Selective, efficient and functional group-tolerant CuOAc-mediated N-arylation of 1H-indoles and 9H-carbazole with aryl iodides under base-free and ligandless conditions

Article abstract of DOI:10.1002/ejoc.200601084

CuOAc-Mediated N-arylation of 1H-indole derivatives and 1H-carbazole with aryl iodides under base-free and ligandless conditions provides the required N-arylazoles with complete N-selectivity and in moderate to good yields. The experimental conditions for

Full text of DOI:10.1002/ejoc.200601084

FULL PAPER
DOI: 10.1002/ejoc.200601084
Selective, Efficient and Functional Group-Tolerant CuOAc-Mediated
N-Arylation of 1H-Indoles and 9H-Carbazole with Aryl Iodides Under
Base-Free and Ligandless Conditions
[a]
[a]
[a]
[a]
Fabio Bellina,* Chiara Calandri, Silvia Cauteruccio, and Renzo Rossi*
Keywords: C–N coupling / Copper / Selectivity / Synthetic methods / Indoles / Carbazole
CuOAc-Mediated N-arylation of 1H-indole derivatives and
H-carbazole with aryl iodides under base-free and li-
gandless conditions provides the required N-arylazoles with
complete N-selectivity and in moderate to good yields. The
experimental conditions for this new version of the Ullmann
reaction allow an unprecedented tolerance of functional
groups and facilitate the workup of the reaction mixtures and
isolation of the required chemically pure reaction products.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
1
Introduction
ation of primary arylamines with 2,2Ј-biphenylene ditri-
[
21a]
[21b]
flates
or 2,2Ј-dihalobiphenyls.
1
-Arylindoles are central structural elements in many
However, several problems limit the synthetic utility of
many of these N-arylation methods. In particular, the
Ullmann-type coupling reactions suffer from limited sub-
strate scope and low to moderate yields, whilst having pre-
dominantly been conducted with aryl halides activated by
electron-withdrawing groups. The utility of the Pd-catalysed
N-arylation of 1H-indoles, meanwhile, is limited by prob-
lems such as C-3 arylation and an intolerance of several
functional groups. Moreover, like the Pd-catalysed N-aryl-
ation of 9H-carbazoles, this reaction involves the use of ex-
pensive phosphane ligands. Even the Cu-catalysed N-aryl-
ation of 1H-indoles is not entirely satisfactory, since the use
pharmacologically important and bioactive compounds. In
fact, these arylazoles are of interest as angiotensin II antag-
onists, melatonin receptor MT agonists, antiallergic
and antipsychotic agents, COX-2 inhibitors and herbi-
cides, and also as synthetic intermediates used to prepare
other biologically active compounds. Moreover, numerous
N-arylindoles bearing 4-fluorophenyl groups are to be
found among the most selective ligands with high affinities
for the G binding site. On the other hand, 9-arylcarba-
zoles have attracted attention because of their luminescent
[
1]
[2]
[3]
1
[4]
[5]
[
6]
[7]
[8]
2
[
9]
[10]
properties and as discotic molecules.
Much consideration has thus been directed towards the
preparation of such N-arylazoles. Methods developed for
the synthesis of 1-arylindoles include the Fischer synthe-
sis,[ Ullmann-type couplings between aryl halides and in-
[17d,17f]
[17a]
of ligands such as -proline,
a 1,2-diaminocycloalkane
1,10-phenanthroline,
or a Schiff base
[17b,17e]
[17c,17g]
in
this method entails increased costs and problems in the iso-
lation of the required chemically pure 1-aryl-1H-indoles
from the multicomponent crude reaction mixtures. Further-
more, the experimental conditions for the Ullmann-type
couplings and the Pd- or Cu-catalysed N-arylation reac-
tions, involving the use of base, result in intolerance of base-
sensitive groups such as phenolic hydroxy groups.
