Assembly of indole-2-carboxylic acid esters through a ligand-free copper-catalysed cascade process

Article abstract of DOI:10.1039/b918345k

A straightforward synthesis of indole-2-carboxylic esters was developed through a ligand-free copper-catalysed condensation/coupling/deformylation cascade process from 2-halo aryl aldehydes or ketones with ethyl isocyanoacetate. The reactions proceeded we

Full text of DOI:10.1039/b918345k

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COMMUNICATION
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Assembly of indole-2-carboxylic acid esters through
a ligand-free copper-catalysed cascade processw
Qian Cai,*a Zhengqiu Li,b Jiajia Wei,a Chengyong Ha,b Duanqing Peia and Ke Ding*a
Received (in Cambridge, UK) 7th September 2009, Accepted 16th October 2009
First published as an Advance Article on the web 4th November 2009
DOI: 10.1039/b918345k
A straightforward synthesis of indole-2-carboxylic esters was
developed through a ligand-free copper-catalysed condensation/
coupling/deformylation cascade process from 2-halo aryl alde-
hydes or ketones with ethyl isocyanoacetate. The reactions
proceeded well for most of the 2-iodo-, bromo-, and chloro-
subtrates under room temperature or mild conditions.
Table 1 Reaction of 2-iodo- or 2-bromo benzenealdehyde with ethyl
isocyanoacetatea
Entry
X
Copper Salts Base
Solvent Time/h Yield (%)b
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
I
I
I
I
I
—
CuI
NaOH DMSO
6
6
6
6
6
6
12
n.d.c,d
77
73
The indole ring systems represent one class of the most
abundant and ubiquitous heterocycles in nature.1 Owing to
their structural diversity and remarkable biological functions,2
great efforts have been devoted to the development of methods
for synthesizing indoles during the last decade.3 The classic
approaches include Japp–Klingemann and Fischer indole
synthesis,4 reduction cyclization,5 metal-catalysed hetero-
annulation6 and others. Recently, copper-catalysed Ullmann-type
reactions have been extensively explored7 to assemble
indoles8–12 and other nitrogen-containing heterocycles.13 For
instance, 2,3-disubstituted indoles have been efficiently syn-
thesized by using copper-catalysed coupling of 2-haloaniline
or 2-halotrifluroacetanilides with b-keto esters or amides.8a,b,9
Despite much progress achieved for the synthesis of indole
derivatives, the preparation of some specific substituted
patterns remains difficult. It is still highly desirable to develop
new methods to further improve the synthetic efficiency for the
highly diversified indoles. Indole-2-carboxylic acid derivatives
have been reported to display a wide range of biological
functions such as cPLA2 inhibition (acid 1),14 histamine H4
receptor antagonism (amide 2),15 and HIV-1 inhibition (amide 3)
(Fig. 1).16 But straightforward methods are relatively rare for
readily and flexibly preparing indole-2-carboxylic acid
derivatives.12a,b In this paper, we describe an efficient method
for the synthesis of indole-2-carboxylic acid esters from 2-halo
aryl aldehydes or ketones catalysed condensation/coupling/
deformylation cascade process under mild conditions.
NaOH DMSO
NaOH DMSO
NaOH DMSO
NaOH DMSO
NaOH DMSO
NaOH DMF
NaOH Toluene 12
NaOH Dioxane 12
NaOH IPrOH
Cs2CO3 DMSO 24
K3PO4 DMSO 24
K2CO3 DMSO 24
NaOH DMSO 24
Cs2CO3 DMSO 24
CuBr
CuCl
Cu2O
CuSO4
CuI
CuI
CuI
CuI
CuI
45
o10e
o10
25
n.d.d
n.d.d
n.d.d
81
9
10
11
12
13
14
15
16
12
CuI
CuI
31
45
Br CuI
Br CuI
Br CuI
60f
66f
Cs2CO3 DMSO
4
70f,g
a
Reaction conditions: Cu salts (0.1 mmol), base (2.0 mmol), 2-iodo-
benzene aldehyde (1.0 mmol), ethyl isocyanoacetate (1.1 mmol),
b
solvent (1.0 mL), N2 atmosphere, room temperature. Isolated
c
yields. No copper salt was added. No desired products. 0.05 mmol
d
e
f
g
Cu2O. 20% CuI was added. 50 1C.
