Heck-type cross-dehydrogenative coupling reactions of indolizines at the 3-position with electron-deficient alkenes through palladium-catalyzed C-H activation

Article abstract of DOI:10.1002/asia.201101050

A cross-dehydrogenative coupling reaction of indolizines with electron-deficient alkenes for the synthesis of 3-alkenyl-substituted indolizines has been reported. The reaction takes place at the 3-position selectively through palladium-catalyzed C-H activation, following a Heck-type cross-coupling reaction under mild and ligand-free conditions. Furthermore, the reaction mechanism of the Pd^II/Pd⁰ catalytic pathway was also confirmed by ¹H NMR spectroscopy.

Full text of DOI:10.1002/asia.201101050

COMMUNICATION
DOI: 10.1002/asia.201101050
Heck-Type Cross-Dehydrogenative Coupling Reactions of Indolizines at the
3-Position with Electron-Deficient Alkenes through Palladium-Catalyzed
À
C H Activation
Huayou Hu,*[a] Yun Liu,[d] Hao Zhong,[a] Yulan Zhu,[a] Chao Wang,*[b] and Min Ji[c]
Carbon–carbon bond formation reactions are one of the
most important processes in chemistry because of their im-
portance in key steps to build more complex molecules from
simple precursors. Among these reactions, carbon–carbon
(sp2–sp2) bond formation can be used for the construction of
biaryls, which are important structural motifs in many or-
ganic molecules. For this reason, the development of new
methods for the synthesis of biheteroaryl scaffolds remains
an ongoing challenge for organic chemists. Inspired by the
need for green and sustainable chemistry,[1] synthetic chem-
of biological activities, including antibacterial,[5a] phospha-
tase and aromatase inhibiting,[5b,c] antioxidant,[5d] antidepres-
sant,[5e] and antitumor activities.[5f] They were also known to
be calcium entry blockers[5g] and 5-hydroxytryptamine re-
ceptor antagonists.[5h] In addition, polycyclic indolizine deriv-
atives were observed to have long-wavelength absorption
and fluorescence in the visible-light region. Furthermore,
the successful synthesis of these types of compounds has fa-
cilitated the development of novel classes of dyes and bio-
logical markers.[6]
À
ists are seeking more efficient ways to construct C C bonds
of heterocyclic compounds. A transition metal catalyzed
cross-dehydrogenative coupling (CDC) reaction with two
À
Several groups have previously reported some palladium-
À
catalyzed C H activation reactions of indolizines at the 3-
position (Scheme 1).[7] As a follow-up to our reported meth-
ods,[8] we herein report a CDC reaction of indolizines with
C H bonds might be a good choice, because installation of
functional groups is unnecessary, thus making synthetic
routes shorter and more efficient.[2] Among them, Heck-
type processes are practically important, because they use
olefins as basic building blocks, and the preparation meth-
ods are always highly stereoselective.[1d]
The indolizine skeleton is abundant in many natural prod-
ucts,[3] such as erythrinan alkaloids,[3,4a] swainsonine,[3,4b] sla-
framine,[3,4c] crepidine,[3,4d] gephyrotoxine,[3,4e] cryptowoli-
ne,[3,4f] and myrmicarin.[3,4g] These natural products as well
as their synthetic derivatives were found to exhibit a variety
[a] Dr. H. Hu, H. Zhong, Prof. Y. Zhu
Jiangsu Key Laboratory for Chemistry of Low-Dimensional Materials
School of Chemistry and Chemical Engineering
Huaiyin Normal University
Huaian 223300 (P. R. China)
Fax : (+86)517-83525100-1
E-mail: njuhhy@hotmail.com
[b] Dr. C. Wang
MOE Engineering Research Center of Biomass Materials
School of Material Science and Engineering
Southwest University of Science and Technology
Mianyang 621010 (P. R. China)
[c] Dr. M. Ji
Institute of Pharmaceutical Engineering
School of Chemistry and Chemical Engineering
Southeast University
Nanjing 210096 (P. R. China)
[d] Dr. Y. Liu
School of Chemistry and Chemical Engineering
Jiangsu Normal University
Xuzhou 221116 (P. R. China)
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201101050.
Scheme 1. Various CDC reactions with other C H activation cross-cou-
pling routes.
884
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 884 – 888

Table 1. Optimization of reaction conditions.
electron-deficient alkenes to synthesize multi-substituted in-
dolizines. The reaction proceeded selectively at the 3-posi-
À
tion through palladium-catalyzed C H activation under
mild conditions.