11]
doles, nucleophilic aromatic substitution,[13] intramolecu-
[12]
lar Pd-catalysed annulation of didehydrophenylalanine de-
rivatives,
halides
ously with diaryliodonium salts, with aryl iodides or bro-
mides in the presence of a suitable ligand or with zeolite
NaY.
[
14]
Pd-catalysed N-arylation of indoles with aryl
and Cu-catalysed N-arylation of indoles vari-
[
8c,15]
[16]
[17]
Recently, in the course of our studies on the development
of new and efficient methods for highly regioselective direct
[
18,19]
On the other hand, 9-arylcarbazoles have been
prepared by Ullmann N-arylation of 9H-carbazoles with
C-arylation of azoles – including free (NH)-indole, -imid-
[
9,20]
aryl halides,
Pd/P(tBu) -catalysed coupling of aryl bro-
[22]
3
azole and -benzimidazole – with aryl halides
we found
mides with carbazole,[
15c]
or Pd-catalysed double N-aryl-
that Pd(OAc) - and CuI-mediated reactions between 1H-
2
indole (1a) and aryl iodides 2 in DMF at 140 °C or in DMA
[
a] Dipartimento di Chimica e Chimica Industriale, University of at 160 °C under base-free and ligandless conditions selec-
Pisa,
tively provided 2-aryl-1H-indoles 3a in moderate yields
Via Risorgimento 35, 56126 Pisa, Italy
Fax: +39-0502219260
[
22c–22e]
(Scheme 1).
E-mail: bellina@dcci.unipi.it
More recently, in an attempt to improve this result by
rossi@dcci.unipi.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
I
examining the role of Pd(OAc) and the nature of the Cu
2
salt in this arylation reaction, we developed a new and inex-
Eur. J. Org. Chem. 2007, 2147–2151
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2147

F. Bellina, C. Calandri, S. Cauteruccio, R. Rossi
FULL PAPER
isolate 3aa in 22% yield (Table 1, Entry 2). On the other
hand, treatment of 1a with 2a without use of Pd(OAc) but
2
in the presence of 2.0 equiv. of CuI gave 3aa in only 6%
GLC yield (Table 1, Entry 3).
Scheme 1.
However, when low-grade CuOAc (97%) was used in
place of CuI, the reaction between 1a and 2a in DMF at
40 °C under base-free and ligandless conditions occurred
at position 1 in 1a rather than at C-2, producing compound
aa cleanly and with complete selectivity in 52% isolated
pensive version of the Ullmann reaction that allows the se-
lective, efficient and functional group-tolerant N-arylation
of 1H-indoles 1 and 9H-carbazole (5) with aryl iodides
1
(Scheme 2).
4
yield (Table 1, Entry 4). A very similar result was obtained
when the reaction was performed in DMPU [1,3-dimethyl-
3,4,5,6-tetrahydro-2(1H)-pyrimidone] (Table 1, Entry 5).
After extensive experimentation, we found that a signifi-
cant improvement in the yield of 4aa could be obtained by
performing the reaction in dry and deaerated DMA (N,N-
dimethylacetamide) at 160 °C in the presence of 1.1 equiv.
of CuOAc with use of a 1.5:1 molar ratio of 1a and 2a
(
Table 1, Entry 6). We also found that CuOAc was an opti-
I
Scheme 2.
mal Cu source for this N-arylation and that the use of (Cu-
OTf) ·toluene or Cu O as sources of the oxygen-containing
2
2
I
Cu derivative gave inferior results (Table 1, Entries 7 and
).
