An efficient, mild, and selective Ullmann-type N-arylation of indoles catalyzed by copper(I) complex

Article abstract of DOI:10.1016/j.tet.2009.03.061

A wide range of N-arylated indoles are selectively synthesized through intermolecular C(aryl)-N bond formation from the corresponding aryl iodides and indoles through Ullmann-type coupling reactions in the presence of a catalytic amount of easily availabl

Full text of DOI:10.1016/j.tet.2009.03.061

Tetrahedron 65 (2009) 4619–4624
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An efficient, mild, and selective Ullmann-type N-arylation of indoles
catalyzed by copper(I) complex
*
R. Koteshwar Rao, Ajay B. Naidu, E.A. Jaseer, Govindasamy Sekar
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600 036, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide range of N-arylated indoles are selectively synthesized through intermolecular C(aryl)–N bond
formation from the corresponding aryl iodides and indoles through Ullmann-type coupling reactions in
the presence of a catalytic amount of easily available N,N,N0,N0-tetramethyl-BINAM–CuI complex under
very mild reaction conditions.
Received 23 December 2008
Received in revised form 16 March 2009
Accepted 23 March 2009
Available online 27 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalyst
Coupling reaction
C–N bond formation
BINAM ligand
Ullmann coupling
1. Introduction
However, this advance in the field of Ullmann coupling is not
sufficient as most of the reactions still require longer reaction time,
Nitrogen containing heterocycles are found in numerous natural
products and biologically active pharmaceutical products. Particu-
larly, N-arylated indole motifs are very important molecules as they
exhibit nanomolar affinity for a1-adrenoceptors in addition to their
affinities for dopamine D2 and serotonin 5-HT2A receptors.1 Also,
N-arylated indoles are prevalent in compounds that are materials of
interest.2 The palladium-catalyzed N-arylation of indoles from the
corresponding aryl halides and indoles used to be the method of
choice.3 However, the high cost of palladium salts, high oxophilicity
high reaction temperature (more than 100 ꢀC), and in some cases
high catalytic loading. Therefore a mild, economic, and efficient
catalytic system is still desirable for this process.
As a part of our ongoing research toward copper-catalyzed
oxidation chemistry,10 very recently we reported 1,10-binaphthyl-
2,20-diamine (BINAM)–Cu(OTf)2 as an efficient catalyst for the
synthesis of diaryl ethers and aryl alkyl ethers via Ullmann-type
coupling.11 In this direction, for the first time we report our initial
finding regarding N,N,N0,N0-tetramethyl-BINAM–copper complex
catalyzed Ullmann type of coupling of indoles with aryl iodides
under very mild reaction conditions.
associated with phosphine ligands, C-3 arylation through
p-com-
plex formation, and tedious multistep processes involved in the
synthesis of these phosphine ligands have rendered Pd unpopular,
particularly for large scale reactions. Copper-catalyzed Ullmann
coupling between an aryl halide and indole is the alternate method
for palladium-catalyzed N-arylation of indole.4 However, copper-
catalyzed Ullmann reaction also suffers from several limitations
such as high reaction temperatures (often 150 ꢀC or as high as
200 ꢀC), use of stoichiometric amounts of copper reagents, mod-
erate yields, and poor substrate generality. In fact, only some of the
efforts taken to improve the efficiency of this reaction started to
bear fruit(s) with the use of copper salts with several ligands such
as racemic trans-1,2-cyclohexyldiamine,5 1,10-phenanthroline,6
2. Results and discussion
In preliminary studies, we used 20 mol % 1,10-binaphthyl-2,20-
diamine (BINAM) L1 (Fig. 1) as ligand with 20 mol % of CuI for the
coupling of iodobenzene with indole in toluene at 110 ꢀC. After 24 h
the coupling reaction provided 89% isolated yield for the corre-
sponding N-arylated indole and not even trace amount of C-arylated
product was isolated (Table 1, entry 1). When the BINAM L1 was
replaced with N,N0-dibenzyl-BINAM L2, the yield for the coupling
reaction was reduced to 61% (entry 2). Usage of N,N0-dimethyl-
BINAM L3 as ligand with CuI further reduced the yield to 21% (entry
3). Surprisingly, when N,N,N0,N0-tetramethyl-BINAM L4 was used as
ligand along with CuI it provided quantitative isolated yield for
diimine ligands,7 -proline,8 and N-hydroxyimides.9
L
* Corresponding author. Tel.: þ91 44 2257 4229; fax: þ91 44 2257 4202.
