Palladium-catalyzed intermolecular C3 alkenylation of indoles using oxygen as the oxidant

Article abstract of DOI:10.1021/ol302840b

A general and efficient palladium-catalyzed intermolecular direct C3 alkenylation of indoles using oxygen as the oxidant has been developed. The reaction is of complete regio- and stereoselectivity. All products are E-isomers at the C3-position, and no Z-

Full text of DOI:10.1021/ol302840b

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Intermolecular C3
Alkenylation of Indoles Using Oxygen
as the Oxidant
Wen-Liang Chen, Ya-Ru Gao, Shuai Mao, Yan-Lei Zhang, Yu-Fei Wang, and
Yong-Qiang Wang*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry
of Education, Department of Chemistry & Materials Science, Northwest University,
Xi0an 710069, P. R. China, and Key Laboratory of Synthetic Chemistry of Natural
Substances, Shanghai Institute of Organic Chemistry, CAS, Shanghai 200032, P. R. China
wangyq@nwu.edu.cn
Received October 15, 2012
ABSTRACT
A general and efficient palladium-catalyzed intermolecular direct C3 alkenylation of indoles using oxygen as the oxidant has been developed. The
reaction is of complete regio- and stereoselectivity. All products are E-isomers at the C3-position, and no Z-isomers or 2-substituted product can
be detected.
3-Vinylindoles, as versatile building blocks, can be
utilized in the synthesis of a number of biologically
significant compounds such as indole alkaloids, carba-
zoles, and carbolines.1ꢀ3 More recently, some of 3-vinyl-
indole compounds have been reported to display interest-
ing biological activities, such as anticancer agents,4
antiviral agents,5 and antibacterial agents.6 In the past
decades, much attention has been paid to the preparation
of 3-vinylindoles. Undoubtedly, an efficient catalytic inter-
molecular direct alkenylation of indoles with alkenes by
regioselective CꢀH functionalization can provide an
atom- and step-economical method for the construction
of 3-vinylindoles.7
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Despite considerable efforts, to date, the intermolecular
direct C3 alkenylation of indoles with alkenes has been
limitied.8,9 In 2005, Gaunt and co-workers realized
ꢀ
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Harada, H.; Ito, T. Bioorg. Med. Chem. Lett. 2010, 20, 3916–3919. (b)
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r
10.1021/ol302840b
XXXX American Chemical Society

