Electronic effect directed Au(I)-catalyzed cyclic C2-H bond functionalization of 3-allenylindoles

Article abstract of DOI:10.1021/ol301408g

Gold-catalyzed cyclization reactions of indoles with an electron-deficient allene at the 3-position led to formation of dihydrocyclopenta[b]indole derivatives in moderate to excellent yields via C2-H bond functionalization of the indole unit. The presence of the electron-withdrawing alkoxycarbonyl, dialkoxyphosphono, or phenyl is crutial for this transformation. The potential synthetic dihydrocyclopenta[b]indole with the electron-withdrawing group has been demonstrated by applying a [3 + 2] cycloaddition reaction to construct the tretracycloskeleton.

Full text of DOI:10.1021/ol301408g

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3616–3619
Electronic Effect Directed Au(I)-Catalyzed
Cyclic C2ꢀH Bond Functionalization
of 3-Allenylindoles
Bo Chen,† Wu Fan,‡ Guobi Chai,§ and Shengming Ma*,†,‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032,
P. R. China, Shanghai Key Laboratory of Green Chemistry and Chemical Process,
Department of Chemistry, East China Normal University, 3663 North Zhongshan Lu,
Shanghai 200062, P. R. China, and Laboratory of Molecular Recognition and Synthesis,
Department of Chemistry, Zhejiang University, Hangzhou 310027, Zhejiang, P. R. China
masm@sioc.ac.cn
Received May 21, 2012
ABSTRACT
Gold-catalyzed cyclization reactions of indoles with an electron-deficient allene at the 3-position led to formation of dihydrocyclopenta[b]indole
derivatives in moderate to excellent yields via C2ꢀH bond functionalization of the indole unit. The presence of the electron-withdrawing
alkoxycarbonyl, dialkoxyphosphono, or phenyl is crutial for this transformation. The potential synthetic dihydrocyclopenta[b]indole with the
electron-withdrawing group has been demonstrated by applying a [3 þ 2] cycloaddition reaction to construct the tretracycloskeleton.
Among heterocyclic compounds, indoles are probably
the most ubiquitous scaffolds.1 Because of their great
structural diversity and important biological activity, in-
doles have become a privileged structure in numerous
areas such as pharmaceuticals, fragrances, agrochemicals,
pigments, and materials science.2 Of particular interest is
the cyclopenta[b]indole structural unit that occurs in a
large number of indole alkaloids such as paxilline, paspa-
line, penitrems, janthitrems, lolitrems, monoterpenoid al-
kaloid yeuhchukene, Fischer indoles, and some reduced
cyclopenta[b]indoles (Figure 1).3 They display a variety of
biological activities: penitrem A and paxilline have become
recognized and used pharmacologically as a selective
blocker of high conductance calcium-activated potassium
channels.3b Thus, the development of simple, efficient, and
general methods to synthesize the cyclopenta[b]indole
skeleton are of high interest.4
On the other hand, the transition-metal-catalyzed CꢀH
bond functionalization has received rapidly growing atten-
tion during the past decades because of its synthetic efficiency
and environmental friendliness.5 In this area, enormous
efforts have also been devoted to the development of the
directed CꢀH bond functionalization of indole compounds.6
† Shanghai Institute of Organic Chemistry.
‡ East China Normal University.
§ Zhejiang University.
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r
10.1021/ol301408g
Published on Web 07/03/2012
2012 American Chemical Society

