Chloromethyl sulfones from sulfonyl chlorides via a one-pot procedure

Article abstract of DOI:10.1081/SCC-120039498

A simplified one-pot transformation of a diverse set of aryl- and heteroaryl-sulfonyl chlorides into the corresponding chloromethyl sulfones is described.

Full text of DOI:10.1081/SCC-120039498

This article was downloaded by: [Pennsylvania State University]
On: 29 May 2012, At: 05:15
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T
3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Chloromethyl Sulfones from
Sulfonyl Chlorides via a
One‐Pot Procedure
Schuyler Antane a , Ronald Bernotas a , Yanfang Li
a , Robert McDevitt a & Yinfa Yan a
a Chemical and Screening Sciences, Wyeth
Research, CN 8000, Princeton, New Jersey,
08543‐8000, USA
Available online: 10 Jan 2011
To cite this article: Schuyler Antane, Ronald Bernotas, Yanfang Li, Robert
McDevitt & Yinfa Yan (2004): Chloromethyl Sulfones from Sulfonyl Chlorides via a
One‐Pot Procedure, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:13, 2443-2449
To link to this article: http://dx.doi.org/10.1081/SCC-120039498
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,

reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should
be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or
damages whatsoever or howsoever caused arising directly or indirectly in
connection with or arising out of the use of this material.

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 13, pp. 2443–2449, 2004
Chloromethyl Sulfones from Sulfonyl
Chlorides via a One-Pot Procedure
*
Schuyler Antane, Ronald Bernotas, Yanfang Li,
Robert McDevitt, and Yinfa Yan
Chemical and Screening Sciences, Wyeth Research
Princeton, New Jersey, USA
ABSTRACT
A simplified one-pot transformation of a diverse set of aryl- and hetero-
aryl-sulfonyl chlorides into the corresponding chloromethyl sulfones
is described.
Key Words: Chloromethyl sulfones; One-pot procedure; Sulfinate salts;
Sulfonyl chlorides.
INTRODUCTION
Chloromethyl sulfones have found use in the preparation of alkenes,[1]
aziridines,[2] and epoxides.[3] Makosza[4a–d] has utilized chloromethyl phenyl
*
Correspondence: Schuyler Antane, Chemicaland ScreeningSciences, Wyeth Research,
CN 8000, Princeton, NJ 08543-8000, USA; E-mail: antanes@wyeth.com.
2443
DOI: 10.1081/SCC-120039498
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2444
Antane et al.
sulfone (1, A ¼ Ph) and chloromethyl-p-tolyl sulfone (1, A ¼ p-CH3Ph) in
vicarious nucleophilic substitution (VNS) reactions with nitroarenes (2) to
afford VNS adducts (3). These adducts have been elaborated into both
3-sulfonyl-substituted indole derivatives (4: Z ¼ CH)[4c,d] and the analogous
indazoles (4: Z ¼ N)[4e] (Sch. 1). Our interest in preparing a diverse set of
3-aryl/heteroarylsulfonyl-indoles and -indazoles 4 via VNS chemistry led
us to investigate simplified methods of preparing a variety of aryl and hetero-
aryl chloromethyl sulfones (1).
Haloalkyl sulfones (e.g., 1) are useful for preventing aquatic organisms
from attaching to fishing nets and ship hulls,[5] in herbicide compositions,[6]
and as bactericidals,[7] antifungals,[7] algaecides,[8] and insecticides.[9]
Chloromethyl sulfones (1) have been prepared by alkylation of sulfinate
salts (6) with chloroform,[10] with bromochloromethane in the presence of
aliquat[11] or, alternatively, in the presence of tetra-alkylammonium or phos-
phonium halides.[12] While there are relatively few commercially available
sulfinate salts, such salts may readily be obtained from a sodium sulfite-
mediated reduction of the corresponding sulfonyl chlorides under aqueous
conditions.[13] In practice, this two-step procedure proved somewhat cumber-
some due to the sulfinate salts’ water solubility and hygroscopic nature, which
made their isolation difficult. In exploring possible improvements to this
two-step procedure, we have found that it was neither necessary nor desirable
to isolate intermediate sulfinate salts (6). The aqueous reaction mixture
containing the reduced sulfonyl chlorides could simply be treated with a
phase transfer catalyst (PTC) and an excess of bromochloromethane to
afford the desired chloromethylsulfones (Sch. 2). This PTC approach proved
to be operationally convenient while generally maintaining good yields
(60–80%). We have applied this method to a wide variety of sulfonyl chlor-
ides summarized in Table 1.
In addition, we have found that more than one sulfonyl group can be
present in the reactant. For example, 1,3-benzenedisulfonyl chloride was trea-
ted with two times the usual reagents to afford 1,3-bis-chloromethanesulfonyl-
benzene (7), albeit in a modest 20% yield.
In summary, we have found a one-pot approach to the synthesis of a
diverse group of chloromethyl sulfones from commercially available sulfonyl
chlorides. Beyond the numerous preventative uses mentioned above, we have

