Copper catalysed domino decarboxylative cross coupling-cyclisation reactions: Synthesis of 2-arylindoles

Article abstract of DOI:10.1016/j.tetlet.2012.06.023

The efficient synthesis of 2-arylindoles and 6H-isoindolo[2,1-a]indol-6-one through copper catalysed domino sp-sp² decarboxylative cross-coupling and subsequent cyclisation reactions of arylpropiolic acids with 2-iodotrifluoroacetanilide has been described. This methodology also demonstrates that indolo[1,2-c]quinazolin-6(5H)-one can be obtained with the elimination of trifluoromethyl anion.

Full text of DOI:10.1016/j.tetlet.2012.06.023

Tetrahedron Letters 53 (2012) 4248–4252
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper catalysed domino decarboxylative cross coupling-cyclisation
reactions: synthesis of 2-arylindoles
Thanasekaran Ponpandian a,b, Shanmugam Muthusubramanian a,
⇑
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
b Orchid Chemicals and Pharmaceuticals Ltd, Department of Medicinal Chemistry, R&D Centre, Chennai 600119, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient synthesis of 2-arylindoles and 6H-isoindolo[2,1-a]indol-6-one through copper catalysed
domino sp-sp2 decarboxylative cross-coupling and subsequent cyclisation reactions of arylpropiolic acids
with 2-iodotrifluoroacetanilide has been described. This methodology also demonstrates that indolo-
[1,2-c]quinazolin-6(5H)-one can be obtained with the elimination of trifluoromethyl anion.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 18 April 2012
Revised 1 June 2012
Accepted 5 June 2012
Available online 12 June 2012
Keywords:
2-Alkynoic acid
2-Iodotrifluoroacetanilide
Decarboxylative cross-coupling
Domino reaction
Copper mediated reactions
Heterocyclic compounds, particularly indole, occur widely in
nature as partial structure of many alkaloids and have unique bio-
logical activities.1 2-Arylindole moiety has been found in many
biologically active molecules.2 Cycloisomerisation reaction of 2-
alkynylanilines using transition metal catalyst3 or Lewis acid4 or
strong base5 was one of the efficient methodologies for the synthe-
sis of 2-substituted indoles. Recently, Liu and Ma6 and Shen and
co-workers7 have independently synthesised the 2-substituted
indoles from protected 2-haloanilines and terminal alkynes using
cuprous iodide as the catalyst. Recently, decarboxylative couplings
have been found to be successful as one of the C–C bond construc-
tion process. The carboxyl group functionalised alkynes are easy to
handle, simple to store, have relatively high boiling point, and
therefore might serve as an alternative to terminal alkynes, which
are difficult to handle (e.g., methylacetylene with low boiling point
of ꢀ23 °C). Carboxylate groups can effectively function as a leaving
group in cross-coupling, in which carbon dioxide is produced as
the by-product.8 Though palladium catalysed decarboxylative cou-
pling reactions are well known, the copper-only-mediated reac-
tions are not very popular. A catalytic domino sequence would
be the attractive method towards developing efficient protocols
that minimise the requisite reagents, solvents, time, separation
processes, cost for the desired transformation and the formation
of waste.9 To the best of our knowledge, there are no reports
describing the decarboxylative coupling to access 2-substituted
indole related skeleton. Inspired by this a decarboxylative route
for preparing 2-substituted indole has been developed and the ob-
served interesting results are presented in this Letter.
Cuprous chloride catalysed decarboxylation of propiolic acids
has been recently reported10 and cuprous iodide/amino acid cata-
lytic system has been used in the cross coupling of aryl and vinyl
halides with various nucleophiles.11 We hypothesised that the
decarboxylative cross coupling and cyclisation of alkynyl carbox-
ylic acids with 2-iodotrifluoroacetanilide could be achieved using
a copper/amino acid catalytic system under proper conditions.
Initially the coupling of 2-iodotrifluoroacetanilide (1a) with phenyl
propiolic acid (2a) has been studied as a model reaction (Table 1).
Liu and Ma6 have found this trifluoroacetyl system is quite suitable
for this type of reactions and hence 1a has been chosen for the
present work. No product was obtained, when the reaction was
performed with (i) cuprous iodide (5 mol %) with
(15 mol %)/potassium carbonate (2 equiv) at 60 °C and (ii) cuprous
iodide (5 mol %) with -proline (15 mol %)/Et3N (2 equiv) at 80 °C in
L-proline
L
DMF (Table 1, entries 1 & 2). However, the expected product, 2-
phenylindole (3a), was obtained in 58% yield when tetra n-butyl-
ammonium fluoride (2 equiv) was used as the base (Table 1, entry
3) whereas 65% of 3a was obtained when potassium carbonate was
used as the base (Table 1, entry 4). Among the catalysts tested, all
copper(I) salts such as CuI, CuCl, CuBr and CuCN showed catalytic
activities (Table 1, entries 4–7). Cuprous bromide was found to
be the best catalyst among the copper salts. The
based ligands were then optimised to improve the yield of 3a
(Table 1, entries 8–10) and -proline gave better yield. This
a-amino acid
L
optimised condition consumed long reaction time (about 15 h)
and gave moderate yield (75%) (Table 1, entry 6). To minimise
⇑
Corresponding author. Tel.: +91 452 2458246; fax: +91 452 2459845.
E-mail address: muthumanian2001@yahoo.com (S. Muthusubramanian).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.023

