Ready synthesis of free N-H 2-arylindoles via the copper-catalyzed amination of 2-bromo-arylacetylenes with aqueous ammonia and sequential intramolecular cyclization

Article abstract of DOI:10.1039/c1ob05549f

A wide range of free N-H 2-arylindoles were synthesised via the copper(ii)-catalyzed amination of 2-bromo-arylacetylenes with aqueous ammonia and sequential intramolecular cyclization. The convenience and atom economy of aqueous ammonia, and the low cost of the copper catalytic system make this protocol readily superior in practical application. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob05549f

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 4983
www.rsc.org/obc
PAPER
Ready synthesis of free N-H 2-arylindoles via the copper-catalyzed amination
of 2-bromo-arylacetylenes with aqueous ammonia and sequential
intramolecular cyclization†
Huifeng Wang, Yaming Li,* Linlin Jiang, Rong Zhang, Kun Jin, Defeng Zhao and Chunying Duan*
Received 10th March 2011, Accepted 13th April 2011
DOI: 10.1039/c1ob05549f
A wide range of free N-H 2-arylindoles were synthesised via the copper(II)-catalyzed amination of
2-bromo-arylacetylenes with aqueous ammonia and sequential intramolecular cyclization. The
convenience and atom economy of aqueous ammonia, and the low cost of the copper catalytic system
make this protocol readily superior in practical application.
Introduction
Indoles are one of the most ubiquitous and important structural
components found in many biologically-active compounds and
natural products.1 Because of this, a large number of methods
have been developed to provide access to a generally applicable
synthesis of this structural motif.2 In this context, transition metal
catalysis has played a remarkable and ever growing role. Recently
developed metal-catalyzed processes have proved complementary
to conventional indole syntheses and allowed reactions to be per-
formed under remarkably mild reaction conditions,3 particularly
Scheme 1 Tandem synthesis of free N-H indoles from 2-bromo-
protocols relying on addition reactions of nitrogen nucleophiles
arylacetylenes.
onto alkynes.4
The previous use of masked ammonia apparently suffers from
low atom economy and the need for an additional deprotecting
step to liberate the primary aryl amine.3a–c Ammonia is considered
one of the most interesting commodity chemicals due to its great
abundance and extremely low cost. Copper-catalyzed amination
with ammonium hydroxide as the nucleophile that allows the
direct transformation of easily accessible 2-arylhaloarenes into
the corresponding free N-H indole derivatives is perhaps the most
convenient route (Scheme 1). Recently, the palladium- and copper-
catalyzed amination of aryl halides with ammonia has gained
increased attention.5
various ligands, copper catalysts, solvents and bases. We realized
that the reaction seemed to be affected by sterically-hindered ortho-
substituents generating some amount of the reduction by-product
1,2-diphenylethyne in most cases. While the most promising
preliminary results were obtained using proline and imine as the
supporting ligand, we observed that the latter provided superior
conversion (100%) and yield (78%) (Scheme 2, L8). We postulated
that the key point to achieving this transformation is the excellent
Results and discussion
We initially tested the amination reaction of 1-bromo-2-
(phenylethynyl)benzene with aqueous ammonia (1 mL) by apply-
ing 10 mol% of CuI in dimethylsulfoxide (DMSO, 1 mL) at 100 ◦C
in a closed vessel. The investigated reaction parameters included
State Key Laboratory of Fine Chemicals, College of Chemical Engineering,
Dalian University of Technology, Dalian, 116012, China. E-mail: ymli@
dlut.edu.cn, cyduan@dlut.edu.cn; Fax: +86 411-84986295; Tel: +86 411-
84986295
† Electronic supplementary information (ESI) available: Full experimental
procedures and characterization data. See DOI: 10.1039/c1ob05549f
Scheme 2 Ligands screened in the amination reaction.
Org. Biomol. Chem., 2011, 9, 4983–4986 | 4983
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 1 The effect of different catalysts, bases and solventsa
Table 3 Synthesis of 2-arylindoles with different acetylene substituentsa
Entry
Cu catalyst
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
CuCl
Cu(OAc)2
Cu2O
Cu(acac)2
Cu(OTf)2
Cu(OOCCF3)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
80 (20)
86 (13)
78 (22)
87 (13)
90 (10)
88 (12)
85 (15)
87 (13)
30 (–)
Entry
1
Aryl bromide
Indole
Yield (%)
87
3a
3b
3c
9
10
DMF
60 (–)
2
3
4
5
85
84
87
83
a Reaction conditions: 1-Bromo-2-(phenylethynyl)benzene (0.4 mmol),
[Cu] (0.04 mmol), L8 (0.08 mmol), base (0.5 mmol), aq. NH3 (1.0 mL)
and solvent (1.0 mL) stirred at 100 ◦C for 18 h under Ar. b GC yield
(1,2-diphenylethyne observed).
