Chloromethyl Phenyl Sulfide1

[7205-91-6]  · C7H7ClS  · Chloromethyl Phenyl Sulfide  · (MW 158.65)

(reactive electrophile for many nucleophiles;2 a-methylenating agent;3 acyl carbanion equivalent;4 phenylthiocarbene,5a,b phenylthiomethyl carbanion,5c and halomethyl phenyl sulfoxide precursors6)

Physical Data: bp 66 °C/0.2 mmHg.

Solubility: sol most organic solvents; insol H2O.

Form Supplied in: liquid; commercially available.

Preparative Methods: there are several preparative methods available.1a,b The two most convenient methods are the reaction of Thioanisole with Sulfuryl Chloride7 and the reaction of Thiophenol with bromochloromethane using 1,8-Diazabicyclo[5.4.0]undec-7-ene8 or an alkali metal hydroxide as the base.9

Handling, Storage, and Precautions: stench; the material should be handled in a well-ventilated fume hood and kept cooled. Freshly prepared material can be stored at 0-5 °C without any appreciable decomposition. It is advisable to use freshly prepared or distilled material for reactions.

Alkylation Reactions.

The reagent reacts readily with silyl enol ethers of ketones, lactones, and esters in the presence of Zinc Bromide or Titanium(IV) Chloride as the Lewis acid. a-Methylated ketones,10 a-methylenated ketones (eq 1),3b,c g-lactones (eq 2),3a and esters (eq 3)3a can be synthesized by this method. The regioselectivity of the introduced substituents is controlled by the structures of the silyl enol ethers.

The a:g ratios in phenylthiomethylation of silyl dienol ethers are controlled by the size of the substituents on the silyl atom and the substituents on the a- and g-positions of the O-silylated dienolate (eq 4).11,12

Phenylthiomethylation-desulfurization of phenols yields C-methylated phenols in moderate yields. The ortho:para ratio is 3:1. A major useful byproduct in some cases, especially when only the para position is free, is a diphenylmethane. The Lewis acid of choice is Tin(IV) Chloride (eq 5).2a Phenylthiomethylation of aromatic hydrocarbons gives a low yield of the C-alkylated product.13,14 Cationic polar [4 + 2] cycloaddition of the reagent with styrene using SnCl4 as a Lewis acid gives a thiochroman (eq 6).15 Allylic silanes can be alkylated by using TiCl4 as a Lewis acid (eq 7).16

Phenylthiomethylation of metal enolates gives moderate yields of the C-alkylated products (eq 8).17


Substituted methylene radicals can be generated from the substituted phenylthiomethylene group.18 N-Alkylation of secondary amines,18 sulfonamides,18 imides,19 and nitriles20 gives the alkylated products. The N-phenylthiomethylated products can be transformed into pyrrolidine derivatives by radical cyclization with Tri-n-butylstannane-Azobisisobutyronitrile (eq 9).18 Phenylthiomethylation of benzimidazole2b and benzotriazole21 occurs at the N-1 position. The N-phenylthiomethylated benzotriazole can be readily alkylated and the product is a versatile 1,1-dipole synthon equivalent (eq 10).21


The O-phenylthiomethylated products of phenols are utilized for the synthesis of aryl arylsulfonylmethyl ethers22 and for protection of the phenol group; the protecting group is more resistant to hydrolysis by Mercury(II) Chloride in 4:1 acetonitrile-water than the methylthiomethyl group.2g


A sulfonium salt is formed by the phenylthiomethylation of the reagent with sulfides. The appropriately substituted sulfonium salt can undergo [2,3]-sigmatropic rearrangement to a dithioacetal derivative,23 which is a potentially useful isoprenoid synthon (eq 11).24 The bis(phenylthio) acetal is a very useful acyl carbanion equivalent precursor.2f,24,25


Phenylthiomethylphosphonate and -phosphine oxide ylides, derived by deprotonation of the corresponding phosphorus derivatives obtained by phenylthiomethylation of the respective phosphorus compounds, undergo the Horner-Wittig reaction with carbonyl compounds to give good yields of vinyl sulfides.2c,4,26 Hydrolysis of the vinyl sulfides yields aldehydes and ketones.4,24 The ylides are acyl anion equivalents (eq 12). Various carbonyl and ylide components are used for the synthesis of ketones and enones.4

(Phenylthiomethylene)triphenylarsorane, derived by deprotonation (n-BuLi/THF) of the corresponding arsonium salt obtained from the reaction of chloromethyl phenyl sulfide and Triphenylarsine in the presence of Sodium Iodide in acetonitrile, reacts with aldehydes giving a-phenylthio epoxides in THF and vinyl sulfides in THF-HMPA. The a-phenylthio epoxides are rearranged with silica gel to a-phenylthio carbonyl compounds which upon desulfurization10 yield methyl ketones. Hydrolysis of the vinyl sulfides gives aldehydes with one-carbon homologation (eq 13).27

Thiocarbene Generation.

