Facile access to polysubstituted indoles via a cascade Cu-catalyzed arylation - Condensation process

Article abstract of DOI:10.1021/jo702059q

(Chemical Equation Presented) CuI/L-proline-catalyzed cross-coupling of 2-halotrifluoroacetanilides with β-keto esters and amides followed by in situ acidic hydrolysis delivered 2,3-disubstituted indoles. The halides bearing a strong electron-withdrawing

Full text of DOI:10.1021/jo702059q

Facile Access to Polysubstituted Indoles via a Cascade Cu-Catalyzed
Arylation-Condensation Process
Yu Chen,† Xiaoan Xie,† and Dawei Ma*,‡
Department of Chemistry, Fudan UniVersity, Shanghai 200433, China, and State Key Laboratory of
Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Lu, Shanghai 200032, China
madw@mail.sioc.ac.cn
ReceiVed September 19, 2007
CuI/L-proline-catalyzed cross-coupling of 2-halotrifluoroacetanilides with â-keto esters and amides followed
by in situ acidic hydrolysis delivered 2,3-disubstituted indoles. The halides bearing a strong electron-
withdrawing group in the 4-position can undergo in situ basic hydrolysis to provide the corresponding
indoles. Polysubstituted indoles can be prepared from substituted 2-halotrifluoroacetanilides with high
regioselectivity.
SCHEME 1. Assembly of Indoles via Coupling of
o-Haloaniline Derivatives and Alkynes
Introduction
The indole structure is probably the most common heterocycle
found in natural products.1 Substituted indoles have been
referred to as “privileged structures” owing to their excellent
binding ability to many receptors.2a This fact led to a great
number of efforts in elaborating and functionalizing indoles over
the past few decades.2-4 From the numerous methods developed
for indole synthesis, one of the most attractive procedures
involves the condensation of o-haloaniline derivatives with
terminal alkynes (Scheme 1)2,5-6 due to the ease of preparation
* Corresponding author. Fax: 86-21-64166128.
† Fudan University.
and modification. However, as this process only delivers
2-substituted indoles 2,5,6 this fact promoted further research
efforts to elaborate 2,3-disubstituted indoles.7 Direct construction
of 2,3-disubstituted indoles 3 from o-haloanilines was achieved
by a palladium-catalyzed reaction of o-haloaniline derivatives
‡ Chinese Academy of Sciences.
(1) For reviews, see: (a) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005,
22, 761. (b) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278. (c)
Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175.
(2) (a) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875. (b)
Kuethe, J. T. Chimia 2006, 60, 543. (c) Horton, D. A.; Bourne, G. T.;
Smythe, M. L. Chem. ReV. 2003, 103, 893 and references cited therein.
(3) For reviews, see: (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1
2000, 1045. (b) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491.
(4) For selected recent examples, see: (a) Saito, A.; Kanno, A.; Hanzawa,
Y. Angew. Chem., Int. Ed. 2007, 46, 3931. (b) Ohno, H.; Ohta, Y.; Oishi,
S.; Fujii, N. Angew. Chem., Int. Ed. 2007, 46, 2295. (c) Trost, B. M.;
McClory, A. Angew. Chem., Int. Ed. 2007, 46, 2074. (d) Cariou, K.; Ronan,
B.; Mignani, S.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2007,
46, 1881. (e) Taber, D. F.; Tian, W. J. Am. Chem. Soc. 2006, 128, 1058.
(5) (a) Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163. (b)
Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org. Chem. 1966, 31, 4071.
(c) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997, 62, 6507.
(6) For recent examples, see: (a) Hiroya, K.; Matsumoto, S.; Sakamoto,
T. Org. Lett. 2004, 6, 2953. (b) Sakai, N.; Annaka, K.; Konakahara, T.
Org. Lett. 2004, 6, 1527. (c) Sun, L.; Huang, X.; Dai, W. Tetrahedron
2004, 60, 10983. (d) Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003,
5, 3843. (e) Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4884.
(7) (a) Lu, B. Z.; Zhao, W.; Wei, H.; Dufour, M.; Farina, V.; Senanayake,
C. H. Org. Lett. 2006, 8, 3271. (b) Nakamura, M.; Ilies, L.; Otsubo, S.;
Nakamura, E. Org. Lett. 2006, 8, 2803. (c) Arcadi, A.; Cacchi, S.; Fabrizi,
G.; Marinelli, F.; Parisi, L. M. J. Org. Chem. 2005, 70, 6213. (d) Amjad,
M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 539. (e) Yue, D.; Larock,
R. C. Org. Lett. 2004, 6, 1037.
10.1021/jo702059q CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/02/2007
J. Org. Chem. 2007, 72, 9329-9334
9329

Chen et al.
with internal alkynes.8 Although this is an efficient process and
has been used widely for the preparation of complex indoles,9
it suffers from poor regioselectivity for most substrates.
