Synthesis of β- And γ-carbolinones via Pd-catalyzed direct dehydrogenative annulation (DDA) of indole-carboxamides with alkynes using air as the oxidant

Article abstract of DOI:10.1021/ol1007839

A palladium-catalyzed direct dehydrogenative annulation (DDA) of indolecarboxamides with internal alkynes via C-H and N-H bond cleavage using air as the oxidant was developed. With this method, both β- and γ-carbolinones can be easily prepared under the mild conditions.

Full text of DOI:10.1021/ol1007839

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2908-2911
Synthesis of ꢀ- and γ-Carbolinones via
Pd-Catalyzed Direct Dehydrogenative
Annulation (DDA) of
Indole-carboxamides with Alkynes Using
Air as the Oxidant
Zhuangzhi Shi,† Yuxin Cui,*,† and Ning Jiao*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, Peking UniVersity, School of
Pharmaceutical Sciences, Peking UniVersity, Xue Yuan Road 38, Beijing 100083,
China, and Shanghai Key Laboratory of Green Chemistry and Chemical Processes,
Department of Chemistry, East China Normal UniVersity, Shanghai 200062, China
jiaoning@bjmu.edu.cn; yxcui@bjmu.edu.cn
Received April 5, 2010
ABSTRACT
A palladium-catalyzed direct dehydrogenative annulation (DDA) of indolecarboxamides with internal alkynes via C-H and N-H bond cleavage
using air as the oxidant was developed. With this method, both ꢀ- and γ-carbolinones can be easily prepared under the mild conditions.
ꢀ-Carbolinone skeletons are found in natural products (Figure
1), which have received considerable attention in view of
their remarkable biological and pharmacological activities.1
For example, the first naturally occurring ꢀ-carbolinone
secofascaplysin A, I, was isolated from the F. reticulata in
1991.2 SL651498, II, was identified as a drug development
candidate from a research program designed to discover
subtype-selective GABAA receptor agonists for the treatment
of generalized anxiety disorder and muscle spasms.3 How-
ever, in contrast, the isomeric γ-carbolinones are less
widespread. One γ-carbolinone ring system is presented in
indolonaphthyridone III, which acts as a conformationally
restricted 5-HT3 receptor antagonist.4
† Peking University.
‡ East China Normal University.
(1) (a) Larsen, L. K.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod.
1994, 57, 419. (b) Mouaddib, A.; Joseph, B.; Hasnaoui, A.; Merour, J.-Y.
Synthesis 2000, 549.
Figure 1. Structures of some biologically active ꢀ- and γ-carbolinones.
(2) Jimenez, C.; Quinoa, E.; Adamczeski, M.; Hunter, L. M.; Crews, P.
J. Org. Chem. 1991, 56, 3403.
(3) Griebel, G.; Perrault, G.; Simiand, J.; Cohen, C.; Granger, P.;
Depoortere, H.; Franc¸on, D.; Avenet, P.; Schoemaker, H.; Evanno, Y.;
Sevrin, M.; George, P.; Scatton, B. CNS Drug ReV. 2003, 9, 3.
The synthesis of ꢀ- and γ-carbolinones has attracted
considerable interest in recent years,5 among which the
10.1021/ol1007839  2010 American Chemical Society
Published on Web 06/01/2010

