Lewis acid-mediated arylation of N-protected bromomethylindoles

Article abstract of DOI:10.1080/00397910802517863

Lewis acid-mediated arylation of N-protected 2/3-bromomethylindoles with different types of arenes is reported. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802517863

Synthetic Communications1, 39: 1241–1256, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802517863
Lewis Acid–Mediated Arylation of N-Protected
Bromomethylindoles
Vasudevan Dhayalan, Neelamegam Ramesh,
and Arasambattu K. Mohanakrishnan
Department of Organic Chemistry, University of Madras,
Guindy Campus, Chennai, India
Abstract: Lewis acid–mediated arylation of N-protected 2=3-bromomethylin-
doles with different types of arenes is reported.
Keywords: Arene, arylation, bromomethylindole, Friedel–Crafts reaction
INTRODUCTION
Over the years, a plethora of substituted indole derivatives have been
synthesized for their medicinal activity. During the past 20 years, a variety
of indole derivatives have been explored as potential antitubulin agents.[1]
In particular, 1-aroyl, 2-aroyl, and 3-aroylindoles have proved to be
novel classes of potent tubulin-inhibitory, antimitotic agents.[2] Recen-
tly, 3-arylthioindole analogs also been explored as tubulin polymerase
inhibitors.[3] Hence, syntheses of different types of substituted indole
derivatives are necessitated to unravel their medicinal activity.
RESULTS AND DISCUSSION
In continuation of our work on studies related to the synthetic elaboration
of bromomethylindoles,[4] we required different types of arylmethylindoles.
Received July 19, 2008.
Address correspondence to Arasambattu K. Mohanakrishnan, Department of
Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025,
India. E-mail: mohan_67@hotmail.com
1241

1242
V. Dhayalan, N. Ramesh, and A. K. Mohanakrishnan
Scheme 1. PdCl2–CuCl2-catalyzed arylation of 1a.
Over the years, a large number of arylation protocols have been developed
for a benzylic system using different types of Pd catalyst.[5] Alternatively,
Lewis acid-mediated arylation of benzylalcohol=benzylacetate to synthesize
a variety of benzylic systems has also been explored.[6] Recently, Knochel
and coworkers reported a copper-mediated arylation of a benzylic system
using in situ generated organometallic reagents.[7] Nevertheless, these recent
developments are yet to be adapted to the arylation of indolylmethylbro-
mides. In particular, the promising antitubulin activity of various types of
aroylindoles prompted us to develop a viable procedure for the synthesis
of various types of 2=3-benzylindole analogs. It should be noted that once
different types of benzylindoles are in hand, their transformation into the
required aroylindoles can be achieved using a published procedure.[8]
Srinivasan and Rajeswaran reported[9] arylation of bromomethylin-
dole 1a with electron-rich arenes using PdCl2 in acetonitrile at reflux in
the presence of CuCl2 to afford the arylated products 2a,b in moderate
yields (Scheme 1).
Because, Lewis acid–mediated arylation of benzyl alcohols is well
established, we thought the arylation of bromo compound 1a could be
carried out in the absence of Pd catalyst. Accordingly, when bromo com-
pound 1a was refluxed with electron-rich arene, anisole, or veratrole in
the presence of 1 eq. of anhydrous cupric chloride using K2CO3 as base
in acetonitrile at reflux, products 2a or 2b formed in 53 and 64% yields,
respectively. Using anhydrous CuCl2, the arylation of bromomethylin-
doles 1a could be carried out with unactivated arenes, namely benzene,
to afford product 2c in 44% yield (Scheme 2). It should be mentioned that
the yield of the arylation products 2a,b isolated using anhydrous CuCl2
alone was found to better than with the expensive PdCl2–CuCl2 system.
Instead of CuCl2, anhydrous ZnBr2 also effectively catalyzed a
smooth arylation of bromo compound 1a with different types of arenes
as well as heteroarenes in acetonitrile at reflux to afford the products
in 2a-k in 40–70% yields (Scheme 3). The results are presented in Table 1.

