Synthesis of 3-Aryl-2-nitroindoles by Palladium-Catalyzed CH-Activation Reactions

Article abstract of DOI:10.1055/s-0035-1560053

3-Aryl-2-nitroindoles were prepared via CH-activation reactions of N-methyl-2-nitroindole.

Full text of DOI:10.1055/s-0035-1560053

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2285–2287
letter
2285
A. Ivanov et al.
Letter
Synlett
Synthesis of 3-Aryl-2-nitroindoles by Palladium-Catalyzed
CH-Activation Reactions
Anton Ivanova
Viktor O. Iaroshenko*a,b
Alexander Villingera
Peter Langer*a,c
ArBr (4 equiv)
Pd(OAc)2 (10 mol%)
K2CO3 (1.4 equiv)
Ar
NO2
NO2
N
N
DMF, 150 °C, 8 h
Me
Me
CH-activation reaction
a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock,
Germany
peter.langer@uni-rostock.de
42–74% yield
11 examples
iva108@googlemail.com
b National Taras Shevchenko University, Department of Chemistry ,
62 Volodymyrska st., Kyiv-33, 01033, Ukraine
c Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a,
18059 Rostock, Germany
Received: 04.06.2015
Accepted after revision: 02.07.2015
Published online: 17.08.2015
DOI: 10.1055/s-0035-1560053; Art ID: st-2015-d0415-l
O
Abstract 3-Aryl-2-nitroindoles were prepared via CH-activation reac-
tions of N-methyl-2-nitroindole.
N
NMe2
N
HN
N
N
H
Key words catalysis, palladium, CH-activation reaction, indole
Me
binedaline, antidepressant
activity against tuberculosis
and leukemia cell lines
The indole moiety is found in a wide range of biological-
ly active compounds, drugs, and natural products. Indoles
are present as the core of neuromodulators and neurotrans-
mitters, such as serotonin and tryptamine, and of well-
known super-potent toxins, such as strychnine and lysergic
acid diethylamide. Indoles have been reported to exhibit
anticancer, immunomodulatory, vasodilator, antihyperten-
sive, antipsychotic, antidepressant, anti-inflammatory, an-
tiviral, and antimicrobic properties.1 Recently, it was found
that simple 3-aryl-substituted indoles show significant ac-
tivity against Gram-positive pathogens.2 Moreover, they ex-
hibit antidepressant, anticancer, and antimicrobial proper-
ties (Figure 1).1
OMe
OMe
MeO
MeO
OMe
OH
N
H
tubulin polymerization inhibitor
Figure 1 Structure of biologically active 3-arylindoles
3-Aryl-substituted indoles have been prepared by Suzuki–
Miyaura reactions of brominated indoles as the starting
materials. Although this synthetic strategy is very efficient,3
it is limited by the need for additional synthetic steps, such
as the synthesis of the required bromoindoles by halogena-
tion and the employment of relatively expensive boronic
acids as starting materials. The use of unsubstituted N-me-
thylindole as a substrate in CH-activation reactions has
been reported,4 although in several cases expensive cata-
lysts4a or reagents4b had to be used to avoid the formation of
regioisomeric mixtures of 2- and 3-arylindoles.4c In this
context, a study of the regioselectivity depending on
the conditions has also been reported.5 It was shown that
for N-unsubstituted indoles the regioselectivity can be con-
trolled by the choice of a base; namely a magnesium salt.
For N-methyl indoles, the authors developed a convenient
method for the selective synthesis of 2-arylindoles (Scheme
2).6 A synthesis of 2-nitro-3-phenylindole was developed
before by Walser et al. based on the functionalization of 2-
acetyl-3-nitro-3-phenyl-3H-indole. The synthesis is, how-
ever, rather complicated and no study of the preparative
scope was reported.7
Regioselective palladium-catalyzed CH-activation reac-
tions of indoles at C-3 have, to the best of our knowledge,
not been reported to date. Nearly all reactions known so far
lead to functionalization of the more electron-poor and,
thus more reactive, C-2. It has been reported that, in case of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2285–2287