Phenylthiocarbene, generated by the reaction of chloromethyl phenyl sulfide with Potassium t-Butoxide in hexane28 or with a phase transfer catalyst5a,b (Benzyltriethylammonium Chloride and 50% Sodium Hydroxide), adds to alkenes5a,b and 1,1-dimethylallene28b yielding phenylthiocyclopropanes and 2-(phenylthio)-1-methylenecyclopropane, respectively, in good yields (eqs 14 and 15). An alternative method for the generation of the phenylthiocarbene is by reaction of bis(phenylthio) acetals with organolithium reagents.29 Phenylthiocyclopropane can also be prepared by the reaction of thiophenol with 1-bromo-3-chloropropane in aqueous potassium hydroxide followed by cyclization of the resulting 3-chloropropyl phenyl sulfide with Potassium Amide in liquid ammonia.30 1-Lithio-1-phenylthiocyclopropane, prepared by deprotonation of phenylthiocyclopropane, has numerous interesting applications in synthesis.31-33

Reaction with Organometallic and Transition Metal Salts.

(h5-Cyclopentadienyl)dicarbonyl(phenylthiomethyl)iron, Cp(CO)2FeCH2SPh, prepared from the reaction of Bis(dicarbonylcyclopentadienyliron) and chloromethyl phenyl sulfide, is used as a methylene transfer agent. Its reaction with cis-cyclooctene gives bicyclo[6.1.0]nonane.34 Phenylthiomethyl carbanion5c is prepared by the reaction of chloromethyl phenyl sulfide with Chromium(II) Chloride and Lithium Iodide35 or with Samarium(II) Iodide (eq 16).36 In the case of the [a-phenylthioalkyl)chromium compound], PhSCHRCrIII, threo selectivity is observed in the addition with aldehydes.

The coupling of organocuprates37 and organotin compounds catalyzed by Tetrakis(triphenylphosphine)palladium(0)38 with chloromethyl phenyl sulfide leads to carbon-carbon bond formation in good yields (eqs 17 and 18).

Oxidation Reactions.

Chloromethyl Phenyl Sulfoxide is prepared in good yield by the oxidation of chloromethyl phenyl sulfide with Sulfuryl Chloride and wet silica gel in methylene chloride (eq 19).6a Fluoromethyl Phenyl Sulfoxide is prepared by the oxidation of Fluoromethyl Phenyl Sulfide with NBS in aqueous MeOH; fluoromethyl phenyl sulfide is prepared from the reaction of chloromethyl phenyl sulfide using Potassium Fluoride and 18-Crown-6 in refluxing acetonitrile (eq 19).6b

Related Reagents.

Benzyl Bromomethyl Sulfide; Benzyl Chloromethyl Sulfide; Chloromethyl Methyl Sulfide; Chloromethyl Phenyl Sulfone; Chloromethyl Phenyl Sulfoxide; Chloromethyl p-Tolyl Sulfide.