E-mail address: gsekar@iitm.ac.in (G. Sekar).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.061

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R.K. Rao et al. / Tetrahedron 65 (2009) 4619–4624
Table 2
N
N
Effect of solvents, ratio of catalyst and bases
N
N
NR1R2
NR1R2
I
L5
L6
L4-CuI
+
H
N
Cs2CO3 (2 equiv.)
solvent
N
Ph
N
H
N
H
N
N
L1: R1 = R2 = H
L2: R1 = H; R2 = Bn
L3: R1 = H; R2 = Me
L4: R1 = R2 = Me
Yielda (%)
L7
L8
Entry
L4
CuI
Solvent
Temp
Time (h)
1
2
3
4
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
5 mol %
10 mol %
10 mol %
20 mol %
10 mol %
10 mol %
10 mol %
d
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
20 mol %
5 mol %
5 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
d
Toluene
DMF
CH3CN
DMSO
THF
Benzene
Dioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
110 ꢀ
C
24
15
18
24
48
72
72
36
30
26
30
48
26
26
36
48
99
96
99
86
67
76
46
87
71
99
82
62
99
97
30
00
110 ꢀC
Figure 1. Ligands for Cu-catalyzed N-arylation of indoles.
82 ꢀ
C
110 ꢀC
5b
6b
7
90 ꢀ
90 ꢀ
C
C
arylated indole through C–N bond formation and the reaction took
24 h for completion at 110 ꢀC (entry 4). When L4 was replaced with
other commercially available nitrogen based ligands such as DBU
(L5), DBN (L6), N,N,N0,N0-tetramethyl ethylenediamine (TMEDA, L7),
and (ꢁ)-sparteine (L8), the isolated yield for the N-arylation of in-
dole reduced by 11–28%. Then the reaction was further screened
with different copper salts along with ligand L4 to reduce the re-
action temperature and reaction time. From the screening of copper
salts we found out CuI to be the best choice in view of reaction time
and yields. The other copper salts took relatively longer reaction
time and poor yields of N-arylated indoles.
The reaction was screened with various solvents and different
bases to increase the efficiency of the coupling reactions and the
results are summarized in Table 2. The reaction was taking place in
several solvents and acetonitrile turned out to be the best among
those examined. In acetonitrile the reaction took place at 82 ꢀC and
the reaction time was reduced to 18 h and it provided quantitative
amount of isolated yield for N-arylated indole (entry 3). Further, the
reaction was carried out with different ratios of ligand L4 and CuI
complex and it was found that 10 mol % ligand–copper combina-
tion also works efficiently to produce quantitative yield of N-ary-
lated indole at 82 ꢀC by taking slightly more time (entry 3 vs 10).
Replacement of expensive and strong base Cs2CO3 by K2CO3 also
gave identical results and low cost of K2CO3 made us to choose it for
this coupling reaction (entry 10 vs 13).
110 ꢀC
8
9
82 ꢀ
82 ꢀ
82 ꢀ
82 ꢀ
82 ꢀ
82 ꢀ
82 ꢀ
82 ꢀ
82 ꢀ
C
C
C
C
C
C
C
C
C
10
11
12c
13d
14e
15
16
d
a
Isolated yield.
Reactions were carried out in pressure tube.
Na2CO3 was used as base.
K2CO3 was used as base.
K3PO4 was used as base.
b
c
d
e
iodobenzene containing electron releasing groups as well as elec-
tron withdrawing groups reacted with indoles to give corre-
sponding N-arylated indoles. Yields were different with electron
rich and electron deficient indoles and iodobenzenes.
Presence of electron releasing groups such as methyl and
methoxy groups on aryl iodide at para and meta position decreased
the yield of the coupling reaction by 10–25% and the reaction took
longer time for completion (entry 1 vs 7–9), where as an electron
withdrawing groups such as keto group and nitro groups on
iodobenzene increased reaction rate and yield for the N-arylation
reaction (entry 5 vs 15 and 1 vs 13). It is very important to mention
that under the reaction condition, the acid and base sensitive ester
functional group remains intact (entries 3, 12, and 14). Bromo-
benzene did not provide any N-arylated indole in the presence of
CuI-tetramethyl-BINAM complex under the optimized conditions.
It is very important to mention that the reaction is very selective to
give only N-arylated product and in none of these cases C-arylation
of indole was observed.
Using the above-mentioned optimized conditions, we initiated
our investigations into the scope of the L4–CuI catalyzed Ullmann-
type coupling reaction and the results are summarized in Table 3.
