TETRAHEDRON

LETTERS
Pergamon Tetrahedron Letters 44 (2003) 6055–6058

InBr3-catalyzed sulfonation of indoles: a facile synthesis of

3-sulfonyl indoles
J. S. Yadav,* B. V. S. Reddy, A. D. Krishna and T. Swamy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Received 7 November 2002; revised 2 June 2003; accepted 13 June 2003

Abstract—Indoles react smoothly with sulfonyl chlorides in the presence of a catalytic amount of indium tribromide at ambient
temperature to afford the corresponding 3-arylsulfonyl indole derivatives in high yields with high regioselectivity.
© 2003 Elsevier Ltd. All rights reserved.

Aryl sulfones and sulfoxides are interesting functional reported.4 In view of the importance of indolyl aryl
groups possessing manifold reactivity for conversion to sulfones as non-nucleoside reverse transcriptase
a variety of organosulfur compounds in the field of inhibitors, a direct and one-pot approach for their
drugs and pharmaceuticals.1 In particular, aryl sulfones synthesis is needed. In recent years, indium halides have
have received much attention as powerful anti-HIV-1 evolved as mild and water-tolerant Lewis acids impart-
agents.2 Indol-3-yl and pyrrol-2-yl aryl sulfones are ing high regio-, stereo- and chemoselectivity in various
found to be highly potent and structurally novel non- organic transformations.5 Compared to conventional
nucleoside reverse transcriptase inhibitors (NNTRIs) Lewis acids, indium halides have advantages of water
for example L-737,126 and PAS.3,4 stability, recyclability and operational simplicity. Par-
ticularly, indium tribromide is found to be a more
effective catalyst than conventional Lewis acids in pro-
moting various transformations including glycosida-
tion, thioacetalization, cyanation of ketones and
conjugate addition reactions.6,7

In this letter we highlight our results on the elec-

trophilic sulfonylation of indoles with sulfonyl chlorides
Indolyl aryl sulfones are generally prepared by indirect using a catalytic amount of indium bromide. Thus
methods which involve the oxidation of indol-3-yl treatment of indole 1 (R=H) with phenylsulfonyl chlo-
sulfides to the corresponding sulfones.3 Alternative ride 2 (Ar=Ph) in the presence of 10% InBr3 in 1,2-
methods such as chlorosulfination and direct mesyla- dichloroethane afforded 3-phenylsulfonyl-1H-indole 3b
tion of more substituted indoles have also been in 87% yield (Scheme 1).

Scheme 1.

Keywords: indium reagents; sulfonylation; indoles; indolyl aryl sulfones.

* Corresponding author. Fax: 91-40-27160512; e-mail: yadav@iict.ap.nic.in

0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01507-7
6056 J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 6055–6058

Scheme 2.