Arylation of N-Protected Bromomethylindoles
1243
Scheme 2. CuCl2-catalyzed arylation of bromomethylindoles with arenas.
The results of various arylation products 2a-k obtained using anhy-
drous ZnBr2 are presented in Table 1. The ZnBr2-mediated arylation of
1a could be performed with mono-, di-, and trisubstituted arenes using
K2CO3 as a base in dry acetonitrile at reflux. With the exception of
1,4-dimethoxybenzene (entry 3), in all other cases only the mono-
arylation products were isolated. Hetero-arylation of 1a was performed
with indole or thiophene to afford the respective products 2j or 2k in
low yields (entries 5, 6).
Next, the ZnBr2-mediated veratrylation of different types of bromo-
methylindoles 3a–g could be carried out using K2CO3 as base in
1,2-dimethoxyethane (DME) at reflux to afford the respective products
4a–g in 52–73% yields. The type of bromo compounds employed and
the resulting arylated products isolated along with their yields are pre-
sented in Table 2. The veratrylation could be smoothly performed with
2-bromomethyl 3a–d as well as 3-bromomethyindoles 3f,g in acceptable
yields. The presence of an electron-withdrawing ester unit at the indole-
3-position significantly reduced the yield of arylation product 4a (entry
1). However, when the ester unit was connected through a vinyl spacer,
the arylation yield was found to be the maximum (entry 2). The bis-ver-
atrylation of 2,3-dibromethylindole 3e could be achieved in 58% yield
(entry 5). In comparison to the isomeric bromo compound 3a, the vera-
trylation of 2-carbethoxy-3-bromomethylindole 3g furnished the respec-
tive arylated product 4g in relatively better yields (entry 7).
Scheme 3. ZuBr2-catalyzed arylation of 1a with arenas and heteroarenes.

1244
V. Dhayalan, N. Ramesh, and A. K. Mohanakrishnan
Table 1. ZnBr2-catalyzed arylation of 1a with arenas and heteroarenes
Entry
1
ArH
Time
Arylated product
Yield (%)a
11 h
6 h
24 h
12 h
15 h
10 h
58
70
41
50
56
57
2
17 h
58
3
8 h
60
4
13 h
48
5
12 h
42
(Continued )

Arylation of N-Protected Bromomethylindoles
Table 1. Continued
1245
Entry
6
ArH
Time
9 h
Arylated product
Yield (%)a
40
aIsolated yield after column chromatography.
Finally, the ZnBr2-mediated arylation of bromomethylindole 1a with
veratrole was carried out using six different types of Lewis acids
(Scheme 4), and the results obtained are presented in Table 3. Among
the various types of Lewis acids employed for veratrylation of 1a, the
maximum 76% yield of arylated product 2b could be obtained using
20 mol% of InBr3 in dry DME at reflux for 5 h. The yield of 2b obtained
was almost comparable with 1 eq. of ZnBr2 as well as 20 mol% InBr3.
Even though the veratylation could be performed with other Lewis acids
such as CuCl2, NiBr2, FeCl3, and Sc(OTf)3, the yield of the arylated pro-
duct 2b obtained was found to be somewhat less. Additionally, these
Lewis acids also required longer reaction period (13–20 h) for completion
of the veratrylation reaction (entries 3–6).
In conclusion, we have synthesized a wide variety of 2=3-benzylindole
via ZnBr2-mediated arylation of the respective indolylmethyl bromides.
The arylation procedure developed herein is simple, clean, and economic-
ally viable for the synthesis of various types of arylmethylindoles. Further
work on transformation of benzylindoles into the corresponding aroyl
indoles and the exploration of their antitubulin activity is in progress.
EXPERIMENTAL
All melting points were uncorrected. Reagents were purchased from com-
mercial sources and used as received without purification. Solvents were
dried by standard procedures. Column chromatography was carried out
on silica gel (grade 60, mesh size 230–400, Merck). IR spectra were
recorded on a Shimadzu Fourier transform infrared (FT-IR) 8300 instru-
1
ment. H and 13C NMR spectra were recorded in CDCl3 using tetra-
methylsilane (TMS) as an internal standard on a Jeol GSX 400 and
Bruker-300 spectrometers. Chemical shift values were quoted in parts
per million (ppm) and coupling constants were quoted in hertz (Hz).

1246
V. Dhayalan, N. Ramesh, and A. K. Mohanakrishnan
Table 2. ZnBr2-catalyzed arylation of bromomethylidnoles 3a–g with veratrole
Entry Bromomethylindoles Time
Arylated product
Yield (%)a
1
20 h
52
2
10 h
73
3
7 h
67
4
5
15 h
70
58
8 h
6
12 h
73
(Continued )

Arylation of N-Protected Bromomethylindoles
1247
Table 2. Continued
Entry Bromomethylindoles Time
Arylated product
Yield (%)a
68
7
6 h
aIsolated yield after column chromatography.
Chemical shift multiplicities were reported as s ¼ singlet, d ¼ doublet,
t ¼ triplet, q ¼ quartet, and m ¼ multiplet. Mass spectra were recorded
on a Jeol DX 303 HF spectrometer. Elemental analyses were carried
out on Perkin-Elmer series II 2400 (IIT Madras) equipment.
General Procedure for Arylation of Bromomethylindole 1a Using CuCl2
CuCl2 (1.09 mmol), K2CO3 (2.18 mmol), and arene (2.18 mmol) were
added to a solution of substrate 1a (1.09 mmol) in dry acetonitrile
(20 mL), The reaction mixture was then refluxed for 20 h under an N2
atmosphere. It was then poured over ice water (30 mL) containing 1 mL
of conc. HCl, extracted with CHCl3 (3 ꢀ 10 mL), and dried (Na2SO4).
Removal of solvent followed by column chromatographic purification
(hexane–EA; 95:5) afforded the arylation product.
General Procedure for Arylation of Bromomethylindole 1a Using ZnBr2
ZnBr2 (1.09 mmol), K2CO3 (2.18 mmol), and arene (2.18 mmol) were
added to a solution of substrate 1a (1.09 mmol) in dry acetonitrile
Scheme 4. Lewis acid–catalyzed arylation of 1a with veratrole.