During our studies of the amino acid promoted Ullmann
reaction, we recently revealed that in some cases an ortho-
substituent effect, directed by NHCOR (amido) groups, enables
the coupling of 2-halotrifluoroacetanilides with phenols,10
2-methyl acetoacetates,11 and primary amines12 to occur at room
temperature or even -45 °C. We envisaged that, under the
influence of an ortho-substituent effect, coupling of 2-iodotri-
fluoroacetanilides 4 with â-keto esters13 should proceed smoothly
affording amides 5, which, upon hydrolysis under basic or acidic
conditions, would generate anilines 6 in which the free amine
would attack the ketone moiety spontaneously to provide 2,3-
disubstituted indoles 7 (Scheme 2). Indeed, two groups have
attempted to assemble 2,3-disubstituted indoles via the Cu-
promoted coupling of 2-iodoaniline with â-keto esters and
â-diketones, but their coupling reactions required higher tem-
peratures (120-130 °C), and only two examples were exam-
ined.14
and 0.5 mL of water. To our delight, this reaction provided the
desired indole 7a in 73% yield at room temperature after 5 h
(Table 1, entry 1). Encouraged by this result, we examined the
reaction by using different iodides and â-keto esters. Some
functionalized â-keto esters, such as benzyl substituted and
olefin embodied â-keto esters 8b and 8c and ethyl 4-benzoxy-
acetoacetate 8d, gave rise to the corresponding 2,3,5-trisubsti-
tuted indoles in satisfactory yields (Table 1, entries 2-4). Under
the same conditions, â-keto amide 8e provided indole 7e in
nearly quantitative yield (Table 1, entry 5).
Good results were also observed with iodides 4b and 4c that
bear ester and nitro groups at the 4-position (Table 1, entries
6-8). However, when 2-iodo-5-acyl-trifluoroacetanilide 4d was
utilized, 2,3,6-trisubstituted indole 7i was isolated in only 51%
yield (entry 9), indicating that the position of the electron-
withdrawing group at the 4- or 5-position of 2-iodotrifluoro-
acetanilides has some influence on the reaction process. In this
case, a side product 9a was produced in about 38% yield, most
likely resulting from deacylation of the corresponding coupling
product 5i under basic conditions (Scheme 3). This side reaction
was also observed by Parkinson and co-workers in their CuI-
catalyzed coupling of aryl iodides and ethyl acetoacetate.13g
Formation of 9a illustrates that in this case, the cleavage step
of the trifluoroacetanilide moiety is slow. This is understandable
because the trifluoroacetanilide moiety in 4d is more stable
toward basic hydrolysis than in 4a. The importance of the
electronic effect to this reaction process was also demonstrated
by the fact that 2-iodo-4-chlorotrifluoroacetanilide 4e gave a
poor yield of 7j (together with about a 30% yield of 9b; Table
1, entry 10).
SCHEME 2. Elaboration of 2,3-Disubstituted Indoles via a
Cascade Coupling-Condensation Process
SCHEME 3. Deacylation of â-Keto Esters 5i and 5j
Results and Discussion
Considering that the trifluoroacetanilide moiety can be cleaved
by basic hydrolysis, we initially tried to run this cascade process
by introducing water to our previous reaction system.13c
Accordingly, the reaction of 2-iodo-4-acyltrifluoroacetanilide
4a with â-keto ester 8a was conducted using 10% mol CuI, 20
mol % L-proline, and 4 equiv of Cs2CO3 in 0.5 mL of DMSO
The requirement of a strong electron-withdrawing group at
the 4-position of 2-iodotrifluoroacetanilides, to ensure quick
base-induced hydrolysis, limits the scope of the present indole
formation process. To overcome this drawback, we decided to
try acidic conditions to produce indoles from the coupling
reaction products. Thus, a CuI/L-proline-catalyzed coupling
reaction of 2-iodo-4-methyltrifluoroacetanilide 4f with 8f was
carried out in DMSO at room temperature. It was found that
after 5 h, the reaction was complete, and the corresponding
coupling product was isolated in 85% yield, which was then
treated with a solution of 22% HCl in MeOH at 80 °C for 1-2
h, affording indole 7k in 84% yield. This result prompted us to
run these two steps in a one-pot reaction. We were pleased to
find that 7k could be isolated in 67% yield after adding 37%
HCl and methanol to the coupling reaction mixture and then
heating at 70 °C for 1 h (Table 2, entry 1).
The newly established reaction conditions offered a solution
to some problems we encountered before, which was evident
from the fact that a good yield of 7j was obtained from 4e via
the acid-induced hydrolysis strategy (Table 2, entry 2). However,
no improvement was observed when applying 4d (Table 2, entry
3), presumably due to heavy deacylation during the coupling
reaction. Using 2-iodo-trifluoroacetanilide 4g as the coupling
partner, a number of activated methylene compounds was tested.
(8) For selected examples, see: (a) Gathergood, N.; Scammells, P. J.
Org. Lett. 2003, 5, 921. (b) Zhou, H.; Liao, X.; Cook, J. M. Org. Lett.
2004, 6, 249. (c) Walsh, T. F.; Toupence, R. B.; Ujjainwalla, F.; Young, J.