10 mol% CuI. However, only the condensated olefin was
isolated as the major byproduct and no desired product was
detected with the absence of CuI. Among several copper
sources examined, CuBr displayed a similar catalytic potency
to that of CuI. Others such as CuCl, Cu2O and CuSO4 were
less active (entries 4–6). Further investigation revealed that
DMSO was the optimal solvent (entries 2, 7–10). Condition
screening also suggested that both NaOH and Cs2CO3 were
highly efficient for the coupling reaction of 2-iodo or 2-bromo
benzenealdehyde at room temperature (entries 11–15).
Although 10 mol% CuI was sufficient to promote the room-
temperature cascade process for 2-iodo aryl aldehydes or
ketones,17 20 mol% CuI was required for the less active 2-bromo
substrates to obtain a good yield in 24 h (entries 14, 15). It is
worth mentioning that the reaction was significantly accelerated
under an elevating temperature of 50 1C (entry 16).
Under optimized conditions, the scope of the cascade
process was explored with various 2-bromo aryl aldehydes
or ketones.18 In general, almost all the tested substrates
successfully yielded the corresponding products with good to
excellent yields (Table 2). Interestingly, obviously better yields
were obtained for the ketone substrates. The reaction was
well tolerated with many other functional groups such as
The investigation was initiated by using the reaction of
2-iodo benzenealdehyde with ethyl isocyanoacetate as a model
(Table 1). We were pleased to find that 1H-indole-2-carboxylate
ethyl ester 5 was obtained in 77% yield under the catalysis of
a Key Laboratory of Regenerative Biology, Institute of Chemical
Biology, Guangzhou Institute of Biomedicine, Health, Chinese
Academy of Sciences, Guangzhou International Business Incubator
D-10, Guangzhou Science Park, Guangzhou, 510663, China.
E-mail: cai_qian@gibh.ac.cn, ding_ke@gibh.ac.cn;
Fax: (+)86-20-32290606
b Key Laboratory of Cellulose and Lignocellulosics Chemistry,
Guangzhou Institute of Chemistry, Chinese Academy of Sciences,
China
w Electronic supplementary information (ESI) available: Experimental
Section, 1H NMR, 13C NMR and HRMS spectra of all new
compounds. See DOI: 10.1039/b918345k
ꢀc
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contained heteroatoms were successfully produced when
2-bromo heteroaryl aldehydes or ketones were applied
(Table 2, entries 6, 7).
Although ligand-free conditions have recently been
explored in copper-catalysed cascade reactions to construct
quinazolinones,19a benzimidazoles19b and benzothiazoles,20
there are only a few successful examples for the use of aryl
chlorides as substrates.7 We further investigated the potential
reactivity of 2-chloro aryl aldehydes or ketones with ethyl
isocyanoacetate. As shown in Table 3, only a trace amount of
indole-2-carboxylic acid ester was detected when o-chlorobenzene
aldehyde 8a reacted with ethyl isocyanoacetate at room
temperature or 50 1C under the optimized combinations.
However, a 20% isolated yield was obtained when the
temperature was elevated to 80 1C (Table 3, entry 1).
Poly-substituted aldehyde 8b also gave a similar result
Fig. 1 Structures of representatives of pharmaceutically important
indole-2-carboxylic acid derivatives.
carboxylic ester, amide, halo, trifluromethyl group or nitro
groups etc. (Table 2, entries 4, 13, 14, 15 and 16). When
2,5-dibromobezne acetone was used as the substrate, only
5-bromo-3-methyl indole-2-carboxyliac acid ethyl ester 7n
was isolated (Table 2, entry 14). This may be due to the fact
that an intramolecular coupling was much more favoured. The
primary amine group or free hydroxyl group was detrimental
to the copper-catalysed cascade reaction, but it could be
compensated by a simple protection of the free amine or
hydroxyl groups (Table 2, entries 11 and 16). It is also
noteworthy that the corresponding products 7f and 7g, which
Table 3 Reaction of 2-chloro aryl aldehydes and ketones with ethyl
isocyanoacetatea
Table 2 Reactions of 2-bromo aryl aldehydes or ketones with ethyl
isocyanoacetatea
Entry
1
Substrate
Product
Yield (%)b
20c
Entry Product
Yield (%) Entry Product
Yield (%)b
2
3
20
45
1
75
63
74
9
65
2
3
10
11
83
4
56
85c
5
6
7
8
9
57
56
60
42
45
4
5
60
72
12
13
45d
87
6
7
60
92
94
14
15
16
90
32e
91
10
66
77
8
11
a
Reaction conditions: CuI (0.1 mmol), Cs2CO3 (2.0 mmol), aryl
bromides (1.0 mmol), ethyl isocyanoacetate (1.1 mmol), DMSO
a
b
c
Reaction conditions: CuI (0.2 mmol), Cs2CO3 (2.0 mmol), aryl
chlorides (1.0 mmol), ethyl isocyanoacetate (1.1 mmol), DMSO
(1.0 mL), N2 atmosphere, 50 1C, 4 h. Isolated yields. Trace product
for the substrate with free hydroxyl on the aryl ring. Performed at
e
room temperature. Similar result was available at room temperature.
d
b
c
(1 mL), N2, 80 1C. Isolated yields. Trace product at R.T. or 50 1C.