1248
V. Dhayalan, N. Ramesh, and A. K. Mohanakrishnan
Table 3. Lewis acid–catalyzed arylation of 1a with veratrole
Entry
Lewisacid
Time
Yield of 2a (%)a
1
2
3
4
5
6
20 mol% InBr3
1eq. ZnBr2
1eq. CuCl2
1eq. FeCl3
1eq. NiBr2
1eq. Sc(OTf)3
5 h
6 h
20 h
17 h
24 h
13 h
76
70
64
55
42
50
aIsolated yield after column chromatography.
(20 mL). The reaction mixture was then refluxed for specified time (refer
to Table 1) under an N2 atmosphere. It was then poured over ice
water (30 mL) containing 1 mL of conc. HCl, extracted with CHCl3
(3 ꢀ 10 mL), and dried (Na2SO4). Removal of solvent followed by
column chromatographic purification (hexane–EA; 95:5) afforded the
arylation product.
General Procedure for Arylation of Bromo Compounds
3a–g Using ZnBr2
ZnBr2 (1.09 mmol), K2CO3 (2.18 mmol), arene (2.18 mmol) were added
to a solution of substrate 3a–g (1.09 mmol) in dry DME (20 mL). The
reaction mixture was then refluxed for specified time (refer to Table 2)
under an N2 atmosphere. It was then poured over ice water (30 mL)
containing 1 mL of conc. HCl, extracted with CHCl3 (3 ꢀ
10 mL), and dried (Na2SO4). Removal of solvent followed by column
chromatographic purification (hexane–EA; 94:6) afforded the arylation
product.
1-Phenylsulfonyl-2-(4-methoxybenzyl)-3-(phenylthio)-1H-indole (2a)
1
Yield: 0.30 g (58%). Mp: 114–115 ꢁC (lit.[9] 117ꢁC). H NMR (400 MHz,
CDCl3): d 3.74 (s, 3H, ꢂOCH3), 4.65 (s, 2H, ꢂCH2), 6.69 (d, J ¼ 8.4 Hz,
2H, Ar-H), 6.96 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.05–7.12 (m, 5H, Ar-H),
7.20–7.24 (m, 3H, Ar-H), 7.33–7.47 (m, 5H, Ar-H), 8.19 (d, J ¼ 8.4 Hz,
1H, Ar-H). 13C NMR (100 MHz, CDCl3): d 31.28, 55.26, 112.32,
113.76, 115.11, 120.03, 124.19, 125.27, 125.45, 126.48, 126.63, 128.79,
128.91, 129.75, 130.10, 130.50, 133.54, 136.21, 136.70, 138.43, 144.76,
158.22.