In our preliminary study, we chose indolizine 1a
(1.0 equiv) and ethyl acrylate 2a (2.0 equiv) as our model
system, PdACHTUNGTRENNUNG(OAc)2 as the catalyst, and CuAHCUTNGTREN(NUGN OAc)2·H2O
(2.5 equiv) as the terminal oxidant (Scheme 2). The results
are shown in Table 1. When the reaction was carried out
Entry PdACHTUNGTRNEUNG
(OAc)2 [mol%] Base (equiv), sol- t [h] T [8C] Yield [%][a]
vent
1[b]
10
10
10
10
10
10
No, DMF
No, TFA
No, DMSO
No, Toluene
No, DMSO
K2CO3(4),
DMSO
72
4.5
55
5d
26
24
60
60
60
80
60
60
60
0
70
40
68
70
2[b]
3[b]
4[b,c]
5[b,d]
6[b]
7[b]
8[b]
9
10
10
5
NaHCO3(4),
DMSO
AcOH(4),
DMSO
NaHCO3(4),
DMSO
KHCO3(4),
DMSO
Na2HPO4(4),
DMSO
NaOAc(4),
DMSO
KHCO3(4),
DMSO
KHCO3(4),
DMSO
4
60
60
60
60
78
14
7
65
81.6
82.3
71
10
11
12
13
14[e]
5
7
5
>24 60
5
18
8
60
60
60
75
2.5
5
74
4
67
[a] Yield of isolated product. [b] 5 equivalents of 2a. [c] 0.2 equivalents of
DMSO as a ligand. [d] 1.5 equivalents of benzoquinone as an oxidant.
[e] 12.5 equivalents of 2a. TFA=trifluoroacetic acid.
Scheme 2. Formation of 4, 1i’, and 3ia as monitored by NMR spectro-
copy.
alkenes. Both terminal and non-terminal alkenes were able
to react with 1 f, whereas sterically hindered alkenes such as
methyl 2-phenylacrylate, dibutyl maleate, and naphthalene-
1,4-dione did not give any desired product (Table 3, en-
tries 9–11).
To reveal the mechanism of this reaction, hydrogen/deute-
rium (H/D) exchange and equivalent experiments were con-
ducted. When 1 f was mixed with 1.0 equivalent of PdACHTUNGTRENNUNG(OAc)2
in [D6]DMSO, dimer 4 was generated rapidly even at room
temperature and in the absence of any base (Scheme 2).
Based on this result, indolizine 1i was chosen as a model,
because it did not dimerize under the same conditions. We
À
under typical C H activation conditions at the 3-position of
indolizine,[7d,e] the known product 3aa[9] was generated in
a moderate yield of 60% (Table 1, entry 1). However, our
results demonstrated that dimethyl sulfoxide (DMSO) was
a better solvent than N,N-dimethyl formamide (DMF;
Table 1, entries 1–4). Notably, addition of potassium bicar-
bonate as a base was superior to stronger bases (such as po-
tassium carbonate)[7b–f] or weak acids (such as acetic
acid).[7a–b] This observation suggested that neutral reaction
conditions were preferred in this kind of reaction (Table 1,
entries 6–12), which is different to that of previously report-
ed methods.[7] In addition, the yield decreased by adding an
excess amount of 2a (Table 1, entries 7, 9, 10, and 14).
With the optimal reaction conditions in hand (Table 1,
entry 10), the scope and generality of this transformation
were examined (Table 2). Indolizines bearing a substituted
group at the 1-position and/or 2-position reacted smoothly
with 2a. However, fused indolizines were found not to react
with 2a at all or gave a complex mixture (Table 2, entries 14
and 15).
added 1i (0.030 mmol), PdACHTNUGTRNEUNG(OAc)2 (0.0015 mmol), and D2O
(0.60 mmol) to [D6]DMSO (0.75 mL), and then H/D ex-
change at the 3-position of 1i was observed (Figure 1). As
shown in Figure 1, after heating at 608C for 24 hours, the
proton peak at the 3-position almost disappeared. These re-
sults indicated the H/D exchange was catalyzed by Pd-
AHCTUNGTRENNUNG
AHCTUNRTGEG(NNNU OAc)2 was added to the solu-
tion of 1i in [D6]DMSO, a new species was formed rapidly
(Figure 2b). After that, 1.0 equivalent of 2a was added to
the mixture, and the product 3ia formed quickly at room
temperature (Figure 2c). After heating at 608C for
0.5 hours, palladium black precipitated on the wall of the
Then, indolizine 1 f was chosen as a model to check the
scope of electron-withdrawing alkenes. As the results show
in Table 3, the reactions were sensitive to sterically hindered
Chem. Asian J. 2012, 7, 884 – 888
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
885

H. Hu, C. Wang et al.
COMMUNICATION
Table 2. Reactions of indolizines with ethyl acrylate.