Various aryl iodides and indoles reacted to give the corresponding
N-arylated indoles under mild reaction conditions. We found that
Table 1
Effect of different ligands and copper salts in N-arylation of indole
I
ligand-Cu salt
(20 mol%)
+
3. Conclusion
Cs2CO3 (2 equiv.)
toluene, 110 °C
N
Ph
N
H
In summary, we have developed an efficient, very mild, experi-
mentally simple, and economically attractive copper-catalyzed
N-arylation of indoles with aryl iodides. Presence of electron releasing
groups in aryl iodide decreases reaction rate and the yield of the cou-
pling reaction whereas presence of an electron withdrawing group
increases reaction rate and yield of the N-arylation reaction. The opti-
mized reaction condition is highly selective to give only N-arylated
indoles as in none of these cases C-arylated product was isolated.
Entry
Ligand
Cu salt
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L4
L4
L4
L4
L4
L4
L4
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
24
40
40
24
30
30
28
48
40
72
40
72
72
72
72
89
61
21
99
83
88
71
78
46
52
19
58
67
66
60
9
CuBr
CuCl
4. Experimental
4.1. General
10
11
12
13
14
15
Cu(OTf)2
Cu(OAc)2$H2O
CuCl2$2H20
Cu(BF4)2$xH2O
CuSO4
All reactions were carried out in reaction tubes under nitrogen
atmosphere. Ligands L2, L3, and L4 were made using literature
procedure.12 Copper(I) iodide was purchased from Aldrich
a
Isolated yield.

R.K. Rao et al. / Tetrahedron 65 (2009) 4619–4624
4621
Table 3
Ullmann coupling of aryl iodide with indoles in the presence of L4–CuI catalyst at 82 ꢀC
Entry
Aryl iodides
Indoles
Product
Time (h)
26
Yielda (%)
99
1
I
N
Ph
N
H
2
3
36
30
72
65
I
I
N
Ph
N
H
O
O
3
3
O
O
N
Ph
N
H
Br
Br
4
5
36
36
34
66
I
I
N
Ph
N
H
O
O
N
Ph
N
H
O
O
6
48
38
I
N
Ph
N
H
7
8
36
36
76
76
I
N
N
H
O
I
N
H
O
N
O
O
9
40
90
N
N
H
I
O
10
11
28
36
94
60
O
I
N
H
N
N
I
N
H
O
3
I
O
N
12
48
82
3
O
O
N
H
O
O
(continued on next page)

4622
R.K. Rao et al. / Tetrahedron 65 (2009) 4619–4624
Table 3 (continued )
Entry
Aryl iodides
Indoles
Product
Time (h)
20
Yielda (%)
I
13
14
15
95
N
N
H
O2N
O2N
Br
O
Br
I
I
24
18
93
98
O
O
N
H
O
N
O
N
O
H
N
N
Br
I
I
O
16
17
72
72
65
97
N
Br
O
O
H
O
O
N
N
H
O
a
Isolated yield.
Chemical Company. Potassium carbonate and indoles were pur-
chased from Spectrochem India Private Limited and used without
further purification. All other reagents are commercially available
and used without further purification. Acetonitrile was purchased
from SRL Chemicals, India and dried over CaH2. Reaction temper-
atures were controlled by Varivolt temperature modulator. Thin-
layer chromatography (TLC) was performed using Merck silica gel
60 F254 precoated plates (0.25 mm) and visualized by UV fluores-
cence quenching on UV analysis cabinet, Deep Vision. Silica gel
(particle size 100–200 mesh) purchased from SRL India was used
for chromatography. 1H and 13C NMR spectra were recorded on
a Bruker 400 MHz instrument, Department of Chemistry, IIT Ma-
690 cmꢁ1; 1H NMR (400 MHz, CDCl3)
7.29 (m, 2H), 7.38–7.42 (m, 2H), 7.54–7.57 (m, 4H), 7.62 (d, J¼8 Hz,
1H), 7.73–7.75 (m, 1H); 13C NMR (100 MHz, CDCl3)
103.7, 110.6,
120.5, 121.3, 122.5, 124.5, 126.6, 128.1, 129.5, 129.7, 136.0, 139.9; MS
(EI, m/z) 194 [MH]þ; HRMS [MH]þ calculated for C14H12N 194.0970,
found 194.0974.