minimization of substrate preactivation in metal-catalyzed
processes led us to investigate the possibility of the direct
dehydrogenative annulation (DDA) of indolecarboxamides
with internal alkynes leading to ꢀ- and γ-carbolinone
derivatives.
Scheme 1. Retrosynthetic Analysis of ꢀ- and γ-Carbolinones
Table 1. Optimization of Reaction Conditions for the
Preparation of 3aaa
intramolecular cyclization through path a, b, or c is the most
common strategy (Scheme 1). For example, Beccalli et al.
described an intramolecular Heck reaction of 2- and 3-io-
doindole derivatives for the synthesis of ꢀ- or γ-carbolino-
nes.6 Padwa and co-workers developed an approach to
ꢀ-carbolinones in high yields through a AuCl3-catalyzed
cycloisomerization of N-propargylindole-2-carboxamides.7
However, several steps are generally required to prepare the
relative complicated substrates for these intramolecular
annulations. Alternatively, we envisioned that the ꢀ- and
γ-carbolinones presumably can be constructed through an
intermolecular annulation between indolecarboxamides and
alkynes via C-C and C-N bond formations (path d,
Scheme 1).
Compared with the traditional methods, C-H activation
presents an advantage of convenience and atom economy,
which has been applied successfully in synthesis of some
aromatic and heteroaromatic compounds such as naphtha-
lenes, indoles, isoquinolines, carbazoles, benzothiazoles, and
pyridines.8 Recently, we developed the direct dehydrogena-
tive annulation (DDA) of simple anilines or biaryls with
internal alkynes to generate indoles, carbazole, and carboline
derivatives using O2 as the oxidant.9 Our interest in the
additives
(equiv)
temp
(°C)
yield
(%)b
entry
oxidant
solvent
1
2
3
4
5
6
7c
8
O2 (1 atm)
O2 (1 atm)
O2 (1 atm)
air
air
air
s
DMF
DMF
DMA
DMA
DMA
DMA
DMA
DMA
100
100
100
100
100
100
100
50
18
58
69
70
76
86
72
92
K2CO3 (3.0)
K2CO3 (3.0)
K2CO3 (1.0)
CsOPiv (1.0)
TBAB (1.0)
TBAB (1.0)
TBAB (1.0)
air
air
a Reaction conditions: 1a (0.20 mmol), 2a (0.25 mmol), Pd(OAc)2 (0.02
mmol), and solvent (2.0 mL) were heated in an open tube for 15 h. DMF
) N,N-dimethylformamide, DMA ) N,N-dimethylacetamide, Piv ) pivalyl,
TBAB ) tetra-n-butylammonium-bromide. b Isolated yield. c 5 mol % of
Pd(OAc)2 was used.
We initiated this project by investigating the reaction of
N-butyl-1-methyl-1H-indole-2-carboxamide (1a) and diphe-
nylethyne (2a) catalyzed by Pd(OAc)2. When O2 was used
as the oxidant in this reaction, the expected ꢀ-carbolinone
product 3aa was successfully produced in 18% yield at 100
°C in DMF (entry 1, Table 1). To our delight, 58% of 3aa
was achieved in the presence of 3.0 equiv of K2CO3 (entry
2, Table 1). It is noteworthy that air could serve as the
oxidant as good as O2 in this reaction (cf. entries 3 and 4).
The reaction in DMA gave better results than that in DMF
(cf. entries 2 and 3, Table 1). Moreover, the amount of the
additive can be reduced to 1 equiv. The additives screen
revealed that the yield of 3aa could be further increased to
86% by using TBAB as the additive (entry 6, Table 1). The
yield decreased slightly with the lower catalyst loading (5
mol %) (cf. entries 6 and 7, Table 1). After screening on
different parameters, the highest yield (92%) of 3aa was
achieved, when the reaction was carried out at 50 °C (entry
8, Table 1).
(4) Clark, R. D.; Miller, A. B.; Berger, J.; Repke, D. B.; Weinhardt,
K. K.; Kowalczyk, B. A.; Eglen, R. M.; Bonhaus, D. W.; Lee, C.-H.; Michel,
A. D.; Smith, W. L.; Wong, E. H. F. J. Med. Chem. 1993, 36, 2645.
(5) (a) Cincinelli, R.; Dallavalle, S.; Merlini, L. Synlett 2008, 1309. (b)
Lu, S.; Zhang, W.; Pan, J.; Zhang, J. Synthesis 2008, 1517. (c) Miki, Y.;
Kuromatsu, M.; Miyatake, H.; Hamamoto, H. Tetrahedron Lett. 2007, 48,
9093. (d) Hudlicky, T.; Rinner, U.; Finn, K. F.; Ghiviriga, I. J. Org. Chem.
2005, 70, 3490. (e) Engler, T. A.; Wanner, J. J. Org. Chem. 2000, 65, 2444.
(f) Wang, S.; Dong, Y.; Wang, X.; Hu, X.; Liu, J.; Hu, Y. Org. Biomol.
Chem. 2005, 3, 911. (g) Mmutlane, E. M.; Harris, J. M.; Padwa, A. J. Org.
Chem. 2005, 70, 8055. (h) Tahri, A.; De Borggraeve, W.; Buysens, K. J.;
Van Meervelt, L.; Compernolle, F.; Hoornaert, G. J. Tetrahedron 1999,
55, 14675. (i) Engler, T. A.; Wanner, J. J. Org. Chem. 2000, 65, 2444.
(6) Baccalli, E. M.; Broggini, G.; Marchesini, A.; Rossi, E. Tetrahedron
2002, 58, 6673.
(7) England, D. B.; Padwa, A. Org. Lett. 2008, 10, 3631.
(8) For a recent review, see: (a) Thansandote, P.; Lautens, M.
Chem.sEur. J. 2009, 15, 5874. For some recent examples, see: (b) Umeda,
U.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2008, 47,
4019. (c) Wu, Y.-T.; Huang, K.-H.; Shin, C.-C.; Wu, T.-C. Chem.sEur. J.
2008, 14, 6697. (d) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int.
Ed. 2009, 48, 572. (e) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009,
131, 12050. (f) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474. (g) Inamoto, K.; Hasegawa,
C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147. (h) Wu¨rtz, S.; Rakshit,
S.; Neumann, J. J.; Dro¨ge, T.; Glorius, F. Angew. Chem., Int. Ed 2008, 47,
7230. (i) Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 5636.
(j) Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem.,
Int. Ed. 2008, 47, 9462. (k) Wan, X.; Xing, D.; Fang, Z.; Li, B.; Zhao, F.;
Zhang, K.; Yang, L.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 12046.
Under these optimized reaction conditions, although free
(NH)-indoles 1b could not be transformed into the desired
products 3ba (entry 2, Table 2), substrate with protecting
groups such as Bn was well tolerated to give 3ca (entry 3,
(9) (a) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N.
Angew. Chem., Int. Ed. 2009, 48, 4572. (b) Shi, Z.; Ding, S.; Cui, Y.; Jiao,
N. Angew. Chem., Int. Ed. 2009, 48, 7895. (c) Ding, S.; Shi, Z.; Cui, Y.;
Jiao, N. Org. Lett. 2010, 12, 1540. (d) Shi, Z.; Zhang, B.; Cui, Y.; Jiao, N.
Angew. Chem., Int. Ed. 2010, 49, 4036.
Org. Lett., Vol. 12, No. 13, 2010
2909