Table 2. (Continued)
Entry Indolizine (1)[a]
Alkenes t [h] Product,
(2)
Yield [%][b]
8
1i 2a
20
3ia, 65
Entry Indolizine (1)[a]
Alkenes t [h] Product,
(2)
Yield [%][b]
9
1j 2a
1k 2a
1l 2 f[c]
20
20
48
3ja, 48
3ka, 62
3lf, 90
1
1b 2a
12
11
3ba, 86
10
11
2
1c 2a
3ca, 68
3df/3df’=3:1,[d]
51
12
13
1m 2a
1n 2a
5
6
3ma, 70
3na, 96
3
4
5
6
1d 2 f[c]
1e 2a
1 f 2a
1g 2a
14
22
4
3ea, 73
3 fa, 84
3ga, 81
Complex mix-
ture
14
15
1p 2a
1q 2a
24
48
22
no reaction
[a] All indolizines were prepared by known literature procedures.[10,11]
[b] Yield of isolated product. [c] 2 f was used for easy separation. [d] 3df’
was a Z isomer.
7
1h 2a
20
3ha, 66
Table 3. Reactions of indolizine 1 f with electron-deficient alkenes.
NMR tube. After filtration, the
1H NMR spectrum of the
mother liquor illustrated that
all of 1i was consumed and 3ia
was produced (Figure 2d). With
these results in hand, we pro-
posed the mechanism of this re-
action as shown in Scheme 3.
Entry
1
Indolizine
Alkenes
t [h]
Product, yield [%][a]
1 f
butyl acrylate 2b
3
3 fb, 92
Firstly, indolizine reacted with
PdACTHNURTGENNUG(OAc)2 to form intermediate
2
1 f
ethyl methacrylate 2c
3
3 fc’, 57[b]
5, which subsequently added
with 2 to generate intermediate
6. Finally, product 3 was gener-
ated by 6 through reductive
elimination.
3
4
5
6
7
8
9
10
11
1 f
1 f
1 f
1 f
1 f
1 f
1 f
1 f
1 f
(E)-methyl but-2-enoate 2d
(E)-1-phenyl-3-(p-tolyl)prop-2-en-1-one 2e
N,N-dimethylacrylamide 2 f
tert-butyl acrylate 2g
acrylonitrile 2h
methyl acrylate 2i
methyl 2-phenylacrylate 2j
dibutyl maleate 2k
naphthalene-1,4-dione 2l
3
3 fd, 50
12
1.5
1.5
4
1.5
24
24
24
3 fe/3 fe’=6:1, 61[b]
3 ff, 87
In conclusion, we have re-
ported a CDC reaction of indo-
lizines with electron-deficient
alkenes to produce 3-alkenyl-
substituted indolizines. The re-
action took place selectively at
the 3-position through palladi-
3 fg, 68
3 fh/3 fh’=2:1, 48[b]
3 fi, 99
N.P.[c]
N.P.[c]
N.P.[c]
[a] Yield of isolated product. [b] 5 equivalents of 2. [c] No expected product.
886
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 884 – 888

Heck-Type Cross-Dehydrogenative Coupling Reactions
À
um-catalyzed C H activation, following a Heck-type cross-
coupling reaction under mild and ligand-free conditions. No-
tably, the reaction was conducted in air, thus the reaction is
not sensitive to moisture. Furthermore, the results of the H/
À
D exchange experiments confirmed that the C H activation
was catalyzed by Pd(OAc)2. Intermediate 5 was observed by
G
1H NMR spectroscopy, and this confirmed the reaction
mechanism. Further studies on the replacement of an exces-
sive amount of CuACTHNUTRGNEUNG(OAc)2 by a greener oxidant such as
oxygen gas is being thoroughly investigated.