ꢀc
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(Table 3, entry 2). Similar to that of 2-iodo or 2-bromo
substrates, the ketones gave much better results (Table 3,
entries 3–11). For example, 45% of ethyl 3-methyl-1H-
indole-2-carboxylate (7h) was obtained when 1-(2-chlorophenyl)-
ethanone (8c) was used as the substrate. The unusual
thienopyrrole carboxyliac acid esters (9h and 7g) were also
successfully synthesized by using 1-(2-chlorothiophen-3-yl)
ketones as the substrates (Table 3, entries 10 and 11). Of note,
thienopyrroles have been used as templates for the discovery
of selective human histamine H4 antagonists or other bio-
active molecules,21a which required several separated steps to
construct the core structure.21
Ed., 2003, 42, 5400; (b) I. P. Beletskaya and A. V. Cheprakov,
Coord. Chem. Rev., 2004, 248, 2337–2364; (c) J. Lindley,
Tetrahedron, 1984, 40, 1433; (d) G. Evano, N. Blanchard and
M. Toumi, Chem. Rev., 2008, 108, 3054.
8 (a) Y. Chen, Y. Wang, Z. Sun and D. Ma, Org. Lett., 2008, 10, 625;
(b) Y. Chen, X. Xie and D. Ma, J. Org. Chem., 2007, 72, 9329;
(c) F. Liu and D. Ma, J. Org. Chem., 2007, 72, 4844.
9 S. Tanimori, H. Ura and M. Kirihata, Eur. J. Org. Chem., 2007,
3977.
10 C. Cacchi, G. Fabrizi and L. M. Parisi, Org. Lett., 2003, 5, 3843.
11 (a) Y. Ohta, S. Oishi, N. Fujii and H. Ohno, Org. Lett., 2009, 11,
1979; (b) Y. Ohta, H. Chiba, S. Oishi, N. Fujii and H. Ohno,
Org. Lett., 2008, 10, 3535.
12 (a) C. Barberis, T. D. Gordon, C. Thomas, X. Zhang and
K. P. Cusack, Tetrahedron Lett., 2005, 46, 8877; (b) K. Okano,
H. Tokuyama and T. Fukuyama, J. Am. Chem. Soc., 2006, 128,
7136; (c) S. Wang, J. Sun, G. Yu, X. Hu, J. O. Liu and Y. Hu, Org.
Biomol. Chem., 2004, 2, 1573.
13 For some recent studies on the syntheses of N-heterocycles by
using Ullmann-type couplings, see: (a) B. Zou, Q. Yuan and
D. Ma, Angew. Chem., Int. Ed., 2007, 46, 2598; (b) X. Yuan,
X. Xu, X. Zhou, J. Yuan, L. Mai and Y. Li, J. Org. Chem., 2007,
72, 1510; (c) F. Bonnaterre, M. Bois-Choussy and J. Zhu, Org.
Lett., 2006, 8, 4351; (d) R. Martin, R. Rodriguez and
S. L. Buchwald, Angew. Chem., Int. Ed., 2006, 45, 7079;
(e) G. Evindar and R. A. Batey, J. Org. Chem., 2006, 71, 1802;
(f) T. Yang, C. Lin, H. Fu, Y. Jiang and Y. Zhao, Org. Lett., 2005,
7, 4781.
In summary, an efficient ligand-free copper-catalysed
condensation/coupling/deformylation cascade process of
2-halo aryl aldehydes or ketones with ethyl isocyanoacetates
was described. The reactions performed well at room
temperature or 50 1C for iodo- and bromo-substituted substrates.
Chloride substituted substrates also successfully yielded the
desired indole-2-carboxylic acid esters with acceptable yields
when the temperature was elevated to 80 1C. Furthermore, the
reaction displayed excellent functional group compatibility
and high chemical selectivity in the presence of a broad range
of functional groups. Our report provides a highly straight-
forward method for the preparation of indole-2-carboxylic
acid esters under mild reaction conditions.