Table 2. Pd(OAc)2-Catalyzed DDA Reaction of
Indole-2-carboxamides 1 and Diphenylethyne 2aa
Table 3. Pd(OAc)2-Catalyzed DDA Reaction of
N-Butyl-1-methyl-1H-indole-2-carboxamide 1a and Internal
Alkynes 2a
a Reaction conditions: 1 (0.20 mmol), 2a (0.25 mmol), Pd(OAc)2 (0.02
mmol), DMA (2.0 mL), in an open tube, at 50 °C, 15 h. b Isolated yield.
c This reaction was carried out at 100 °C.
a Reaction conditions: 1a (0.20 mmol), 2 (0.25 mmol), Pd(OAc)2 (0.02
mmol), DMA (2.0 mL), in an open tube, at 50 °C, 15 h. b Isolated yield.
c The structures and the ratio of the regioisomers were determined by 1H-1H
1
NOESY and H NMR analysis, respectively.
Table 2). Notably, 1-methyl-1H-indole-2-carboxamide 1d
was successfully converted to the desired product 3da, which
can easily be transformed into other ꢀ-carboline derivatives.10
Moreover, the substrate 1g containing the N-tert-butyl
substituent produced 3da in 40% yield with the release of
the tert-butyl group (entry 7, Table 2). N-Phenyl-substituted
substrate 1h can also be converted into the interesting product
3ha in 81% yield (entry 8, Table 2).
results indicate that diarylacetylenes with electron-withdraw-
ing or electron-donating groups proceeded well (42-72%,
entries 1-3, Table 3). When unsymmetrical alkynes, such
as 1-phenylpropyne, 1-phenyl-1-hexyne, or phenylcyclopro-
pylacteylene, were employed, two regioisomers were ob-
tained in 79-89% yield with good regioselectivity (entries
4-6, Table 3). Moreover, alkyl-substituted alkynes such as
dec-5-yne (2h) were converted to 3ah in good yield (entry
7, Table 3).
The scope of alkynes was then investigated using N-butyl-
1-methyl-1H-indole-2-carboxamide (1a) as a partner. These
We next attempted the synthesis of γ-carbolinones under
the above optimized conditions. However, N-butyl-1-methyl-
1H-indole-3-carboxamide (1i) reacted with diphenylethyne
(2a) producing the desired product 3ia only in 25% yield
(Scheme 2). The yield increased to 55% when the reaction
(10) For some examples, see: (a) Kuwada, T.; Fukui, M.; Hata, T.;
Choshi, T.; Nobuhiro, J.; Ono, Y.; Hibino, S. Chem. Pharm. Bull. 2003,
51, 20. (b) Naoko, K.; Tominari, C.; Takeshi, K.; Eiichi, S.; Satoshi, H.
Heterocycles 2000, 53, 1877. (c) Franz, B.; Dirk, H. Tetrahedron 1994,
50, 12329. (d) Georges, D.; Jack, D.; Guy, Q. J. Heterocycl. Chem 1983,
20, 967.
2910
Org. Lett., Vol. 12, No. 13, 2010