8
Results and Discussion
Encouraged by the promising result shown in Entry 6 in
This work was initiated by investigation of the role of Table 1, we then applied the experimental conditions used
I
Pd(OAc) and the nature of the Cu salt on the Pd- and in this entry to N-arylation reactions of 1H-indoles 1a–d
2
Cu-mediated arylation of 1H-indole (1a) with aryl iodides. with aryl iodides 2a–f. Compounds 1 included a particular
We found that whereas treatment of 1a with 2.0 equiv. of 4- derivative, indoxyl acetate (1c), never before successfully
iodoanisole (2a) in DMF at 140 °C for 48 h in the presence used in a Cu-catalysed N-arylation. On the other hand, io-
of 5 mol-% Pd(OAc) and 2.0 equiv. of CuI produced the dides 2 included an electron-neutral derivative (2b) and
2
2-aryl derivative 3aa in 35% isolated yield (Table 1, En- compounds bearing either electron-withdrawing or elec-
try 1), an analogous reaction performed without use of CuI tron-donating groups, as well as one derivative – 4-iodo-
furnished a crude reaction mixture containing 3aa and a phenol (2f) – previously unsuccessfully used in an attempted
small amount of 3-(4-methoxyphenyl)-1H-indole (7a). Cu-catalysed N-arylation of 1H-indole reported in the lite-
[
17e]
Chromatographic purification of this mixture allowed us to rature.
Table 1. Regioselective C-2 or N-1 arylation of 1H-indole (1a) with 4-iodoanisole (2a).
Entry[a]
Pd(OAc)
CuX (equiv.)
1a/2a
molar ratio
Solvent
Product
Yield (%)[c]
2
[mol-%]
1
2
5
5
–
–
–
–
–
–
CuI (2.0)
–
CuI (2.0)
CuOAc (2.0)
CuOAc (2.0)
CuOAc (1.1)
0.5
0.5
0.5
0.5
0.5
1.5
0.5
1.5
DMF
DMF
DMF
DMF
DMPU
DMA
DMF
DMA
3aa
3aa
3aa
4aa
4aa
4aa
4aa
4aa
35
22
(6)
52
52
70
[
b]
3
4
5
6
7
8
(CuOTf)
Cu
2
·toluene (1.0)
(37)
33
2
O (0.55)
[
7
a] The reactions were run at 140 °C, unless otherwise stated. [b] The crude reaction mixture was contaminated with a small amount of
a. [c] Isolated chemical yields. In parenthesis, GLC yield evaluated with naphthalene as an internal standard.
2
148 Eur. J. Org. Chem. 2007, 2147–2151
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

CuOAc-Mediated N-Arylation Reactions
FULL PAPER
Table 2. N-Arylation of 1H-indoles 1 with aryl iodides 2.
Entry[a]
1
2
1-Aryl-1H-indole derivative 4
R
Ar
Isolated yield (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1c
1d
1d
2b
2c
2d
2e
2f
2a
2a
2a
2d
4ab
4ac
4ad
4ae
4af
4ba
4ca
4da
4dd
H
H
H
H
H
C
6
H
C H
3 6 4
C H
2 6 4
5
76
66
63
36
49
60
49
54
55
4-CF
4-NO
3,4,5-(MeO)
6 4
4-HOC H
3 6 2
C H
COOMe
OCOMe
CHO
CHO
4-MeOC
4-MeOC
4-MeOC
6
6
6
H
H
H
4
4
4
2 6 4
4-NO C H
[a] The reactions were run in DMA at 160 °C for 48 h with 1.1 equiv. of 97% CuOAc and a 1.5:1 molar ratio between 1 and 2.
volve oxidative addition of the aryl iodide to the N–CuI
derivative, followed by reductive elimination. Uncertainty
remains, however, since no mechanistic studies on Cu-cata-
lysed N-arylation resulting in full elucidation of the cata-
lytic pathway have been reported in the literature.[
17c,17g,23]
Moreover, the mechanistic pathway proposed above is not
suitable to explain the fact that the CuOAc-mediated N-
arylations of 1H-indoles and 9H-carbazole under base-free
As shown in Table 2, these couplings between aryl io-
and ligandless conditions are reactions that require the use
dides 2 and 1H-indoles 1 afforded the required 1-aryl-1H-
indoles in moderate to good yields. Table 2 also shows that
the presence of electron-withdrawing or electron-donating
groups at the 4-positions in the aryl iodides had no impact
on the efficiencies of the arylation reactions. Moreover, a
phenolic hydroxy group at the 4-position of the aryl iodide
was well tolerated. In fact, the CuOAc-mediated reaction
of stoichiometric amounts, rather than catalytic quantities,
of CuOAc.