14 (a) M. Lehr, Arch. Pharm., 1996, 329, 386; (b) M. Lehr, J. Med.
Chem., 1997, 40, 2694.
15 J. A. Jablonowski, C. A. Grice, W. Chai, C. A. Dvorak,
J. D. Venable, A. K. Kwok, K. S. Ly, J. Wei, S. M. Baker,
P. J. Desai, W. Jiang, S. J. Wilson, R. L. Thurmond,
L. Karlsson, J. P. Edwards, T. W. Lovenberg and
N. I. Carruthers, J. Med. Chem., 2003, 46, 3957.
16 G. La Regina, A. Coluccia, F. Piscitelli, A. Bergamini, A. Sinistro,
A. Covazza, G. Maga, A. Samuele, S. Zanoli, E. Novellino,
M. Artico and R. Silverstri, J. Med. Chem., 2007, 50, 5034.
17 We also explored 2-iodobenzene ethyl ketone, which delivers the
corresponding product 7h with 78% yield at room temperature for
6 h.
18 All the aryl bromides tested in Table 2 were also tested at room
temperature and deliver the corresponding products with moderate
yields from 40–70% in 24 h, while 1-(5-amino-2-bromophenyl)
ethanone gave the product 7o at about 30% at room temperature.
19 (a) X. Liu, H. Fu, Y. Jiang and Y. Zhao, Angew. Chem., Int. Ed.,
2009, 48, 348; (b) D. Yang, H. Fu, L. Hu, Y. Jiang and Y. Zhao,
J. Org. Chem., 2008, 73, 7841.
We thank the Knowledge Innovation Program of the
Chinese Academy of Sciences, the 100-talent program of
CAS, National Natural Science Foundation (Grant
20802077, 90813033) and National High Technology Research
and Development Program (Grant 2008AA02Z420,
#
#
2009CB940904) for their financial support.
Notes and references
1 For recent reviews of indole containing natural products, see:
(a) T. Kawasaki and K. Higuchi, Nat. Prod. Rep., 2005, 22, 761;
(b) M. Somei and F. Yamada, Nat. Prod. Rep., 2004, 21, 278;
(c) M. Lounasmaa and A. Tolvanen, Nat. Prod. Rep., 2000, 17, 175.
2 For a review, see: D. A. Horton, G. T. Bourne and M. L. Smythe,
Chem. Rev., 2003, 103, 893.
20 D. Ma, S. Xie, P. Xue, X. Zhang, J. Dong and Y. Jiang, Angew.
Chem., Int. Ed., 2009, 48, 4222.
3 (a) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106,
2875; (b) S. Patil and J. K. Buolamwini, Curr. Org. Synth., 2006, 3,
477.
4 (a) B. Robinson, The Fiscer Indole Synthesis, Wiley-Interscience,
New York, 1982; (b) R. R. Phillips, Org. React., 1959, 10, 143.
5 (a) P. G. Tsoungas and A. I. Diplas, Curr. Org. Chem., 2004, 8,
21 (a) J. D. Venable, H. Cai, W. Chai, C. A. Dvorak, C. A. Grice,
J. A. Jablonowski, C. R. Shah, A. K. Kwok, K. S. Ly, B. Pio,
J. Wei, P. J. Desai, W. Jiang, S. Nguyen, P. Ling, S. J. Wilson,
P. J. Dunford, R. L. Thunmond, T. W. Lovenberg, L. Karlsson,
N. I. Carruthers and J. P. Edwards, J. Med. Chem., 2005, 48, 8289;
(b) W. W. Gale, A. N. Scott and H. R. Snyder, J. Org. Chem.,
1964, 29, 2160; (c) R. W. Friesen and J. A. Mancini, J. Med.
Chem., 2008, 51, 4059–4067; (d) J. B. Blair, D. Marona-Levicka,
A. Kanthasamy, V. L. Lucaites, D. L. Nelson and D. E. Nichols,
J. Med. Chem., 1999, 42, 1106–1111.
1579; (b) B. C. G. Soderberg, Curr. Org. Chem., 2000, 4, 727.
¨
6 (a) G. Zeni and R. C. Larock, Chem. Rev., 2006, 106, 4644;
(b) I. Ojima, M. Tzamarioudaki, Z. Li and R. J. Donovan, Chem.
Rev., 1996, 96, 635.
7 For recent reviews about copper-catalysed Ullmann-type coupling
reactions, see: (a) S. V. Ley and A. W. Thomas, Angew. Chem., Int.
ꢀc
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Chem. Commun., 2009, 7581–7583 | 7583