Arylation of N-Protected Bromomethylindoles
1249
1-Phenylsulfonyl-2-(3, 4-dimethoxybenzyl)-3-(phenylthio)-1H-indole (2b)
Yield: 0.39 g (70%). Mp:171–172 ꢁC (lit.[9] 173–174ꢁC). 1H NMR
(300 MHz, CDCl3): d 3.62 (s, 3H, ꢂOCH3), 3.85 (s, 3H, ꢂOCH3), 4.70
(s, 2H, ꢂCH2), 6.69 (d, J ¼ 8.1 Hz, 2H, Ar-H), 6.77 (d, J ¼ 8.2 Hz, 1H,
Ar-H), 7.01 (d, J ¼ 6.9 Hz, 2H, Ar-H), 7.09–7.18 (m, 3H, Ar-H), 7.22–
7.28 (m, 3H, Ar-H), 7.35–7.51 (m, 5H, Ar-H), 8.25 (d, J ¼ 8.4 Hz, 1H,
Ar-H). 13C NMR (75 MHz, CDCl3): d 31.68, 55.67, 55.98, 111.21,
112.13, 112.35, 115.20, 120.13, 121.05, 124.25, 125.37, 125.51, 126.44,
128.88, 128.95, 130.49, 130.55, 133.59, 136.24, 136.78, 138.51, 144.57,
147.68, 148.84.
1-Phenylsulfonyl-2-benzyl-3-(phenylthio)-1H-indole (2c)
Yield: 0.20g (41%). Mp: 120–122 ꢁC. 1H NMR (300 MHz, CDCl3): d 4.78
(s, 2H, ꢂCH2), 7.02 (d, J ¼ 6.6 Hz, 2H, Ar-H), 7.12–7.30 (m, 11H, Ar-H),
7.37–7.46 (m, 4H, Ar-H), 7.51 (t, J ¼ 7.8 Hz, 1H, Ar-H), 8.25 (d, J ¼ 8.4 Hz,
Hz, 1H, Ar-H). 13C NMR (75 MHz, CDCl3): d 32.23, 112.76, 115.15,
120.11, 124.25, 125.35, 125.55, 126.38, 126.55, 126.61, 128.40, 128.77,
128.94, 128.99, 129.49, 130.54, 133.64, 136.18, 136.72, 138.09, 138.40,
144.25. Mass (m=z) %: 455 (Mþ, 45%). Anal. calcd. for C27H21NO2S2: C,
71.18; H, 4.65; N, 3.07%. Found: C, 71.01; H, 4.89; N, 3.27%.
1-Phenylsulfonyl-2-(3,4-dimethylbenzyl)-3-(phenylthio)-1H-indole (2d)
1
Yield: 0.26 g (50%). Mp: 96–98 ꢁC. H NMR (300 MHz, CDCl3): d 2.23
(s, 3H, ꢂCH3), 2.43 (s, 3H, ꢂCH3), 4.61 (s, 2H, ꢂCH2), 6.26 (d,
J ¼ 7.8 Hz, 1H, Ar-H), 6.52 (d, J ¼ 7.8 Hz, 1H, Ar-H), 6.98–7.01 (m,
2H, Ar-H), 7.01–7.28 (m, 7H, Ar-H), 7.34–7.46 (m, 4H, Ar-H), 7.49 (d,
J ¼ 7.2 Hz, 1H, Ar-H), 8.27 (d, J ¼ 7.8 Hz, 1H, Ar-H). 13C NMR (75
MHz, CDCl3): d 19.78, 20.86, 28.83, 114.97, 119.99, 124.09, 125.22,
125.46, 126.47, 126.58. 126.64, 127.19, 128.76, 128.86, 128.89, 130.37,
130.94, 133.32, 133.43, 135.53, 135.81, 136.29, 136.81, 138.55, 144.02.
Mass (m=z) %: 483 (Mþ, 52%). Anal. calcd. for C29H25NO2S2: C,
72.02; H, 5.21; N, 2.90%. Found: C, 72.22; H, 5.50; N, 2.65%.
1-Phenylsulfonyl-2-(2,4-dimethylbenzyl)-3-(phenylthio)-1H-indole (2e)
1
Yield: 0.29 g (56%). Mp: 102 ꢁC. H NMR (300 MHz, CDCl3): d 2.14 (s,
3H, ꢂCH3), 2.34 (s, 3H, ꢂCH3), 4.53 (s, 2H, ꢂCH2), 6.17 (d, J ¼ 7.8 Hz,