d
6.74 (d, J¼3.6 Hz, 1H), 7.20–
d
4.3. 9-Phenyl-2,3,4,9-tetrahydro-1H-carbazole
(Table 3, entry 2)13
Colorless liquid; Rf 0.60 (1:19 ethyl acetate/hexanes); FTIR (neat)
3055, 2923, 2856, 1597, 1494, 1449, 744, 696 cmꢁ1 1H NMR
;
dras. 1H NMR spectra were reported relative to Me4Si (
residual CHCl3
7.26 ppm). 13C NMR were reported relative to
CDCl3 ( 77.16 ppm). FTIR spectra were recorded on a Nicolet 6700
d 0.0 ppm) or
(400 MHz, CDCl3)
7.00–7.01 (m, 2H), 7.09–7.14 (m, 1H), 7.23–7.27 (m, 3H), 7.35–7.45
(m, 3H); 13C NMR (100 MHz, CDCl3)
21.3, 23.3, 23.4, 23.6, 110.0,
d 1.78 (m, 4H), 2.49 (br s, 2H), 2.70 (br s, 2H),
(
d
d
d
spectrometer, Department of Chemistry, IIT Madras and are
reported in frequency of absorption (cmꢁ1). High resolution mass
spectra (HRMS) were recorded on Q-Tof Micro mass spectrometer,
Department of Chemistry, IIT Madras.
111.1, 117.9, 119.7, 121.4, 127.1, 127.4, 127.9, 129.4, 135.9, 137.4, 138.2.
4.4. Methyl 4-(1-phenyl-1H-indol-3-yl)-butanoate
(Table 3, entry 3)
Colorless liquid; Rf 0.58 (1:9 ethyl acetate/hexanes); FTIR (neat)
4.2. Typical experimental procedure (Table 3, entry 1)
3051, 2924, 2852, 1732, 1599, 1499, 1451, 1219, 738, 694 cmꢁ1 1H
;
N,N,N0,N0-Tetramethyl-BINAM L4 (17 mg, 0.05 mmol), CuI
(9.5 mg, 0.05 mmol), indole (58.6 mg, 0.5 mmol), and K2CO3
(138.2 mg, 1 mmol) were taken in a 10 mL reaction tube equipped
with a septum. The reaction tube was evacuated and back-filled
with nitrogen. Acetonitrile (2.2 mL) was added to the reaction
mixture at room temperature. To the resulting solution was added
iodobenzene (153 mg, 0.75 mmol), and then the reaction tube was
sealed with glass stopper and the reaction mixture was heated for
26 h at 82 ꢀC. The reaction mixture was allowed to cool to room
temperature and the solvent was evaporated. The crude residue
was directly purified by column chromatography on silica gel using
ethyl acetate/hexanes as the eluent to afford 1-phenyl-indole7
95.2 mg, 99% (Table 3, entry 1). Colorless oil; Rf 0.63 (1:20 ethyl
acetate/hexanes); FTIR (neat): 3052, 2922, 1593, 1502, 1451, 736,
NMR (400 MHz, CDCl3)
d
1.98–2.05 (m, 2H), 2.35 (t, J¼7.4 Hz, 2H),
2.78 (t, J¼7.4 Hz, 2H), 3.58 (s, 3H), 7.07–7.16 (m, 3H), 7.23–7.25 (m,
1H), 7.38–7.44 (m, 4H), 7.47 (d, J¼8.0 Hz, 1H), 7.56 (d, J¼7.6 Hz, 1H);
13C NMR (100 MHz, CDCl3)
d 24.6, 25.4, 33.9, 51.5, 110.6, 116.9, 119.4,
120.0, 122.6, 124.3, 125.4, 126.2, 129.1, 129.7, 136.4, 140.1, 174.2; MS
(EI, m/z) 294 [MH]þ; HRMS [MH]þ calculated for C19H20NO2
294.1494, found 294.1492.
4.5. 5-Bromo-1-phenyl-1H-indole (Table 3, entry 4)14
Colorless liquid; Rf 0.76 (1:9 ethyl acetate/hexanes); FTIR (neat)
3057, 2923, 1593, 1501, 1448, 788, 751, 705 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
6.53 (t, J¼2.4 Hz, 1H), 7.16–7.51 (m, 8H), 7.72 (s,
1H); 13C NMR (100 MHz, CDCl3)
d
103.1, 112.1, 113.7, 123.7, 124.5,

R.K. Rao et al. / Tetrahedron 65 (2009) 4619–4624
4623
125.3,127.0,129.2,129.9,131.1,134.8,139.5; MS (EI, m/z) 272 [MH]þ;
J¼3.6 Hz, 1H), 7.07–7.17 (m, 2H), 7.24 (d, J¼3.2 Hz, 1H), 7.47 (d,
J¼8.4 Hz, 2H), 7.52 (d, J¼8.0 Hz, 1H), 7.58 (d, J¼7.6 Hz, 1H), 7.98 (d,
HRMS [MH]þ calculated for C14H11NBr 272.0075, found 272.0080.