R.; Goulet, M. T. Tetrahedron 2001, 57, 5233.
(9) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63,
7652.
(10) Cai, Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276.
(11) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050.
(12) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598.
(13) For recent studies on the CuI-catalyzed coupling between aryl halides
and activated methylene compounds, see: (a) Hennessy, E. J.; Buchwald,
S. L. Org. Lett. 2002, 4, 269. (b) Cristau, H.-J.; Cellier, P. P.; Spindler,
J.-F.; Taillefer, M. Chem.sEur. J. 2004, 10, 5607. (c) Xie, X.; Cai, G.;
Ma, D. Org. Lett. 2005, 7, 4693. (d) Jiang, Y.; Wu, N.; Wu, H.; He, M.
Synlett 2005, 2703. (e) Fang, Y.; Li, C. J. Org. Chem. 2006, 71, 6427. (f)
Lu, B.; Ma, D. Org. Lett. 2006, 8, 6115. (g) Zeevaart, J. G.; Parkinson, C.
J.; de Koning, C. B. Tetrahedron Lett. 2007, 48, 3289. (h) Lu, B.; Wang,
B.; Zhang, Y.; Ma, D. J. Org. Chem. 2007, 72, 5337.
(14) (a) Suzuki, H.; Thiruvikraman, S. V.; Osuka, A. Synthesis 1984,
616. (b) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J. Org. Chem.
1993, 58, 7606. During the submission of this manuscript, Tanimori and
co-workers disclosed their studies on the synthesis of indoles via binol-
promoted CuI-catalyzed coupling of 2-iodoaniline with â-keto esters, but
no substituted 2-iodoanilines were explored. See: Tanimori, S.; Ura, H.;
Kirhata, M. Eur. J. Org. Chem. 2007, 3977.
9330 J. Org. Chem., Vol. 72, No. 24, 2007

Facile Access to Polysubstituted Indoles
TABLE 1. Indole Synthesis via CuI/L-Proline-Catalyzed Coupling of 2-Iodotrifluoroacetanilides with â-Keto Esters and Amides with in Situ
Base-Induced Hydrolysisa
a Reaction conditions: iodide 4 (0.25 mmol), â-keto ester or acetoacetanilide 8 (0.5 mmol), CuI (0.025 mmol), L-proline (0.05 mmol), Cs2CO3 (1 mmol),
DMSO (0.5 mL), H2O (0.5 mL), rt, 5-24 h. b Isolated yield.
It was found that both R-aliphatic and R-aromatic â-keto esters
were suitable for this process, delivering the corresponding
2-alkyl and 2-aryl indoles in good yields (Table 2, entries 4-6).
It is noteworthy that t-butyl substituted â-keto ester 8h worked
well to afford indole 7m in 82% yield (Table 2, entry 5),
indicating that our method is suitable for the elaboration of
sterically hindered indoles.
12 in Table 2). Therefore, the process under acidic conditions
is more generally applicable than the one involving base-induced
hydrolysis.
We then explored if these two processes could be applied to
2-bromotrifluoroacetanilides (Table 3). It was found that the
coupling step was rather sluggish at room temperature, but
complete conversion could be achieved by raising the reaction
temperature to 30-50 °C. For substrates with an electron-
withdrawing group at the 4-position of 2-bromotrifluoroaceta-
nilides, using mixed solvents (DMSO/H2O) was useful for
cleaving the trifluoroacetanilide moiety and directly afforded
substituted indoles in good yields (Table 3, entries 1-3), while
bromides bearing no electron-withdrawing groups delivered the
desired indoles through acidic hydrolysis (Table 3, entries 4-7).
In conclusion, an efficient and high yielding cascade process
for the assembly of 2,3-substituted indoles was developed, based
on the CuI/L-proline-catalyzed coupling of 2-halotrifluoroac-
etanilides with â-keto esters and amides followed by in situ
acidic hydrolysis. It is noteworthy that this procedure can also
be carried out by in situ basic hydrolysis of the trifluoroaceta-
nilide moiety. However, this procedure requires a strong
electron-withdrawing group in the 4-position of the 2-halotri-
fluoroacetanilides. Various functional groups survived our
From â-keto amide 8e, indole 7o was prepared in 66% yield,
demonstrating that variations at the 3-position of indoles are
possible (Table 2, entry 7). Two 2-iodotrifluoroacetanilides
bearing a methoxy group at either the 4- or the 5-position were
compatible with the reaction conditions, leading to indoles 7p
and 7q in reasonable yields (Table 2, entries 8 and 9). While
2,4-diiodo-6-chlorotrifluoroacetanilide 4j was used, 2,3,5,7-
tetrasubstituted indole 7r was isolated as a single product (Table
2, entry 10), which provides further evidence that the ortho-
substituent effect of the NHCOCF3 group assists in the coupling
reaction. The 5-iodo group of 7r allows further coupling to
produce more diverse indoles. The orientation of the ester group
in 2-iodotrifluoroacetanilides seems to have little influence on
the outcome of the reaction under acidic conditions, as good
yields were observed from 4b and 4k (compare entries 11 and
J. Org. Chem, Vol. 72, No. 24, 2007 9331

Chen et al.