palladium(II)-catalyzed direct and solvent-controlled re-
gioselective alkenylation of indoles using Cu(OAc)2 (1.8
equiv) asoxidant.10 Then Djakovitch and Rouge described
a heterobimetallic [Pd/Cu]-catalyzed C3-alkenylation
of N-unprotected indoles with acrylate in the presence
of bubbling air in 2007.11 Recently Jiao et al. reported
organocatalytic direct C3-alkenylation of indoles with
R,β-unsatured aldehydes using DDQ (1.3 equiv) as
oxidant.12 Despite these important advances, some chal-
lenging issues still remained; for example, (1) large excess
of oxidants was used to regenerate the catalyst;10 (2)
stiochiometric amounts of the reduced external oxidant
(suchasCu(OAc)2,10 DDQ12) wereproducedaswaste;and
(3) substratescope waslimited and somecaseswereof poor
selectivity.11 Herein, we disclose a general, efficient and
structurally versatile palladium(II)-catalyzed intermolecu-
lar C3 alkenylation of indoles with alkenes under an O2
atmosphere, characterized by complete regio- and stereo-
selectivity. Compared with Cu(OAc)2 and DDQ, oxygen is
an ideal oxidant and offers attractive industrial prospects
in terms of green and sustainable chemistry while produc-
ing no reduced waste.13
electropositive [Pd(II)O2CCF3]þ species, which, compared
with [PdOAc]þ, is easier to form σ-indole-Pd complexes
through electophilic substitution of CꢀH bonds at indole
3-position,14 1 equiv of TFA was added to the reaction
system. To our delight, the reaction gave the alkenylation
product with complete C3 regioselectivity and E stereo-
selectivity, and the yield improved remarkably to 45%
(entry 2). Next, the amount of TFA was investigated, and
the best result was gotten when 8 equiv of TFA was used
(entries 3ꢀ5). After careful solvent screening, DMSO
proved to be the best solvent (entry 6). Temperature
dramatically affected the reaction rate; the reaction was
done within 3.5 h at 60 °C, and higher temperature led to a
significant drop in the yield due to the decomposition of
starting material and product (entries 7ꢀ9). Pd(TFA)2
(TFA = trifluoroacetate) turned out to be an acceptable
catalyst for the reaction. Nevertheless, in the absence of
trifluoroacetic acid, the reaction would proceed incomple-
tely (entries 10ꢀ11). By using other palladium source and
acids, the same reaction proceeded but less efficiently
(entries 12ꢀ15). It is noteworthy that the reaction rate
and the yield was obviously dropped when air was used as
oxidant instead of oxygen (entry 16). Accordingly, the
reaction conditions were optimized as follows: Pd(OAc)2
(10 mol %), TFA (8 equiv) under an oxygen atmosphere in
DMSO at 60 °C.
Table 1. Optimization of Reaction Conditionsa
With the optimal reaction condition in hand, we moved
on to explore the scope of the alkenylation reaction. First,
we studied the effect of electronic and structural variations
on the alkene (Table 2). The present reaction tolerated a
variety of alkenes. Monosubstituted alkenes, not only
electrophilic alkenes but also the more challenging non-
activated styrene, reacted with 1a to give the correspond-
ing alkenylation products with complete regio- and stereo-
selectivity in good yields (53ꢀ83%) (entries 1ꢀ4).
enty
cat
acid (equiv) temp (°C) time (h) yield (%)g
1b
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
rt
rt
45
45
45
30
30
30
<10
45
TFA (1)
TFA (5)
TFA (8)
TFA (10)
TFA (8)
TFA (8)
TFA (8)
TFA (8)
TFA (8)
3
rt
69
87
86
4
rt
5
rt
6c
7
rt
e70
(8) (a) Fujiwara, Y.; Maruyama, O.; Yoshidomi, M.; Taniguchi, H.
J. Org. Chem. 1981, 46, 851–855. (b) Itahara, T.; Ikeda, M.; Sakakibara,
T. J. Chem. Soc., Perkin Trans. 1 1983, 1361–1363. (c) Murakami, Y.;
Yokoyama, Y.; Aoki, T. Heterocycles 1984, 22, 1493–1496. (d) Jia, C.;
Lu, W.; Kitamura, T.; Fujiwara, Y. Org. Lett. 1999, 1, 2097–2100. (e)
Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004,
126, 3700–3701. (f) Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun.
2005, 1854–1856. (g) Yu, H.; Yu, Z. Angew. Chem., Int. Ed. 2009, 48,
60
90
120
60
60
60
60
60
60
60
3.5
85
8
2
65
9
0.5
4.5
40
10 Pd(TFA)2
11b Pd(TFA)2
12 PdCl2
72
24
45d
45
TFA (8)
TFA (8)
3.5
3.5
3.5
3.5
4.5
ꢀ
2929–2933. (h) Garcıa-Rubia, A.; Arrayas, R. G.; Carretero, J. C.
´
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13 Pd(OH)2
60
14 Pd(PPh3)2Cl2 TFA (8)
nd
e45
75
15e Pd(OAc)2
16f Pd(OAc)2
acids (8)
TFA (8)
(9) For C3 alkenylation of indoles with the directing group: (a)
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´
a Reaction conditions: 1a (1 mmol), 2a (1.5 mmol), catalyst (0.1 mmol),
O2 (1 atm) and acid in DMSO (5 mL) at the specified temperature. b No
acid. c Solvents: EtOAc, DMF, THF, n-hexane, toluene, acetone,
CH3CN, dioxane, Et2O, CH2Cl2, CHCl3, CH3NO2, EtOH. d The con-
version was 81%. e Acids: HCO2H, AcOH, PhCO2H, tartaric acid,
p-toluenesulfonic, salicylic acid, boric acid, oxalic acid, maleic acid,
fumaric acid. f Using air as oxidant. g Isolated yield.
Chem.;Eur. J. 2010, 16, 9676–9685. (d) Ueyama, T.; Mochida, S.;
Fukutani, T.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706–
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2012, 14, 736–739. (f) Ackermann, L.; Wang, L.; Wolfram, R.; Lygin,