1250
V. Dhayalan, N. Ramesh, and A. K. Mohanakrishnan
1H, Ar-H), 6.43 (d, J ¼ 7.8 Hz, 1H, Ar-H), 6.90–7.11 (m, 8H, Ar-H), 7.17
(d, J ¼ 7.58 Hz, 1H, Ar-H), 7.25–7.34 (m, 4H, Ar-H), 7.41 (d, J ¼ 7.5 Hz,
1H, Ar-H), 8.19 (d, J ¼ 8.4 Hz, 1H, Ar-H). 13C NMR (75 MHz, CDCl3):
d 19.82, 20.89, 28.86, 112.87, 115.00, 120.03, 124.12, 125.26, 125.49,
126.51, 126.61, 126.66, 127.21, 128.89, 128.93, 130.39, 130.98, 133.36,
133.47, 135.56, 135.84, 136.31, 136.84, 138.56, 144.06. Mass (m=z) %:
483 (Mþ, 65%). Anal. calcd. for C29H25NO2S2: C, 72.02; H, 5.21; N,
2.90%. Found: C, 72.27; H, 5.01; N, 2.63%.
1-Phenylsulfonyl-2-(2,4-dimethoxybenzyl)-3-(phenylthio)-1H-indole (2f)
Yield: 0.32 g (57%). Mp: 138–140 ꢁC. 1H NMR (400 MHz, CDCl3): d 3.73
(s, 3H, ꢂOCH3), 3.83 (s, 3H, ꢂOCH3), 4.61 (s, 2H, ꢂCH2), 6.11 (d,
J ¼ 4.8 Hz, 1H, Ar-H), 6.44 (d, J ¼ 6.3 Hz, 2H, Ar-H), 6.95 (d, J ¼ 5.4 Hz,
Hz, 2H, Ar-H), 7.04–7.09 (m, 3H, Ar-H), 7.24–7.29 (m, 3H, Ar-H), 7.36
(t, J ¼ 5.7 Hz, 1H, Ar-H), 7.43–7.48 (m, 2H, Ar-H), 7.57 (d, J ¼ 5.7 Hz,
2H, Ar-H), 8.28 (d, J ¼ 6.3 Hz, 1H, Ar-H). 13C NMR (100 MHz, CDCl3):
d 25.86, 55.24, 55.46, 98.38, 103.73, 113.00, 115.08, 119.22, 119.86,
124.05, 125.08, 125.30, 126.48, 126.57, 128.74, 128.99, 130.53, 133.54,
136.32, 136.88, 138.53, 144.06, 157.72, 159.31. Mass (m=z) %: 515 (Mþ,
31%). Anal. calcd. for C29H25NO4S2: C, 67.55; H, 4.89; N, 2.72%. Found:
C, 67.31; H, 4.59; N, 2.50%.
1-Phenylsulfonyl-2-(2,5-dimethylbenzyl)-3-(phenylthio)-1H-indole (2g)
Yield: 0.30 g (58%). Mp: 154–155 ꢁC. 1H NMR (300 MHz, CDCl3): d 1.89
(s, 3H, ꢂCH3), 2.50 (s, 3H, ꢂCH3), 4.70 (s, 2H, ꢂCH2), 6.13 (s, 1H, Ar-
H), 6.88 (d, J ¼ 7.5 Hz, 1H, Ar-H), 7.00–7.23 (m, 8H, Ar-H), 7.32–7.46
(m, 5H, Ar-H), 7.60 (d, J ¼ 7.8 Hz, 1H, Ar-H), 8.38 (d, J ¼ 8.4 Hz, 1H,
Ar-H). 13C NMR (75 MHz, CDCl3): d 20.02, 21.43, 29.59, 113.36,
115.54, 120.61, 124.65, 125.83, 126.09, 127.17, 127.29, 127.44, 128.55,
129.35, 129.48, 130.64, 130.94, 133.60, 134.11, 135.74, 136.63, 136.95,
137.33, 139.01, 144.44. Mass (m=z) %: 483 (Mþ, 49%). Anal. calcd. for
C29H25NO2S2: C, 72.02; H, 5.21; N, 2.90%. Found: C, 72.24; H, 5.40;
N, 2.60%.
2,5-Bis[(1-phenylsulfonyl-3-phenylthioindol-2-yl)methyl]-1,4-
dimethoxybenzene (2h)
Yield: 0.29 g (60%). Mp: 244–248 ꢁC. 1H NMR (300 MHz, CDCl3): d 3.30
(s, 6H, ꢂOCH3), 4.62 (s, 4H, ꢂCH2), 5.97 (s, 2H, Ar-H), 7.00–7.11 (m,

