Copper-catalyzed C-C bond formation through C-H functionalization: Synthesis of multisubstituted indoles from N-aryl enaminones

Article abstract of DOI:10.1002/anie.200902440

A variety of functionalities, including the whole range of halogen substituents, are tolerated in the title reaction, an intramolecular approach for the construction of a multisubstituted indole skeleton from readily available enaminones (see scheme; phen=1,10-phenanthroline). The indole products are also prepared directly in high yield from α, β-ynones and primary amines.

Full text of DOI:10.1002/anie.200902440

Communications
DOI: 10.1002/anie.200902440
Synthesis Design
À
À
Copper-Catalyzed C C Bond Formation through C H
Functionalization: Synthesis of Multisubstituted Indoles from N-Aryl
Enaminones**
Roberta Bernini, Giancarlo Fabrizi, Alessio Sferrazza, and Sandro Cacchi*
Because of the economic attractiveness and good functional
tolerance of copper-catalyzed methods and hence their
potential in large-scale applications, during the past few
years there have been remarkable advances in the use of
copper catalysis in organic synthesis. An impressive number
of Ullmann coupling reactions have been described starting
from aryl halides and suitable reagents.[1] Recent reports[2]
have shown that copper catalysis can also be used in the
by using CuI, Li2CO3, and 1,10-phenanthroline (phen) in
dimethyl acetamide (DMA) after 48 h (Table 1, entry 1).
Optimization studies were then performed that varied the
Table 1: Optimization of the reaction conditions.[a]
À
À
formation of C heteroatom and C C bonds through selective
À
catalytic activation of aryl C H bonds, a topic of intense
Entry
Base
Solvent
T [8C]
t [h]
Yield of 2a [%][b]
current interest that, for the most part, has witnessed the use
of palladium-, rhodium-, and ruthenium-based catalysts.[3] In
1
2
Li2CO3
Li2CO3
Li2CO3
Li2CO3
K2CO3
Cs2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
DMA
DMSO
1,4-dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
100
100
100
100
100
100
80
100
100
120
100
100
48
24
24
24
96
24
48
30
24
24
24
24
63
66
–
80
48
51
42
61
–
À
particular, intramolecular copper-catalyzed ortho C H func-
À
À
3[c]
4
tionalizations through C N and C O bond-forming reactions
have been shown to form benzimidazoles[2c] and benzoxazo-
les[2d] from amidines and anilides, respectively. Herein, we
disclose a new synthesis of multisubstituted indoles from
N-aryl enaminones that involves an intramolecular copper-
5
6
7[d]
8[e]
9[f]
10[g]
11[h]
12[i]
À
À
catalyzed aryl C H functionalization through C C bond
formation.[4] The indole moiety is prevalent in a vast array of
biologically active natural and nonnatural compounds. Con-
sequently, despite the existence of numerous methods for the
synthesis of indole derivatives,[5] the development of new,
more efficient procedures is a subject of great importance.
N-Aryl enaminones 1 were readily prepared through
Sonogashira cross-coupling of terminal alkynes with aroyl
chlorides,[6] followed by the conjugate addition of anilines
with the resultant a,b-ynones.[7]
–
50
73
DMF
DMF
[a] Unless otherwise stated, reactions were carried out on a 0.25 mmol
scale in 2.5 mL anhydrous solvent under an air atmosphere. [b] Yields of
isolated products. [c] 1a was recovered in 94% yield. [d] 1a was
recovered in 44% yield. [e] With 5 mol% phen. [f] Without CuI; 1a was
recovered in 91% yield. [g] Without phen, in the presence of 30% CuI; 1a
was recovered in 90% yield. [h] Under oxygen (balloon). [i] Under argon
(balloon).
We initiated our study by examining whether the enam-
inone 1a could be converted into the corresponding indole
2a. Reactions were usually carried out under an atmosphere
of air. After an initial screen of copper catalysts (CuSO4,
CuCl2, CuI), we found that 2a could be isolated in 63% yield
nature of solvents, bases, temperature, and the excess phen.