Chloromethyl Sulfones from Sulfonyl Chlorides
2445
Scheme 1.
used these intermediates to produce a variety 3-arylsulfonyl- and 3-heteroaryl-
sulfonyl indoles and -indazoles as intermediates for potential therapeutic
agents, which we will describe in due course.
EXPERIMENTAL
1H NMR spectra (400 MHz) were recorded in d6-DMSO using a Varian
Unity plus spectrometer. Mass spectra were recorded on a Finnigan Trace
MS or a Micromass LCT. Bromochloromethane, sodium sulfite, tetra-butyl-
ammonium bromide, and most aryl/heteroaryl sulfonyl chlorides (5) were
available from Aldrich. Other sulfonyl chlorides were obtained from Fluka
(5d), Maybridge (5f, 5g), Acros (5j), and Lancaster (5k).
General Procedure
A stirred mixture of sulfonyl chloride 5 (4.4 mmol), sodium sulfite
(1.03 g, 8.2 mmol), and sodium bicarbonate (0.726 g, 8.06 mol) in water
(5 mL) is heated at ca. 1008C for 1 hr. The crude sodium sulfinate solution
is allowed to cool for 30 min, and then treated with bromochloromethane
(5 mL, 76.9mmol) and tetra-N-butyl ammonium bromide (0.140g, 0.4 mmol).
The resultant mixture is heated at 758C overnight. All solvents are removed
in vacuo at 508C. The residue is diluted with dichloromethane (or ethyl acetate)
and filtered through a plug of silica gel to give the desired chloromethyl
Scheme 2.