A. V. Org. Lett. 2012, 14, 728–731.
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Initially, we investigated the reaction of N-methyl indole
(1a) and ethyl acrylate (2a) with 10 mol % Pd(OAc)2 as the
catalyst and oxygen as the oxidant in DMSO (Table 1).
The reaction was found to proceed in low conversion
(<10%) (entry 1). Considering that trifluoroacetic acid
(TFA) and Pd(OAc)2 can facilitate the generation of more
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Alkenylation of N-Methyl Indole with Alkenesa
Table 3. Alkenylation of Indole with Alkenesa
a Reaction conditions: 1a (1 mmol), 2 (1.5 mmol), Pd(OAc)2 (0.1 mmol),
O2 (1 atm) and TFA (8 mmol) in DMSO (5 mL) at 60 °C. b Isolated yield.
c After hydrogenation.
Particularly noticeable is the performance of 1,2-disubsti-
tuted alkenes in the reaction in view of the small number of
precedents and lower reactivity of this kind of olefin in
oxidative alkenylation (FujiwaraꢀMoritani) reactions.15
Under these reaction conditions, (E)-methyl crotonate and
cyclohexene underwent a smooth reaction with 1a to afford
the corresponding trisubstituted alkene products 3af (75%
yield) and 3ag (60% yield, the desired product was unstable
and it was hydrogenated prior to isolation) (entries 5ꢀ6).
Then we examined the alkenylation of N-unprotected
indoles with alkenes. Gratifyingly, indole is suitable sub-
strate for this process (Table 3). The reaction of indole with
a variey of electron-deficient and nonactivated monosub-
stituted alkenes proceeded efficiently to produce the cor-
responding C3 alkenylation products with complete selec-
tivity in moderate to excellent yields (55ꢀ97%) (entries
1ꢀ6). Indole phosphonate 3bi could also be generated
from vinyl phosphonate 2i in moderate yield (entry 7).
Pleasingly, alkenes with more substituents, such as 1,1- or
a Reaction conditions: 1b (1 mmol), 2 (1.5 mmol), Pd(OAc)2 (0.1 mmol),
O2 (1 atm) and TFA (8 mmol) in DMSO (5 mL) at 60 °C. b Isolated yield.
c 3 mmol 2i for 1 mmol 1b. d After hydrogenation.
1,2-disubstituted alkenes, successfully coupled with indole
to give the corresponding C3 alkenylation products in
good yield (70ꢀ85%) (entries 8ꢀ11).
Finally, we undertook a study of the influence of the
substitution pattern of the indole ring by using ethyl
acrylate as model olefin (Table 4). Indoles possessing
either electron-withdrawing groups or electron-donating
groups were smoothly reacted and provided C3 alkenyla-
tionproducts3ingood toexcellent yields (65ꢀ90%), albeit
1-styrylindole (1g) proved to be less reactive than other
substituted indoles. Some functional substituents such as
Br, F and MeO were compatible under these conditions,
which could be further transformed into other functionalities.
A plausible mechanism for the reaction is shown in
Scheme 1. Pd(OAc)2 is treated with TFA to get active
(15) (a) Beck, E. M.; Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am.
Chem. Soc. 2006, 128, 2528–2529. (b) Beck, E. M.; Hatley, R.; Gaunt,
M. J. Angew. Chem., Int. Ed. 2008, 47, 3004–3007. (c) Zhang, Y.-H.; Shi,
B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072–5074. (d) Lu, Y.;
Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
5916–5921.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Alkenylation of Indoles with Ethyl Acrylatea
Scheme 1. Plausible Mechanism for the Transformation
In summary, we have developed a general, simple and
efficient method for the intermolecular direct C3 alkenyla-
tion of indoles using palladium(II) as catalyst and oxygen
as the oxidant. The reaction can proceed well without
Cu(II) and shows complete regio- and stereoselectivity.
All products are E-isomers at the C3-position, and no
Z-isomers or 2-substituted product can be detected by
analyzing the reaction mixtures. The method should have
many applications in organic and medical chemistry.
Detailed mechanistic investigations and application to
other types of heteroaromatic compounds are currently
underway.
a Reaction conditions: 1a (1 mmol), 2 (1.5 mmol), Pd(OAc)2 (0.1
mmol), O2 (1 atm) and TFA (8 mmol) in DMSO (5 mL) at 60 °C.
b Isolated yield.
Acknowledgment. This research was supported by Na-
tional Natural Science Foundation of China (NSFC-
20872183, 20972126), the Program for New Century Ex-
cellent Talents in University of the Ministry of Education
China (NCET-10-0937), and Education Department of
Shaanxi Provincial Government (09JK776).
Pd(O2CCF3)þ,14,16 which affords the C3-palladated spe-
cies II through electrophilic addition of indole and follow-
ing rearomatization. Then coordination of alkene and
insertion of CdC bond results in the palladium(II) com-
plex IV. Indole/alkene adduct would be released from IV
upon syn βꢀH elimination, and the Pd0 can be reoxidized
to Pd(O2CCF3)þ by O2 in the presence of TFA to complete
the catalytic cycle.10,11
Supporting Information Available. Detailed experimen-
tal procedures including spectroscopic and analytical
data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara,
Y. Science 2000, 287, 1992–1995.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX