Chloromethyl Phenyl Sulfoxide1

[7205-94-9]  · C7H7ClOS  · Chloromethyl Phenyl Sulfoxide  · (MW 174.65)

(synthesis of a,b-epoxy sulfoxides;2a-c one-carbon homologating agent3)

Physical Data: bp 120-121 °C/4 mmHg.

Solubility: sol CHCl3 and THF.

Preparative Methods: chlorination of methyl phenyl sulfoxide with either Sulfuryl Chloride4 in methylene chloride or N-Chlorosuccinimide5 in chloroform gives a good yield of the product. A one-pot procedure starting with Thioanisole consists of chlorination with sulfuryl chloride in methylene chloride6 followed by oxidation with the same reagent in the presence of wet silica gel.7 Another alternative is to employ Silver(I) Nitrate and sulfuryl chloride in acetonitrile.8

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

a,b-Epoxy Sulfoxides.

Epoxy sulfoxides are prepared by the reaction of the chloromethyl phenyl sulfoxide carbanion (PhSOCHClM) with carbonyl compounds. When ketones are used as electrophiles, either a one-step Darzens-type condensation using Potassium t-Butoxide in t-BuOH2b,c or a two-step route involving the addition of a-lithiochloromethyl phenyl sulfoxide (best generated by the reaction of PhSOCH2Cl with Lithium Diisopropylamide; n-Butyllithium has been used, but caution should be taken due to the possible desulfinylation reaction) to ketones to give a-chloro-b-hydroxy sulfoxides (chlorohydrins), followed by treatment with Potassium Hydroxide in aqueous methanol (eq 1; R1, R2 = alkyl, aryl).2a,3c

With aldehydes (eq 1; R1 = H, R2 = alkyl), only the two-step route can be used satisfactorily.2b A high degree of diastereoselectivity is observed in the formation of the chlorohydrins.2a Thermal2b or Lewis acid-catalyzed3c reactions of the epoxy sulfoxides (R1 and/or R2 = alkyl) give a,b-unsaturated aldehydes with one-carbon homologation. This process has been applied to the synthesis of (±)-suaveolin (eq 2).9

Thermal elimination of the chlorohydrins derived from aldehydes (R1 or R2 = H) provides chloromethyl ketones10 in good yields (eq 3). One-carbon ring expansion11 of the chlorohydrins derived from cyclic ketones can be induced by Lithium Diisopropylamide through an a-sulfinyl carbenoid intermediate (eq 3). Eliminative deoxygenation3b of the chlorohydrins with low-valent titanium gives vinyl sulfides (eq 3). 1-Chlorovinyl sulfoxides derived from the chlorohydrins undergo the Fritsch-Wiechell rearrangement with t-Butyllithium to give terminal alkynes (eq 4).12

Lithiochloromethyl phenyl sulfoxide gives 1,2-addition products with enones.13 The transformation of a chlorohydrin [R1-R2 = -(CH2)3-] to an a,b-unsaturated g-hydroxycyclohexanecarbaldehyde14 has been demonstrated (eq 5).

Addition to Imines.

The addition of lithiochloromethyl phenyl sulfoxide to aryl imines provides sulfinylaziridines as a mixture of cis and trans isomers which undergo 1,3-dipolar cycloaddition with Dimethyl Acetylenedicarboxylate (DMAD), giving N-aryl-2,3,4-trisubstituted pyrroles (eq 6).15

Alkylation with Alkyl Halides.

Chloroalkyl phenyl sulfoxides, available from alkylation of lithiochloromethyl phenyl sulfoxide with alkyl bromides or iodides, give high yields of terminal vinyl chlorides upon pyrolysis16 and undergo the sila-Pummerer rearrangement with LDA and Chlorotrimethylsilane to yield thiol esters (eq 7).17

Direct chlorination of alkyl phenyl sulfoxides with NCS is a useful alternative method for the preparation of chloroalkyl phenyl sulfoxides.18 Addition of lithiochloroalkyl phenyl sulfoxide to carbonyl compounds gives the chlorohydrins which can be transformed via a,b-epoxy sulfoxides into carbonyl compounds with one-carbon homologation,19 a-sulfenylated ketones and aldehydes,20 a-amino ketones and aldehydes,21 a-acetoxy ketones,22 alkyl vinyl ketones and divinyl ketones,23 epoxides and allylic alcohols,24 2-acyl cyclic ethers and 3-keto cyclic ethers,25 a-chloro and a-alkoxy ketones,26 a,b-unsaturated ketones,26 (E)-1-acylbutadienes,27 1,3-dihydroxy ketones,28 functionalized cyclohexane derivatives,29 spiro-methylenecyclopropanes,30 and a-fluoro ketones.31

Eliminative deoxygenation of chloroalkyl phenyl sulfoxides using Trimethylsilyl Trifluoromethanesulfonate with Triethylamine as a base gives a-chlorovinyl phenyl sulfides.32

Bromomethyl and Iodomethyl Phenyl Sulfoxides.

a-Lithio anions derived from bromomethyl phenyl sulfoxide33a-c and iodomethyl phenyl sulfoxide34a,b react with carbonyl compounds and alkyl iodides in an analogous manner to the chloromethyl phenyl sulfoxide.35a,b a-Phenylsulfinyl radicals generated from either chloroalkenyl or bromoalkenyl phenyl sulfoxide undergo radical cyclization to cyclopentane derivatives together with the reduction products (eq 8).36 Debromination of bromomethyl phenyl sulfoxide also occurs with Octacarbonyldicobalt on alumina.37