Arylation of N-Protected Bromomethylindoles
1251
10H, Ar-H), 7.22–7.25 (m, 6H, Ar-H), 7.38–7.46 (m, 10H, Ar-H), 8.31 (d,
J ¼ 7.8 Hz, 2H, Ar-H). 13C NMR (75 MHz, CDCl3): d 26.34, 55.90,
111.70, 113.16, 115.15, 120.00, 124.12, 125.04, 125.27, 125.48, 126.53,
126.57, 128.90, 130.41, 133.66, 136.30, 136.90, 138.32, 143.48, 150.71.
Mass (m=z) %: 892 (Mþ, 32%). Anal. calcd. for C50H40N2O6S4: C,
67.24; H, 4.51; N, 3.14%. Found: C, 67.06; H, 4.74; N, 3.39%.
1-Phenylsulfonyl-2-(2,4,6-trimethylbenzyl)-3-(phenylthio)-1H-indole (2i)
1
Yield: 0.26 g (48%). Mp: 122 ꢁC. H NMR (300 MHz, CDCl3): d 1.92 (s,
6H, ꢂCH3), 2.16 (s, 3H, ꢂCH3), 4.50 (s, 2H, ꢂCH2), 6.58 (s, 2H, Ar-H),
6.69–6.72 (m, 2H, Ar-H), 7.01 (d, J ¼ 4.5 Hz, 3H, Ar-H), 7.21 (t,
J ¼ 6.9 Hz, 1H, Ar-H), 7.33–7.40 (m, 4H, Ar-H), 7.54 (t, J ¼ 6.6 Hz,
1H, Ar-H), 7.65–7.68 (m, 2H, Ar-H), 8.34 (d, J ¼ 6.6 Hz, 1H, Ar-H).
13C NMR (75 MHz, CDCl3): d 20.53, 20.80, 28.79, 111.72, 115.16,
119.84, 124.17, 124.90, 125.25, 126.08, 126.45, 128.46, 128.96, 129.23,
131.27, 131.35, 133.78, 135.79, 136.86, 136.98, 137.22, 139.03, 143.76.
Mass (m=z) %: 497 (Mþ, 38%). Anal. calcd. for C30H27NO2S2: C,
72.40; H, 5.47; N, 2.81%. Found: C, 72.24; H, 5.69; N, 2.99%.
1-Phenylsulfonyl-2-((1H-indol-3-yl)methyl)-3-(phenylthio)-1H-indole (2j)
Yield: 0.22g (42%). Mp: 162–164 ꢁC. 1H NMR (300 MHz, CDCl3): d 4.86
(s, 2H, ꢂCH2), 6.66 (s, 1H, Ar-H), 7.03–7.30 (m, 10H, Ar-H), 7.36–7.52 (m,
6H, Ar-H), 7.76 (d, J ¼ 7.8 Hz, 2H, Ar-H), 8.29 (d, J ¼ 7.5 Hz 1H, Ar-H).
13C NMR (75 MHz, CDCl3): d 110.94, 112.95, 115.32, 119.21, 119.56,
120.04, 122.05, 123.09, 124.24, 125.24, 125.48, 126.27, 126.63, 127.09,
128.71, 128.91, 129.14, 130.71, 133.42, 136.02, 136.42, 137.05, 138.44,
145.06. Mass (m=z) %: 494 (Mþ, 42%). Anal. calcd. for C29H22N2O2S2:
C, 70.42; H, 4.48; N, 5.66%. Found: C, 70.65; H, 4.19; N, 5.50%.
1-Phenylsulfonyl-3-(phenylthio)-2-((thiophen-2-yl)methyl)-1H-indole (2k)
1
Yield: 0.20 g (40%). Mp: 128 ꢁC. H NMR (300 MHz, CDCl3): d 4.89
(s, 2H, ꢂCH2), 6.82 (d, J ¼ 4.5 Hz, 2H, Ar-H), 6.97 (d, J ¼ 6.9 Hz, 2H,
Ar-H), 7.07–7.13 (m, 4H, Ar-H), 7.15–7.36 (m, 4H, Ar-H), 7.41–7.49
(m, 4H, Ar-H), 8.17 (d, J ¼ 8.4 Hz, 1H, Ar-H). 13C NMR (75 MHz,
CDCl3): d 27.14, 112.34, 115.12, 120.24, 124.27, 125.48, 125.55, 126.09,
126.51, 126.61, 126.71, 128.92, 129.05, 130.35, 133.71, 135.91, 136.59,
138.40, 140.94, 143.76. Mass (m=z) %: 461 (Mþ, 71%). Anal. calcd.