Table 1. Indium tribromide-catalyzed sulfonation of indolesa

 J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 6055–6058 6057

A variety of indoles reacted smoothly with sulfonyl Schoktz, R. J.; Narayanan, V. L.; Clanton, D. J.; Pede-
chlorides under similar conditions to give the corre- monte, R.; Wassmundt, F. W.; Buckheit, R. W., Jr.;
sponding 3-arylsulfonyl indole derivatives in high Decker, W. D.; White, E. L.; Bader, J. P.; Boyd, M. R.
yields.8 In all cases, the reactions proceeded efficiently Antimicrob. Agents. Chemother. 1993, 37, 754–760.
in dichloroethane at reflux temperature with high 3. (a) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C.;
regioselectivity. No N-substituted products were Rooney, C. S.; Balani, S. K.; Condra, J. H.; Emini, E. A.;
observed under these reaction conditions. This is proba- Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.;
bly due to the stabilization of the imine–enamine com- O’Brien, J. A.; Sardana, V. V.; Schleif, W. A.; Theohar-
plex by the Lewis acid during sulfonylation as shown in rides, A. D.; Anderson, P. S. J. Med. Chem. 1993, 36,
Scheme 2. 1291; (b) Artico, M.; Silvestri, R.; Pagnozzi, E.; Bruno, B.;
Novellino, E.; Greco, G.; Massa, S.; Ettorre, A.; Loi, G.;
The nature of the substituents on the aromatic ring Scintu, F.; La Colla, P. J. Med. Chem. 2000, 43, 1886–
shows some effects on this conversion. Activated 1891.
indoles gave the products in excellent yields (see Table 4. (a) Unangst, P. C.; Connor, D. T.; Stabler, S. R. J.
1). However, the treatment of N-protected indoles such Heterocyclic Chem. 1987, 24, 817–820; (b) Shen, J.-K.;
as N-ethyl or N-methyl derivatives with p-toluene sul- Katayama, H. J. Chem. Soc., Perkin Trans. 1 1994, 1871–
fonyl chloride in dichloroethane at 75–80°C for 7–9 h 1877; (c) Shen, J.-K.; Katayama, H. Chem. Pharm. Bull.
afforded the corresponding 3-phenylsulfonyl indole 1992, 2879–2884; (d) Silvestri, R.; De Martino, G.;
derivatives in 65 and 70% yields, respectively. All prod- Sbardella, G. Org. Prep. Proced. Int. 2002, 34, 507–510.
ucts were characterized by 1H NMR, IR and mass 5. (a) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149; (c)
spectroscopy and also by comparision with authentic Babu, G.; Perumal, P. T. Aldrichim. Acta 2000, 33, 16; (b)
compounds.3,4 In contrast, metal triflates such as Ghosh, R. Indian J. Chem. 2001, 40B, 550–557.
In(OTf)3, Sc(OTf)3 and Yb(OTf)3 gave the products in 6. (a) Bandini, M.; Giorgio Cozzi, P.; Melchiorre, P.; Umani-
moderate yields (45–60%). The best results were Ronchi, A. Tetrahedron Lett. 2001, 42, 3041–3043; (b)
obtained when indium tribromide was used as the Ceschi, M. A.; Felix, L. A.; Peppe, C. Tetrahedron Lett.
catalyst. Similar yields and selectivity were also 2000, 41, 9695–9699; (c) Bandini, M.; Giorgio Cozzi, P.;
obtained with 10% ZrCl4 and 10% BiCl3 under similar Giocomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi,
conditions. However, in the absence of catalyst, the A. J. Org. Chem. 2002, 67, 3700–3704.
reaction of phenyl sulfonyl chloride and indole did not 7. (a) Yadav, J. S.; Reddy, B. V. S.; Raju, A. K.; Rao, C. V.
yield any product even after a long reaction time under Tetrahedron Lett. 2002, 43, 5437–5440; (b) Yadav, J. S.;
reflux. This method does not require any additives or Reddy, B. V. S. Synthesis 2002, 511–514.
anhydrous conditions and no precautions need to be 8. Experimental procedure: A mixture of indole (2 mmol),
taken to exclude moisture from the reaction media. The sulfonyl chloride (2.5 mmol) and InBr3 (10 mol%) in
solvents 1,2-dichloroethane and toluene were found to dichloroethane or toluene (10 mL) was stirred at reflux
give the best results. An acid chloride also reacted temperature for an appropriate time (Table 1). After com-
smoothly with 2-methyl indole to generate a 3-acyl plete conversion, as indicated by TLC, the reaction mix-
derivative under similar conditions (entry k). The scope ture was diluted with water (10 mL) and extracted with
of indium tribromide-catalyzed sulfonylation of indoles dichloromethane (2×10 mL). The combined organic layers
was investigated with respect to various indoles and were dried over anhydrous Na2SO4, concentrated in vacuo
sulfonyl chlorides and the results are presented in Table and the resulting product was purified by column chro-
1. matography on silica gel (Merck, 100–200 mesh, ethyl
acetate–hexane, 1:9) to afford pure indolyl aryl sulfone.
In summary, indium tribromide was found to be a Spectral data for selected products:
novel and highly efficient Lewis acid catalyst for the 3-(4-Methylphenylsulfonyl)-1H-indole (3a): 1H NMR (200
direct synthesis of 3-arylsulfonyl indole derivatives from MHz, CDCl3): l 2.20 (s, 3H), 6.78–6.85 (m, 4H), 6.97–7.10
indoles and aryl sulfonyl chlorides under mild reaction (m, 2H), 7.20–7.30 (m, 2H), 7.45 (d, 1H, J=8.0 Hz), 8.15
conditions. This method is also useful for the acylation (brs, NH). IR (KBr) w: 3325, 1579, 1445, 1380, 1296, 1226,
of indoles with acid halides. 1141, 1090, 751 cm−1. EIMS: m/z: 271 M+, 206, 195, 178,
130, 119, 82, 47. Anal. calcd for C15H13NO2S (271.33): C,
66.40; H, 4.83; N, 5.16; S, 11.82. Found: C, 66.51; H, 4.91;
Acknowledgements N, 5.23; S, 11.76. HRMS calcd for C15H13NO2S: 271.0667.
Found: 271.0673.
3-(4-Chlorophenylsulfonyl)-2-methyl-1H-indole (3e): 1H
B.V.S and T.S. thank CSIR, New Delhi for the award NMR (200 MHz, CDCl3): l 2.40 (s, 3H), 6.80–6.95 (m,
of fellowships. 2H), 7.05–7.25 (m, 5H), 7.50 (d, 1H, J=8.0 Hz), 8.05 (brs,
NH, 1H). (KBr) w: 3327, 1580, 1441, 1387, 1298, 1225,
1144, 1091, 757 cm−1. EIMS: m/z: 305 M+, 273, 207, 162,
References 147, 73, 55. Anal. calcd for C15H12ClNO2S (305.77): C,
58.92; H, 3.96; Cl, 11.59; N, 4.58; S, 10.48. Found: C,
1. (a) Holland, H. L. Chem. Rev. 1988, 88, 473–485; (b) 58.85; H, 3.88; Cl, 11.66; N, 4.67; S, 10.39. HRMS calcd
Block, E. Angew. Chem., Int. Ed. Engl. 1992, 31, 1135– for C15H12ClNO2S: 305.0277. Found: 305.0281.
1178. 5-Methoxy-3-(4-methylphenylsulfonyl)-1H-indole (3i): 1H
2. McMohan, J. B.; Gulakowsky, R. J.; Weislow, O. S.; NMR (200 MHz, CDCl3): l 2.38 (s, 3H), 3.80 (s, 3H), 6.80
6058 J. S. Yada6 et al. / Tetrahedron Letters 44 (2003) 6055–6058

