Highly regioselective palladium-Catalyzed oxidative coupling of indolizines and vinylarenes via C-H bond cleavage

Article abstract of DOI:10.1021/ol902315w

[Chemical Equation Presented] A highly regloselective oxidative coupling reaction between indolizines and vinylarenes has been accomplished In the presence of palladium catalysts to give only the branched α-product In high efficiency. The regioselectivity Is promoted significantly by bidentate nitrogen Uganda.

Full text of DOI:10.1021/ol902315w

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5606-5609
Highly Regioselective
Palladium-Catalyzed Oxidative Coupling
of Indolizines and Vinylarenes via C-H
Bond Cleavage
Yuzhu Yang, Kai Cheng, and Yuhong Zhang*
Department of Chemistry, Zhejiang UniVersity, Hangzhou 310027, People’s Republic
of China
yhzhang@zju.edu.cn
Received October 6, 2009
ABSTRACT
A highly regioselective oxidative coupling reaction between indolizines and vinylarenes has been accomplished in the presence of palladium
catalysts to give only the branched r-product in high efficiency. The regioselectivity is promoted significantly by bidentate nitrogen ligands.
Vinylation is one of the fundamental transformations of
organic synthesis. Among the various vinylation methods,1
the cross-coupling of aryl halides and olefins (the Heck
reaction, Scheme 1) is one of the most efficient approaches
with the advantage of high functional group tolerance.2 The
major drawbacks of this methodology include low regiose-
lectivity with unsymmetrical olefins for R-products and the
requirement of prehalogenation of arenes, thereby creating
a significant amount of salt waste and more reaction steps.
Recently, C-H bond functionalization has attracted much
attention,3 and processes capable of achieving the oxidative
vinylation of arenes using transition metal catalysts have been
reported, in which aromatic sp2 C-H bonds are coupled with
olefins without the need for prior halogenation or metalliza-
tion.4 For instance, Fujiwara and co-workers have reported
the palladium-assisted oxidative coupling of arenes and
aromatic heterocycles with olefins.5 Gaunt and co-workers
(3) (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res.
2008, 41, 1013–1025. (b) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed.
2008, 47, 7497–7500. (c) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am.
Chem. Soc. 2008, 130, 10848–10849. (d) Do, H.-Q.; Daugulis, O. J. Am.
Chem. Soc. 2007, 129, 12404–12405. (e) Li, Z.; Cao, L.; Li, C.-J. Angew.
Chem., Int. Ed. 2007, 46, 6505–6507. (f) Li, Z.; Capretto, D. A.; Rahaman,
R.; He, C. Angew. Chem., Int. Ed. 2007, 46, 5184–5186. (g) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174–238. (h) Yang, S. D.;
Sun, C. L.; Fang, Z.; Li, B. J.; Li, Y. Z.; Shi, Z. J. Angew. Chem., Int. Ed.
2008, 47, 1473–1476. (i) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2009, 48, 5094–5115. (j) Godula, K.; Sames, D.
Science 2006, 312, 67–72. (k) Dyker, G. Angew. Chem., Int. Ed. 1999, 38,
1698–1712. (l) Kozhushkov, S. I.; Yufit, D. S.; Ackermann, L. Org. Lett.
2008, 10, 3409–3412. (m) Zhao, X.; Yu, Z. J. Am. Chem. Soc. 2008, 130,
8136–8137. (n) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129,
11904–11905. (o) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem.
Soc. 2008, 130, 2448–2449.
(1) (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34,
633–639. (b) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem.
Soc. 2002, 124, 11250–11251. (c) Lu, W.; Jia, C.; Kitamura, T.; Fujiwara,
Y. Org. Lett. 2000, 2, 2927–2930. (d) El-Batta, A.; Jiang, C.-C.; Zhao, W.;
Anness, R.; Cooksy, A. L.; Bergdahl, M. J. Org. Chem. 2007, 72, 5244–
5259. (e) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am.
Chem. Soc. 2008, 130, 16170–16171. (f) Tsuchikama, K.; Kasagawa, M.;
Endo, K.; Shibata, T. Org. Lett. 2009, 11, 1821–1823. (g) Matano, Y.;
Imahori, H. J. Org. Chem. 2004, 69, 5505–5508. (h) Nakamura, M.; Endo,
K.; Nakamura, E. J. Am. Chem. Soc. 2003, 125, 13002–13003. (i) Matsuura,
Y.; Tamura, M.; Kochi, T.; Sato, M.; Chatani, N.; Kakiuchi, F. J. Am. Chem.
Soc. 2007, 129, 9858–9859. (j) Ueno, S.; Kochi, T.; Chatani, N.; Kakiuchi,
F. Org. Lett. 2009, 11, 855–858. (k) Takami, K.; Yorimitsu, H.; Oshima,
K. Org. Lett. 2004, 6, 4555–4558. (l) Watanabe, S.; Ikeda, T.; Kataoka, T.;
Tanabe, G.; Muraoka, O. Org. Lett. 2003, 5, 565–567.
(2) (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009–
3066. (b) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945–
2963. (c) Reetz, M. T.; Lohmer, G.; Schwickardi, R. Angew. Chem., Int.
Ed. 1998, 37, 481–483. (d) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc.
2001, 123, 6989–7000.
(4) (a) Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z.-J. J. Am. Chem. Soc.
2007, 129, 7666–7673. (b) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem.
Soc. 2009, 131, 5072–5073. (c) Tani, M.; Sakaguchi, S.; Ishii, Y. J. Org.
Chem. 2004, 69, 1221–1226.
10.1021/ol902315w  2009 American Chemical Society
Published on Web 11/19/2009