Table 2 Effect of the volume ratio of aq. NH3/DMSOa
3d
3e
Entry
Aq. NH3 : DMSO
Yield (%)b
1
2
3
4
5
6
1 : 9
1 : 3
2 : 3
1 : 1
2 : 1
3 : 1
70 (30)
88 (12)
92 (8)
90 (10)
50 (–)
6
7
3f
83
20 (–)
a Reaction conditions: 1-Bromo-2-(phenylethynyl)benzene (0.4 mmol),
Cu(OTf)2 (0.04 mmol), L8 (0.08 mmol), K2CO3 (0.5 mmol), aq. NH3 and
DMSO stirred at 100 ◦C for 18 h under Ar. b GC yield (1,2-diphenylethyne
observed).
3g
68c
coordination of ligand L8 to the Cu catalyst and its high solubility
in the aqueous DMSO system.6
8
9
3h
3i
3j
88c
83c
57
The development of an applicable ortho-hindered amination
procedure requires further assessment of the catalyst activity.
Studies revealed that reactions conducted with water-soluble
Cu(II) catalysts resulted in high reactivities in aqueous DMSO. It
was found that Cu(OTf)2 was the most efficient catalyst, producing
the corresponding primary aryl amine in 90% yield (Table 1, entry
5). Bases have an insignificant influence on the catalyst activity
(Table 1, entries 7 and 8), while solvents play an important role in
the chemical process (Table 1, entries 9 and 10). DMSO turns out
to be the most efficient solvent among the solvents DMF, NMP
and DMSO.
The effect of the volume ratio of aq. NH3 to DMSO on the model
reaction was further investigated. The results described below
indicate that the balance between the reactivity and selectivity
is important. Generally, the more that DMSO added, the higher
the reactivity and the lower the selectivity. Initially, increasing the
volume ratio of aq. NH3/DMSO resulted in a positive effect on the
reaction selectivity and yield (Table 2, entries 1–3). As expected, an
excess of ammonium hydroxide also introduced an excess of water
into the system, resulting in a low conversion. An aq. NH3/DMSO
volume ratio of 2 : 3 proved to be the best combination. In a typical
protocol, 10 mol% Cu(OTf)2, 20 mol% ligand L8 and K2CO3 in
DMSO/aq. NH3 (3 : 2) at 100 ◦C were employed.
10
a Reaction conditions: 2-Arylhaloarene (0.4 mmol), Cu(OTf)2 (0.04 mmol),
L8 (0.08 mmol), K2CO3 (0.5 mmol), aq. NH3 (1.0 mL) and DMSO (1.5 mL)
stirred at 100 ◦C for 18 h under Ar. b Reaction conditions: After removing
the water by extraction, the residue was treated with ZnBr2 (0.2 mmol) and
toluene (4 mL), and refluxed 110 ◦C for 6 h. c Refluxed at 110 ◦C for 15 h.
Sequential intramolecular cyclization via the addition reactions of
aryl amines with 2-ethynylarenes allowed the direct synthesis of
free N-H indoles in good yields. Of importance is that chloro,
fluoro, trifluoromethyl, trifluoromethoyl, methyl ketone, nitro
and thienyl substituents were well tolerated under the reaction
conditions employed (Table 3 and Table 4).
As shown in Table 3, under these conditions, the reaction toler-
ates a number of different substituents, either on the nucleophile
or the electrophile, providing the corresponding indole. In general,
different acetylene substituents on the 1-bromo-2-ethynylarene
have no significant influence at the amination stage, and both
electron-rich and electron-deficient arylacetylenes worked well, as
detected by GC or LC. However, for the stage of the nitrogen
To further exploit this new methodology, a tandem protocol
was developed for the conversion of 2-bromo-arylacetylenes to
2-arylindoles, where the initially formed 2-arylethynylaniline was
treated with toluene, facilitated by the Lewis acid catalyst ZnBr2.7
4984 | Org. Biomol. Chem., 2011, 9, 4983–4986
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 4 Synthesis of 2-arylindoles with different aryl bromidesa
reaction is also suggested (Table 4, 4d–4g). We also observed
that aryl bromides were more reactive substrates. Consequently,
amination reactions of aryl bromides with chloro substituents
showed an interesting chemoselectivity, proceeding exclusively at
the bromo group (Table 4, 4c and 4d).