2446
Antane et al.
Table 1. Preparation of chloromethyl sulfones 1.
Ar Yield of 1 (%)
ArSO2Cl
5a
5b
5c
5d
5e
5f
1-Naphthalene
2-Fluorobenzene
63
77
31
64
76
18
72
75
63
71
75
83
29
2-(Trifluoromethyl)-benzene
1-(8-Quinoline)
2-[5-Chloro-thiophene]
2-[5-Chloro-3-methyl-benzothiophene]
4-[2,1,3-benzothiadiazole]
4-Iodobenzene
5g
5h
5i
3,4-Dimethoxybenzene
4-Methanesulfonylbenzene
4-Bromo-2,5-difluoro-benzene
3-Trifluoromethylbenzene
2,4,6-Trimethylbenzene
5j
5k
5l
5m
sulfone of sufficient purity. In some cases, further purification by crystalliza-
tion (1j: methanol; 1m: hexanes) or by column chromatography (1f: hexanes/
ethyl acetate) was required.
Examples
1-[(Chloromethyl)sulfonyl]naphthalene (1a). M.p. 94–968C. 1H NMR
(d6-DMSO): 8.66 (1H, d, J ¼ 7.9 Hz), 8.43 (1H, d, J ¼ 8.2 Hz), 8.30 (1H, d,
J ¼ 7.3 Hz), 8.19 (1H, d, J ¼ 8.1 Hz), 7.73–7.83 (3H, m), 5.42 (2H, s). MS
(EI) m/z: 240/242 (Mþ.). Anal. calcd for C11H9ClO2: C, 54.89; H, 3.77.
Found: C, 54.48; H, 3.74.
Chloromethyl-2-fluorophenyl sulfone (1b). Oil. 1H NMR (d6-DMSO):
7.88–7.94 (2H, m), 7.52–7.60 (2H, m), 5.37 (2H, s). MS (EI) m/z: 208/210
(Mþ.). Anal. calcd for C7H6ClFO2S: C, 40.30; H, 2.90. Found: C, 40.24; H,
2.79.
Chloromethyl 2-(trifluoromethyl)phenyl sulfone (1c). M.p. 60–628C.
1H NMR (d6-DMSO): 8.25–8.28 (1H, m), 8.12–8.14 (1H, m), 8.03–8.06 (2H,
m), 5.33 (2H, s). MS (EI) m/z: 258/260 (Mþ.). Anal. calcd for
C8H6ClF3O2S: C, 37.15; H, 2.34. Found: C, 37.28; H, 2.11.
8-[(Chloromethyl)sulfonyl]quinoline (1d). M.p. 140–1428C. 1H NMR
(d6-DMSO): 9.13–9.14 (1H, m), 8.64 (1H, d, J ¼ 8.4 Hz), 8.47–8.50 (2H, m),
7.89 (1H, t, J ¼ 7.58 Hz), 7.78–7.81 (1H, m), 5.74 (2H, s). MS (EI) m/z: 242/
244 (M þ H). Anal. calcd for C10H8ClNO2S: C, 49.69; H, 3.34; N, 5.80.
Found: C, 49.32; H, 3.32; N, 5.69.