halide,7aꢀe organometallic reagent,7f,g arene,7h,i terminal
alkyne,7j radical,7kꢀm or carbometalation with carbonꢀ
carbon double8 or triple bonds9 has been well documented.
However, such a reaction with allenes has not been well
established as pioneered by Barluenga and Toste et al. with
the cyclization of N-allenylindoles.10 We envisioned that
3-allene-substituted indoles could offer an efficient ap-
proach to the cyclopenta[b]indole skeleton. The cyclic
CdC bond may provide further opportunity to build an
extra ring via cycloaddition reaction (Scheme 1). However,
because of the high strain of the dihydrocyclopenta[b]-
indole product and the less nucleophilicity of C2-indole, it
would be a challenge to realize such a cyclization reaction.
Herein, we disclose our recent realization of such an
approach using a gold catalyst.11,12
Figure 1. Some biologically active compounds containing the
cyclopenta[b]indole unit.
Itiswell-known that the C2-positionof indolesismuchless
reactive than the C3 site. The C2ꢀH bond functionaliza-
tion of indoles followed by a coupling reaction with a
Scheme 1. Allene Approach to Cyclopenta[b]indole
(4) For the synthesis of the cyclopenta[b]indole frameworks, see: (a)
Harrison, C. A.; Leineweber, R.; Moody, C. J.; Williams, J. M. J.
J. Chem. Soc., Perkin Trans. 1 1995, 1127–1130. (b) Ishikura, M.;
Matsuzaki, Y.; Agata, I. Chem. Commun. 1996, 2409–2410. (c) Venkatesh,
C.; Singh, P. P.; Ila, H.; Junjappa, H. Eur. J. Org. Chem. 2006, 5378–5386.
(d) Balskus, E. P.; Walsh, C. T. J. Am. Chem. Soc. 2009, 131, 14648–14649.
(e) Tseng, N.-W.; Lautens, M. J. Org. Chem. 2009, 74, 1809–1811. (f)
Churruca, F.; Fousteris, M.; Ishikawa, Y.; von Wantoch Rekowski, M.;
Hounsou, C.; Surrey, T.; Giannis, A. Org. Lett. 2010, 12, 2096–2099. (g)
Xu, B.; Guo, Z.-L.; Jin, W.-Y.; Wang, Z.-P.; Peng, Y.-G.; Guo, Q.-X.
Angew. Chem., Int. Ed. 2012, 51, 1059–1062.
At first, we chose indoleꢀallene 1a as a model to explore
such a concept. However, after many screenings, the for-
mation of this desired product was not observed and an
unknown product was formed (Scheme 2).
(5) For a monograph, see: Yu, J., Shi, Z., Eds. CꢀH Activation;
Springer: Berlin, 2010.
(6) For reviews on the functionalization of indoles, see: (a) Bartoli,
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9644.
Scheme 2. Initial Experiments
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followed by coupling with an organic halide, see: (a) Itahara, T. J. Chem.
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Singh, J.; Tandon, V.; Larock, R. C. Angew. Chem., Int. Ed. 2009, 48,
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Commun. 2010, 46, 150–152. (d) Jafarpour, F.; Hazrati, H. Adv. Synth.
Catal. 2010, 352, 363–367. (e) Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011,
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2010, 16, 5876–5881. (g) Mu, X.; Chen, S.; Zhen, X.; Liu, G. Chem.;
Eur. J. 2011, 17, 6039–6042. Coupling with an arene: (h) Pintori, D. G.;
Greaney, M. F. J. Am. Chem. Soc. 2011, 133, 1209–1211. (i) Stuart,
D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072–
12073. Coupling with a terminal alkyne: (j) Yang, L.; Zhao, L.; Li, C.-J.
Chem. Commun. 2010, 46, 4184–4186. Coupling with a radical: (k) Bhat,
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J. W.; Narayanam, J. M. R.; Krabbe, S. W.; Stephenson, C. R. J. Org.
Lett. 2009, 12, 368–371.
We then switched to indoleꢀallenoate 1b with an elec-
tron-withdrawing methoxycarbonyl group. We were
pleased to observe that when the reaction was conducted
with 5 mol % each of Au(PPh3)Cl and AgBF4 in toluene,
(10) There are very limited reports on the C2ꢀH bond activation of
indoles followed by the reaction with allene: (a) Barluenga, J.; Piedrafita,
ꢀ
ꢀ
ꢀ
M.; Ballesteros, A.; Suarez-Sobrino, A. L.; Gonzalez, J. M. Chem.;Eur.
J. 2010, 16, 11827–11831. (b) Zeldin, R. M.; Toste, F. D. Chem. Sci. 2011,
2, 1706–1709.
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followed by the reaction with a carbonꢀcarbon double bond, see: (a)
Trost, B. M.; Godleski, S. A.; Genet, J. P. J. Am. Chem. Soc. 1978, 100,
3930–3931. (b) Baran, P. S.; Corey, E. J. J. Am. Chem. Soc. 2002, 124,
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Chem. Soc. 2004, 126, 10250–10251. (f) Capito, E.; Brown, J. M.; Ricci,
A. Chem. Commun. 2005, 1854–1856. (g) Bandini, M.; Melloni, A.;
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Soc. 2006, 128, 1424–1425. (h) Bandini, M.; Eichholzer, A. Angew.
(11) For selected reviews of gold-catalyzed reactions, see: (a) Ma, S.;
€
Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200–203. (b) Furstner,
A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–3449. (c) Gorin,
D. J.; Toste, F. D. Nature 2007, 446, 395–403. (d) Hashmi, A. S. K.
Chem. Rev. 2007, 107, 3180–3211. (e) Li, Z.; Brouwer, C.; He, C. Chem.
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3208–3221. (g) Rudolph, M.; Hashmi, A. S. K. Chem. Soc. Rev. 2012, 41,
2448–2462. For a seminal report on Au-catalyzed reaction of allenyl
ketones, see: (h) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem., Int. Ed. 2000, 39, 2285–2288.
(12) For reactions of 2-allenyl indoles, see: (a) Zhang, Z.; Liu, C.;
Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc.
2006, 128, 9066–9073. (b) Liu, C.; Widenhoefer, R. A. Org. Lett. 2007, 9,
1935–1938. Intermolecular hydroarylation of allenes with indoles:
(c) Toups, K. L.; Liu, G. T.; Widenhoefer, R. A. J. Organomet. Chem.
2009, 694, 571–575. (d) Wang, M.-Z.; Zhou, C.-Y.; Guo, Z.; Wong, E.
L.-M.; Wong, M.-K.; Che, C.-M. Chem. Asian. J. 2011, 6, 812–824.
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R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, 6511–6515.
(9) For selected examples on the C2ꢀH bond activation of indoles
followed by the reaction with a carbonꢀcarbon triple bond, see: (a)
Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 1105–
1109. (b) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am. Chem.
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Org. Lett., Vol. 14, No. 14, 2012
3617