described the solvent-controlled regioselective vinylation at
the C2- and C3-position of indoles through the palladium-
catalyzed C-H functionalization reaction.6 Procedures have
also been developed for installation of olefins through
directed C-H functionalization and decarboxylation by Pd-
catalyzed oxidative vinylation of indole carboxylic acids.7
On the other hand, regioselectivity has been the most
important topic for the vinylation in terms of internal olefins
(linear ꢀ-product) and terminal olefins (branched R-product).
Although the Stille reaction and Suzuki reaction have been
used for the synthesis of branched olefins (Scheme 1),8 there
is no example for the direct oxidative vinylation to furnish
the terminal olefins (R-product). In the course of our studies
of the direct C-H bond functionalization,9 we became
interested in the direct vinylation of indolizines owing to
the prevalence of the indolizine unit in bioactive natural
products and pharmaceutical heterocycles.10 Herein, we
describe the first protocol for highly regioselective vinylation
of indolizines by palladium catalysis in the presence of 20
mol % 2,2′-bipyridine and 1 equiv of Ag2CO3 to give only
the branched R-products.
obstacle to the development of a regioselective palladium-
catalyzed vinylation. To reduce the amount of ꢀ-product
formed, we employed the bidentate ligand 1,10-phenanthro-
line. In this case, a remarkable improvement in regioselec-
tivity was achieved to give only R-substituted product,
although the activity of the reaction was reduced (entry 4).
This result highlights the key role of ligand in the regiocon-
trol of the reaction. We were pleased to observe that the
combination of 10 mol % Pd(OAc)2 and 20 mol % 2,2′-
bipyridine further improved the regioselectivity to give only
the R-product in 64% yield (entry 5). Further optimization
indicated that the use of 5 equiv of styrene improved the
yield of 3a to 84% (entry 6). Other bidentate ligands did
not favor the expected regioselective process (entries 7-9).
A screen of catalyst systems showed that PdCl2 and Pd(dba)2
were ineffective in the reaction (Table 1, entries 10-11). In
addition, the oxidant was crucial to the reaction, and no
product was detected in the absence of oxidants. Among the
oxidants tested, Ag2CO3 was more effective in oxidizing
Pd(0) to Pd(II) to afford catalytic turnover, while other
oxidants such as AgOAc and CuCl allowed the reaction to
proceed (entries 12-14). An amount of 2 equiv of Ag(I)
was required for the reaction to proceed, and a decrease in
the amount of Ag(I) resulted in a reduced yield (entry 15).
Scheme 1. Synthesis of Branched Olefins
Table 1. Effect of Metals, Oxidants, and Ligands on the
Reactiona
entry
catalyst
oxidant
ligand
yield %b
Our initial investigation in the reaction of indolizine 1a
with styrene in the presence of 10 mol % Pd(OAc)2 gave
poor regioselectivity and low yield; the R/ꢀ ratio was
approximately 1:1.8, and the yield was 44% (Table 1, entry
1). When monodentate ligand was introduced, PPh3 was less
effective than pyridine. This promoted the reactivity to give
a 74% isolated yield (entries 2-3). However, the competitive
formation of both R-product and ꢀ-product was a major
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
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
PdCl2
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
AgOTf
16 (28)
11 (15)
37 (37)
46
PPh3
pyridine
L1
L2
L2
L3
L4
L5
L2
L2
L2
L2
L2
64
84c
32 (28)c
34 (25)c
26 (<5)c
25
(5) Fujiwara, Y.; Maruyama, O.; Yoshidomi, M.; Taniguchi, H. J. Org.
Chem. 1981, 46, 851–855.
<5
62
(6) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2005, 44, 3125–3129.
41
(7) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10,
1159–1162.
CuCl
Ag2CO3
75c
(8) (a) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 7600–7605. (b) Peyroux, E.; Berthiol, F.; Doucet, H.; Santelli, M. Eur.
J. Org. Chem. 2004, 1075–1082.
L2
36d
a Reaction conditions: styrene (0.6 mmol), indolizine 1a (0.3 mmol),
catalyst (0.03 mmol, 10 mol %), oxidant (2 equiv), KOAc (2 equiv), ligand
(0.06 mmol, 20 mol %), DMF (2 mL), 100 °C, 24 h. b Isolated yields of
R-product. The yield of ꢀ-product was presented in parentheses. c 5 equiv
of styrene is used. d 0.5 equiv of Ag2CO3 was used. L1 ) 1,10-
phenanthroline, L2 ) 2,2′-bipyridine, L3 ) 1,2-bis(diphenylphosphino)et-
hane, L4 ) 6,6′-bi-2-picoline, L5 ) 2,9-dimethyl-1,10-phenanthroline, dba
) dibenzylideneacetone.
(9) (a) Huang, L.; Zhang, X.; Zhang, Y. Org. Lett. 2009, 11, 3730–
3733. (b) Cheng, K.; Huang, L.; Zhang, Y. Org. Lett. 2009, 11, 2908–
2911. (c) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428–
7431. (d) Cheng, K.; Yao, B.; Zhao, J.; Zhang, Y. Org. Lett. 2008, 10,
5309–5312.
(10) (a) Li, H.; Xia, Z.; Chen, S.; Koya, K.; Ono, M.; Sun, L. Org.
Process Res. DeV. 2007, 11, 246–250. (b) Ostby, O. B.; Dalhus, B.;
Gundersen, L.-L.; Rise, F.; Bast, A.; Haenen, G. R. M. M. Eur. J. Org.
Chem. 2000, 22, 3763–3770. (c) Hagishita, S.; Yamada, M.; Shirahase, K.;
Okada, T.; Murakami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.; Ueno,
M.; Chikazawa, Y.; Yamada, K.; Ono, T.; Teshirogi, I.; Ohtani, M. J. Med.
Chem. 1996, 39, 3636–3658.
We next studied the generality of this regioselective
oxidative coupling reaction by varying the electronic and
Org. Lett., Vol. 11, No. 24, 2009
5607