Experimental Section
General Procedure
Indolizine 1a (0.20 mmol), ethyl acrylate 2a (0.40 mmol), PdACHTUNGTRENNUNG(OAc)2
(0.010 mmol), CuACHTNUTRGNEG(UN OAc)2·H2O (0.44 mmol), and KHCO3 (0.60 mmol)
were mixed with DMSO (2.0 mL). The mixture was heated at 608C for
2 h in air. Then the mixture was cooled to room temperature, poured
into water, and extracted with CHCl3. The combined layers were washed
with saturated brine, dried with Na2SO4, and filtered. Solvent was re-
moved by reduced pressure. The residue was purified by silica-gel flash
chromatography (eluted by petroleum ether/ethyl acetate, 5:1).
Figure 1. H/D exchange was observed by 1H NMR spectroscopy.
a) 0.030 mmol 1i, 0.60 mmol D2O in 0.75 mL [D6]DMSO, b) 5% Pd-
ACHTUNGTRENNUNG
Acknowledgements
Huayou Hu is grateful to Jiangsu Province NSF (Grant No.:
BK2011408), Jiangsu Province Department of Education (Grant No.:
10KJB150002), JSKLCLDM (Grant No.: JSKC11093), HYNU (Grant
No.: 11HSGJBZ10) and NBRPC (Grant No.: 2011CB933503) for their fi-
nancial support. Yun Liu thanks financial support by JSNU (Grant No.:
08XLR07). Chao Wang would like to acknowledge the financial support
of SWUST (Grant No.: 09zx7119) and MOHRSS (Grant No.: 11s0104).
À
Keywords: C H activation · cross-coupling · heck reaction ·
heterocycles · synthetic methods
[1] For reviews on green chemistry, see: a) C.-J. Li, B. M. Trost, Proc.
Natl. Acad. Sci. USA 2008, 105, 13197–13202; b) P. T. Anastas, J. C.
Warner in Green Chemistry: Theory and Practice, Oxford University
Press, New York, 1998.
[2] For recent reviews of dehydrogenative cross-coupling reactions, see:
a) C. J. Li, Acc. Chem. Res. 2009, 42, 335–344; b) J. A. Ashenhurst,
Chem. Soc. Rev. 2010, 39, 540–548; c) C. Jia, T. Kitamura, Y. Fuji-
wara, Acc. Chem. Res. 2001, 34, 633–639; d) C. S. Yeung, V. M.
Dong, Chem. Rev. 2011, 111, 1215–1292; e) X. Bugaut, F. Glorius,
Angew. Chem. 2011, 123, 7618–7620; Angew. Chem. Int. Ed. 2011,
50, 7479–7481; f) H. Li, Z. Shi, Prog. Chem. 2010, 22, 1414–1433;
g) X. Guo, Z. Li, C. Li, Prog. Chem. 2010, 22, 1434–1441.
1
Figure 2. Observation of 5 by H NMR spectroscopy. a) 1i in [D6]DMSO,
b) 1i with 1.0 equiv Pd(OAc)2 in [D6]DMSO, c) 1i with 1.0 equiv Pd-
(OAc)2 and 1.0 equiv 2a in [D6]DMSO, d) after heating at 608C for 0.5 h
and filtered.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[3] a) W. Flisch in Comprehensive Heterocyclic Chemistry, Vol. 4 (Eds.:
A. R. Katritzky, C. W. Rees), Pergamon, Oxford, 1984, pp. 476–495;
b) J. Ewing, G. K. Hughes, E. Ritchie, W. C. Taylor, Nature 1952,
169, 618–619.
[4] a) E. Reimann, Prog. Chem. Org. Nat. Prod. 2007, 88, 1–62; b) J. P.
Michael, Nat. Prod. Rep. 2008, 25, 139–165; c) J. P. Michael, Nat.
Prod. Rep. 2003, 20, 458–475; d) M. Elander, Chem. Commun.
1973, 28; e) J. W. Daly, T. F. Spande, H. M. Garraffo, J. Nat. Prod.
2005, 68, 1556–1575; f) M. Leboeuf, A. Cave, A. Ranaivo, H. Mos-
kowitz, Canadian Journal of Chemistry 1989, 67, 947–952; g) S. A.
Snyder, A. M. ElSohly, F. Kontes, Angew. Chem. 2010, 122, 9887–
9892; Angew. Chem. Int. Ed. 2010, 49, 9693–9698.
Scheme 3. Proposed mechanism of the coupling reaction.