Entry Aryl bromide
1
Indole
Yield (%)
4a 82
Conclusions
In conclusion, we have explored a convenient, efficient and
atom economic synthesis of free N-H 2-arylindoles from 2-
arylhaloarenes via a sequential amination and cyclization. By
applying this elegant protocol, a wide range of electron-rich and
electron-deficient 2-phenylindoles were obtained. We believe that
this simple and effective catalyst system will find wide applications
in the synthesis of related indoles.
2
3
4
4b 90
4c 82
4d 80
Experimental
General information
All reagents were obtained from commercial sources (>99%)
and used without further purification unless otherwise noted.
The reactions were carried out under an argon atmosphere and
the products were isolated by column chromatography on silica
gel (200–300 mesh) using petroleum ether (60–90 ◦C) and ethyl
acetate as eluates. Compounds described in the literature were
5
6
4e 69c
4f 69c
1
characterized by comparison of their H and 13C NMR spectra
7
8
9
4g 88c
4h 77c
4i 70c
with the reported data. 1H, 13C and 19F NMR spectra were
recorded in CDCl3 or DMSO-d6 and chemical shifts are reported
in parts per million relative to TMS. MS data were gathered on
a HP1100 instrument. High resolution mass spectrometric data
(HRMS) were gathered on an HPLC-Q-Tof MS. HPLC analyses
were tested on a Waters 2695–2996 instrument.
General procedure for the synthesis of 2-arylhaloarenes
a Reaction conditions: 2-Arylhaloarene (0.4 mmol), Cu(OTf)2 (0.04 mmol),
L8 (0.08 mmol), K2CO3 (0.5 mmol), aq. NH3 (1.0 mL) and DMSO (1.5 mL)
stirred at 100 ◦C for 18 h under Ar. b Reaction conditions: After removing
the water by extraction, the residue was◦treated with ZnBr2 (0.2 mmol)
and toluene (4 mL), and refluxed at 110 C for 6 h. c Refluxed at 110 ◦C
for 15 h.
2-Bromo-anilines were obtained from commercial sources or were
conveniently be prepared by the NBS bromination of anilines
along with a catalytic amount of ammonium acetate (NH4OAc)
in CH3CN, as described in the literature.8
2-Bromo-iodides were prepared based on the Sandmeyer reac-
tion, as described in the literature.3f
2-Arylhaloarenes were prepared based on the Sonogashira
coupling reaction, as described in the literature.9
addition reaction, the electron-deficient arylacetylenes proceeded
slower than the electron-rich and electron-neutral arylacetylenes
(Table 3, 3g–3i). In this situation, a longer time for complete
cyclization was required, presumably due to the reduced electron
density of the acetylene.
Under similar conditions, we were able to extend this copper
catalytic protocol to the coupling of ammonia with the aryl
bromide moiety bearing various functional groups. We found that
the electronic and steric effects of the attached groups at the aryl
bromide moiety were not ignored for either the initial amination or
the sequential cyclization. The yields of products bearing a strong
electron-withdrawing substituent were diminished (Table 4, 4e and
4f), a trend opposite to that observed for the copper-catalyzed
coupling of ammonia with aryl halides.5 The high reactivity
of the amination for electron-deficient aryl bromides was also
accompanied by an increase of the dehalogenation side reaction.
For the complete cyclization, prolonging the time of the addition
General procedure for the synthesis of 2-arylindoles
Amination. A flame-dried test tube with a magnetic stirring
bar was charged with 2-arylhaloarene (0.4 mmol), Cu(OTf)2
(0.04 mmol), picolinaldehyde oxime (0.08 mmol), K2CO3
(0.5 mmol) and aq. NH3 (1.0 mL) in DMSO (1.5 mL), and stirred
at 100 ◦C under argon. The mixture was reacted at 100 ◦C for
18 h and then cooled to room temperature. The resulting mixture
was extracted with ethyl acetate (3 ¥ 25 mL). The combined
organic layers were dried over Na2SO4 and then concentrated
under vacuum.
Cyclization. The residue was direct treated with ZnBr2
(0.2 mmol) and toluene (4 mL), and refluxed at 110 ◦C for 6
or 15 h. After cyclization completion had been detected by HPLC,
the toluene was removed under vacuum and the residue then
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 4983–4986 | 4985
©

View Article Online
purified by column chromatography on silica gel with an eluent
of petroleum ether and ethyl acetate. All the physical data of the
known compounds were in agreement with values reported in the
literature.
