Chloromethyl p-Tolyl Sulfone

[7569-26-8]  · C8H9ClO2S  · Chloromethyl p-Tolyl Sulfone  · (MW 204.68)

(synthesis of a,b-epoxy sulfones and alkylated sulfones;1 reacts with electrophilic arenes and heterocyclic arenes;2 source of a-p-tolylsulfonyl radicals1a)

Physical Data: mp 81-82 °C.

Solubility: sol THF, CHCl3, CH2Cl2, and most organic solvents.

Preparative Methods: by oxidation of the corresponding sulfoxide3 or by reaction of sodium p-toluenesulfinate with bromochloromethane.4

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

a,b-Epoxy Sulfones.

The chemistry of chloromethyl p-tolyl sulfone resembles that of chloromethyl phenyl sulfone (see Chloromethyl Phenyl Sulfone). a,b-Epoxy p-tolyl sulfones derived from carbonyl compounds are conveniently prepared by a one-step Darzens-type condensation using Benzyltriethylammonium Chloride (TEBA) as phase-transfer catalyst, and 50% Sodium Hydroxide as a base (eq 1).4a,5 trans-a,b-Epoxy p-tolyl sulfones, and a mixture of cis and trans isomers, are obtained from aldehydes and unsymmetrical ketones, respectively.

a,b-Epoxy p-tolyl sulfones can also be prepared by the epoxidation of a,b-unsaturated p-tolyl sulfones with alkaline Hydrogen Peroxide (giving trans-a,b-epoxy p-tolyl sulfones)6 and potassium chlorite (producing cis-a,b-epoxy p-tolyl sulfones).7

a,b-Epoxy p-tolyl sulfones undergo reactions similar to those of a,b-epoxy phenyl sulfones. Rearrangement with Boron Trifluoride Etherate gives the expected a-tolylsulfonyl substituted carbonyl products (eq 2).5b The reaction with sodium diethyl phosphite gives synthetically useful a-keto phosphonates (eq 3).8

Alkylation Reactions.

Alkylation of chloromethyl p-tolyl sulfone with alkyl halides can be effected either by using a phase-transfer catalyst or n-Butyllithium as a base (eqs 4 and 5).5a,9 p-Tolylsulfonylchloromethylmagnesium, prepared by the reaction with Ethylmagnesium Bromide, is stable and undergoes normal Grignard reactions, e.g., carbonylation and carbonyl addition reactions.10

Reaction of a-Alkylated Sulfones.

Racemic and optically active a-chloro-b-keto p-tolyl sulfones, prepared by oxidation of the corresponding sulfoxides, undergo Favorskii rearrangement to give a-alkyl amides. This process can be used to synthesize optically active a-alkyl amides by the asymmetric Favorskii rearrangement (eq 6).11 a-Chloro-a-alkyl-b-keto p-tolyl sulfones undergo metal-halogen exchange with n-butyllithium to give the corresponding enolates which can be protonated to give substituted a-p-tolylsulfonyl derivatives (eq 7).12

Vicarious Nucleophilic Aromatic Substitution of Hydrogen (VNS).

The chloromethyl p-tolyl sulfone carbanion behaves similarly to the corresponding phenyl analog in the vicarious nucleophilic substitution of hydrogen (VNS) with electrophilic arenes and heterocyclic arenes.2 The reaction with 1,4-dicyanonaphthalene gives both the VNS product and the corresponding bis(cyclopropane) derivative (eq 8).13 The reaction with 6-nitroquinoxaline gives the normal VNS product (eq 9),13 whereas the reaction with 6-azaquinoxaline gives either VNS and/or the corresponding bis(cyclopropane) products depending on temperature, the base used and its concentration (eq 10).14

Radical Reactions.

The a-p-tolylsulfonylmethyl radical, generated using either Tri-n-butylstannane, Azobisisobutyronitrile,15 or Hexabutyldistannane with UV irradiation,16 adds to enol ethers, enamines, and silyl enol ethers. The addition to enamines shows considerable syn diastereoselectivity which can be explained on the basis of an allylic 1,3-strain model (eq 11). When an alkenic or alkynic moiety is present in the a-substituent of the a-p-tolylsulfonylmethyl radical, cyclization can occur to give five-membered ring compounds (eqs 12 and 13).15b,17


1. (a) Magnus, P. D. T 1977, 33, 2019. (b) Durst, T. In Comprehensive Organic Chemistry; Barton, D. H. R., Ed.; Pergamon: Oxford, 1979; Vol. 3, p 171. (c) Krief, A. COS 1991, 3, 85. (d) Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon: Oxford, 1993.
2. (a) Makosza, M.; Winiarski, J. ACR 1987, 20, 282. (b) Makosza, M. S 1991, 103.
3. Cinquini, M.; Colonna, S. JCS(P1) 1972, 1883.
4. Vogt, P. F.; Tavares, D. F. CJC 1969, 47, 2875.
5. (a) Jonczyk, A.; Banko, K.; Makosza, M. JOC 1975, 40, 266. (b) Houwen-Claassen, A. A. M.; McFarland, J. W.; Lammerink, B. H. M.; Thijs, J.; Zwanenburg, B. S 1983, 628.
6. Zwanenburg, B.; Wiel, J. T. TL 1970, 935.
7. Curci, R.; DiFuria, F. TL 1974, 4085.
8. Koh, Y. J.; Oh, D. Y. TL 1993, 34, 2147.
9. Bőhme, H.; Stammberger, W. LA 1971, 754, 56.
10. Stetter, H.; Steinbeck, K. LA 1972, 766, 89.
11. (a) Satoh, T.; Oguro, K.; Shishikura, J.; Kanetaka, N.; Okada, R.; Yamakawa, K. TL 1992, 33, 1455. (b) Satoh, T.; Motohashi, S.; Kimura, S.; Tokutake, N.; Yamakawa, K. TL 1993, 34, 4823. (c) Satoh, T.; Oguro, K.; Shishikura, J.; Kanetaka, N.; Okada, R.; Yamakawa, K. BCJ 1993, 66, 2339.
12. Satoh, T.; Shishikura, J.; Hayashi, Y.; Yamakawa, K. CL 1992, 381.
13. Makosza, M.; Glinka, T.; Ostrowski, S.; Rykowski, A. CL 1987, 61.
14. Ostrowski, S.; Makosza, M. T 1988, 44, 1721.
15. (a) Renaud, P. TL 1990, 31, 4601. (b) Renaud, P.; Schubert, S. AG(E) 1990, 29, 433. (c) Schubert, S.; Renaud, P.; Carrupt, P.-A.; Schenk, K. HCA 1993, 76, 2473.
16. Harendza, M.; Junggebauer, J.; Lessmann, K.; Neumann, W. P.; Tews, H. SL 1993, 286.
17. Ueno, Y.; Khare, R. K.; Okawara, M. JCS(P1) 1983, 2637.

Vichai Reutrakul & Manat Pohmakotr

Mahidol University, Bangkok, Thailand



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