Pyrolysis of bromohydrins gives bromomethyl ketones.35a Solvolysis of iodohydrins of cyclic ketones with Silver(I) Nitrate in 95% ethanol provides vinyl sulfones, a-hydroxy sulfones, and/or one-carbon ring expansion products depending on the ring size, presumably through a common phenylsulfinyl carbenium ion.35b,38


1. Venier, C. G.; Barager, H. J., III. OPP 1973, 6, 77.
2. (a) Durst, T. JACS 1969, 91, 1034. (b) Reutrakul, V.; Kanghae, W. TL 1977, 1377. (c) Durst, T.; Tin, K.-C.; Reinach-Hirtzbach, F. D.; Decesare, J. M.; Ryan, M. D. CJC 1979, 57, 258.
3. (a) Taber, D. F.; Gunn, B. P. JOC 1979, 44, 450. (b) Reutrakul, V.; Poochaivatananon, P. TL 1983, 24, 531. (c) Satoh, T.; Itoh, M.; Ohara, T.; Yamakawa, K. BCJ 1987, 60, 1839.
4. Tin, K.-C.; Durst, T. TL 1970, 4643.
5. Jung, F.; Tin, K. C.; Durst, T. IJS(B) 1973, 8, 1.
6. Trost, B. M.; Kunz, R. A. JOC 1974, 39, 2648.
7. Hojo, M.; Masuda, R. TL 1976, 613.
8. Kim, Y. H.; Shin, H. H.; Park, Y. J. S 1993, 209.
9. Trudell, M. L.; Cook, J. M. JACS 1989, 111, 7504.
10. Reutrakul, V.; Kanghae, W. TL 1977, 1225.
11. Satoh, T.; Hayashi, Y.; Mizu, Y.; Yamakawa, K. TL 1992, 33, 7181.
12. Satoh, T.; Hayashi, Y.; Yamakawa, K.; BCJ 1993, 66, 1866.
13. Mahidol, C.; Reutrakul, V.; Panyachotipun, C.; Turongsomboon, G.; Prapansiri, V.; Bandara, B. M. R. CL 1989, 163.
14. Satoh, T.; Motohashi, S.; Yamakawa, K. TL 1986, 27, 2889.
15. Mahidol, C.; Reutrakul, V.; Prapansiri, V.; Panyachotipun, C. CL 1984, 969.
16. Reutrakul, V.; Thamnusan, P. TL 1979, 617.
17. More, K. M.; Wemple, J. JOC 1978, 43, 2713.
18. See for example: Satoh, T.; Kumagawa, T.; Sugimoto, A.; Yamakawa, K. BCJ 1987, 60, 301.
19. Satoh, T.; Kaneko, Y.; Izawa, T.; Sakata, K.; Yamakawa, K. BCJ 1985, 58, 1983.
20. Satoh, T.; Kumagawa, T.; Yamakawa, K. BCJ 1985, 58, 2849.
21. Satoh, T.; Kaneko, Y.; Sakata, K.; Yamakawa, K. BCJ 1986, 59, 457.
22. Satoh, T.; Motohashi, S.; Yamakawa, K. BCJ 1986, 59, 946.
23. Satoh, T.; Kumagawa, T.; Sugimoto, A.; Yamakawa, K. BCJ 1987, 60, 301.
24. Satoh, T.; Kaneko, Y.; Yamakawa, K. BCJ 1986, 59, 2463.
25. Satoh, T.; Iwamoto, K. I.; Sugimoto, A.; Yamakawa, K. BCJ 1988, 61, 2109.
26. Satoh, T.; Sugimoto, A.; Yamakawa, K. CPB 1987, 35, 4632.
27. Satoh, T.; Motohashi, S.; Yamakawa, K. CPB 1988, 36, 1169.
28. Satoh, T.; Sugimoto, A.; Itoh, M.; Yamakawa, W. BCJ 1989, 62, 2942.
29. Satoh, T.; Kawase, Y.; Yamakawa, K. JOC 1990, 55, 3962.
30. Satoh, T.; Kawase, Y.; Yamakawa, K. BCJ 1991, 64, 1129.
31. Satoh, T.; Shishikura, J.; Yamakawa, K. CPB 1990, 38, 1798.
32. Miller, R. D.; Hässig, R. SC 1984, 14, 1285.
33. (a) Iriuchijima, S.; Tsuchihashi, G. S 1970, 588. (b) Jung, F.; Tin, K. C.; Durst, T. IJS(B) 1973, 8, 1. (c) Drabowicz, J. S 1986, 831.
34. (a) Hojo, M.; Masuda, R.; Saeki, T.; Uyeda, S. S 1976, 697. (b) Jóczyk, A.; Pytlewski, T. S 1978, 883.
35. (a) Reutrakul, V.; Tiensripojamarn, A.; Kusamran, K.; Nimgirawath, S. CL 1979, 209. (b) Reutrakul, V.; Panyachotipun, C.; Hahnvajanawong, V.; Sotheeswaran, S. TL 1984, 25, 1825.
36. Tsai, Y.-M.; Ke, B.-W.; Lin, C.-H. TL 1990, 31, 6047.
37. Alper, H.; Gopal, M. JOC 1983, 48, 4390.
38. Venier, C. G.; Wing, F. A., Jr.; Barager, H. J., III. TL 1980, 21, 3159.

Vichai Reutrakul & Manat Pohmakotr

Mahidol University, Bangkok, Thailand



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