Chloromethyl Sulfones from Sulfonyl Chlorides
2447
2-Chloro-5-[(chloromethyl)sulfonyl]thiophene (1e). M.p. 83–858C.
1H NMR (d6-DMSO): 7.80 (1H, d, J ¼ 4.3 Hz), 7.46 (1H, d, J ¼ 4.1 Hz),
5.45 (2H, s). MS (EI) m/z: 230/232/234 (Mþ.). Anal. calcd for
C5H4Cl2OS2: C, 25.98; H, 1.74. Found: C, 26.33; H, 1.74.
5-Chloro-2-[(chloromethyl)sulfonyl]-3-methyl-l-benzothiophene (1f ).
M.p. 159–1618C. 1H NMR (d6-DMSO): 8.14–8.17 (2H, m), 7.62–
7.65 (1H, m), 5.41 (2H, s), 2.68 (3H, s). MS (EI) m/z: 294/296/298
(Mþ.). Anal. calcd for C10H8Cl2O2S2: C, 40.69; H, 2.73. Found: C, 40.76;
H, 2.56.
4-[(Chloromethyl)sulfonyl]-2,1, 3-benzothiadiazole (1g). M.p. 142–
1448C. 1H NMR (d6-DMSO): 8.58 (1H, d, J ¼ 8.8 Hz), 8.42 (1H, d,
J ¼ 7.2 Hz), 7.98–8.01 (1H, m), 5.56 (2H, s). MS (EI) m/z: 248/250 (Mþ.).
Anal. calcd for C7H5ClN2O2S2: C, 33.81; H, 2.03; N, 11.26. Found: C,
33.66; H, 1.94; N, 11.08.
1-Chloromethanesulfonyl-4-iodo-benzene (1h). M.p. 170–1728C.
1H NMR (d6-DMSO): 8.07 (2H, d, J ¼ 8.5 Hz), 7.65 (2H, d, J ¼ 8.7 Hz),
5.29 (2H, s). MS (EI) m/z: 316 (Mþ.). Anal. calcd for C7H6ClIO2S: C,
26.56; H, 1.91. Found: C, 26.55; H, 1.68.
4-Chloromethanesulfonyl-1,2-dimethoxy-benzene (1i). M.p. 96–988C.
1H NMR (d6-DMSO): 7.48 (1H, d, J ¼ 8.5 Hz), 7.36 (1H, s), 7.19 (1H, d, J ¼
8.7 Hz), 5.20 (2H, s), 3.84 (3H, s), 3.82 (3H, s). MS (EI) m/z: 250 (Mþ.). Anal.
calcd for C9H11ClO4S2: C, 43.12; H, 4.42. Found: C, 43.22; H, 4.52.
1-Chloromethanesulfonyl-4-methanesulfonyl-benzene (1j). M.p. 177–
1
1798C. H NMR (d6-DMSO): 8.17–8.24 (4H, dd, J ¼ 8.8, 17.4Hz), 5.43
(2H, s), 3.32 (3H, s). MS (ES) m/z: 266.9 ([M 2 H]2). Anal. calcd for
C8H9ClO4S2: C, 35.75; H, 3.38. Found: C, 35.83; H, 2.97.
1-Bromo-4-chloromethanesulfonyl-2,5-difluoro-benzene (1k). M.p. 50–
1
528C. H NMR (d6-DMSO): 8.16–8.20 (1H, m), 7.81–7.84 (1H, m), 5.40
(2H, s). MS (EI) m/z: 304 (Mþ.). Anal. calcd for C7H4BrClF2O2S: C, 27.52;
H, 1.32. Found: C, 27.86; H, 1.56.
1-Chloromethanesulfonyl-3-trifluoromethyl-benzene (1l). M.p. 66–
1
688C. H NMR (d6-DMSO): 8.25 (1H, s), 8.20 (2H, t, J ¼ 7.8 Hz), 8.03
(1H, t, J ¼ 7.7 Hz), 5.45 (2H, s). MS (EI) m/z: 258 (Mþ.). Anal. calcd for
C8H6ClF3O2S: C, 37.15; H, 2.34. Found: C, 37.31; H, 2.24.
2-Chloromethanesulfonyl-1, 3,5-trimethyl-benzene (1m). M.p. 89–918C.
1H NMR (d6-DMSO): 7.09 (2H, s), 5.12 (2H, s), 2.57 (6H, s), 2.26 (3H, s). MS
(EI) m/z: 232 (Mþ.). Anal. calcd for C10H13ClO2S: C, 51.61; H, 5.63. Found:
C, 51.63; H, 5.28.
1,3-bis-Chloromethanesulfonyl-benzene (7). M.p. 149–1518C. 1H NMR
(d6-DMSO): 8.38 (1H, s), 8.34 (2H, d, J ¼ 7.8 Hz), 8.03 (1H, t, J ¼ 7.9 Hz),
5.45 (4H, s). MS (ES) m/z: 300.9 ([M 2 H]2). Anal. calcd for C8H8BrCl2O4-
S2: C, 31.69; H, 2.66. Found: C, 32.07; H, 2.41.