the expected product 2b was cleanly formed albeit in 37%
NMR yield after 19 h at 130 °C, while 48% of the starting
material was unreacted as determined by NMR analysis
(entry 1, Table 1). The structure of compound 2b was further
unambiguously confirmed by the X-ray crystal diffraction
study.13 Next, we focused our attention on the effect of
different silver salts and observed that by applying AgOTf
the yield of product 2b was improved to 95% NMR yield
(entries 1ꢀ3, Table 1)! In the absence of Au(PPh3)Cl or
AgOTf, the transformation did not occur (entries 4ꢀ5,
Table 1). AuCl3 showed a poor catalytic activity in this
reaction (entry 6, Table 1). We also examined the solvent
effect and observed that toluene is the best (entries 7ꢀ10,
Table 1). When the reaction was conducted at 110 °C, 2b was
also formed in 95% NMR yield (entry 11, Table 1). The
reaction was very slow at 80 °C or room temperature (entries
14 and 15, Table 1). Therefore, we defined entry 11 in Table 1
as the standard conditions.
Table 2. Substrate Scopea
Table 1. Optimization of the Reaction Conditionsa
a The reaction was carried out by using 0.5 mmol of 1, 5 mol % of
Au(PPh3)Cl, and 5 mol % of AgOTf in 2 mL of toluene in a Schlenk
tube. b 0.2 mmol of 1b and 1g was used. c 10 mol % of Au(PPh3)Cl and
10 mol % of AgOTf were used. d The reaction was carried out at 115 °C.
temp
time 2bb 1bb
entry
Au
Ag
(°C)
solvent
(h) (%) (%)
1 Au(PPh3)Cl AgBF4
2 Au(PPh3)Cl AgSbF6
3 Au(PPh3)Cl AgOTf
130 toluene
130 toluene
130 toluene
130 toluene
130 toluene
130 toluene
19.3 37
19 80
19.3 95
48
13
0
substituent on the indole unit (R1) may be an alkyl, alkoxy,
or halide group (2bꢀk); the protecting group on the nitro-
gen atom R2 may be Ts, Bz, SO2Ph, CO2Ph, or CO2Me
(2lꢀo); when R3 and R4 are different alkyl or cycloalkyl
groups, 2p and 2q were also formed in good yields.
The electron-withdrawing group may also be PO(OEt)2
(2r) or Ph (2s). In addition, the reaction may be easily
conducted on a scale of 1 g of the substrate 1o in a similar
yield (Scheme 3). It should be noted that when the terminal
sp2 allene carbon atom is monoalkyl substituted, the
reaction became complicated.
4
ꢀ
AgOTf
24
24
24
0
0
85
80
76
0
5 Au(PPh3)Cl
6 AuCl3
ꢀ
ꢀ
8
7 Au(PPh3)Cl AgOTf
8 Au(PPh3)Cl AgOTf
9 Au(PPh3)Cl AgOTf
10 Au(PPh3)Cl AgOTf
11 Au(PPh3)Cl AgOTf
12 (JohnPhos)- AgOTf
AuCl
130 mesitylene 21
130 1,4-dioxane 10
63
75
0
0
130 DMSO
130 DMF
21
22.5
9
23
12
0
0
110 toluene
110 toluene
95
94
9
0
13 (IPr)AuCl
AgOTf
110 toluene
80 toluene
rt toluene
9
22
22
92
16
5
0
78
73
14 Au(PPh3)Cl AgOTf
15 Au(PPh3)Cl AgOTf
a The reaction was carried out using 1b (0.2 mmol) in toluene (2 mL)
in a Schlenk tube. b The yields were determined by NMR using mesity-
lene or CH2Br2 as internal standard.
Scheme 3. Reaction of Substrates with Other Electron-With-
drawing Groups and the Gram-Scale Reaction of 1o
The scope of this transformation was investigated
under the standard conditions. Various differently sub-
stituted indolylallenes may afford the cyclopenta[b]indole
derivatives in moderate to excellent yields (Table 2). The
(13) Crystal data for 2b: C22 H21 N O4 S, MW = 395.46, monoclinic;
space group C2/c, final R indices [I > 2δ(I)], R1 = 0.0362, wR2 =
0.0950; a = 15.4952(6) A, b = 19.4413(8) A, c = 13.8414(6) A, R = 90°,
β = 107.3010(10) o, γ = 90 o, V = 3981.0(3) A3, T = 173(2) K, Z = 8.
Reflections collected/unique 22907/3517 [R(int) = 0.0251], number of
observations [>2δ(I)] 3152, parameters: 257. CCDC 873147 contains
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
3618
Org. Lett., Vol. 14, No. 14, 2012