Conclusions
In summary, we have developed highly selective and ef-
between 1a and 2f under base-free and ligandless conditions ficient Cu-mediated C–N coupling reactions of 1H-indoles
gave the required 1-aryl-1H-indole 4f in 49% isolated yield and 9H-carbazole with aryl iodides. This new and inexpen-
(Table 2, Entry 5).
sive version of the classical Ullmann reaction, which does
These satisfactory results induced us also to investigate not require the use of base or ligand, offers an unprece-
the N-arylation of 9H-carbazole (5) with aryl iodides by a dented tolerance of functional groups both in the 1H-in-
method very similar to that employed for the synthesis of doles and in the aryl iodides and works well with both elec-
1
-aryl-1H-indoles 4 and we were pleased to find that 5 was tron-rich and electron-poor aryl iodides. Interestingly, the
effectively coupled with iodides 2a and 2d in DMA at experimental conditions for this method facilitate the
60 °C for 48 h in the presence of 1.1 equiv. of CuOAc to workup of the reaction mixtures and the isolation of the
give 9-aryl-9H-carbazoles 6a and 6b in 86 and 73% yields, required chemically pure N-aryl derivatives. Because of
1
respectively.
these attributes, we believe that this method will find more
general applications in organic synthesis.
Experimental Section
General Procedure for the Cu-Mediated Synthesis of N-Arylindoles
4: A 1H-indole derivative 1 or 9H-carbazole (5) (1.5 mmol),
CuOAc (0.13 g, 1.1 mmol) and the aryl iodide 2 (1.0 mmol) were
placed in a reaction vessel under a stream of argon. The reaction
vessel was fitted with a silicon septum and evacuated and back-
filled with argon, and this sequence was repeated twice. Dearated
DMA (5 mL) was then added by syringe at room temperature un-
der a stream of argon and the mixture was stirred under argon at
With regard to the mechanism of these Cu-mediated N-
arylation reactions, we speculated that it involves N–Cu
derivatives resulting from reactions between CuOAc and
the azoles 1 and 5 in the presence of DMA or DMF, which
are solvents with mildly basic characteristics. The subse-
I
quent steps of this mechanism might be similar to those
160 °C for 48 h. After this period, the reaction – monitored by
proposed by Cristeau et al.[
17c]
for a mechanistic pathway GLC and GLC-MS analyses of a sample of the crude reaction mix-
for Cu-catalysed N-arylations. In particular, they might in- ture after it had been treated with a saturated aqueous NH
4
Cl solu-
Eur. J. Org. Chem. 2007, 2147–2151
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2149

F. Bellina, C. Calandri, S. Cauteruccio, R. Rossi
FULL PAPER
tion and extracted with AcOEt – was complete. The reaction mix-
ture was then allowed to cool to room temperature, diluted with
= 158.9, 141.4 (2 C), 130.3, 128.6 (2 C), 125.8 (2 C), 123.1 (2 C),
120.2 (2 C), 119.6 (2 C), 115.1 (2 C), 109.7 (2 C), 55.6 ppm. EI-
MS: m/z (%) = 274 (20) [M + 1] , 273 (100) [M] , 259 (10), 258
(50), 230 (13), 228 (22), 202 (7). GLC analysis proved a chemical
purity higher than 99% for 6a.
+
+
AcOEt and poured into a saturated aqueous NH
4
Cl solution, and
the resulting mixture was stirred in the open air for 0.5 h and then
extracted with toluene. The organic extract was washed with brine,
dried, filtered through Celite® and concentrated under reduced
pressure, and the residue was purified either by crystallization or
by MPLC on silica gel. This procedure was employed to prepare
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and characterization for
compounds 4ac–ae, 4ba–da, 4dd and 6b.