TABLE 2. Indole Synthesis via CuI/L-Proline-Catalyzed Coupling of 2-Iodotrifluoroacetanilides with â-Keto Esters and Amides Followed by
Acid-Induced Hydrolysisa
a Reaction conditions: iodide 4 (0.25 mmol), â-keto ester or acetoacetanilide 8 (0.5 mmol), CuI (0.025 mmol), L-proline (0.05 mmol), Cs2CO3 (1 mmol),
DMSO (0.5 mL), rt, 3-20 h; then 37% HCl (2 mL), MeOH (2 mL), 60-80 °C, 0.5-2.5 h. b Isolated yield.
TABLE 3. Indole Synthesis via CuI/L-Proline-Catalyzed Coupling of 2-Bromotrifluoroacetanilides with â-Keto Estersa
a Reaction conditions: bromide 10 (0.25 mmol), â-keto ester or acetoacetanilide 8 (0.5-0.75 mmol), CuI (0.05 mmol), L-proline (0.1 mmol), Cs2CO3 (1
mmol), DMSO (0.5 mL), H2O (0.5 mL, for entries 1-3), 30-50 °C, 24 h; then added was 37% HCl, MeOH, 60-80 °C, 1-2 h (for entries 4-7). b Isolated
yield. c Coupling step took 48 h.
9332 J. Org. Chem., Vol. 72, No. 24, 2007

Facile Access to Polysubstituted Indoles
7.80 (dd, J ) 1.4, 8.2 Hz, 1H), 8.72 (d, J ) 1.4 Hz, 1H), 11.13 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 21.68, 26.67, 30.18, 50.94,
103.77, 111.03, 122.43, 123.66, 126.76, 131.27, 137.64, 155.46,
165.95, 199.08; ESI-MS m/z 260 (M + H)+; HRMS calcd for
C15H17NO3 (M+) 259.1208, found 259.1206.
reaction conditions, including ketones, esters, and nitro, iodo,
olefin, chloro, and benzoxy moieties. Our method allows the
assembly of a wide range of substituted indoles in an efficient
manner, thereby providing a useful tool in organic synthesis.
Ethyl 5-Acetyl-2-benzyl-1H-indole-3-carboxylate 7b. 1H NMR
(400 MHz, d6-acetone) δ 1.41 (t, J ) 7.3 Hz, 3H), 2.60 (s, 3H),
4.38 (q, J ) 7.3 Hz, 2H), 4.59 (s, 2H), 7.12-7.45 (m, 6H), 7.80
(d, J ) 8.6 Hz, 1H), 8.79 (d, J ) 1.2 Hz, 1H), 11.15 (br s, 1H);
13C NMR (100 MHz, d6-acetone) δ 14.05, 25.88, 33.10, 59.40,
105.08, 111.30, 122.34, 123.28, 126.60, 126.82, 128.61, 128.81,
131.30, 138.21, 138.57, 148.12, 164.99, 197.06; ESI-MS m/z 322
(M + H)+; HRMS calcd for C20H19NO3 (M+) 321.1365, found
321.1366.
Ethyl 5-Acetyl-2-(but-3-enyl)-1H-indole-3-carboxylate 7c. 1H
NMR (400 MHz, CDCl3) δ 1.47 (t, J ) 7.3 Hz, 3H), 2.50-2.56
(m, 2H), 2.70 (s, 3H), 3.30 (t, J ) 7.3 Hz, 2H), 4.43 (q, J ) 7.3
Hz, 2H), 4.97-5.09 (m, 2H), 5.84-5.90 (m, 1H), 7.36 (d, J ) 8.8
Hz, 1H), 7.88 (dd, J ) 1.8, 8.8 Hz, 1H), 8.82 (s, 1H), 9.68 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 14.58, 26.77, 27.57, 33.19,
59.93, 105.24, 111.20, 116.07, 122.45, 123.91, 126.99, 131.23,
137.14, 137.79, 149.56, 165.68, 199.45; ESI-MS m/z 286 (M +
H)+; HRMS calcd for C17H19NO3 (M+) 285.1365, found 285.1368.
Experimental Section
General Procedure for the Synthesis of Polysubstituted
Indoles from Aryl Iodides via Base-Induced Hydrolysis. A
Schlenk tube was charged with aryl iodide (0.25 mmol), CuI (5
mg, 0.025 mmol), L-proline (6 mg, 0.05 mmol), and Cs2CO3 (326
mg, 1 mmol), evacuated, and backfilled with argon. A â-keto ester
or amide (0.5 mmol), DMSO (0.5 mL), and H2O (0.5 mL) were
successively added. The reaction mixture was stirred at room
temperature (rt) until the conversion was completed as monitored
by TLC (5-24 h). The mixture was partitioned between ethyl
acetate and saturated NH4Cl, and the organic layer was washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(eluting with 20:1 to 1:1 petroleum ether/ethyl acetate) to provide
the desired product.