1252
V. Dhayalan, N. Ramesh, and A. K. Mohanakrishnan
for C25H19NO2S3: C, 65.05; H, 4.15; N, 3.03%. Found: C, 65.25; H,
4.43; N, 3.27%.
Ethyl-1-phenylsulfonyl-2(3,4-dimethoxybenzyl)-1H-indole-3-
carboxylate (4a)
Yield: 0.29 g (52%). Mp: 134–136 ꢁC. IR (KBr): 1701 (CO2Et), 1379 &
1
1189 (SO2Ph) cmꢂ1. H NMR (300 MHz, CDCl3): d 1.40 (t, J ¼ 7.2 Hz,
Hz, 3H, ꢂCH3), 3.75 (s, 3H, ꢂOCH3), 3.84 (s, 3H, ꢂOCH3), 4.41 (q,
J ¼ 7.2 Hz, 2H, ꢂOCH2), 5.00 (s, 2H, ꢂCH2), 6.70 (s, 2H, Ar-H),
6.77 (s, 1H, Ar-H), 7.26 (t, J ¼ 3.6 Hz, 2H, Ar-H), 7.35–7.38 (m, 2H,
Ar-H), 7.46–7.49 (m, 3H, Ar-H), 8.16–8.19 (m, 1H, Ar-H), 8.21–8.24
(m, 1H, Ar-H). 13C NMR (75 MHz, CDCl3): d 14.35, 31.20, 55.80,
55.95, 60.64, 111.18, 112.28, 113.21, 114.67, 120.70, 122.04, 124.45,
125.17 126.52, 127.27, 128.97, 130.32, 133.80, 136.05, 138.51, 146.58,
147.57, 148.78, 164.60. Mass (m=z) %: 479 (Mþ, 39%). Anal. calcd.
for C26H25NO6S: C, 65.12; H, 5.25; N, 2.92%. Found: C, 65.35; H,
5.01; N, 2.68%.
(E)-Methyl-1-phenylsulfonyl-3-(2-(3,4-dimethoxybenzyl)-1H-indol-3-
yl)acrylate (4b)
1
Yield: 0.41 g (73%). Mp: 138 ꢁC. H NMR (300 MHz, CDCl3): d 3.71 (s,
3H, ꢂCOOCH3), 3.78 (s, 3H, ꢂOCH3), 3.82 (s, 3H, ꢂOCH3), 4.60 (s, 2H,
ꢂCH2), 6.56–6.68 (m, 4H, Ar-H), 7.20 (t, J ¼ 8.1 Hz, 2H, Ar-H), 7.36–
7.42 (m, 5H, Ar-H), 7.84 (d, J ¼ 6.9 Hz, 1H, Ar-H), 7.91 (d, J ¼ 15.9 Hz,
Hz, 1H, vinylic-CH), 8.25 (d, J ¼ 8.1 Hz, 1H, Ar-H). 13C NMR (75 MHz,
CDCl3): d 30.82, 51.72, 55.79, 55.97, 111.34, 111.94, 115.15, 117.51,
119.15, 120.13, 120.52, 124.40, 125.27, 126.46, 127.26, 128.94, 130.06,
133.71, 135.67, 136.81, 138.47, 141.57, 147.81, 148.99, 167.53. Mass
(m=z) %: 491 (Mþ, 45%). Anal. calcd. for C27H25NO6S: C, 65.97; H,
5.13; N, 2.85%. Found: C, 65.79; H, 5.39; N, 2.62%.
1-Phenylsulfonyl-2-(3,4-dimethoxybenzyl)-3-methyl-1H-indole (4c)
Yield: 0.38 g (67%). Mp: 108–110 ꢁC. 1H NMR (300 MHz, CDCl3): d 2.23
(s, 3H, ꢂCH3), 3.72 (s, 3H, ꢂOCH3), 3.83 (s, 3H, ꢂOCH3), 4.39 (s, 2H,
ꢂCH2), 6.65 (t, J ¼ 8.4 Hz, 3H, Ar-H), 7.18 (t, J ¼ 7.8 Hz, 2H, Ar-H),
7.25–7.32 (m, 3H, Ar-H), 7.37–7.47 (m, 3H, Ar-H), 8.20 (d, J ¼ 6.9 Hz,
1H, Ar-H). 13C NMR (75 MHz, CDCl3): d 9.20, 30.83, 55.77, 55.97,

