Copper-Catalyzed Oxidative Coupling-Annulation: One-Pot Synthesis of Indolizines from 2-Alkylazaarenes with Alkenes

Article abstract of DOI:10.1055/s-0034-1378785

A novel copper-catalyzed highly selective oxidative coupling-annulation of 2-alkylazaarenes with terminal alkenes was achieved. This process provides a simple, efficient, and atom-economic way to construct indolizines in good yields.

Full text of DOI:10.1055/s-0034-1378785

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2024–2028
letter
2024
J.-l. Liu et al.
Letter
Synlett
Copper-Catalyzed Oxidative Coupling–Annulation: One-Pot Syn-
thesis of Indolizines from 2-Alkylazaarenes with Alkenes
Jing-ling Liua,b
Ying Liang*a
Heng-shan Wangb
Ying-ming Pan*b
air
Cu(OAc)2 (20 mol%), 80 °C
R
N
Ar
+
R
N
DMSO, 12 h
Ar
a School of Life and Environmental Sciences, Guilin University of
Electronic Technology, Guilin, 541004, P. R. of China
yingl@aliyun.com
18 examples
isolated yields: 75–90%
b Key Laboratory for the Chemistry and Molecular Engineering
of Medicinal Resources (Ministry of Education of China),
School of Chemistry and Pharmaceutical Sciences of Guangxi
Normal University, Guilin, 541004, P. R. of China
panym2013@hotmail.com
Received: 17.05.2015
Accepted after revision: 10.06.2015
Published online: 29.07.2015
(Scheme 1, a).17 For these reasons, a straightforward, conve-
nient, and highly regioselective route to synthesize indol-
izines from simple olefins has emerged as an attractive and
challenging goal.
Recently, the use of copper-catalyzed reactions has
emerged as a versatile tool for developing syntheses due to
their numerous advantages, namely their relatively high ef-
ficiency, low cost, water compatibility, mild reaction condi-
tions, operational simplicity, and eco-friendly catalytic re-
actions.18 Herein, we describe a novel copper-catalyzed
highly selective oxidative coupling–annulation of 2-al-
kylazaarenes with terminal alkenes for the formation of in-
dolizines under mild conditions (Scheme 1, b).
To identify the suitable conditions for the process, great
number of solvents and metal salts were initially screened
using styrene (1a, 0.5 mmol) with ethyl 2-(pyridine-2-yl)
acetate (2a, 0.5 mmol) as a model system (Table 1). Initially,
the reaction of 1a and 2a failed to afford the desired prod-
uct in the presence of CuSO4·5H2O in DMSO at 80 °C for 12
hours (Table 1, entry 1). But the reaction successfully gave
3aa20 in 80% yield when CuSO4·5H2O was replaced by
Cu(OAc)2 (Table 1, entry 2). According to our efforts, CuCl2
and CuCl could also provide the indolizine product, albeit in
a low yield (Table 1, entries 3 and 5), but other Cu(II) salts
such as Cu(OTf)2 were totally ineffective (Table 1, entry 4).
Furthermore, with the AuBr3 as the catalysts, the target
product 3aa was also not increased at all (Table 1, entry 6).
In addition, in the presence of other catalysts such as FeCl3,
BiCl3, or AgOAc, the process was totally ineffective (Table 1,
entries 7–9). Further study suggested that solvents had a
strong effect on this process. The reactions were merely in
lower yields or totally restrained when they were per-
formed in other solvents (Table 1, entries 10–16). It is noted
that no desired product could be obtained when the reac-
tion was conducted under argon atmosphere (Table 1, entry
DOI: 10.1055/s-0034-1378785; Art ID: st-2015-w0377-l
Abstract A novel copper-catalyzed highly selective oxidative cou-
pling–annulation of 2-alkylazaarenes with terminal alkenes was
achieved. This process provides a simple, efficient, and atom-economic
way to construct indolizines in good yields.
Key words indolizines, alkenes, 2-alkylazaarenes, oxidative coupling,
annulation
Indolizines are among the most important constituents
in a wide range of natural products, pharmaceuticals, and
materials.1 Functionalized indolizines have shown many
important biological activities including antibacterial,2 an-
tiviral,3 anti-HIV,4 anti-inflammatory,5 5-HT3 receptor an-
tagonist,6 muscular relaxant,7 phosphatase inhibitive,8 and
antioxidizing.9 In this regard, there are many reports for
the synthesis of indolizines, such as Scholtz reaction,10
Tschitschibabin reaction,11 starting from N-substituted pyr-