General Procedure for the Synthesis of Polysubstituted
Indoles from Aryl Iodides via Acid-Induced Hydrolysis. A
Schlenk tube was charged with aryl iodide (0.25 mmol), CuI (5
mg, 0.025 mmol), L-proline (6 mg, 0.05 mmol), and Cs2CO3 (326
mg, 1 mmol), evacuated, and backfilled with argon. A â-keto ester
or amide (0.5 mmol) and DMSO (0.5 mL) were successively added.
The reaction mixture was stirred at rt until the conversion was
completed as monitored by TLC (3-20 h). To this solution, MeOH
(2 mL) and 37% HCl (2 mL) were added. The resultant mixture
was heated at 60-80 °C for 0.5-2.5 h. The cooled solution was
partitioned between ethyl acetate and water. NaHCO3 was added
to neutralize the solution to pH 7-8 before the organic layer was
separated. After being washed with water and brine, the solution
was dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (eluting with
20:1 to 1:1 petroleum ether/ethyl acetate) to provide the desired
product.
Ethyl 5-Acetyl-2-(benzyloxymethyl)-1H-indole-3-carboxylate
1
7d. H NMR (400 MHz, CDCl3) δ 1.44 (t, J ) 7.3 Hz, 3H), 2.68
(s, 3H), 4.40 (q, J ) 7.3 Hz, 2H), 4.71 (s, 2H), 5.13 (s, 2H), 7.20-
7.45 (m, 6H), 7.90 (d, J ) 8.6 Hz, 1H), 8.76 (s, 1H), 9.42 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 14.62, 26.71, 60.08, 65.73,
73.77, 104.35, 111.44, 122.76, 123.63, 126.66, 128.17, 128.33,
128.72, 131.65, 137.23, 137.35, 145.99, 165.21, 198.69; ESI-MS
m/z 352 (M + H)+; HRMS calcd for C21H21NO4 (M+) 351.1471,
found 351.1475.
5-Acetyl-2-methyl-N-phenyl-1H-indole-3-carboxamide 7e. 1H
NMR (400 MHz, d6-DMSO) δ 2.58 (s, 3H), 2.63 (s, 3H), 7.04 (t,
J ) 7.6 Hz, 1H), 7.29-7.33 (m, 2H), 7.43 (d, J ) 8.6 Hz, 1H),
7.72-7.79 (m, 3H), 8.41 (s, 1H), 9.76 (s, 1H), 12.01 (s, 1H); 13C
NMR (100 MHz, d6-DMSO) δ 13.77, 27.18, 110.55, 111.47,
120.45, 122.03, 123.53, 126.48, 129.12, 130.18, 138.00, 140.27,
141.82, 164.24, 198.02; ESI-MS m/z 293 (M + H)+; HRMS calcd
for C18H16N2O2 (M+) 292.1212, found 292.1213.
3-Ethyl 5-Methyl 2-Methyl-1H-indole-3,5-dicarboxylate 7f. 1H
NMR (400 MHz, d6-DMSO) δ 1.32 (t, J ) 7.3 Hz, 3H), 2.63 (s,
3H), 3.82 (s, 3H), 4.26 (q, J ) 7.3 Hz, 2H), 7.40 (d, J ) 8.7 Hz,
1H), 7.72 (dd, J ) 1.4, 8.7 Hz, 1H), 8.60 (s, 1H), 12.12 (s, 1H);
13C NMR (100 MHz, d6-DMSO) δ 14.29, 14.95, 52.34, 59.58,
104.23, 111.73, 122.81, 123.12, 123.30, 127.01, 138.03, 146.95,
165.17, 167.62; ESI-MS m/z 262 (M + H)+; HRMS calcd for
C14H15NO4 (M+) 261.1001, found 261.1005.
General Procedure for the Synthesis of Polysubstituted
Indoles from Aryl Bromides via Base-Induced Hydrolysis. A
Schlenk tube was charged with aryl bromide (0.25 mmol), CuI (10
mg, 0.05 mmol), L-proline (12 mg, 0.10 mmol), and Cs2CO3 (326
mg, 1 mmol), evacuated, and backfilled with argon. A â-keto ester
or amide (0.5 mmol), DMSO (0.5 mL), and H2O (0.5 mL) were
successively added. After the reaction mixture was stirred at 40-
50 °C for 24 h, it was partitioned between ethyl acetate and saturated
NH4Cl. The organic layer was washed with brine, dried over Na2-
SO4, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (eluting with 20:1 to 1:1 petroleum
ether/ethyl acetate) to provide the desired product.