Chem. Asian J. 2012, 7, 884 – 888
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
887

H. Hu, C. Wang et al.
COMMUNICATION
[5] a) A. K. Ghosh, G. Bilcer, G. Schiltz, Synthesis 2001, 2203–2229;
b) B. List, C. Castello, Synlett 2001, 1687–1689; c) P. Sonnet, P. Dal-
lemagne, J. Guillon, C. Enguehard, S. Stiebing, J. Tanguy, R.
Bureau, S. Rault, P. Auvray, S. Moslemi, P. Sourdaine, G. E. Seralini,
Bioorg. Med. Chem. Lett. 2000, 8, 945–949; d) O. B. Østby, B.
Dalhus, L.-L. Gundersen, F. Rise, A. Bast, G. R. M. M. Haenen,
Eur. J. Org. Chem. 2000, 3763–3770; e) B. E. Maryanoff, J. L.
Vaught, R. P. Shank, D. F. McComsey, M. J. Costanzo, S. O. Nortey,
J. Med. Chem. 1990, 33, 2793–2797; f) V. H. Lillelund, H. H. Jensen,
X. Liang, M. Bols, Chem. Rev. 2002, 102, 515–554; g) J. Gubin,
H. D. Vogelaer, H. Inion, C. Houben, J. Lucchetti, J. Mahaux, G.
Rosseels, M. Peiren, M. Clinet, P. Polster, P. Chatelain, J. Med.
Chem. 1993, 36, 1425–1433; h) J. Bermudez, C. S. Fake, G. F. Joiner,
K. A. Joiner, F. D. King, W. D. Miner, G. J. Sanger, J. Med. Chem.
1990, 33, 1924–1929.
[6] a) F. D. Saeva, H. R. Luss, J. Org. Chem. 1988, 53, 1804–1806;
b) G. L. Fletetcher, S. L. Bender, D. H. Wadsworth, US Patent
4577024, 1986; [Chem. Abstr. 1984, 100, 122772]; c) H. Sonnen-
schein, G. Henrich, U. Resch-Genger, B. Schulz, Dyes Pigm. 2000,
46, 23–27; d) A. Vlahovici, M. Andrei, I. Druta, J. Lumin. 2002, 96,
279–285; e) A. Vlahovici, I. Druta, M. Andrei, M. Cotlet, R.
Dinica, J. Lumin. 1999, 82, 155–162; f) A. V. Rotaru, L. D. Druta, T.
Deser, T. J. Mueller, Helv. Chim. Acta 2005, 88, 1798–1812; g) F.
Delattre, P. Woisel, G. Surpateanu, F. Cazier, P. Blach, Tetrahedron
2005, 61, 3939–3945.
[7] a) C.-H. Park, V. Ryabova, I. V. Seregin, A. W. Sromek, V. Gevorgy-
an, Org. Lett. 2004, 6, 1159–1162; b) B. Liꢁgault, D. Lapointe, L.
Caron, A. Vlassova, K. Fagnou, J. Org. Chem. 2009, 74, 1826–1834;
c) B. Liu, X. Qin, K. Li, X. Li, Q. Guo, J. Lan, J. You, Chem. Eur. J.
2010, 16, 11836–11839; d) J. Xia, X.-Q. Wang, S.-L. You, J. Org.
Chem. 2009, 74, 456–458; e) Y. Yang, K. Cheng, Y. Zhang, Org.
Lett. 2009, 11, 5606–5609; f) Y. Yang, L. Chen, Z. Zhang, Y. Zhang,
Org. Lett. 2011, 13, 1342–1345.
[8] a) Y. Liu, H.-Y. Hu, Q.-J. Liu, H.-W. Hu, J.-H. Xu, Tetrahedron
2007, 63, 2024–2033; b) H. Hu, K. Shi, R. Hou, Z. Zhang, Y. Zhu, J.
Zhou, Synthesis 2010, 4007–4014; c) Y. Liu, H.-Y. Hu, Y. Zhang, H.-
W. Hu, J.-H. Xu, Org. Biomol. Chem. 2010, 8, 4921–4926.
[9] T. Sasaki, K. Kanematsu, A. Kakehi, G. Ito, Tetrahedron 1972, 28,
4947–4958.
[10] N. P. Buu-Hoi, P. Jacquignon, N. D. Xuong, D. Lavit, J. Org. Chem.
1954, 19, 1370–1375.
[11] L. Zhang, F. Liang, L. Sun, Y. Hu, H. Hu, Synthesis 2000, 1733–
1737.
Received: December 26, 2011
Published online: March 2, 2012
888
www.chemasianj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2012, 7, 884 – 888