steric properties of vinylarenes. As can be seen from Figure
1, the reaction of vinylarenes with electron-donating groups
in the aryl ring worked well to give the corresponding
oxidative coupling products in good to high yields (3b-3g).
However, vinylarenes with strongly electron-withdrawing
groups such as -CN and -NO2 were incompatible with the
reaction, and no desired products were detected. The presence
of moderate electron-withdrawing groups (bromo, chloro,
fluoro) was tolerated in the reaction and afforded the desired
products smoothly (3h-3l). Steric hindrance decreased the
reactivity of the reaction. For instance, ortho-substituted
vinylarenes delivered relatively lower yields compared with
their para- or meta-analogues (3d, 3g, and 3l). It is worth
noting that carbon-halogen bonds tolerated the reaction
conditions to give the halogen-containing products. Byprod-
ucts from cross-coupling of indolizine and the C-X bond
in halo-substituted vinylarenes were not detected,11 showing
the excellent chemoselectivity. Pure products from ethyl
acrylate and acylonitrile were not obtained because separation
of the products from the byproduct was very difficult.
1,2-dicarboxylate was inactive (entry 8). The presence of
another electron-withdrawing group (-CO2Et) in the in-
dolizine might render the heterocycles highly electron
deficient and retard electrophilic palladation. Poor reactivity
was also observed for other heteroarenes such as indoles and
pyridines.
Table 2. Reaction of Styrene with Various Indolizinesa
Figure 1. Reaction of indolizine 1a with vinylarenes.
The oxidative coupling reaction was further extended to
various indolizines as shown in Table 2. Methyl indolizine-
1-carboxylate, ethyl indolizine-1-carboxylate, and n-butyl
indolizine-1-carboxylate afforded the desired products 3a,
3n, and 3o in good yield (entries 1-3). When 1-(indolizin-
1-yl)ethanone reacted with styrene, a 70% yield was obtained
(entry 4). Indolizine-1-carbonitrile and 2-methylindolizine-
1-carbonitrile showed good reactivity to give the desired
direct coupling products in high yield (entries 5 and 6).
Methyl 7-methylindolizine-1-carboxylate was a good sub-
strate for the reaction (entry 7). However, diethyl indolizine-
a Reaction conditions: styrene (1.5 mmol), indolizines (0.3 mmol),
Pd(OAc)2 (0.03 mmol, 10 mol %), Ag2CO3 (1 equiv), KOAc (2 equiv),
2,2′-bipyridine (0.06 mmol, 20 mol %), DMF (2 mL), 100 °C, 24 h.
b Isolated yield.
According to the proposal of Cabri and others for the Heck
reaction,12 monodentate ligands lead to a neutral pathway
dominating formation of the linear olefins due to the easy
(11) Reaction between C-X bond and indolizines has been reported,
see: Park, C. H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan,
V. Org. Lett. 2004, 6, 1159–1162.
(12) (a) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2–7. (b) Mo,
J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751–760. (c) Schenck,
H.; Akermark, B.; Svensson, M. J. Am. Chem. Soc. 2003, 125, 3503–3508.
5608
Org. Lett., Vol. 11, No. 24, 2009