These investigations revealed that the utilization of dimethyl
sulfoxide (DMSO) gave a similar yield but in half the time
(Table 1, entry 2), whereas 1,4-dioxane led to the recovery of
the starting enaminone in almost quantitative yield (Table 1,
entry 3). A satisfactory result was obtained when dimethyl-
formamide (DMF) was used as solvent: 2a was isolated in
80% yield (Table 1, entry 4). The use of K2CO3 (Table 1,
entry 5) or Cs2CO3 (Table 1, entry 6) resulted in lower yields,
as did decreasing the reaction temperature (Table 1, entry 7)
or the excess phen (Table 1, entry 8). No indole formation was
observed upon omitting CuI (Table 1, entry 9) or phen even
after increasing the amount of CuI to 30 mol% and the
reaction temperature to 1208C (Table 1, entry 10). Interest-
ingly, compound 2a was isolated in only 50% yield when the
reaction was carried out under an atmosphere of oxygen
(Table 1, entry 11) and was formed in good yield under an
argon atmosphere (Table 1, entry 12).
[*] Prof. G. Fabrizi, Dr. A. Sferrazza, Prof. S. Cacchi
Dipartimento di Chimica e Tecnologie del Farmaco
Sapienza, Universitꢀ di Roma
P.le A. Moro 5, 00185 Roma (Italy)
Fax: (+39)06-4991-2780
E-mail: sandro.cacchi@uniroma1.it
Dr. R. Bernini
Dipartimento A.B.A.C., Universitꢀ degli Studi della Tuscia e
Consorzio Universitario “La Chimica per l’Ambiente”, Viterbo (Italy)
[**] This work was carried out in the framework of the National Projects
“Stereoselezione in Sintesi Organica: Metodologie ed Applicazioni”
supported by the Ministero dell’Universitꢀ e della Ricerca (MUR)
and by Sapienza, Universitꢀ di Roma.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902440.
8078
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 8078 –8081

Angewandte
Chemie
The scope and generality of the process was next explored
under the optimized conditions (Table 1, entry 4).[8] As shown
in Table 2, a great variety of enaminones can be converted
into the corresponding indoles. Several useful functional
groups are tolerated both in the enone and the N-aryl
fragment, including the whole range of halogen substituents.
The ability to incorporate the latter makes this reaction
particularly attractive for increasing the molecular complex-
Table 2: Copper-catalyzed synthesis of indoles 2 from enaminones 1.[a]
Entry
Product [yield in %][b]
Entry
14
Product [yield in %][b]
Entry
21
Product [yield in %][b]
1
2
H: 2a [80]
5-MeO,7-Me:
2m [68]
2s [83]
2b [84]
3
5-MeO:2c [76]
5-Me: 2d [84]
15
16
17
22
23
24
4
5
6
2n [72]
2o [57]
2t [66]
2u [75]
6-MeO/4-MeO
50:50: 2e [79]
5-F: 2 f [75]
5-Cl: 2g [53]
5-Br: 2h [60]
7
8
X=
2p [80]
2v [66]
9
5-I: 2i [72]
18
19
20
25
26
27
10
11
12
7-Br: 2j [51]
2q [58]
2w [76]
4,6-Me2: 2k [78]
6-EtO2C/4-EtO2C
64:36: 2l [82]
2r [65]
2x [56]
2y [56]
13
5-MeCO: [–]
[–][c]
[a] Reactions were carried out on a 0.25 mmol scale. [b] Yields of isolated products. [c] The starting N-methyl derivative of 1a was recovered in 90%
yield.
Angew. Chem. Int. Ed. 2009, 48, 8078 –8081
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8079

Communications
ity, for example by transition-metal-catalyzed coupling reac-
To make this overall approach to indoles more attractive
from a synthetic standpoint, we explored their formation
through a process that omits the isolation of the enaminone
intermediates. Addition of DMF and the reagents required
for the cyclization step to the crude methanolic mixture
resulting from the conjugate addition of the aniline to the a,b-
ynone led to moderate yields. For example, 2a was isolated in
only 50% overall yield after 48 h by using this protocol. In
addition, no indole product was formed when the overall
process was carried out with methanol or DMF as the sole
solvents for the two steps. Control experiments revealed that
the cyclization does not proceed in methanol and that the
enaminone product is not formed in DMF. Finally, we found
that good results could be obtained by adding DMF, CuI,
phen, and Li2CO3 to the crude mixture derived from the
reaction of anilines with a,b-ynones after evaporation of the
volatile materials. Under these conditions, 2a was isolated in
66% overall yield (Scheme 2).
tions. The presence of substituents at both meta positions of
the aniline fragment does not hamper the reaction (Table 2,
entries 11 and 14). However, when there is only one
substituent meta to the nitrogen atom, the cyclization affords
regioisomeric derivatives with both electron-donating
(Table 2, entry 5) and electron-withdrawing (Table 2,
entry 12) groups. No indole formation was observed with
the enaminone containing an acetyl group para to the
nitrogen atom (Table 2, entry 13). However, the appropri-
ately protected derivative afforded the desired product in
good yield (Table 2, entry 16). The cyclization of the
N-methyl derivative of 1a was also attempted. However, no
indole formation was observed and the starting material was
recovered almost unchanged (Table 2, entry 20).
The formation of 2j from the corresponding N-(2-
bromophenyl)enaminone 1j (Table 2, entry 10) is remarkable
in that 7-bromoindoles are key intermediates in the prepa-
ration of biologically active compounds via Suzuki–Miyaura
cross-coupling reactions.[9] Its formation is the result of a C H
À
activation process that is favored over the possible indole
À
À
formation through substitution of the C C bond for the C Br
bond.
À
À
This C H bond versus C Br bond selectivity represents a
distinct advantage of the present method and was found to
depend on a subtle combination of base and halide effects.
Control experiments revealed that the cyclization to give the
indole derivative occurs preferentially at the carbon atom
bound to Br when K2CO3 is substituted for Li2CO3
(Scheme 1). Under these conditions, no evidence of 2j was
obtained and the dehalogenated indole 3 was isolated in 30%
yield. Interestingly, the benzoxazepine product 4 was also
isolated in 36% yield. Most probably it is generated by an
Scheme 2. Synthesis of indoles from anilines and a,b-ynones omitting
the isolation of enaminone intermediates.
A plausible pathway for this indole synthesis is outlined in
Scheme 3. The reaction of 1 with CuI under basic conditions
presumably leads to the formation of complex A. The ate
complex B is subsequently formed through nucleophilic
attack of the ortho carbon atom of the aniline fragment to
copper promoted by the extraction of the hydrogen bound to
the carbon atom a to the carbonyl group. Protonation of B
followed by a rearomatization/tautomerization process leads
to the formation of C. The indole product 2 is generated by
reductive elimination of CuH, which reacts with the conjugate
acid of the base affording hydrogen and regenerating the
active copper catalytic species.
À
À
intramolecular C Br functionalization involving a C O
bond-forming reaction. When the enaminone 1j’, which
bears an o-iodo substituent on the aniline fragment, was
used as the starting substrate, only part of the reaction was
À
found to proceed through the C H functionalization pathway
in the presence of Li2CO3. The corresponding 7-iodoindole
was obtained in only 27% yield and the main product was the
dehalogenated indole 3. Use of K2CO3 as the base led to the
conversion of 1j’ into 3 in excellent yield and no evidence of
benzoxazepine was obtained.
Scheme 1. Influence of halide and carbonate base on the copper-
catalyzed cyclization of N-(2-halophenyl)enaminones.
Scheme 3. Possible reaction pathway for the copper-catalyzed cycliza-
tion of 1 to 2.
8080 www.angewandte.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 8078 –8081

Angewandte
Chemie
Landsberg, R. Vicente, Org. Lett. 2008, 10, 3081 – 3084; f) R. J.
Phipps, M. J. Gaunt, Science 2009, 323, 1593 – 1597.
To probe the action of a mechanism involving the
intermediacy of complex C and the subsequent reductive
elimination to afford CuH, we treated 1a under standard
conditions in the presence of methyl cinnamate. a,b-Unsatu-
rated esters are known to undergo conjugate reduction in the
presence of CuH intermediates generated in situ.[10] A slower
reaction rate was observed and 2a was isolated in 30% yield
after 24 h (compare with Table 1, entry 4). The starting
enaminone was recovered in 60% yield. Methyl 3-phenyl-
propanoate, derived from the reduction of the carbon–carbon
double bond, was isolated in 5% yield. This corresponds to
approximately 16% of reduced product that forms through
the intervention of CuH generated from C. An intramolecular
competition experiment using ortho-deuterium-labeled 1a
was also performed. This experiment allowed us to determine
the absence of an isotope effect (kH/kD = 1.0; 1008C),[11] which
suggests that a hydrogen-abstraction step does not occur in
the rate-limiting step. Both these results, combined with the
observation that the reaction does not require the presence of
oxygen (reactions were carried out under an atmosphere of
air for simplicity), are consistent with the proposed mecha-
nism.