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A. Ivanov et al.
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unsubstituted benzofuran, the desired 3-substituted prod-
uct could be obtained, however, only as a minor component
in a 9:1 mixture.8 Corresponding reactions for benzothio-
phenes are possible, but require expensive catalysts and
proceed in low yields.9 Recently, a more efficient protocol
using simple palladium on carbon has been reported.10
Our aim was to develop a new synthesis of 3-arylated
indoles by CH-activation cross-coupling reactions of suit-
able 2-functionalized indole derivatives. We chose the nitro
group11 as an activating group, as it exhibits a strong elec-
tron-withdrawing effect and can be efficiently used as a
catalyst-directing group in CH-activation reactions.12 In ad-
dition, the nitro group can be transformed to the biological-
ly relevant amino group.
Table 1 Optimization of the Synthesis of 2b
Entry
Catalyst (mol%)
Additive
Yield of 2b (%)a
c
1
2
3
4
5
6
7
8
9
10
Pd(PPh3)2Cl2 (10)
Pd(PPh3)4 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (20)
Pd(OAc)2 (10)
Pd2(dba)3 (10)
PivOH, CuI
–
–
c
–
–
57
60
54
74
56
55
62
PCy3
PivOH, CuI
b
–
Ph3P
–
PivOH
–
c
1-Methyl-2-nitroindole (1) was prepared, by the meth-
od developed by Pelkey and Gribble,6 starting with o-nitro-
benzaldehyde. The nitro group of the latter was trans-
formed into an azide. Subsequent cyclization gave 2-ni-
troindole which was methylated (Scheme 1).12
–
a Isolated yields. Conditions: catalyst, ArBr (Ar = 3-F3CC6H4, 3.0 equiv),
K2CO3, 150 °C, 8 h, DMF.
b 4.0 equiv of ArBr.
c Low conversion.
O
O
Using our optimized reaction conditions, the scope of
the reaction was studied. The reaction of 1 with various
aryl bromides afforded indoles 2a–k in moderate to good
yields (Table 2). The best yields were observed for reactions
of aryl bromides containing electron-withdrawing substitu-
ents (2b–e,h). Reactions of 1 with electron-rich 3- and 4-
methoxybromide resulted in the formation of mixtures.
ii
i
NO2
NO2
N
N3
H
iii
NO2
Table 2 Synthesis of 2a–m13,14
N
Me
1
2
Ar
Ph
Yield of 2 (%)a
Scheme 1 Synthesis of the starting indole 1. Reagents and conditions:
(i) NaN3, DMF, 60 °C; (ii) 1) MeNO2, KOH, EtOH, 0 °C; 2) Ac2O, pyridine,
0 °C to 25 °C; 3) xylenes, 140 °C; (iii) NaH, MeI, DMF, 25 °C.
2a
2b
2c
2d
2e
2f
52
74
71
57b
63b
55
59
62
44
42
48
–
3-F3CC6H4
4-F3CC6H4
3-O2NC6H4
4-NCC6H4
The conditions of the reaction of 1 with 1-bromo-3-(tri-
fluoromethyl)benzene were optimized (Scheme 2, Table 1).
The reaction of the starting materials in the presence of
Pd(PPh3)2Cl2, CuI, PivOH, and K2CO3 in DMF resulted in low
conversion (Table 1, entry 1). The use of Pd(OAc)2 (10 mol%)
proved to be the most efficient. Interestingly, the use of li-
gands or the employment of higher catalyst amounts did
not result in an improvement of the yield. Best results were
found for a simple catalyst system using Pd(OAc)2 and
K2CO3 in DMF, using four equivalents of the aryl bromide
(Table 1, entry 6).
3-ClC6H4
2g
2h
2i
4-OHCC6H4
4-EtO2CC6H4
3-pyridyl
2j
1-naphtyl
2k
2l
9-phenanthrene
4-MeOC6H4
3-MeOC6H4
2m
19c
Ar
a Yield of isolated products.
b A small amount of impurity could not be separated.
ArBr
NO2
NO2
N
N
conditions
The structures of 2a and 2b were independently con-
Me
2a–m
Me
see Table 1
firmed by X-ray crystal-structure analysis (Figure 2 and Fig-
ure 3).
1
Scheme 2 Synthesis of 3-aryl-2-nitroindoles 2a–m
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A. Ivanov et al.
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References and Notes
(1) Kumar Kaushik, N.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C. H.;