2448
Antane et al.
ACKNOWLEDGMENT
Physical analysis was provided by Discovery Analytical Chemistry.
REFERENCES
1. (a) Lee, J.W.; Oh, D.Y. A convenient one-pot synthesis of a-functionalized
a,b-unsaturated sulfones. Synth. Commun. 1990, 20 (2), 273–277;
(b) Bordwell, F.G.; Cooper, G.D. The mechanism of formation of olefins
by the reaction of sodium hydroxide with a-halo sulfones. J. Am. Chem.
Soc. 1951, 73, 5184–5190.
2. Reutrakul, V.; Prapansiri, V.; Panyachotipun, C. A new method for the
synthesis of 2-phenylsulfonylaziridines via the reaction of a-halosulfonyl
carbanion with imines. Tetrahedron Lett. 1984, 25 (18), 1949–1952.
3. (a) Adamczyk, M.; Dolence, E.K.; Watt, D.S.; Christy, M.R.;
Reibenspies, J.H.; Anderson, O.P. A new procedure for the one-carbon
homologation of ketones to a-hydroxy aldehydes. J Org. Chem. 1984,
49 (8), 1378–1382; (b) Dolence, E.K.; Adamczyk, M.; Watt, D.S.;
Russell, G.B.; Horn, D.H.S. A stereoselective synthesis of 1,2-diols from
a-hydroxyaldehydes. Tetrahedron Lett. 1985, 26 (9), 1189–1192;
(c) Arai, S.; Ishida, T.; Shioiri, T. Asymmetric synthesis of a,b-epoxy sul-
fones under phase-transfer catalyzed Darzens reaction. Tetrahedron Lett.
1998, 39 (45), 8299–8302; (d) Nagashima, E.; Suzuki, K.; Ishikawa, M.;
Sekiya, M. Carbon–carbon bond forming reaction of bis(chloromethyl)
sulfone with carbonyl compounds: general route to aromatic 2-chlorovinyl
compounds and a-hydroxyaldehydes. Heterocycles 1985, 23 (8), 1873–
1879.
4. (a) Golinski, J.; Makosza, M. “Vicarious” nucleophilic substitution of
hydrogen in aromatic nitro compounds. Tetrahedron Lett. 1978, 37,
3495–3498; (b) Makosza, M.; Chylinska, B.; Mudryk, B. Reactions of
organic anions. 113. Vicarious nucleophilic substitution of hydrogen in
nitropyridines by a-chloroalkyl phenyl sulfone carbanions. Liebigs
Ann. Chem. 1984, 1, 8–14; (c) Wojciechowski, K.; Makosza, M. Reac-
tions of organic anions. 125. New synthesis of substituted indole deriva-
tives via vicarious nucleophilic substitution of hydrogen. Tetrahedron
Lett. 1984, 62, 4793–4794; (d) Wojciechowski, K.; Makosza, M. Reac-
tions of organic anions. Part 132. A facile synthesis of 3-sulfonyl-substi-
tuted indole derivatives. Synthesis 1986, (8), 651–653; (e) Takahashi, M.;
Suga, D. Synthesis of 2-aryl-3-(arylsulfonyl)indoles and 2-anilino-3-
(arylsulfonyl)indoles from 2-[(arylsulfonyl)methyl]anilines using the
aza-Wittig reaction of iminophosphoranes. Synthesis 1998, (7), 986–990.

Chloromethyl Sulfones from Sulfonyl Chlorides
2449
5. Oishi, Y.; Watanabe, T.; Kusa, K.; Kazama, M.; Koniya, K. Diphenyl-
amines and their Use as Pesticides Against Aquatic Organisms. JP
63,243,067, October 7, 1988.
6. Shigematsu, S.; Yamada, Y.; Kimura, I. Herbicidal Composition for Rice.
JP 58,128,305, July 30, 1983.
7. Becker, F.C.; Li, J.P. N-Substituted Maleimides in Liquid Concentrates.
US 4,247,559, January 27, 1981.
8. Mori, K.; Izawa, T.; Konya, K.; Yazawa, C. 4(Chloromethylsulfonyl)-
2,6-dinitrohalobenzenes. JP 54,090,145, July 17, 1979.
9. Eckstein, Z.; Zawistowska, M.; Palut, D.; Polubiec, E. Aromatic deriva-
tives of chloromethyl sulfones. Przem. Chem. 1966, 45 (6), 314–320.
10. Ejmocki, Z.; Krassowska, B.; Olczak, I.; Eckstein, Z. New chloromethyl-
sulfonyl substituted phenoxyacetic acid derivatives. Pol. J. Chem. 1980,
54 (11–12), 2153–2159.
11. Bram, G.; Loupy, A.; Roux-Schmitt, M.C.; Sansoulet, J.; Strzalko, T.;
Seyden-Penne, J. Organic syntheses without solvent: preparation of sul-
fones and dithioacetals. Synthesis 1987, (1), 56–59.
12. Nakayama, Y.; Takayama, M.; Yamaguchi, T.; Sekiya, S. Chloroalkyl
Phenyl Sulfones. JP 58,208,265, December 3, 1983.
13. Field, L.; Clark, R.D. Methyl p-tolyl sulfone. Org. Synth. 1958, 38,
62–65.
Received in the USA March 3, 2004