Arylation of N-Protected Bromomethylindoles
1253
111.22, 111.83, 115.04, 118.15, 118.66, 120.34, 123.41, 124.51, 128.70,
131.04, 131.23, 133.12, 134.96, 136.56, 138.95, 147.52, 148.87. Mass
(m=z) %: 421 (Mþ, 66%). Anal. calcd. for C24H23NO4S: C, 68.39; H,
5.50; N, 3.32%. Found: C, 68.55; H, 5.28; N, 3.50%.
1-Phenylsulfonyl-3-bromo-2-(3,4-dimethoxybenzyl)-1H-indole (4d)
1
Yield 0.39 g (70%). Mp: 102 ꢁC. H NMR (300 MHz, CDCl3): d 3.73 (s,
3H, ꢂOCH3), 3.84 (s, 3H, ꢂOCH3), 4.51 (s, 2H, –CH2), 6.68–6.76 (m,
3H, Ar-H), 7.19 (t, J ¼ 7.5 Hz, 2H, Ar-H), 7.30–7.42 (m, 5H, Ar-H),
7.49–7.52 (m, 1H, Ar-H), 8.18 (d, J ¼ 7.2 Hz, 1H, Ar-H). 13C NMR (75
MHz, CDCl3): d 31.92, 55.79, 55.98, 103.54, 111.26, 112.10, 115.04,
119.65, 120.81, 124.26, 125.69, 126.41, 128.87, 128.90, 129.94, 133.56,
135.91, 136.88, 138.37, 147.78, 148.91. Mass (m=z) %: 485 (Mþ, 33%),
487 (Mþ þ 2, 37%). Anal. calcd. for C23H20BrNO4S: C, 56.80; H, 4.14;
N, 2.88%. Found: C, 56.55; H, 4.38; N, 2.67%.
1-Phenylsulfonyl-2,3-bis(3,4-dimethoxybenzyl)-1H-indole (4e)
1
Yield 0.36 g (58%). Mp: 70–72 ꢁC. H NMR (300 MHz, CDCl3): d 3.62
(s, 3H, ꢂOCH3), 3.63 (s, 3H, ꢂOCH3), 3.80 (s, 3H, ꢂOCH3), 3.81 (s,
3H, ꢂOCH3), 4.01 (s, 2H, ꢂCH2), 4.44 (s, 2H, ꢂCH2), 6.54–6.67 (m,
6H, Ar-H), 7.17–7.20 (m, 3H, Ar-H), 7.23–7.35 (m, 2H, Ar-H), 7.37–
7.45 (m, 3H, Ar-H), 8.23 (d, J ¼ 8.4 Hz, 1H, Ar-H). 13C NMR (75
MHz, CDCl3): d 29.73, 30.98, 55.69, 55.91, 111.17, 111.59, 111.83,
115.21, 119.41, 120.06, 120.51, 121.25, 123.60, 124.59, 126.26, 128.74,
130.53, 131.06, 131.66, 133.22, 136.02, 136.09, 138.88, 147.52, 148.55.
Mass (m=z) %: 557 (Mþ, 51%). Anal. calcd. for C32H31NO6S: C, 68.92;
H, 5.60; N, 2.51%. Found: C, 68.73; H, 5.32; N, 2.75%.
1-Phenylsulfonyl-2-bromo-3-(3,4-dimethoxybenzyl)-1H-indole (4f)
1
Yield: 0.41 g (73%). Mp: 105 ꢁC. H NMR (300 MHz, CDCl3): d 3.71 (s,
3H, ꢂOCH3), 3.82 (s, 3H, ꢂOCH3), 3.96 (s, 2H, ꢂCH2), 6.57–6.71 (m,
3H, Ar-H), 7.19 (t, J ¼ 7.8 Hz, 1H, Ar-H), 7.28–7.35 (m, 2H, Ar-H),
7.42 (t, J ¼ 7.8 Hz, 2H, Ar-H), 7.56 (t, J ¼ 7.5 Hz, 1H, Ar-H), 7.87 (d,
J ¼ 7.8 Hz, 2H, Ar-H), 8.31 (d, J ¼ 8.4 Hz, 1H, Ar-H). 13C NMR (75
MHz, CDCl3): d 30.94, 55.77, 55.89, 109.98, 111.24, 111.54, 115.61,
119.09, 120.10, 124.07, 124.94, 125.17, 127.02, 129.08, 129.79, 130.73,
133.96, 137.78, 138.14, 147.64, 148.99. Mass (m=z) %: 485 (Mþ, 45%),

1254
V. Dhayalan, N. Ramesh, and A. K. Mohanakrishnan
487 (Mþ þ 2, 48%). Anal. calcd. for C23H20BrNO4S: C, 56.80; H, 4.14; N,
2.88%. Found: C, 56.98; H, 4.35; N, 2.64%.
Ethyl-1-phenylsulfonyl-3-(3,4-dimethoxybenzyl)-1H-indole-2-
carboxylate (4g)
Yield: 0.38 g (68%). Mp: 114–116 ꢁC. IR (KBr): 1716 (CO2Et), 1372 &
1
1190 (SO2Ph) cmꢂ1. H NMR (300 MHz, CDCl3): d 1.40 (t, J ¼ 7.2 Hz,
3H, ꢂCH3), 3.77 (s, 3H, ꢂOCH3), 3.81 (s, 3H, ꢂOCH3), 4.04 (s, 2H,
-CH2), 4.46 (q, J ¼ 7.2 Hz, 2H, ꢂOCH2), 6.70 (s, 2H, Ar-H), 6.80 (s,
1H, Ar-H), 7.16 (t, J ¼ 7.8 Hz, 1H, Ar-H), 7.33–7.39 (m, 4H, Ar-H),
7.48 (t, J ¼ 7.2 Hz, 1H, Ar-H), 7.87 (d, J ¼ 7.8 Hz, 2H, Ar-H), 8.01 (d,
J ¼ 8.4 Hz, 1H, Ar-H). 13C NMR (75 MHz, CDCl3): d 14.11, 30.12,
55.83, 55.88, 62.29, 111.17, 111.94, 115.54, 120.50, 121.07, 124.28,
126.83, 127.12, 127.85, 128.82, 128.95, 129.88, 131.08, 133.79, 137.13,
137.32, 147.66, 148.99, 162.57. Mass (m=z) %: 479 (Mþ, 48%). Anal.
calcd. for C26H25NO6S: C, 65.12; H, 5.25; N, 2.92%. Found: C, 65.31;
H, 5.48; N, 2.65%.
ACKNOWLEDGMENTS
We thank the University Grants Commission, New Delhi (32-194=
2006=(SR)), for the financial support. The authors thank Department
of Science and Technology-Fund for Improvement of Science and Tech-
nology (DST-FIST) for use of the 300-MHz NMR facility.
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