J¼8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 26.6, 105.2, 110.7, 121.2,
4.6. 5-Methoxy-1-phenyl-1H-indole (Table 3, entry 5)15
121.5, 123.0, 123.4, 127.4, 130.0, 130.1, 134.8, 135.6, 143.9, 196.7; MS
(EI, m/z) 236 [MH]þ; HRMS [MH]þ calculated for C16H14NO
236.1075, found 236.1067.
Colorless liquid; Rf 0.78 (1:9 ethyl acetate/hexanes); FTIR (neat)
2931, 2835, 1594, 1487, 1463, 1444, 1254, 1151, 799, 754, 705 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
(dd, J¼2.4, 8.8 Hz, 1H), 7.20 (d, J¼2.4 Hz, 1H), 7.35–7.38 (m, 2H),
7.51–7.54 (m, 5H); 13C NMR (100 MHz, CDCl3)
56.0, 102.9, 103.4,
d
3.92 (s, 3H), 6.66 (d, J¼2.8 Hz, 1H), 6.94
4.12. 1-(3,5-Dimethylphenyl)-1H-indole (Table 3, entry 11)18
d
Colorless liquid; Rf 0.50 (hexanes); FTIR (neat) 3046, 2921, 2854,
111.5, 112.6, 124.2, 126.4, 128.5, 129.7, 130.0, 131.2, 140.1, 154.7; MS
(EI, m/z) 224 [MH]þ; HRMS [MH]þ calculated for C15H14NO
224.1075, found 224.1072.
1599, 1467, 1208, 732, 705 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.28
(s, 6H), 6.55 (d, J¼3.2 Hz, 1H), 6.88 (s, 1H), 7.01–7.11 (m, 4H), 7.20 (d,
J¼3.2 Hz, 1H), 7.46 (d, J¼8.4 Hz, 1H), 7.57 (d, J¼7.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 21.5, 103.3, 110.8,120.3, 121.2, 122.2, 122.3, 128.1,
4.7. 1-(1-Phenyl-1H-indol-3-yl)-ethanone (Table 3, entry 6)15
128.2, 129.4, 136.0, 139.5, 139.8; MS (EI, m/z) 222 [MH]þ; HRMS
[MH]þ calculated for C16H16N 222.1283, found 222.1287.
Colorless solid, mp 143–145 ꢀC (lit.15 145 ꢀC); Rf 0.48 (1:1 ethyl
acetate/hexanes); FTIR (neat) 3096, 3045, 1639, 1595, 1530, 1494,
4.13. Methyl 4-(1-(3-methoxyphenyl)-1H-indol-3-yl)-
butanoate (Table 3, entry 12)
1223, 748, 693 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.59 (s, 3H),
7.28–7.37 (m, 2H), 7.45–7.49 (m, 2H), 7.52–7.60 (m, 4H), 7.94 (s, 1H),
8.45–8.47 (m, 1H); 13C NMR (100 MHz, CDCl3)
27.9, 110.9, 118.8,
d
Colorless viscous liquid; Rf 0.45 (1:9 ethyl acetate/hexanes); FTIR
122.9, 123.3, 124.1, 125.1, 126.7, 128.2, 130.1, 134.8, 137.2, 138.6,
193.5; MS (EI, m/z) 258 [MNa]þ; HRMS [MH]þ calculated for
C16H14NO 236.1075, found 236.1074.
(neat) 2948, 2848, 1732, 1594, 1492, 1460, 1204, 1176, 1044, 779,
740, 694 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.10 (m, 2H), 2.44 (t,
J¼7.4 Hz, 2H), 2.86 (t, J¼7.6 Hz, 2H), 3.67 (s, 3H), 3.87 (s, 3H),
6.86–6.89 (m, 1H), 7.03–7.04 (m, 1H), 7.07–7.09 (m, 1H), 7.15–7.24
(m, 3H), 7.4 (t, J¼8.0 Hz,1H), 7.59 (d, J¼8.4 Hz,1H), 7.64 (d, J¼8.0 Hz,
4.8. 1-p-Tolyl-1H-indole (Table 3, entry 7)3b
1H); 13C NMR (100 MHz, CDCl3)
d 24.6, 25.4, 33.9, 51.6, 55.6, 110.1,
Colorless liquid; Rf 0.67 (1:19 ethyl acetate/hexanes); FTIR (neat)
110.8, 111.8, 116.5, 116.9, 119.4, 120.1, 122.6, 125.4, 129.2, 130.4, 136.3,
141.2, 160.8, 174.2; MS (EI, m/z) 346 [MNa]þ; HRMS [MNa]þ calcu-
lated for C20H21NO3Na 346.1419, found 346.1419.