mediate D may be formed due to the relatively easy
dissociation of the monodentate nitrogen ligand, and such a
complex should easily form intermediate E to finally give
the linear ꢀ-product. Ag2CO3 would serve as an oxidant to
regenerate the Pd(II).
Scheme 2. Plausible Reaction Mechanism
Of particular note is the performance of a 3-substituted
indolizine like N,N-diphenylindolizin-3-amine in this reaction
in the presence of bidentate ligand 2,2′-bipyridine which
gives rise to a mixture of R- and ꢀ-substituted vinylation
products; the effect of the bidentate ligand on regiocontrol
was still obvious, the R-product being mainly obtained
(Scheme 3). This result illustrates that the nitrogen atom in
indolizines could be playing a potential role in the formation
of branched R-isomer products.14 Further research is required
for the elucidation of the detailed mechanism.
Scheme 3. Regioselectivity of 3-Substituted Indolizine
dissociation of the ligand. In contrast, the ionic pathway
results in the branched olefins being favored in the presence
of bidentate ligands. Indeed, we have found excellent
regioselectivity with a wide range of vinylarenes and
indolizines by exploiting the bidentate nitrogen ligands to
give only the branched olefins. Indolizines are classified as
electron-rich aromatic heterocycles, and their transformations
catalyzed by palladium show strong electrophilic character
with reactions occurring at the most electron-rich C3-
position.13 On the basis of the previous chemistry and our
results, we propose a plausible mechanism for this new
oxidative coupling reaction, as shown in Scheme 2. The
electrophilic palladation first occurs preferentially at the C3-
position of indolizine, and the subsequent deprotonation leads
to the formation of intermediate A. The following coordina-
tion of vinylarenes to intermediate A may take place in two
different ways: (1) An ionic intermediate B is preferentially
formed in the presence of bidentate nitrogen ligands, which
leads to the primary formation of intermediate C to afford
the branched R-product. (2) Alternatively, a neutral inter-
In summary, we have observed the first example of a
palladium-catalyzed oxidative vinylation process that exhibits
excellent regioselectivity to furnish essentially only branched
olefins in the presence of bidentate nitrogen ligands. The
approach has extended the scope of regioselective C-H
functionalization of indolizines.
Acknowledgment. Funding from the Natural Science
Foundation of China (No. 20872126) and Zhejiang Provincial
Natural Science Foundation of China (R407106) is acknowl-
edged.
Supporting Information Available: Experimental pro-
cedure and characterization of all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL902315W
(14) (a) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001,
123, 8217–8225. (b) Itami, K.; Nokami, T.; Ishimura, Y.; Mitsudo, K.;
Kamei, T.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 11577–11585.
(13) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 7742–7743.
Org. Lett., Vol. 11, No. 24, 2009
5609