1-aryl-1H-indoles 4aa–4af, 4ba–4da, 4dd and 9-aryl-9H-carbazoles
6
a–b.
Acknowledgments
1
-(4-Methoxyphenyl)-1H-indole (4aa): The crude product obtained
from the CuOAc-mediated reaction between 1H-indole (1a) and 4-
iodoanisole (2a) (Table 1, Entry 6) was purified by MPLC on silica
gel with a mixture of hexane and toluene (70:30) as eluent to give
We thank the University of Pisa for financial support.
[24]
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kov, J. Med. Chem. 1998, 41, 3624–3634.
4
5
1
1
2
aa (156 mg, 70%) as a colourless solid: m.p. 56–58 °C (ref. m.p.
7–58 °C). H NMR (300 MHz, CDCl ): δ = 7.67 (d, J = 7.8 Hz,
3
1
H), 7.45 (d, J = 8.4 Hz, 1 H), 7.38 (m, 2 H), 7.26 (d, J = 3.2 Hz,
H), 7.19 (t, J = 6.5 Hz, 1 H), 7.14 (t, J = 6.5 Hz, 1 H), 7.01 (m,
1
3
H), 6.64 (dd, J = 3.0 and 0.6 Hz, 1 H), 3.85 (s, 3 H) ppm.
): δ = 158.2, 136.3, 132.8, 129.0, 128.3,
26.0 (2 C), 122.1, 121.0, 120.1, 114.7 (2 C), 110.3, 102.9, 55.6 ppm.
C
[
3] P. C. Unangst, D. T. Connor, S. S. Stabler, R. J. Weikert, M. E.
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1
3
+
+
EI-MS: m/z (%) = 224 (17) [M + 1] , 223 (100) [M] , 209 (11), 208
71), 190 (7), 180 (19), 178 (10), 152 (17). GLC analysis proved a
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(
chemical purity higher than 99% for 4aa. The spectroscopic data
3
738.
for this compound were in agreement with those previously re-
[
5] H. Sano, T. Noguchi, A. Tanatani, Y. Hashimoto, H. Miyachi,
[
25]
ported.
Bioorg. Med. Chem. 2005, 13, 3079–3091.
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1-Phenyl-1H-indole (4ab): The crude product obtained from the
vember 1, 1996).
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CuOAc-mediated reaction between 1H-indole (1a) and phenyl io-
dide (2b) (Table 2, Entry 1) was purified by MPLC on silica gel
[
with a mixture of hexane and toluene (95:5) as eluent to give 4ab
[
1
(
147 mg, 76%) as a pale yellow oil. H NMR (300 MHz, CDCl
3
):
δ = 7.69 (m, 1 H), 7.57 (m, 1 H), 7.51 (m, 3 H), 7.38 (m, 2 H), 7.35
(
m, 2 H), 7.20 (m, 3 H), 7.01 (m, 2 H), 6.68 (dd, J = 3.2 and 0.8 Hz,
H), 3.85 (s, 3 H) ppm. C NMR (75.5 MHz, CDCl ): δ = 139.8,
3
13
1
1
1
35.9, 129.6 (2 C), 129.3, 127.9, 126.4, 124.4, 122.3, 121.1, 120.3,
[9] M. Martinez-Palau, E. Perea, F. Lopez-Calahorra, D. Velasco,
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[10] E. Perea, F. Lopez-Calahorra, D. Velasco, H. Finkelmann,
Mol. Cryst. Liq. Cryst. 2001, 365, 1651–1658.
+
10.5, 106.3 ppm. EI-MS: m/z (%) = 194 (15) [M + 1] , 193 (100)
+
+
[M] , 192 (16) [M – 1] , 191 (8), 165 (20), 96 (5), 90 (6), 89 (8).
GLC analysis showed that 4ab had chemical purity higher than
[
11] For representative examples, see: a) S. Wagaw, B. H. Yang, S. L.
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9
8%. The spectroscopic data for this compound were in agreement
[17c]
with those previously reported.