3039, 2921, 1514, 1454, 1329, 730 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
2.34 (s, 3H), 6.57 (d, J¼2.8 Hz,1H), 7.05–7.14 (m, 2H), 7.20–7.22 (m,
3H), 7.29 (d, J¼8.0 Hz, 2H), 7.44 (d, J¼8.0 Hz, 1H), 7.59 (d, J¼7.6 Hz,
1H); 13C NMR (100 MHz, CDCl3)
21.2, 103.3, 110.6, 120.3, 121.2,
d
4.14. 1-(3-Nitrophenyl)-1H-indole (Table 3, entry 13)19
122.3, 124.5, 128.2, 129.3, 130.3, 136.2, 136.4, 137.4; MS (EI, m/z) 208
[MH]þ; HRMS [MH]þ calculated for C15H14N 208.1126, found
208.1124.
Pale yellow solid, mp 66–68 ꢀC (lit.19 67–68 ꢀC); Rf 0.45 (1:19
ethyl acetate/hexanes); FTIR (neat) 3090, 2923, 2358, 1525, 1483,
1451, 1341, 1206, 727, 677 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 6.68
4.9. 1-(4-Methoxyphenyl)-1H-indole (Table 3, entry 8)3b
(d, J¼2.8 Hz, 1H), 7.13–7.23 (m, 2H), 7.29 (d, J¼3.6 Hz, 1H), 7.49–7.52
(m, 1H), 7.63 (t, J¼8.0 Hz, 2H), 7.78–7.81 (m, 1H), 8.11–8.13 (m, 1H),
White solid, mp 57–59 ꢀC (lit.16 59.5–60.5 ꢀC); Rf 0.68 (1:19 ethyl
8.31–8.32 (m, 1H); 13C NMR (100 MHz, CDCl3)
d 105.5, 110.1, 118.9,
acetate/hexanes); FTIR (neat) 3051, 2924, 2838, 1511, 1456, 1289,
121.0, 121.4, 121.7, 123.4, 127.4, 129.7, 129.8, 130.7, 135.6, 141.1, 149.3;
MS (EI, m/z) 239 [MH]þ; HRMS [MH]þ calculated for C14H10N2O2
239.0821, found 239.0824.
1241, 1027, 833, 734 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 3.79 (s, 3H),
6.57 (d, J¼3.1 Hz, 1H), 6.93–6.96 (m, 2H), 7.05–7.14 (m, 2H), 7.19 (d,
J¼3.2 Hz, 1H), 7.30–7.34 (m, 2H), 7.37 (d, J¼8.2 Hz, 1H), 7.60 (d,
J¼7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
55.7, 103.0, 110.5, 114.9,
4.15. 1-(4-(5-Bromo-1H-indol-1-yl)phenyl)-ethanone
(Table 3, entry 14)
120.2, 121.2, 122.3, 126.2, 128.4, 129.1, 133.1, 136.6, 158.5; MS (EI,
m/z) 224 [MH]þ; HRMS [MH]þ calculated for C15H14NO 224.1075,
found 224.1079.
Pale brown solid, mp 112–114 ꢀC; Rf 0.42 (1:9 ethyl acetate/
hexanes); FTIR (neat) 3108, 2922, 1678, 1599, 1517, 1449, 1266, 841,
4.10. 1-(3-Methoxyphenyl)-1H-indole (Table 3, entry 9)16
761, 721 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.66 (s, 3H), 6.67 (d,
J¼3.2 Hz,1H), 7.34 (dd, J¼2.0, 8.8 Hz,1H), 7.37 (d, J¼3.6 Hz,1H), 7.49
Colorless liquid; Rf 0.63 (1:19 ethyl acetate/hexanes); FTIR (neat)
(d, J¼8.8 Hz, 1H), 7.58 (d, J¼8.4 Hz, 2H), 7.82 (d, J¼1.6 Hz, 1H), 8.13
3055, 2946, 2835, 1595, 1483, 1458, 1208, 1040, 731, 688 cmꢁ1
;
1H
(d, J¼8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d 26.7, 104.5, 112.1,
NMR (400 MHz, CDCl3)
d
3.77 (s, 3H), 6.59 (d, J¼3.2 Hz, 1H), 6.81
114.3, 123.5, 124.0, 125.9, 128.7, 130.3, 131.6, 134.3, 135.1, 143.4,
196.9; MS (EI, m/z) 314 [MH]þ; HRMS [MH]þ calculated for
C16H13BrNO 314.0181, found 314.0176.