T. Ponpandian, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 4248–4252
4249
Table 1
Optimisation of reaction conditiona
O
I
O
OH
Cu(I), Ligand
solvent, base
Sealed tube, N2 atm
N
H
CF3
N
H
1a
2a
3a
Entry
Cu(I) (5 mol %)
Ligand (15 mol %)
Base (2 equiv)
Solvent
T (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
CuI
K2CO3
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
60
80
80
80
80
80
80
24
24
15
15
24
15
24
N/R
N/R
58
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
L-Proline
CuI
CuI
TBAFꢁH2O
K2CO3
K2CO3
K2CO3
K2CO3
CuI
65
CuCl
CuBr
CuCN
60
75
55
8
9
10
CuBr
CuBr
CuBr
N,N-Dimethyl glycine
N-Methyl glycine
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
80
80
80
24
24
24
64
62
68
L
L
L
L
L
L
L
-4-Hydroxy proline
11
12
13
14
15
16
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMSO
DMA
H2O
100
120
120
100
100
100
7
76
-Proline
3
73
75c
-Proline
0.5
3
-Proline
90
-Proline
7
63
-Proline
24
N/R
-Proline
a
All of the reactions were carried out with substrate 1a (5 mmol), 2a (5 mmol), copper catalyst (5 mol %), ligand (15 mol %) and base (10 mmol) in the solvent (10 mL)
under N2 atmosphere in a sealed tube.
b
Isolated yield.
Microwave condition.
c
the reaction time, the reaction was conducted at higher tempera-
ture and also under microwave condition. The reaction got
completed in 7 h at 100 °C and 3 h at 120 °C, but under the latter
condition, the yield was slightly decreased (Table 1, entry 12) com-
pared to the former one (Table 1, entry 11). When the reaction was
carried out under microwave irradiation at 120 °C, 75% of 3a was
obtained requiring 30 min for complete conversion (Table 1, entry
13). DMSO was found superior to other solvents tested, which
afforded excellent yield of 3a at 100 °C in 3 h (Table 1, entry 14).
The green solvent water was not effective in bringing out this
transformation (Table 1, entry 16).
The scope of this methodology was extended to other arylpropi-
olic acids 2 and differently substituted 2-iodotrifluoroacetanilides,
1 (Table 2). Several methods are available for the synthesis of aryl-
propiolic acids 2 and the arylpropiolic acids employed in this
investigation were prepared by Sonogashira reaction12 at room
Table 2
Synthesis of 2-aryl substituted indolesa
O
CuBr (5 mol%)
R
I
R
O
OH
L-proline (15 mol%)
R'
+
R'
N
H
CF3
K2CO3 (2 equ), DMSO
100 oC, 3 h
N
H
1
2
3
Entry
Iodide 1
Alkynoic acid 2
Product 3
Yieldb (%)
1
2
3
4
5
6
7
8
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = H, 1a
R = COOCH3, 1b
R = CN, 1c
R = Br, 1d
R0 = 3,4-Difluorophenyl, 2b
R’ = 3-Fluoro-4-ethoxyphenyl, 2c
R0 = 3-Bromophenyl, 2d
R0 = 4-Bromophenyl, 2e
R0 = 4-Chlorophenyl, 2f
R0 = 2-Fluorophenyl, 2g
R0 = 4-Carboxyphenyl, 2h
R0 = 4-Methoxycarbonylphenyl, 2i
R0 = 3-Methoxycarbonylphenyl, 2j
R0 = 4-Nitrophenyl, 2k
R0 = 2-Thienyl, 2l
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
80
85
88
84
90
81
70
75
84
79
71
76
78
86
9
10
11
12
13
14
R0 = Phenyl, 2a
R0 = Phenyl, 2a
R0 = Phenyl, 2a
a
Reaction condition: alkynoic acid 2 (5 mmol), 1 (5 mmol), CuBr (5 mol %),
Isolated yield.
L
-proline (15 mol%) and K2CO3 (10 mmol) in DMSO (10 mL) at 100 °C for 3 h.
b