[3] For recent reviews, see: a) V. Ritleng, C. Sirlin, M. Pfeffer,
Chem. Rev. 2002, 102, 1731 – 1769; b) J. Hassan, M. Sꢀvignon, C.
Gozzi, E. Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359 – 1469;
c) F. Kakiuchi, N. Chatani, Adv. Synth. Catal. 2003, 345, 1077 –
1101; d) D. Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007,
107, 174 – 238; For recent selected examples, see: [Pd] e) J. Zhao,
D. Yue, M. A. Campo, R. C. Larock, J. Am. Chem. Soc. 2007,
129, 5288 – 5295; f) S. Yang, B. Li, X. Wan, Z. Shi, J. Am. Chem.
Soc. 2007, 129, 6066 – 6067; g) K. Inamoto, T. Saito, M. Katsuno,
T. Sakamoto, K. Hiroya, Org. Lett. 2007, 9, 2931 – 2934; h) K. L.
Hull, M. S. Sanford, J. Am. Chem. Soc. 2007, 129, 11904 – 11905;
i) D. R. Stuart, E. Villemure, K. Fagnou, J. Am. Chem. Soc. 2007,
129, 12072 – 12073; j) S. Wꢁrtz, S. Rakshit, J. J. Neumann, T.
Drꢂge, F Glorius, Angew. Chem. 2008, 120, 7340 – 7343; Angew.
Chem. Int. Ed. 2008, 47, 7230 – 7233; k) T. Kesharwani, R. C.
Larock, Tetrahedron 2008, 64, 6090 – 6102; [Rh] l) B. J. Stokes,
H. Dong, B. E. Leslie, A. L. Pumphrey, T. G. Driver, J. Am.
Chem. Soc. 2007, 129, 7500 – 7501; m) K. Williams Fiori, J.
Du Bois, J. Am. Chem. Soc. 2007, 129, 562 – 568; n) J. C. Lewis,
R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc. 2007, 129, 5332 –
5333; [Ru] o) S. Oi, E. Aizawa, Y. Ogino, Y. Inoue, J. Org. Chem.
2005, 70, 3113 – 3119; p) L. Ackermann, A. Althammer, R. Born,
Angew. Chem. 2006, 118, 2681 – 2685; Angew. Chem. Int. Ed.
2006, 45, 2619 – 2622; q) Y. Matsuura, M. Tamura, T. Kochi, M.
Sato, N. Chatani, F. Kakiuchi, J. Am. Chem. Soc. 2007, 129,
9858 – 9859; r) S. Oi, R. Funayama, T. Hattori, Y. Inoue,
Tetrahedron 2008, 64, 6051 – 6059; s) L. Ackermann, M.
Mulzer, Org. Lett. 2008, 10, 5043 – 5045; t) L. Ackermann, R.
Vicente, A. Althammer, Org. Lett. 2008, 10, 2299 – 2302.
In conclusion, an efficient copper-catalyzed approach to
the construction of a multisubstituted indole skeleton from
readily available N-aryl enaminones has been developed. The
new method tolerates a variety of useful functionalities
including the whole range of halogen substituents. With
N-(2-bromophenyl)enaminone a remarkable selectivity was
[4] Recently, a synthesis of indoles from N-aryl enamines in the
À
absence of transition metals, via oxidative C C bond formation
À
observed that favors C H functionalization in comparison to
mediated by phenyliodine(III) diacetate, has been reported: W.
Yu, Y. Du, K. Zhao, Org. Lett. 2009, 11, 2417 – 2420.
[5] For reviews on the synthesis of indole derivatives, see: a) G. W.
Gribble, J. Chem. Soc. Perkin Trans. 1 2000, 1045 – 1075; b) S.
Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873 – 2920; c) G. R.