Methyl 2-Methyl-3-(phenylcarbamoyl)-1H-indole-5-carboxy-
1
late 7g. H NMR (400 MHz, d6-DMSO) δ 2.60 (s, 3H), 3.80 (s,
3H), 6.98-7.78 (m, 7H), 8.40 (s, 1H), 9.73 (s, 1H), 11.90 (s, 1H);
13C NMR (100 MHz, d6-DMSO) δ 13.66, 52.31, 110.35, 111.53,
120.42, 121.96, 122.44, 122.92, 123.60, 126.64, 129.15, 137.95,
140.11, 141.58, 164.23, 167.75; ESI-MS m/z 309 (M + H)+; HRMS
calcd for C18H16N2O3 (M+) 308.1161, found 308.1162.
t-Butyl 2-Methyl-5-nitro-1H-indole-3-carboxylate 7h. 1H NMR
(400 MHz, d6-acetone) δ 1.64 (s, 9H), 2.72 (s, 3H), 7.49 (d, J )
8.7 Hz, 1H), 8.01 (dd, J ) 2.3, 8.7 Hz, 1H), 8.59 (d, J ) 2.3 Hz,
1H), 11.27 (br s, 1H); 13C NMR (100 MHz, d6-acetone) δ 13.28,
27.93, 79.84, 106.83, 111.22, 117.11, 117.34, 126.95, 138.08,
142.73, 147.39, 163.99; ESI-MS m/z 277 (M + H)+; HRMS calcd
for C14H16N2O4 (M+) 276.1111, found 276.1140.
Ethyl 6-Acetyl-2-benzyl-1H-indole-3-carboxylate 7i. 1H NMR
(400 MHz, CDCl3) δ 1.46 (t, J ) 7.3 Hz, 3H), 2.61 (s, 3H), 4.45
(q, J ) 7.3 Hz, 2H), 4.62 (s, 2H), 7.25-7.40 (m, 5H), 7.83 (d, J
) 8.8 Hz, 1H), 7.93 (s, 1H), 8.17 (d, J ) 8.8 Hz, 1H), 8.67 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 14.62, 26.88, 34.27, 59.98,
105.08, 111.78, 121.27, 122.30, 127.31, 129.15, 129.27, 131.28,
General Procedure for the Synthesis of Polysubstituted
Indoles from Aryl Bromides via Acid-Induced Hydrolysis. A
Schlenk tube was charged with aryl bromide (0.25 mmol), CuI (10
mg, 0.05 mmol), L-proline (12 mg, 0.10 mmol), and Cs2CO3 (326
mg, 1 mmol), evacuated, and backfilled with argon. A â-keto ester
(0.75 mmol) and DMSO (0.5 mL) were successively added. After
the resultant reaction mixture was stirred at 30-50 °C for 24-48
h, MeOH (2 mL) and 37% HCl (2 mL) were added, and then the
mixture was stirred at 60-80 °C for 1-2 h. The cooled solution
was partitioned between ethyl acetate and water. NaHCO3 was
added to neutralize the solution to pH 7-8 before the organic layer
was separated. After being washed with water and brine, the solution
was dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (eluting with 20:1
to 1:1 petroleum ether/ethyl acetate) to provide the desired product.
Methyl 5-Acetyl-2-isopropyl-1H-indole-3-carboxylate 7a. 1H
NMR (400 MHz, d6-acetone) δ 1.37 (d, J ) 7.3 Hz, 6H), 2.60 (s,
3H), 3.89 (s, 3H), 4.10-4.20 (m, 1H), 7.43 (d, J ) 8.2 Hz, 1H),
J. Org. Chem, Vol. 72, No. 24, 2007 9333

Chen et al.
131.80, 134.49, 136.95, 149.62, 165.28, 198.48; ESI-MS m/z 322
(M + H)+; HRMS calcd for C20H19NO3 (M+) 321.1365, found
321.1369.
Methyl 7-Chloro-5-iodo-2-isopropyl-1H-indole-3-carboxylate
7r. 1H NMR (400 MHz, CDCl3) δ 1.39 (d, J ) 7.3 Hz, 6H), 3.94
(s, 3H), 4.08-4.18 (m, 1H), 7.50 (d, J ) 1.4 Hz, 1H), 8.34 (d, J
) 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.63, 26.37, 51.08,
84.61, 103.58, 117.03, 129.14, 129.61, 130.24, 131.03, 154.55,
165.27; ESI-MS m/z 378 (M + H)+; HRMS calcd for C13H13NO2-
ClI (M+) 376.9679, found 376.9684.
Dimethyl 2-Isopropyl-1H-indole-3,5-dicarboxylate 7s. 1H NMR
(400 MHz, d6-acetone) δ 1.36 (d, J ) 7.3 Hz, 6H), 3.86 (s, 3H),
3.88 (s, 3H), 4.10-4.18 (m, 1H), 7.44 (d, J ) 8.7 Hz, 1H), 7.81
(dd, J ) 1.8, 8.7 Hz, 1H), 8.76 (s, 1H); 13C NMR (100 MHz, d6-
acetone) δ 21.90, 27.22, 50.94, 51.97, 103.85, 111.88, 124.01,
124.07, 124.51, 127.57, 138.75, 156.22, 166.08, 168.19; ESI-MS
m/z 276 (M + H)+; HRMS calcd for C15H17NO4 (M+) 275.1158,
found 275.1155.