(dd, 1H, J=1.8, 8.0 Hz), 6.90–6.98 (m, 4H), 7.05 (d, 1H, (200 MHz, CDCl3) l: 1.30 (s, 3H), 1.60 (s, 3H), 2.35 (dd,
J=8.0 Hz), 7.15 (d, 1H, J=8.0 Hz), 7.20 (d, 1H, J=8.0 1H, J=8.1, 8.5 Hz), 2.60 (s, 3H), 2.98 (d, 1H, J=8.1
Hz), 8.10 (brs, NH, 1H). IR (KBr) w: 3333, 1580, 1440, Hz), 7.20–7.35 (m, 4H), 7.85 (d, 1H, J=8.0 Hz), 8.65 (brs,
1389, 1299, 1227, 1149, 1097, 760 cm−1. FAB Mass: m/z: NH, 1H). IR (KBr) w: 3345, 3089, 1620, 1415, 1297, 1108,
301 M+, 275, 246, 185, 165, 123, 109, 91, 75, 41. Anal. 967, 770 cm−1. EIMS: m/z: 355 M+, 297, 262, 197,
calcd for C16H15NO3S (301.35): C, 63.77; H, 5.02; N, 4.65; 158, 130, 103, 77, 39. Anal. calcd for C18H17ClF3NO
S, 10.64. Found: C, 63.68; H, 5.11; N, 4.71; S, 10.71. (358.78): C, 60.77; H, 4.82; Cl, 9.96; F, 16.02; N, 3.94.
HRMS calcd for C16H15NO3S: 301.0772. Found: 301.0779. Found: C, 60.81; H, 4.87; Cl, 9.89; F, 16.19; N, 3.99.
3-(2-Chloro-3,3,3-trifluoro-(E)-1-propenyl)-2,2-dimethylcyclo- HRMS calcd for C18H17ClF3NO: 356.1029. Found:
propyl-2-methyl-1H-3-indolylmethanone (3k): 1H NMR 356.1025.