Verma, A. K.; Choi, E. H. Molecules 2013, 18, 6620.
(2) Leboho, T. C.; Michael, J. P.; van Otterloa, W. A. L.; van Vuurenb,
S. F.; de Koning, C. B. Bioorg. Med. Chem. Lett. 2009, 19, 4948.
(3) Yang, J.; Liu, S.; Zheng, J.-F.; Zhou, J. Eur. J. Org. Chem. 2012,
6248.
(4) (a) Join, B.; Jamamoto, T.; Itami, K. Angew. Chem. Int. Ed. 2009,
48, 3644. (b) Phipps, R. J.; Grimster, N. P.; Guant, M. J. J. Am.
Chem. Soc. 2008, 130, 8172. (c) Dwight, T. A.; Rue, N. R.; Charyk,
D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137.
(5) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127,
8050.
(6) Yu, J.-Q.; Shi, Z. Top. Curr. Chem. 2010, 292.
(7) Walser, A.; Blount, J. F.; Fryer, R. I. J. Org. Chem. 1973, 33, 3077.
(8) Yanagisawa, S.; Itami, K. Tetrahedron 2011, 67, 4425.
(9) Ueda, K.; Yanagisawa, S.; Yamaguchi, J.; Itami, K. Angew. Chem.
Int. Ed. 2010, 49, 8946.
(10) Tang, D.-T. D.; Collins, K. D.; Glorius, F. J. Am. Chem. Soc. 2013,
135, 7450.
Figure 2 Ortep plot of 2a (50% probability level)
(11) Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38, 5603.
(12) Seelfeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess, W. J.;
DeWolf, W. E. Jr; Elkins, P. A.; Head, M. S.; Jakas, D. R.; Janson, C.
A.; Keller, P. M.; Manley, P. J.; Moore, T. D.; Payne, D. J.; Pearson,
S.; Polizzi, B. J.; Qiu, X.; Rittenhouse, S. F.; Uzinskas, I. N.; Wallis,
N. G.; Huffman, W. F. J. Med. Chem. 2003, 46, 1627.
(13) General Procedure for the Synthesis of 2a–m
In a Schlenk flask 1 (100 mg, 0.57 mmol), appropriate aryl
bromide (2.28 mmol, 4 equiv), Pd(OAc)2 (0.057 mmol, 10 mol%),
K2CO3 (0.8 mmol, 1.4 equiv), and DMF (5 mL) were added under
argon atmosphere and stirred at 150 °C overnight. The reaction
mixture was then evaporated to dryness, and the product was
isolated by column chromatography (silica gel, hexane–EtOAc)
or via semipreparative HPLC (MeOH–H2O).
(14) 1-Methyl-2-nitro-3-phenylindole (2a)
Starting with 1 (100 mg, 0.57 mmol), bromobenzene (358 mg,
0.24 ml, 2.28 mmol), Pd(OAc)2 (12.8 mg, 0.057 mmol, 10 mol%),
K2CO3 (111 mg, 0.8 mmol), and DMF (5 mL), 2a was isolated as a
yellow solid (72 mg, 52%), mp 118–119 °C. 1H NMR (300 MHz,
Figure 3 Ortep plot of 2b (50% probability level)
3
DMSO-d6): δ = 4.09 (s, 3 H, CH3), 7.28 (t, JH–H = 7.52 Hz, 1 H,
ArH), 7.49–7.61 (m, 7 H, ArH), 7.78 (d, 3JH–H = 8.5 Hz, 1 H, ArH).
13C NMR (75 MHz, DMSO-d6): δ = 32.6 (CH3), 111.8 (CH), 118.6
(C), 121.8 (C), 122.4 (CH), 124.0 (C), 127.8 (CH), 127.9 (CH),
128.42 (CH), 129.9 (CH), 131.3 (C), 136.1 (C), 138.1 (C). IR (KBr):
1612 (w), 1548 (w), 1501 (m), 1458 (s), 1365 (s), 1303 (s), 1246
(s), 1208 (m), 1178 (m), 1157 (m), 1130 (m), 1113 (m), 1091
(m), 1069 (m), 1028 (m), 978 (w), 923 (m), 897 (m), 858 (w),
779 (m), 769 (m), 753 (s), 740 (s), 699 (s), 642 (m), 604 (s), 550
(m) cm–1. MS (EI, 70 eV): m/z (%) = 253 (18), 252 (M+, 100), 235
(15), 223 (10), 222 (20), 221 (10), 207 (25), 206 (12), 205 (21),
204 (20), 195 (12), 194 (15), 192 (10), 191 (24), 190 (36), 181
(21), 178 (12), 166 (10), 165 (49), 164 (19), 163 (20), 152 (15),
151 (10). HRMS (EI, 70 eV): m/z calcd for C15H12O2N2 [M+]:
252.08933; found: 252.08938.
In summary, we have developed a convenient approach
to 3-aryl-2-nitroindoles by palladium-catalyzed CH-activa-
tion reactions of 3-nitroindole 1 with a range of aryl bro-
mides. These reactions provide a convenient approach to
indole derivatives that are not readily available by other
methods.
Acknowledgement
Financial support by the DAAD (scholarship for A.I.) is gratefully ac-
knowledged.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560053.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2285–2287