3-Ethyl 6-Methyl 2-Phenyl-1H-indole-3,6-dicarboxylate 7t. 1H
NMR (400 MHz, d6-acetone) δ 1.24 (t, J ) 7.3 Hz, 3H), 3.88 (s,
3H), 4.24 (q, J ) 7.3 Hz, 2H), 7.47-7.80 (m, 6H), 8.18 (d, J )
0.9 Hz, 1H), 8.24 (d, J ) 8.2 Hz, 1H); 13C NMR (100 MHz, d6-
acetone) δ 13.77, 51.39, 59.30, 104.33, 113.57, 121.48, 122.26,
124.55, 127.97, 129.30, 130.01, 131.58, 131.86, 135.15, 147.43,
164.30, 167.02; ESI-MS m/z 324 (M + H)+; HRMS calcd for
C19H17NO4 (M+) 323.1158, found 323.1160.
Ethyl 2-(But-3-enyl)-5-methyl-1H-indole-3-carboxylate 7u. 1H
NMR (400 MHz, CDCl3) δ 1.44 (t, J ) 7.3 Hz, 3H), 2.46 (s, 3H),
2.46-2.51 (m, 2H), 3.23 (t, J ) 7.3 Hz, 2H), 4.40 (q, J ) 7.3 Hz,
2H), 4.99-5.10 (m, 2H), 5.81-5.92 (m, 1H), 7.01 (dd, J ) 1.4,
8.2 Hz, 1H), 7.19 (d, J ) 8.2 Hz, 1H), 7.93 (s, 1H), 8.52 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 14.69, 21.79, 27.62, 33.20,
59.57, 103.82, 110.39, 116.04, 121.30, 123.95, 127.55, 131.24,
132.86, 137.51, 147.55, 166.10; ESI-MS m/z 258 (M + H)+; HRMS
calcd for C16H19NO2 (M+) 257.1416, found 257.1419;
Ethyl 2-(But-3-enyl)-5-chloro-1H-indole-3-carboxylate 7j. 1H
NMR (400 MHz, CDCl3) δ 1.45 (t, J ) 7.3 Hz, 3H), 2.45-2.55
(m, 2H), 3.26 (t, J ) 7.3 Hz, 2H), 4.42 (q, J ) 7.3 Hz, 2H), 5.01-
5.12 (m, 2H), 5.80-5.92 (m, 1H), 7.12-7.28 (m, 2H), 8.09 (d, J
) 1.4 Hz, 1H), 8.64 (br, 1H); 13C NMR (100 MHz, CDCl3) δ 14.65,
27.46, 32.99, 59.85, 104.15, 111.15, 116.26, 121.17, 122.79, 127.62,
128.36, 132.94, 137.27, 148.81, 165.58; ESI-MS m/z 278 (M +
H)+; HRMS calcd for C15H16ClNO2 (M+) 277.0870, found 277.0874.
Ethyl 2,5-Dimethyl-1H-indole-3-carboxylate 7k. 1H NMR (400
MHz, d6-acetone) δ 1.37 (t, J ) 6.9 Hz, 3H), 2.38 (s, 3H), 2.67 (s,
3H), 4.30 (q, J ) 6.9 Hz, 2H), 6.93 (dd, J ) 1.4, 8.2 Hz, 1H), 7.21
(d, J ) 8.2 Hz, 1H), 7.84 (s, 1H); 13C NMR (400 MHz, d6-acetone)
δ 13.31, 14.16, 20.99, 58.68, 103.36, 110.60, 120.82, 123.18,
127.78, 129.95, 133.39, 144.10, 165.44; ESI-MS m/z 218 (M +
H)+; HRMS calcd for C13H15NO2 (M+) 217.1103, found 217.1100.
Methyl 2-Isopropyl-1H-indole-3-carboxylate 7l. 1H NMR (400
MHz, CDCl3) δ 1.36 (d, J ) 6.9 Hz, 6H), 3.94 (s, 3H), 4.11-4.15
(m, 1H), 7.20-7.35 (m, 3H), 8.11 (d, J ) 8.7 Hz, 1H), 8.68 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 21.90, 26.42, 50.91, 102.86,
110.88, 121.62, 121.85, 122.46, 127.17, 134.53, 153.81, 166.53;
ESI-MS m/z 218 (M + H)+; HRMS calcd for C13H15NO2 (M+)
217.1103, found 217.1104.
Methyl 2-t-Butyl-1H-indole-3-carboxylate 7m. 1H NMR (400
MHz, CDCl3) δ 1.62 (s, 9H), 3.94 (s, 3H), 7.19-7.40 (m, 3H),
8.10-8.12 (m, 1H), 8.57 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
28.64, 33.86, 50.97, 103.59, 110.83, 121.92, 121.98, 122.40, 128.47,
132.97, 154.56, 166.14; ESI-MS m/z 232 (M + H)+; HRMS calcd
for C14H17NO2 (M+) 231.1259, found 231.1261.
