Chloromethyl Phenyl Sulfone1

[7205-98-3]  · C7H7ClO2S  · Chloromethyl Phenyl Sulfone  · (MW 190.65)

(synthesis of a,b-epoxy sulfones1 and aziridines;2 reacts with electrophilic arenes, heterocyclic arenes, and alkenes;3 source of the a-phenylsulfonylmethyl radical1a)

Physical Data: mp 52 °C.

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

Preparative Methods: several methods are available.4 The most convenient is the reaction of Sodium Benzenesulfinate dihydrate with bromochloromethane in dimethyl sulfoxide.4c

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

a,b-Epoxy Sulfones.

Epoxy sulfones are prepared by the reaction of the chloromethyl phenyl sulfone carbanion (PhSO2CHClM) with carbonyl compounds. The one-step Darzens-type condensation can be effected by using a phase transfer catalyst, benzyltriethylammonium chloride in 50% sodium hydroxide (eq 1).5 A less satisfactory two-step method involves the addition of a-lithiochloromethyl phenyl sulfone to carbonyl compounds at low temperature to give isolable b-hydroxy-a-chloro sulfones which are cyclized by Potassium Hydroxide in methanol (eq 2).5c,6 The phase-transfer catalyst method gives trans-epoxy sulfones from aldehydes and mixtures of isomers from unsymmetrical ketones. In the two-step method the stereochemistry of the epoxy sulfones is not always determined by the stereochemistry of the b-hydroxy-a-chloro sulfones.7 a,b-Epoxy sulfones can also be prepared by the epoxidation of a,b-unsaturated sulfones with alkaline Hydrogen Peroxide (giving trans-a,b-epoxy sulfones),8 potassium chlorite (producing cis-a,b-epoxy sulfones),9 1,1-Di-t-butyl Peroxide and alkyllithium (stereospecific),10 t-Butyl Hydroperoxide (nonstereospecific),10 and m-Chloroperbenzoic Acid.11

a,b-Epoxy sulfones undergo rearrangement-elimination either with Boron Trifluoride Etherate or thermally in a similar manner to a,b-epoxy sulfoxides. Normally, a-phenylsulfonyl carbonyl compounds or their mixture with the corresponding a,b-unsaturated carbonyl compounds are the final products (eq 3).5c,6

Reaction with a Lewis acid (i.e. Magnesium Bromide) gives good yields of the a-bromo carbonyl compounds (eq 4).5c,12

Ring opening of a,b-epoxy sulfones with Sodium Azide in DMF gives a-azido aldehydes which can be converted to a-azido nitriles by the Beckmann elimination (eq 5).13 One-carbon homologation of ketones to a-hydroxy aldehydes is effected by the reaction of the a,b-epoxy sulfones with hydroxide ion generated by adding water to Potassium t-Butoxide (eq 6).14 b-Keto phosphonates, valuable synthetic intermediates, are prepared by the reaction of a-substituted-a,b-epoxy sulfones with Diethyl Phosphonite (eq 7).15

The acidic a-hydrogen of a,b-epoxy sulfones can be removed with n-Butyllithium at -102 °C to give the a-lithio-a,b-epoxy sulfone carbanion which reacts with Chlorotrimethylsilane, aldehydes, ketones, and alkyl halides to give the corresponding adducts which can undergo further chemical transformations. This process demonstrates the equivalency of the a,b-epoxy sulfones to the acyl anion (eq 8).16

Addition to Imines.

N-Aryl(phenylsulfonyl)aziridines are prepared by the reactions of the a-lithiochloromethyl phenyl sulfone with diaryl imines. The aziridines and alkylated aziridines, formed by the alkylation of the a-lithio-N-aryl(phenylsulfonyl)aziridines, undergo [1,3]-dipolar cycloaddition with Dimethyl Acetylenedicarboxylate to give substituted pyrroles (eq 9).2b Bis(phenylsulfonyl)aziridine is formed by the reaction of the chloromethyl phenyl sulfone carbanion with quinazoline (eq 10);2a 1,5-, 1,6-, 1,7-, and 1,8-naphthyridines react similarly to give the corresponding phenylsulfonylaziridines.2a

Vicarious Nucleophilic Substitution of Hydrogen (VNS).

