynska, A. JOC 1978, 43, 473.
11. Arai, Y.; Kuwayama, S.; Takeuchi, Y.; Koizumi, T. SC 1986, 16, 233.
12. (a) Mikolajczyk, M.; Grzejszczak, S.; Midura, W.; Zatorski, A. S 1975, 278. (b) Mikolajczyk, M.; Grzejsczak, S.; Midura, W.; Zatorski, A. S 1976, 396.
13. Hoffman, R. W.; Maak, N. TL 1976, 2237.
14. Gröbel, B.-T.; Seebach, D. S 1977, 357.
15. (a) Campbell, M. M.; Jigajinni, V. B.; MacLean, K. A.; Wightman, R. H. TL 1980, 21, 3305. (b) Jigajinni, V. B.; Wightman, R. H. CC 1981, 87.

Vichai Reutrakul & Manat Pohmakotr

Mahidol University, Bangkok, Thailand



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