1. (a) Barrett, G. C. In Comprehensive Organic Chemistry; Barton, D. H. R., Ed.; Pergamon: Oxford, 1979; Vol. 3, Chapter 11.4. (b) Dilworth, B. M.; McKervey, M. A. T 1986, 42, 3731.
2. (a) Fleming, I. C 1980, 34, 265. (b) Katritzky, A. R., Ramer, W. H.; Lam, J. N. JCS(P1) 1987, 775. (c) Coutrot, P.; Laurenco, C.; Petrova, J.; Savignac, P. S 1976, 107. (d) Davies, H. M. L.; Crisco, L. V. T. TL 1987, 28, 371. (e) Fleming, I.; Iqbal, J. S 1982, 937. (f) Jigajini, V. B.; Wightman, R. H. CC 1981, 87. (g) Holton, R. A.; Nelson, R. V. SC 1980, 10, 911.
3. (a) Paterson, I.; Fleming, I. TL 1979, 993. (b) Paterson, I.; Fleming, I. TL 1979, 995. (c) Paterson, I. T 1988, 44, 4207.
4. Grayson, J. I.; Warren, S. JCS(P1), 1977, 2263.
5. (a) Boche, G.; Schneider, D. R. TL 1975, 4247. (b) Bhupathy, M.; Cohen, T. TL 1987, 28, 4797. (c) Kreif, A. T 1980, 36, 2531.
6. (a) Hogo, M.; Masuda, R. TL 1976, 613. (b) Wemple, J.; More, K. M. S 1977, 791.
7. (a) Bordwel, F. G.; Pitt, B. M. JACS 1955, 77, 572. (b) Trost, B. M.; Kunz, R. A. JOC 1974, 39, 2648.
8. Ono, N.; Miyake, H.; Saito, T.; Kaji, A. S 1980, 952.
9. Goralski, C. T.; Burk, G. A. JOC 1977, 42, 3094.
10. Fleming, I.; Rowley, M. T 1986, 42, 3181.
11. Fleming, I.; Lee, V. T. TL 1981, 22, 705.
12. Fleming, I.; Iqbal, J. TL 1983, 24, 2913.
13. Hojo, M.; Masuda, R. SC 1975, 5, 173.
14. Tamura, Y.; Annoura, H.; Fuji, M.; Okura, M.; Ishibashi, H. CPB 1986, 34, 540.
15. Tamura, Y.; Ishiyama, K; Mizuki, Y; Maeda, H.; Ishibashi, H. TL 1981, 22, 3773.
16. Sato, T.; Hanayama, K.; Fujisawa, T. TL 1988, 29, 2197.
17. Groth, U., Huhn, T.; Richter, N. LA 1993, 49.
18. (a) Padwa, A.; Nimmesgern, H.; Wong, G. S. K. JOC 1985, 50, 5620. (b) Padwa, A.; Dent, W.; Nimmesgern, H.; Venkatramanan, M. K.; Wong, G. S. K. CB 1986, 119, 813.
19. (a) Worley, J. W. JOC 1979, 44, 1178. (b) Shiozaki, M.; Hiraoka, T.; Yanagisawa, H. H 1986, 24, 1007.
20. Thakur, D. K.; Vankar, Y. D. S 1983, 223.
21. Katrizky, A. R.; Yang, Z.; Lam, J. N.; Cundy, D. J. H 1993, 36, 1367.
22. Schank, K.; Schmitt, H. G. CB 1978, 111, 3497.
23. Ratovelomanana, V.; Julia, S. SC 1978, 8, 87.
24. Gröbel, B.-T.; Seebach, D. S 1977, 357.
25. (a) Langler, R. F.; Marini, Z. A.; Pincock, J. A. CJC 1978, 56, 903. (b) Campbell, M. M.; Jigajinni, V. B.; MacLean, K. A.; Wightman, R. H. TL 1980, 21, 3305.
26. Theobald, P. G.; Okamura, W. H. JOC 1990, 55, 741.
27. Boubia, B.; Moiskowski, C.; Manna, S.; Falck, J. R. TL 1989, 30, 6023.
28. (a) Schöllkopf, U.; Woerner, F. P.; Wiskott, E. CB 1966, 99, 806. (b) Singleton, D. A.; Church, K. M. JOC 1990, 55, 4780.
29. Ramig, K.; Bhupathy, M.; Cohen, T. JOC 1989, 54, 4404.
30. Trost, B. M.; Keeley, D. E.; Arndt, H. C.; Rigby, J. H.; Bogdanowicz, M. J. JACS 1977, 99, 3080.
31. Trost, B. M.; Vladuchick, W. C. S 1978, 821.
32. (a) Trost, B. M.; Keeley, D. E.; Arndt, H. C.; Rigby, J. H. Bogdanowicz, M. J. JACS 1977, 99, 3088. (b) Cohen, T.; Matz, J. R. TL 1981, 22, 2455. (c) Byers, J. H.; Spencer, T. A. TL 1985, 26, 717.
33. Trost, B. M. ACR 1974, 7, 85.
34. O'Connor, E. J.; Brandt, S.; Helquist, P. JACS 1987, 109, 3739.
35. Nakatsukasa, S.; Takai, K.; Utimoto, K. JOC 1986, 51, 5045.
36. Yamashita, M.; Kitagawa, K.; Ohhara, T.; Iida, Y.; Masumi, A.; Kawasaki, I.; Ohta, S. CL 1993, 653.
37. Germon, C.; Alexakis, A.; Normant, J. F. S 1984, 43.
38. Bhatt, R. K.; Shin, D.-S.; Falck, J.; Mioskowski, C. R. TL 1992, 33, 4885.

Vichai Reutrakul & Manat Pohmakotr

Mahidol University, Bangkok, Thailand

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.