Humphrey, J. T. Kuethe, Chem. Rev. 2006, 106, 2875 – 2911; see
also: d) G. Zeni, R. C. Larock, Chem. Rev. 2004, 104, 2285 –
2309; e) F. Alonso, I. P. Beletskaya, M. Yus, Chem. Rev. 2004,
104, 3079 – 3159; f) I. Nakamura, Y. Yamamoto, Chem. Rev.
2004, 104, 2127 – 2198; g) L. Ackermann, Synlett 2007, 507 – 526;
h) K. Krꢁger (nꢀe Alex), A. Tillack, M. Beller, Adv. Synth.
Catal. 2008, 350, 2153 – 2167.
À
C Br functionalization and affords 7-bromoindoles, key
intermediates in the synthesis of biologically active com-
pounds. Indole products can also be prepared from a,b-
ynones and primary amines by a sequential process that omits
the isolation of the enaminone intermediates. Since multi-
substituted indoles are formed by assembling 2-haloaroyl
chlorides, terminal alkynes, and primary amines, a wide
variety of indole derivatives can be synthesized by using this
protocol, which can be particularly useful for the preparation
of compound libraries.
[6] A. S. Karpov, T. J. Mꢁller, Org. Lett. 2003, 5, 3451 – 3454.
[7] T. Sakamoto, T. Nagano, Y. Kondo, H. Yamanaka, Synthesis
1990, 215 – 218.
Received: May 7, 2009
Revised: July 22, 2009
Published online: September 22, 2009
[8] See the Supporting Information for data and more experimental
details.
[9] See, for example: a) M. Kaiser, M. Groll, C. Renner, R. Huber,
L. Moroder, Angew. Chem. 2002, 114, 817 – 820; Angew. Chem.
Int. Ed. 2002, 41, 780 – 783; b) A. Berthelot, S. Piguel, G.
Le Dour, J. Vidal, J. Org. Chem. 2003, 68, 9835 – 9838; c) N.
Basse, S. Piguel, D. Papapostolou, A. Ferrier-Berthelot, N.
Richy, M. Pagano, P. Sarthou, J. Sobczak-Thepot, M. Reboud-
Ravaux, J. Vidal, J. Med. Chem. 2007, 50, 2842 – 2850; d) R.
Faust, P. J. Garratt, M. A. Trujillo Pꢀrez, V. J.-D. Piccio, C.
Madsen, A. Stenstrom, B. Frolund, K. Davidson, M.-T. Teh, D.
Sugden, Bioorg. Med. Chem. 2007, 15, 4543 – 4551.
[10] a) D. H. Appella, Y. Moritani, R. Shintani, E. M. Ferreira, S. L.
Buchwald, J. Am. Chem. Soc. 1999, 121, 9473 – 9474; b) V.
Jurkauskas, J. P. Sadighi, S. L. Buchwald, Org. Lett. 2003, 5,
2417 – 2420.
[11] See the Supporting Information for measurement of the
deuterium isotope effect.
À
Keywords: C C coupling · copper · heterogeneous catalysis ·
indoles · synthesis design
.
[1] For recent reviews, see: a) S. V. Ley, A. W. Thomas, Angew.
Chem. 2003, 115, 5558 – 5607; Angew. Chem. Int. Ed. 2003, 42,
5400 – 5449; b) G. Evano, N. Blanchard, M. Toumi, Chem. Rev.
2008, 108, 3054 – 3131; c) C. Deutsch, N. Krause, B. H. Lipshutz,
Chem. Rev. 2008, 108, 2916 – 2927.
[2] a) X. Chen, X.-S. Hao, C. E. Goodhue, J.-Q. Yu, J. Am. Chem.
Soc. 2006, 128, 6790 – 6791; b) H.-Q. Do, O. Daugulis, J. Am.
Chem. Soc. 2007, 129, 12404 – 12405; c) G. Brasche, S. L.
Buchwald, Angew. Chem. 2008, 120, 1958 – 1960; Angew.
Chem. Int. Ed. 2008, 47, 1932 – 1934; d) S. Ueda, H. Nagasawa,
Angew. Chem. 2008, 120, 6511 – 6513; Angew. Chem. Int. Ed.
2008, 47, 6411 – 6413; e) L. Ackermann, H. K. Potukuchi, D.
Angew. Chem. Int. Ed. 2009, 48, 8078 –8081
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8081