Scheme 4. Synthetic Applications
Scheme 5. Isotopic Labeling Experiments and Possible
Mechanism
The CꢀCl bond in the indole skeleton in 2h may
smoothly undergo a Suzuki-coupling reaction with orga-
noboronic acid under the catalysis of Pd(OAc)2-LB-phos
(Scheme 4).14 As expected, the dihydrocyclopenta[b]indole
2o may further undergo a 1,3-dipolar cycloaddtion reac-
tion to construct the tretracycloskeleton 3o (Scheme 4).15
Running the reaction of 1o in the presence of 10 equiv of
d4-acetic acid in toluene provided 2o-d in 82% isolated
yield with 84% d-incorporation, while the same reaction in
d8-toluene afforded the 2o-d in 89% isolated yield with
86% d-incorporation (Scheme 5), indicating the formation
of a vinylgold intermediate which was quenched with
d4-acetic acid. On the basis of this observation, a possible
reaction mechanism was proposed as shown in Scheme 5.
The relatively electron-rich CdC bond in the allene
moiety, selectively activated by the coordination with the
cationic gold atom, would be attacked by the indole C2
atom via the intermediacy of A and/or A0 to afford
vinylgold complex B. During this process, the aromaticity
of the indole ring is broken.16 Subsequent deprotonative
rearomatization and demetalation would afford 2o-d and
regenerate the cationic gold catalyst.17
In summary, we have demonstrated a gold(I)-catalyzed
cyclization reaction of 3-allene-substituted indoles provid-
ing an efficient entry to cyclopenta[b]indole derivatives via
C2ꢀH bond functionalization of the indole unit. The
electron-withdrawing group in the allene moiety is crucial
for this transformation for the selective activation of the
two CdC bonds in the allene moiety. The cyclopenta-
[b]indole derivatives 2o could further undergo a [3 þ 2]
cycloaddition reaction affording the tetracycloskeleton.
The electron-withdrawing functionality may also provide
further opportunities of synthetic elaboration. Because of
the potential of the products3 and the ready availability of
the starting materials,18 this method may be useful in
organic synthesis and medicinal chemistry. Further re-
search in this area including the synthetic application is
ongoing in our laboratory.
Acknowledgment. Financial support from the Major State
Basic Research Development Program (2009CB825300)
and National Natural Science Foundation of China
(21172192) is greatly appreciated. We thank Mr. Qiu
Youai in this group for reproducing the results presented
for 2e, 2k, and 2l in Table 2.
Supporting Information Available. Detailed experimen-
tal procedures and characterization data for all the
products. This material is available free of charge via
the Internet at http://pubs.acs.org.
€
(14) (a) Lu, B.; Fu, C.; Ma, S. Chem.;Eur. J. 2010, 16, 6434–6437.
(18) The starting materials may be easily prepared according to the
reported methods: (a) Li, Y.; Zou, H.; Gong, J.; Xiang, J.; Luo, T.;
Quan, J.; Wang, G.; Yang, Z. Org. Lett. 2007, 9, 4057–4060. (b) Yu, F.;
Lian, X.; Zhao, J.; Yu, Y.; Ma, S. J. Org. Chem. 2009, 74, 1130–1134. (c)
Pu, X.; Qi, X.; Ready, J. M. J. Am. Chem. Soc. 2009, 131, 10364–10365.
€
(b) Lu, B.; Fu, C.; Ma, S. Tetrahedron Lett. 2010, 51, 1284–1286.
(15) Hisashi, T.; Satoshi, K.; Takahiro, K.; Takashi, O.; Hiroaki, I.;
Toshifumi, T.; Kiyoshi, N.; Makoto, T.; Kenichi, Y.; Rie, M.; Masatoshi,
N. PCT Int. Appl. WO 2008/082009, 2008.
(16) Roche, S. P.; Porco, J. A. Angew. Chem., Int. Ed. 2011, 50, 4068–
4093.
(17) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232–5241.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3619