4250
T. Ponpandian, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 4248–4252
O
Pd(PPh3)2Cl2 (2 mol%)
O
OH
CuI (4 mol%)
i-Pr2NH (2.5 equ)
DMF, rt, 5 h
Ar
+
Ar
I
OH
2
Ar = Phenyl/ 3,4-Difluorophenyl/ 3-Fluoro-4-ethoxyphenyl/ 3 or 4-Bromophenyl/
2-Fluorophenyl/ 4-Carboxyphenyl/ 3 or 4-Methoxycarbonylphenyl/ 4-Nitrophenyl/
2-Thienyl/ 2-Trifluoroacetamidophenyl
Scheme 1. Synthesis of arylpropiolic acids.
temperature. A reaction between aryl iodide and propiolic acid in
the presence of Pd(PPh3)2Cl2/CuI catalytic system afforded the re-
quired arylpropiolic acids (Scheme 1). As shown in Table 2, various
alkynyl carboxylic acids and 2-iodotrifluoroacetanilide derivatives
smoothly underwent sequential reactions to afford the desired
product 3 in good to excellent yields.13 Interestingly when arylpro-
piolic acid bearing the carboxyl group was subjected to the reac-
tion, sp-decarboxylation is preferred over sp2-decarboxylation
(Table 2, entry 7). The heteroaryl alkynoic acid also undergoes this
transformation in good yield (Table 2, entry 11). Reaction with
alkylpropiolic acid, 2-butynoic acid, afforded moderate yield of
the desired product 4 (Scheme 2). The corresponding alkyne, meth-
ylacetylene, may not undergo this transformation. In the case of
2-butynoic acid, copper acetylide formed after decarboxylation
and undergo sequential reactions with stoichiometric amount of
2-butynoic acid.
As shown in Table 2, the reaction between 2-iodotrifluoroacet-
anilide and 3-(4-(methoxycarbonyl)phenyl)propiolic acid or 3-
(3-(methoxycarbonyl)phenyl)propiolic acid afforded the desired
indole nucleus (Table 2, entries 8 & 9). However when the
methoxycarbonyl group is at the ortho position of the phenyl ring,
an isoindolone derivative, 6H-isoindolo[2,1-a]indol-6-one (5), was
obtained in good yield (Scheme 2) through a sequential decarboxy-
lative cross coupling–cycloisomerisation–cyclisation reactions. 6H-
Isoindolo[2,1-a]indol-6-one is the core structure for a number of
biologically active compounds14 and it was also used as the inter-
mediate for the synthesis of NorA efflux pump inhibitors.2d,15
This protocol was further applied to the reaction between 2-tri-
fluoroacetamido phenyl propiolic acid and 2-iodotrifluoroacetani-
lide which afforded indolo[1,2-c]quinazolin-6(5H)-one 7 in 60%
yield, instead of the expected quinazoline nucleus 6 through the
elimination of water (Scheme 2). Interestingly, the elimination of
R = CH3
N
H
4
, 50%
H3COOC
R =
O
I
O
OH
+
R
F3C
N
H
(2m)
N
O
2
1a
5
86%
F3COCHN
R =
(2n)
H2O
N
N
F3C
6
N
H
HN
O
F3C
N
CHF3
N
H
O
7
60%
Reaction condition: CuBr (5 mol%), L-proline (15 mol%), K2CO3 (2 equ), DMSO, 100 oC, 5 h
Scheme 2. Reaction between 2-alkynoic acid and 2-iodotrifluoroacetanilide.