Education Department of Liaoning Province (2009S021), and the
Program for Changjiang Scholars and Innovative Research Team
in University (IRT0711).
2-(3,5-Dimethoxyphenyl)-1H-indole (3e)
References
Following the general procedure, the crude product was purified
by a silica gel column using ethyl acetate/petroleum ether (1 : 5–
1 : 1), giving a pale orange solid. Yield: 83 mg, 83%. H NMR
(400 MHz, CDCl3): d = 8.36 (br, 1H), 7.62 (d, J = 7.6, 1H), 7.38
(d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H),
6.81–6.80 (m, 3H), 6.4 (s, 1H), 3.86 (s, 6H). 13C NMR (100 MHz,
CDCl3) d = 161.2, 137.8, 136.7, 134.3, 129.1, 122.4, 120.7, 120.3,
110.9, 103.6, 100.4, 99.7, 55.5. HR-ESI-MS: [M - H]- m/z calc.
for C16H14NO2 252.1025, found: 252.1023. GC-MS (EI) m/z: 253
(M+, 100%). m.p.: 124–125 ◦C.
1 G. Evano, N. Blanchard and M. Toumi, Chem. Rev., 2008, 108, 3054–
3131.
2 (a) G. Fabrizi, Chem. Rev., 2005, 105, 2873–2920; (b) G. R. Humphrey
and J. T. Kuethe, Chem. Rev., 2006, 106, 2875–2911; (c) S. Cacchi,
G. Fabrizi and A. Goggiamani, Org. Biomol. Chem., 2011, 9, 641–
652.
3 (a) B. Z. Lu, W. Y. Zhao, H. X. Wei, M. Dufour, V. Farina and C. H.
Senanayake, Org. Lett., 2006, 8, 3271–3274; (b) L. Ackermann, S.
Barfusser and H. K. Potukuchi, Adv. Synth. Catal., 2009, 351, 1064–
1072; (c) R. C. Hodgkinson, J. Schulz and M. C. Willis, Org. Biomol.
Chem., 2009, 7, 432–434; (d) H. Sakai, K. Tsutsumi, T. Morimoto and
K. Kakiuchi, Adv. Synth. Catal., 2008, 350, 2498–2502; (e) N. Halland,
M. Nazare, O. R’kyek, J. Alonso, M. Urmann and A. Lindenschmidt,
Angew. Chem., Int. Ed., 2009, 48, 6879–6882; (f) T. Jensen, H. Pedersen,
B. Bang-Andersen, R. Madsen and M. Jorgensen, Angew. Chem., Int.
Ed., 2008, 47, 888–890; (g) S. D. Yang, C. L. Sun, Z. Fang, B. H. Li,
Y. Z. Li and Z. J. Shi, Angew. Chem., Int. Ed., 2008, 47, 1473–1476;
(h) N. Halland, M. Nazare, J. Alonso, O. R’kyek and A. Lindenschmidt,
Chem. Commun., 2011, 47, 1042–1044.
1
1-(2-Phenyl-1H-indol-6-yl)ethanone (4f)
Following the general procedure, the crude product was purified by
a silica gel column using ethyl acetate/petroleum ether (1 : 5–1 : 1),
1
giving a orange solid. Yield: 65 mg, 69%. H NMR (400 MHz,
4 (a) C. Koradin, W. Dohle, A. L. Rodriguez, B. Schmid and P. Knochel,
Tetrahedron, 2003, 59, 1571–1587; (b) K. Hiroya, S. Itoh and T.
Sakamoto, J. Org. Chem., 2004, 69, 1126–1136; (c) N. Sakai, K. Annaka
and T. Konakahara, Org. Lett., 2004, 6, 1527–1530; (d) N. Sakai, K.
Annaka, A. Fujita, A. Sato and T. Konakahara, J. Org. Chem., 2008,
73, 4160–4165; (e) V. Terrasson, J. Michaux, A. Gaucher, J. Wehbe, S.
Marque, D. Prim and J. M. Campagne, Eur. J. Org. Chem., 2007, 5332–
5335; (f) E. Tyrrell, L. Whiteman and N. Williams, Synthesis, 2009,
829–835; (g) Y. Yin, W. Y. Ma, Z. Chai and G. Zhao, J. Org. Chem.,
2007, 72, 5731–5736; (h) J. S. Kim, J. H. Han, J. J. Lee, Y. M. Jun, B. M.