Scheme 2
.
Pd(OAc)2-Catalyzed DDA Reaction of
Scheme 3
.
Plausible Mechanism for the DDA Reaction of 1
with 2
Indole-3-carboxamides 1 and Internal Alkynes 2a,,b,,c
a Reaction conditions: 1 (0.20 mmol), 2 (0.25 mmol), Pd(OAc)2 (0.02
mmol), DMA (2.0 mL), O2 (1 atm), at 100 °C, 20 h. b Isolated yield. c The
structures and the ratio of the regioisomers were determined by 1H-1H
NOESY and 1H NMR analysis, respectively. The above-described structure
is the main isomer.
(Scheme 2). Furthermore, 1-methyl-N-phenyl-1H-indole-3-
carboxamide (1j) reacted with 2a, providing 3ha in good
yield (85%).
A plausible mechanism for the reaction of 1 with alkynes
2 is illustrated in Scheme 3. The initiated electrophilic
aromatic palladation11 affords PdII intermediates A,12 which
appear to be the key process for the DDA reaction. The
resulting intermediates A subsequently insert into alkynes 2
to produce vinylic palladium(II) intermediates B, which
undergo proton abstraction13 to afford seven-membered
palladacycles C.14 Subsequent reductive elimination gener-
ates the ꢀ- or γ-carbolinones as well as a Pd0 complex that
can be reoxidized to the PdII species by air or O2 (Scheme
3).
In conclusion, we have demonstrated a novel palladium-
catalyzed direct dehydrogenative annulation (DDA) of in-
dolecarboxamides with internal alkynes using air or O2 (1
atm) as the oxidant. The reaction provides a new strategy
for the synthesis of synthetically and medicinally important
ꢀ- and γ-carbolinone derivatives with H2O as the byproduct
via C-H and N-H bond cleavage. Studies are ongoing in
our laboratory to discover the synthetic applications.
was performed at 100 °C. Moreover, the reaction efficiently
produced 3ia in 78% yield using O2 (1 atm) instead of air
as the oxidant in DMA at 100 °C (Scheme 2). Under these
conditions, both aryl- and alkyl-substituted alkynes are
tolerant of this transformation, leading to the corresponding
γ-carbolinones (42-85% yields, Scheme 2). Compared with
the reactions of 1a with unsymmetrical alkynes (entries 4-6,
Table 3), the regioselectivities in the synthesis of corre-
sponding γ-carbolinones from 1i with 2e or 2f are lower
(11) (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b) Phipps,
R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (c)
Beck, E. M.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528.
(d) Grimster, N. P.; Gauntlett, C.; Godfrey, C. M. R.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2005, 44, 3125. (e) Ferreira, E. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2003, 125, 9578. (f) Dwight, T. A.; Rue, N. R.; Charyk, D.;
Josselyn, R.; Deboef, B. Org. Lett. 2007, 9, 3137. (g) Kong, A.; Han, X.;
Lu, X. Org. Lett. 2006, 8, 1339. (h) Fujiwara, Y.; Moritani, I.; Danno, S.;
Asano, R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166. (i) Moritanl, I.;
Fujiwara, Y. Tetrahedron Lett. 1967, 1119.
(12) The formation of intermediates A is not an amide-directed C-H
activation process compared with Guimond’s recent somewhat similar work:
(a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132,
6908. For other work on amide-directed C-H activation to form hetero-
cycles, see: (b) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008,
47, 6452. (c) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058. (d)
Li, B.; Tian, S.; Fang, Z.; Shi, Z. Angew. Chem., Int. Ed. 2008, 47, 1115.
(13) (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34,
Acknowledgment. Financial support from Peking Uni-
versity, National Science Foundation of China (Nos. 20702002,
20872003), and National Basic Research Program of China
(973 Program 2009CB825300) is greatly appreciated. We
also thank Wei Jia in this group for reproducing the results
of 3da and 3fa.
´
633. (b) Echavarren, A. M.; Go´mez-Lor, B.; Gonza´lez, J. J.; de Frutos, O.
Synlett 2003, 585.
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) (a) Larock, R. C.; Doty, M. J.; Tian, Q.; Zenner, J. M. J. Org.
Chem. 1997, 62, 7536. (b) Zhang, H.; Larock, R. C. J. Org. Chem. 2002,
67, 9318. (c) Zhang, H.; Larock, R. C. J. Org. Chem. 2003, 68, 5132. (d)
Kawasaki, S.; Satoh, T.; Miura, M.; Nomura, M. J. Org. Chem. 2003, 68,
6836.
OL1007839
Org. Lett., Vol. 12, No. 13, 2010
2911