Ethyl 2-Phenyl-1H-indole-3-carboxylate 7n. 1H NMR (400
MHz, CDCl3) δ 1.29 (t, J ) 6.9 Hz, 3H), 4.26 (q, J ) 6.9 Hz,
2H), 7.20-7.61 (m, 8H), 8.20 (d, J ) 7.3 Hz, 1H), 8.82 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 14.41, 59.86, 104.61, 111.26,
122.13, 122.19, 123.24, 127.69, 128.15, 129.23, 129.72, 132.12,
135.32, 144.75, 165.66; ESI-MS m/z 266 (M + H)+; HRMS calcd
for C17H15NO2 (M+) 265.1103, found 265.1104.
Ethyl 2-(4-Acetyl-2-(2,2,2-trifluoroacetamido)phenyl)acetate
1
9a. H NMR (400 MHz, CDCl3) δ 1.31 (t, J ) 7.3 Hz, 3H), 2.62
(s, 3H), 3.73 (s, 2H), 4.22 (q, J ) 7.3 Hz, 2H), 7.38 (d, J ) 7.8
Hz, 1H), 7.83 (dd, J ) 1.4, 7.8 Hz, 1H), 8.45 (s, 1H), 10.23 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 14.03, 26.79, 39.05, 62.65,
124.87, 126.42, 131.31, 131.63, 134.72, 137.59, 155.66, 172.40,
197.00; ESI-MS m/z 335 (M + NH4)+; HRMS calcd for C14H14F3-
NO4 (M+) 317.0875, found 317.0871.
2-Methyl-N-phenyl-1H-indole-3-carboxamide 7o. 1H NMR
(400 MHz, d6-DMSO) δ 2.62 (s, 3H), 6.98-7.83 (m, 9H), 9.56 (s,
1H), 11.57 (s, 1H); 13C NMR (100 MHz, d6-DMSO) δ 13.68,
109.09, 111.51, 120.04, 120.25, 120.57, 121.72, 123.23, 126.78,
129.04, 135.23, 140.16, 140.42, 164.68; ESI-MS m/z 251 (M +
H)+; HRMS calcd for C16H14N2O (M+) 250.1106, found 250.1110.
Ethyl 6-Methoxy-2-phenyl-1H-indole-3-carboxylate 7p. 1H
NMR (400 MHz, CDCl3) δ 1.31 (t, J ) 7.3 Hz, 3H), 3.85 (s, 3H),
4.30 (q, J ) 7.3 Hz, 2H), 6.86 (d, J ) 2.0 Hz, 1H), 6.94 (dd, J )
2.0, 8.6 Hz, 1H), 7.42-7.46 (m, 3H), 7.63-7.67 (m, 2H), 8.10 (d,
J ) 8.6 Hz, 1H), 8.43 (br, 1H); 13C NMR (100 MHz, CDCl3) δ
14.42, 55.74, 59.77, 94.46, 104.74, 111.79, 121.89, 123.04, 128.21,
129.08, 129.61, 132.25, 136.01, 143.44, 157.12, 165.39; ESI-MS
m/z 296 (M + H)+; HRMS calcd for C18H17NO3 (M+) 295.1208,
found 295.1205.
Methyl 2-Isopropyl-5-methoxy-1H-indole-3-carboxylate 7q.
1H NMR (400 MHz, CDCl3) δ 1.35 (d, J ) 7.3 Hz, 6H), 3.87 (s,
3H), 3.93 (s, 3H), 4.05-4.13 (m, 1H), 6.84 (dd, J ) 2.8, 8.8 Hz,
1H), 7.22 (d, J ) 8.8 Hz, 1H), 7.63 (d, J ) 2.8 Hz, 1H), 8.54 (br
s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.78, 26.49, 50.71, 55.86,
102.76, 103.80, 111.40, 112.18, 128.07, 129.33, 153.96, 155.66,
166.32; ESI-MS m/z 248 (M + H)+; HRMS calcd for C14H17NO3
(M+) 247.1208, found 247.1206.
Ethyl 2-(5-Chloro-2-(2,2,2-trifluoroacetamido)phenyl)acetate
1
9b. H NMR (400 MHz, CDCl3) δ 1.23 (t, J ) 7.3 Hz, 3H), 3.55
(s, 2H), 4.14 (q, J ) 7.3 Hz, 2H), 7.18 (d, J ) 2.3 Hz, 1H), 7.26
(dd, J ) 2.3, 8.7 Hz, 1H), 7.75 (d, J ) 8.7 Hz, 1H), 10.07 (br s,
1H); 13C NMR (100 MHz, CDCl3) δ 14.02, 38.70, 62.61, 116.01
(q, J ) 287 Hz), 125.87, 128.08, 128.81, 131.06, 132.09, 132.95,
155.66 (q, J ) 37 Hz), 172.54; ESI-MS m/z 327 (M + NH4)+;
HRMS calcd for C12H11ClF3NO3 (M+) 309.0380, found 309.0385.
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation of
China (Grants 20621062 and 20572119) for their financial
support.
Supporting Information Available: Copies of 1H and 13C NMR
spectra for all new products. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO702059Q
9334 J. Org. Chem., Vol. 72, No. 24, 2007