Lee and B. H. Kim, Tetrahedron Lett., 2008, 49, 3733–3738.
5 (a) Y. Aubin, C. Fischmeister, C. M. Thomas and J.-L. Renaud, Chem.
Soc. Rev., 2010, 39, 4130–4145; (b) J. L. Klinkenberg and J. F. Hartwig,
Angew. Chem., Int. Ed., 2011, 50, 86–95; (c) Q. L. Shen and J. F. Hartwig,
J. Am. Chem. Soc., 2006, 128, 10028–10029; (d) D. S. Surry and S. L.
Buchwald, J. Am. Chem. Soc., 2007, 129, 10354–10355; (e) G. D. Vo
and J. F. Hartwig, J. Am. Chem. Soc., 2009, 131, 11049–11061; (f) J.
Kim and S. Chang, Chem. Commun., 2008, 3052–3054; (g) N. Xia and
M. Taillefer, Angew. Chem., Int. Ed., 2009, 48, 337–339; (h) H. H. Xu
and C. Wolf, Chem. Commun., 2009, 3035–3037; (i) D. P. Wang, Q. Cai
and K. Ding, Adv. Synth. Catal., 2009, 351, 1722–1726; (j) L. Q. Jiang,
X. Lu, H. Zhang, Y. W. Jiang and D. W. Ma, J. Org. Chem., 2009, 74,
4542–4546; (k) Z. Q. Wu, Z. Q. Jiang, D. Wu, H. F. Xiang and X. G.
Zhou, Eur. J. Org. Chem., 2010, 1854–1857; (l) R. J. Lundgren, B. D.
Peters, P. G. Alsabeh and M. Stradiotto, Angew. Chem., Int. Ed., 2010,
49, 4071–4074.
CDCl3) d = 8.84 (br, 1H), 8.14 (s, 1H), 7.76–7.72 (m, 3H), 7.65
(d, J = 8.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.6 Hz,
1H), 6.87 (s, 1H), 2.68 (s, 1H); 13C NMR (100 MHz, CDCl3)
d = 198.3, 141.8, 136.3, 133.2, 131.6, 131.5, 129.2, 128.6, 125.5,
120.8, 120.2, 111.9, 100.2, 26.84. HR-ESI-MS: [M + Na]+ m/z
calc. for C16H14NO2 258.0895, found: 258.0897. GC-MS (EI) m/z:
220 (100%), 235 (M+, 70%). m.p.: 212–213 ◦C.
2-Phenyl-6-(trifluoromethoxy)-1H-indole (4h)
Following the general procedure, the crude product was purified
by a silica gel column using ethyl acetate/petroleum ether (1 : 3),
1
giving a white solid. Yield: 85 mg, 77%. H NMR (400 MHz,
CDCl3) d = 8.36 (br, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.57 (d, J =
8.4 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H),
7.26 (s, 1H), 7.00 (dd, J1 = 8.0 Hz, J2 = 1.0 Hz, 1H), 6.80 (d, J =
1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d = 145.15, 139.43,
136.36, 131.88, 129.14, 128.12, 127.97, 125.19, 124.62, 121.88 (q,
J = 255 Hz, 1C), 114.39, 103.96, 99.87. 19F NMR (400 MHz,
CDCl3) d = -57.9. MS (API, m/z): 278.0 [M + H]+. HR-ESI-MS:
[M + H]+ m/z calc. for C16H11NOF3 278.0793, found: 278.0788.
m.p.: 167–168 ◦C.
6 H. J. Cristau, P. P. Cellier, J. F. Spindler and M. Taillefer, Eur. J. Org.
Chem., 2004, 695–709.
7 K. Okuma, J. Seto, K. Sakaguchi, S. Ozaki, N. Nagahora and K. Shioji,
Tetrahedron Lett., 2009, 50, 2943–2945.
8 B. Das, K. Venkateswarlu, A. Majhi, V. Siddaiah and K. R. Reddy,
J. Mol. Catal. A: Chem., 2007, 267, 30–33.
9 T. Kashiki, S. Shinamura, M. Kohara, E. Miyazaki, K. Takimiya, M.
Ikeda and H. Kuwabara, Org. Lett., 2009, 11, 2473–2475.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Project no. 20876021 and 20923006), the
4986 | Org. Biomol. Chem., 2011, 9, 4983–4986
This journal is
The Royal Society of Chemistry 2011
©