The chloromethyl phenyl sulfone carbanion undergoes vicarious nucleophilic substitution of hydrogen (VNS) in electrophilic arenes, heterocyclic arenes, and alkenes3 to give phenylsulfonylmethyl functionalized compounds. The most common starting aromatic compounds for this reaction are nitroarenes (eq 11).17 The reaction can be applied to ortho-, meta-, para- and polysubstituted nitroarenes. The VNS reaction with electrophilic arenes is complementary to the Friedel-Crafts reaction.3a

Electrophilic heterocyclic arenes (nitrothiophenes, 2-nitrofuran, N-protected nitropyrroles, N-protected nitroimidazoles, nitropyrazoles, nitropyridines, nitroquinolines, N-protected nitroindole, and 1,2,4-triazine)18 undergo the VNS reaction with the chloromethyl phenyl sulfone carbanion (e.g. eqs 12 and 13).3b,18 These reactions provide a convenient way to introduce the phenylsulfonylmethyl group into these compounds. Electrophilic alkenes with electron-withdrawing groups which can provide high stabilization of negative charge and b-substituents facilitating the abstraction of a geminal proton, can undergo the VNS reaction (eq 14).19 The principle of the VNS reaction has been applied in the synthesis of a precursor of aklavinone, an anthracycline antibiotic (eq 15).20

Radical Reaction.

The phenylsulfonylmethyl radical, generated by the reaction of chloromethyl phenyl sulfone with Tri-n-butylstannane and Azobisisobutyronitrile in refluxing benzene, adds diastereoselectively to enamines to give the syn adduct as the major product. The origin of the diastereoselectivity is explained on the basis of an allylic 1,3-strain model (eq 16).1d,21

a-Alkyl phenylsulfonylmethyl radicals, generated from the corresponding a-bromo- or a-chloroalkyl phenyl sulfones, undergo tandem radical cyclization to cyclopentane derivatives (eqs 17 and 18).22,23 The method provides a quick entry to these molecules.


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) Golinski, J.; Makosza, M.; Rykowski, A. TL 1983, 24, 3279. (b) Reutrakul, V.; Prapansiri, V.; Panyachotipun, C. TL 1984, 25, 1949.
3. (a) Makosza, M.; Winiarski, J. ACR 1987, 20, 282. (b) Makosza, M. S 1991, 103.
4. (a) Bordwell, F. G.; Pitt, M. B. JACS 1955, 77, 572. (b) Cinquini, M.; Colonna, S. JCS(P1) 1972, 1883. (c) Makosa, M.; Golinski, J.; Baran, J. JOC 1984, 49, 1488.
5. (a) Jonczyk, A.; Banko, K.; Makosza, M. JOC 1975, 40, 266. (b) Vogt, P. F.; Tavares, D. F. CJC 1969, 47, 2875. (c) Durst, T.; Tin, K.-C.; de Reinach-Hirtzbach, F.; Decesare, J. M.; Ryan, M. D. CJC 1979, 57, 258.
6. Durst, T.; Tin, K. C. TL 1970, 2369.
7. Grossert, J. S.; Sotheeswaran, S.; Dharmaratne, H. R. W.; Cameron, T. S. CJC 1988, 66, 2870.
8. Zwanenberg, B.; ter Weil, J. TL 1970, 935.
9. Curci, R.; DiFuria, F. TL 1974, 4085.
10. Meth-Cohn, O.; Moore, C.; Taljaard, H. C. JCS(P1) 1988, 2663.
11. Yamamoto, M.; Suzuki, K.; Tanaku, S.; Yamada, K. BCJ 1987, 60, 1523.
12. (a) de Reinach-Hirtzbach, F.; Durst, T. TL 1976, 3677. (b) Bégué, J.-P.; Bonnet-Delpon, D.; Charpentier-Morize, M.; Sansoulet, J. CJC 1982, 60, 2087.
13. Barone, A. D.; Snitman, D. L.; Watt, D. S. JOC 1978, 43, 2066.
14. Adamczyk, M.; Dolence, E. K.; Watt, D. S.; Christy, M. R.; Reibenspies, J. H.; Anderson, O. P. JOC 1984, 49, 1378.
15. Koh, Y. J.; Oh, D. Y.; TL 1993, 34, 2147.
16. (a) Ashwell, M.; Jackson, R. F. W. CC 1988, 645. (b) Hewkin, C. T.; Jackson, R. F. W. TL 1990, 31, 1877. (c) Ashwell, M.; Clegg, W.; Jackson, R. F. W. JCS(P1) 1991, 897. (d) Dunn, S. F. C.; Jackson, R. F. W. JCS(P1) 1992, 2863.
17. Golinski, J.; Makosza, M. TL 1978, 3495.
18. Makosza, M.; Golinski, J.; Rykowski, A. TL 1983, 24, 3277.
19. Makosza, M.; Kwast, A. T 1991, 47, 5001.
20. Murphy, R. A.; Cava, M. P. TL 1984, 25, 803.
21. Schubert, S.; Renaud, P.; Carrupt, P.-A.; Schenk, K. HCA 1993, 76, 2473.
22. Tsai, Y.-M.; Kee, B.-W.; Lin, C.-H. TL 1990, 31, 6047.
23. Reutrakul, V.; Poolsanong, C.; Pohmakotr, M. TL 1989, 30, 6913.

Vichai Reutrakul & Manat Pohmakotr

Mahidol University, Bangkok, Thailand



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