T. Ponpandian, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 4248–4252
4251
O
OH
CuBr (5 mol%)
L-proline (15 mol%)
I
+
OH
+
K2CO3 (2 equ)
DMF, 100 oC,15 h
O
O
O
O
O
8
9
Scheme 3. Reaction between 2-iodobenzoic acid and phenylpropiolic acid.
3. (a) Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org. Chem. 1966, 31, 4071; (b)
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S.; Sakamoto, T. J. Org. Chem. 1997, 62, 6507; (d) Rodrigues, L.; Koradin, C.;
Dohle, W.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2488; (e) Sanz, R.;
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trifluoromethyl anion (as fluoroform) has been noticed, which is a
very rare phenomenon.16 The structure of indolo[1,2-c]quinazo-
lin-6(5H)-one 7 was confirmed by spectral data (ESI-MS, 1H NMR,
13C NMR and FT IR) and also matched with the previously
reported.17 Recently, Ma’s group18 have synthesised the 2-trifluo-
romethylindole and 2-trifluoromethylbenzimidazole derivatives
from 2-iodotrifluoroacetanilide with ethyl acetoacetate and pri-
mary amine respectively using CuI/L-proline catalytic system,
where no case of trifluoromethyl anion elimination has been
reported.
When the reaction between 2-iodobenzoic acid and phenylpro-
piolic acid was effected under same condition, either 8 or 9 were
not obtained. But when DMF was used as the solvent instead of
DMSO, a mixture of isocoumarin 8 and phthalide 9 was obtained
in equal amount with an overall yield of 52% (Scheme 3).
In summary, we have developed the methodology for the syn-
thesis of 2-aryl indoles related skeleton starting from propiolic acid
and aryl iodides. This conversion tolerates a wide range of func-
tional groups which can be useful for further synthetic transforma-
tion. Additionally, the synthesis of 6H-isoindolo[2,1-a]indol-6-one
and [1,2-c]quinazolin-6(5H)-one has been achieved under the
same condition. The described protocol is more convenient for
the preparation of the target compounds in comparison with the
literature methods2–7 and good to excellent yields can be achieved
using readily available starting materials.
6. Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844.
7. Wang, R.; Mo, S.; Lu, Y.; Shen, Z. Adv. Synth. Catal. 2011, 353, 713.
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A.; Park, S. A.; Lee, Y.; Chi, K. W.; Jung, Y. H.; Kim, I. S. J. Org. Chem. 2011, 76,
2214; (c) Moon, J.; Jang, M.; Lee, S. J. Org. Chem. 2009, 74, 1403; (d) Pan, D.;
Zhang, C.; Ding, S.; Jiao, N. Eur. J. Org. Chem. 2011, 2011, 4751; (e) Yeung, P. Y.;
Chung, K. H.; Kwong, F. Y. Org. Lett. 2011, 13, 2912; (f) Zhao, D.; Gao, C.; Su, X.;
He, Y.; You, J.; Xue, Y. Chem. Commun. 2010, 46, 9049; (g) Moon, J.; Jeong, M.;
Nam, H.; Ju, J.; Moon, J. H.; Jung, H. M.; Lee, S. Org. Lett. 2008, 10, 945; (h)
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2010, 75, 1550; (i) Yu, M.; Pan, D.; Jia, W.; Chen, W.; Jiao, N. Tetrahedron Lett.
2010, 51, 1287; (j) Luo, J.; Lu, Y.; Liu, S.; Liu, J.; Deng, G. J. Adv. Synth. Catal. 2011,
353, 2604; (k) Goossen, L. J.; Rodriguz, N.; Gooban, K. Angew. Chem., Int. Ed.
2008, 47, 3100; (l) Kim, H.; Lee, P. H. Adv. Synth. Catal. 2009, 351, 2827; (m) Li,
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Acknowledgments
The authors thank DST, New Delhi for assistance under the IRH-
PA program for the NMR facility at Madurai Kamaraj University,
Orchid Chemicals and Pharmaceuticals Ltd for providing facilities
and Dr. Sridharan Rajagopal of Orchid research laboratory for his
support.
9. Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
10. Kolarovic, A.; Faberova, Z. J. Org. Chem. 2009, 74, 7199.
11. (a) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276; (b) Ma, D.; Cai,
Q. Acc. Chem. Res. 2008, 41, 1450.
12. (a) Newman, M. S.; Merrill, S. H. J. Am. Chem. Soc. 1955, 77, 5549; (b) Gooben, L.
J.; Rodriguez, N.; Manjolinho, F.; Lange, P. P. Adv. Synth. Catal. 2010, 352, 2913;
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13. General procedure for the synthesis of 3, 4, 5, 7, 8 and 9. To a mixture of
Pd(PPh3)2Cl2 (2 mol %), CuI (4 mol %) and DMF (15 mL) taken in a flask, aryl
iodide (10 mmol), propiolic acid (12 mmol) and diisopropylamine (25 mmol)
were added in that sequence under nitrogen atmosphere. After stirring the
reaction mixture at room temperature for 5 h, the resulting mixture was
diluted with ethyl acetate, filtered through celite bed, the filtrate was washed
with cold aqueous KOH solution (1 ꢂ 100 mL) and acidified with dilute sulfuric
acid (10% solution) at 0 °C. The solid obtained was extracted with
dichloromethane and the extract was washed with water, brine solution and
dried over anhydrous sodium sulfate. The organic layer was concentrated in
vacuo at 40 °C, dried to get the arylpropiolic acid. Arylpropiolic acid (5 mmol)
or 2-butynoic acid (5 mmol) was transferred into a 30 mL glass tube and then
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 06.
023.
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iodo compound (5 mmol), L-proline (15 mol %), cuprous bromide (5 mol %) and
potassium carbonate (10 mmol) in DMSO or DMF (10 mL) were added in that
order. The sealed tube was then subjected to a vacuum and refilled with
nitrogen for five times under stirring at room temperature. The tube was
placed in an oil bath and heated with stirring at 100 °C for 3–5 h. After the
reaction, the reaction mixture was mixed with ethyl acetate and washed with
water, brine solution and dried over anhydrous sodium sulfate. Removal of the

4252
T. Ponpandian, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 4248–4252
solvent in vacuo and purification of the residue by silica-gel column
chromatography with hexane/ethyl acetate afforded the desired product. See
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