(dd, J¼1.6, 8.4 Hz, 1H), 6.97 (t, J¼2.0 Hz, 1H), 7.01 (d, J¼8.0 Hz, 1H),
7.06–7.15 (m, 2H), 7.25 (d, J¼3.2 Hz, 1H), 7.32 (t, J¼8.0 Hz, 1H), 7.51
(d, J¼8.4 Hz, 1H), 7.59 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
55.6,103.7,110.3,110.8,112.1, 116.7,120.5,121.3,122.5,128.0,129.5,
4.16. 1-(4-(5-Methoxy-1H-indol-1-yl)phenyl)-ethanone
(Table 3, entry 15)
130.4, 135.9, 141.1, 160.7; MS (EI, m/z) 224 [MH]þ; HRMS [MH]þ
calculated for C15H14NO 224.1075, found 224.1071.
Colorless solid, mp 99–101 ꢀC; Rf 0.32 (1:9 ethyl acetate/hex-
4.11. 1-(4-(1H-Indol-1-yl)phenyl)-ethanone (Table 3,
anes); FTIR (neat) 3096, 2921, 2852, 1665, 1593, 1509, 1463, 1260,
entry 10)17
1150.0, 840, 805, 758, 725 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 2.65
(s, 3H), 3.88 (s, 3H), 6.66 (d, J¼3.2 Hz, 1H), 6.91 (dd, J¼2.4, 8.8 Hz,
1H), 7.14 (d, J¼2.4 Hz, 1H), 7.36 (d, J¼3.2 Hz, 1H), 7.54 (d, J¼8.8 Hz,
1H), 7.58–7.61 (m, 2H), 8.09–8.12 (m, 2H); 13C NMR (100 MHz,
White solid 84–86 ꢀC (lit.18 85–87 ꢀC); Rf 0.42 (1:9 ethyl acet-
ate/hexanes); FTIR (neat) 3057, 2922, 1671, 1595, 1512, 1454, 1269,
731 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
2.52 (s, 3H), 6.61 (d,
CDCl3) d 26.7, 56.0, 103.3, 105.0, 111.6, 113.0, 123.0, 127.9, 130.2,

4624
R.K. Rao et al. / Tetrahedron 65 (2009) 4619–4624
130.6, 130.7, 134.5, 144.1, 155.1, 196.9; MS (EI, m/z) 266 [MH]þ;
of Chemistry, IIT Madras under the IRPHA scheme and ESI-MS
facility under the FIST programme.
HRMS [MH]þ calculated for C17H16NO2 266.1181, found 266.1175.
4.17. 5-Bromo-1-(3-methoxyphenyl)-1H-indole
(Table 3, entry 16)
References and notes
Pale brown solid, mp 69–71 ꢀC; Rf 0.65 (1:9 ethyl acetate/hex-
1. (a) Balle, T.; Perregaard, J.; Ramirez, T. M.; Larsen, K. A.; Soby, K. K.; Liljefors, T.;
Andersen, K. J. Med. Chem. 2003, 46, 265–283; (b) Arnt, J.; Skarsfeldt, T. Neuro-
psychopharmacology 1998, 18, 63–101.
anes); FTIR (neat) 2925, 2839, 1595, 1483, 1451, 1208, 1171, 1042,
785, 703 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 3.85 (s, 3H), 6.59 (d,
2. McCormick, M. T.; Liu, Q.; Wang, S. Org. Lett. 2007, 9, 4087–4090.
´
3. (a) Mann, G.; Hartwig, J. F.; Driver, M. S.; Fernandez, R. C. J. Am. Chem. Soc. 1998,
J¼3.2 Hz, 1H), 6.89–6.92 (m, 1H), 6.99–7.05 (m, 2H), 7.27–7.32 (m,
2H), 7.39–7.44 (m, 2H), 7.79 (d, J¼1.2 Hz, 1H); 13C NMR (100 MHz,
120, 827–828; (b) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Roman, L. M. A. J. Org. Chem. 1999, 64, 5575–5580; (c) Old, D. W.; Harris, M. C.;
Buchwald, S. L. Org. Lett. 2000, 2, 1403–1406.