4-(1H-Indol-1-yl)phenol (4af): The crude product obtained from the
[12] For representative examples, see: a) Y. Murakami, T. Watanabe,
T. Hagiwara, Y. Akiyama, H. Ishii, Chem. Pharm. Bull. 1995,
CuOAc-mediated reaction between 1H-indole (1a) and 4-iodo-
phenol (2f) (Table 2, Entry 5) was purified by MPLC on silica gel
43, 1281–1286; b) Y. Kato, M. M. Conn, J. Rebek Jr, J. Am.
with a mixture of toluene and AcOEt (90:10) as eluent to give 4af
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Chem. Pharm. Bull. 1977, 25, 3110–3114.
1
(
102 mg, 49%) as an orange oil. H NMR (200 MHz, CDCl
3
): δ =
7
7
=
1
.68 (dd, J = 7.0 and 3.2 Hz, 1 H), 7.44 (m, 1 H), 7.32 (m, 2 H),
.25 (d, J = 3.1 Hz, 1 H), 7.18 (m, 2 H), 6.91 (m, 2 H), 6.64 (d, J
3.1 Hz, 1 H) ppm. 13C NMR (50.3 MHz, CDCl
36.3, 132.9, 128.9, 128.3, 126.2 (2 C), 122.2, 121.0, 120.1, 116.2 (2
3
): δ = 154.2, [13] For representative examples, see: a) W. J. Smith III, J. S. Sawyer,
Heterocycles 1999, 51, 157–160; b) W. J. Smith III, J. S. Sawyer,
+
Tetrahedron Lett. 1996, 37, 299–302.
C), 110.4, 102.9 ppm. EI-MS: m/z (%) = 210 (16) [M + 1] , 209
+
+
[14] J. A. Brown, Tetrahedron Lett. 2000, 41, 1623–1626.
(
100) [M] , 208 (15) [M – 1] , 181 (14), 180 (13), 152 (8), 89 (6).
11NO (209.25): calcd. C 80.36, H 5.30; found: C 80.29, H
.19%. GLC analysis proved a chemical purity higher than 99%
for 4af.
[
15] For representative examples, see: a) D. W. Old, M. C. Harris,
S. L. Buchwald, Org. Lett. 2000, 2, 1403–1406; b) G. A. Grasa,
M. S. Viciu, J. Huang, S. P. Nolan, J. Org. Chem. 2001, 66,
14
C H
5
7729–7737; c) M. Watanabe, M. Nishiyama, T. Yamamoto, Y.
Koie, Tetrahedron Lett. 2000, 41, 481–483; d) M. Romero, Y.
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dron 2006, 62, 9010–9016.
9
-(4-Methoxyphenyl)-9H-carbazole (6a): The crude product ob-
tained from the CuOAc-mediated reaction between 9H-carbazole
9) and 4-iodoanisole (2a) was purified by MPLC on silica gel with
a mixture of toluene and petroleum ether (30:70) as eluent to give
(
[
[
16] T. Zhou, Z.-C. Chen, Synth. Commun. 2002, 32, 903–907.
17] For representative examples, see: a) M. Kuil, E. K. Bekedam,
G. M. Visser, A. van den Hoogenband, J. W. Terpstra, P. C. J.
Kamer, P. W. N. M. van Leewen, G. P. F. van Strijdonck, Tetra-
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J. N. Park, Synlett 2002, 427–430; c) H.-J. Cristeau, P. P. Cellier,
[21]
6a (235 mg, 80%) as a colourless solid: m.p. 150–152 °C (ref.
1
3
m.p. 147–149 °C). H NMR (200 MHz, CDCl ): δ = 8.14 (dd, J =
7
7
.7 and 0.7 Hz, 2 H), 7.46 (m, 2 H), 7.41 (m, 2 H), 7.30 (m, 4 H),
.10 (m, 2 H), 3.90 (s, 3 H) ppm. 13C NMR (50.3 MHz, CDCl
): δ
3
2150
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Eur. J. Org. Chem. 2007, 2147–2151

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