4. For reviews, see: (a) Lindley, J. Tetrahedron 1984, 40, 1433–1456; (b) Beletskaya,
I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337–2364.
5. Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
11684–11688.
CDCl3)
d 55.7, 103.2, 110.5, 112.2, 112.5, 113.7, 116.7, 123.7, 125.3,
129.2, 130.6, 131.2, 134.7, 140.6, 160.8; MS (EI, m/z) 301 [M]þ; HRMS
[M]þ calculated for C15H12BrNO 301.0102, found 301.0107.
4.18. 5-Methoxy-1-(3-methoxyphenyl)-1H-indole
6. Tang, B.; Guo, S.; Zhang, M.; Li, J. Synthesis 2008, 1707–1716.
7. Periasamy, M.; Vairaprakash, P.; Dalai, M. Organometallics 2008, 27,
1963–1966.
(Table 3, entry 17)3c
8. Chouhan, G.; Wang, D.; Alper, H. Chem. Commun. 2007, 4809–4811.
9. Ma, H. C.; Jiang, X. Z. J. Org. Chem. 2007, 72, 8943–8946.
10. (a) Mannam, S.; Kumar, S. A.; Sekar, G. Adv. Synth. Catal. 2007, 349, 2253–2258;
(b) Mannam, S.; Sekar, G. Tetrahedron Lett. 2008, 49, 1083–1086; (c) Mannam,
S.; Sekar, G. Tetrahedron Lett. 2008, 49, 2457–2460.
11. (a) Naidu, A. B.; Raghunath, O. R.; Prasad, D. J. C.; Sekar, G. Tetrahedron Lett.
2008, 49, 1057–1061; (b) Naidu, A. B.; Sekar, G. Tetrahedron Lett. 2008, 49,
3147–3151.
12. (a) Benson, S. C.; Cai, P.; Colon, M.; Haiza, M. A.; Tokles, M.; Snyder, J. K. J. Org.
Chem. 1988, 53, 5335–5341; (b) Shi, M.; Duan, W. L.; Rong, G. B. Chirality 2004,
16, 642–651.
13. (a) Moran, R. J.; Cramer, C.; Falvey, D. E. J. Org. Chem. 1997, 62, 2742–2751; (b)
Miyata, O.; Kimura, Y.; Naito, T. Synthesis 2001, 1635–1638.
14. Mino, T.; Harada, Y.; Shindo, H.; Sakamoto, M.; Fujita, T. Synlett 2008, 614–620.
15. Bekolo, H. Can. J. Chem. 2007, 85, 42–46.
Colorless liquid; Rf 0.51 (1:9 ethyl acetate:hexanes); FTIR (neat)
2945, 2841, 1601, 1485, 1445, 1222, 795, 733 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d
3.87 (s, 3H), 3.88 (s, 3H), 6.60 (d, J¼3.2 Hz, 1H),
6.89 (dd, J¼2.0, 9.2 Hz, 2H), 7.04 (t, J¼2.0 Hz, 1H), 7.08–7.10 (m, 1H),
7.14 (d, J¼2.4 Hz, 1H), 7.33 (d, J¼3.2 Hz, 1H), 7.41 (t, J¼8.0 Hz, 1H),
7.51 (d, J¼9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 55.6, 56.0, 102.8,
103.4, 110.0, 111.6, 111.9, 112.6, 116.4, 128.4, 130.0, 130.5, 131.1, 141.2,
154.7, 160.7; MS (EI, m/z) 254 [MH]þ; HRMS [MH]þ calculated for
C16H16NO2 254.1181, found 254.1181.
Acknowledgements
16. Baldoli, C.; Maiorana, S.; Licandro, E.; Casiraghi, L.; Zinzalla, G.; Seneci, P.;
Magistris, E. D.; Paio, A.; Marchioro, C. J. Comb. Chem. 2003, 5, 809–813.
17. Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 496–499.
18. Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727–7729.
We thank DST (Project No.: SR/S1/OC-06/2008), New Delhi for
the financial support. R.K.R. and E.A.J. thank CSIR, New Delhi and
A.B.N. thanks UGC, New Delhi for SRF. We thank DST, New Delhi, for
the funding toward the 400 MHz NMR machine to the Department
19. Khan, M. A.; Polya, J. B. J. Chem. Soc. Sec. C Org. 1970, 85–91.