role ring,12 Knoevenagel condensation–intramolecular al-
dol-type cyclization protocol,13 multicomponent coupling
reactions (MCR),14 cycloaddition reactions of pyridines with
alkenyldiazoacetates,15 and C–H functionalization reac-
tion.16 However, some of these methods require tedious
workup, harsh reaction conditions, or long reaction times.
Others involve multistep synthetic operations or result in
low yields. On the other hand, although numerous alterna-
tive successful examples have been reported in the litera-
ture for the preparation of indolizines, less attention has
been paid to investigate cycloaddition reactions of 2-al-
kylazaarenes with alkenes. Lei et al. reported in 2015 that a
direct oxidative coupling–annulation of 2-pyridinyl-β-es-
ters with alkenes provides a way for the synthesis of indol-
izines in 25–59% yields; nevertheless, the reaction need
three equivalents of TBHP and one equivalent of NaOAc
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J.-l. Liu et al.
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a) previous work
O
TBHP (3 equiv)
NaOAc (1 equiv)
O
N
R
OEt
+
N
OEt
I2 (20 mol%)
80 °C, DCE, 20 h
R
9 examples, 25–59% yields
b) this work
Ar
air
Cu(OAc)2 (20 mol%)
R
N
+
R
N
80 °C, DMSO, 12 h
Ar
73–90% yields
Scheme 1 Comparison of Lei’s and our work.
17). Hence, the combination of 20 mol% Cu(OAc)2 in DMSO
at 80 °C for 12 hours was found to be the best reaction con-
ditions for this copper-catalyzed crossing-coupling–cycliza-
tion–oxidation process.
Table 1 Optimization of Reaction Conditionsa
O
O
catalyst
N
+
Ph
With the optimized reaction conditions in hand, various
terminal alkenes 1 were allowed to react with different 2-
alkylazaarenes 2 to access the corresponding indolizine
products 3 (Scheme 2). The reaction was readily extended
to a variety of aryl-substituted terminal alkenes. Promoted
by Cu(OAc)2, almost all the aryl-substituted terminal
alkenes are effective under the standard conditions. It is
noteworthy that steric effects had little influence on this
sequential reaction. Regardless of the substitution pattern
of the aryl ring (ortho or para) of the aryl olefins used in the
reaction, it gave the corresponding indolizine products in a
same yield (Scheme 2, 3ba and 3ca). The terminal aryl
alkene 1d possessing an electron-donating group at the aryl
ring (Ar = 4-MeOC6H4) reacted without a hitch and afforded
the desired product 3da[20] in 90% yield. Substrates 1e and
1f possessing an electron-withdrawing group (Ar = 4-FC6H4,
4-BrC6H4) at the benzene ring also reacted smoothly and af-
forded the desired products 3ea and 3fa[20] in 75% and 78%
yields, respectively. Obviously, electron-rich terminal
alkenes provided the desired products in higher yields than
electron-poor terminal alkenes did. Unfortunately, the reac-
tion of styrenes with strong electron-deficient substituents,
such as CF3 and COOMe, failed to afford the desired prod-
ucts. Additionally, terminal alkene containing a naphtha-
lene moiety could also be employed to yield the indolizine
scaffold without any difficulties (Scheme 2, entry 3ga).
What’s more, heterocyclic substituted alkene devoted to
promote the synthesis of indolizine ring (Scheme 2, entry
3ha). However, the reactions of aliphatic alkenes (e.g., pent-
1-ene) and internal alkenes (e.g. trans-stilbene) failed to af-
ford the desired products.
OEt
N
OEt
80 °C, solvent
Ph
1a
2a
3aa
Entry
Catalyst
Solvent
Yield (%)b
1
2
CuSO4·5H2O
Cu(OAc)2
CuCl2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
1,4-dioxane
AcOH
DCE
0
80
20
0
3
4
Cu(OTf)2
CuCl
5
10
20
0
6
AuBr3
7
FeCl3
8
BiCl3
0
9
AgOAc
0
10
11
12
13
14
15
16
17c
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
30
10
10
0
PhCl
PhMe
THF
0
0
DMF
0
DMSO
0
a Reaction conditions: styrene (1a, 0.5 mmol), ethyl 2-(pyridine-2-yl)ace-
tate (2a, 0.5 mmol), catalyst (20 mol% to 2a), solvent (2.0 mL), 80 °C, 12 h.
b Isolated yield of pure product based on 2a.
c The reaction was conducted under argon atmosphere.
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air
Cu(OAc)2 (20 mol%)
R1
N
R1
Ar
+
N
80 °C, DMSO, 12 h
Ar
2
1
3
O
O
O
N
O
Et
O
N
Et
N
N
O
Et
Me
Et
O
O
Me
Me
O
3aa 80%
3ba 83%
3ca 83%
3da 90%
O
O
O
N
O
Et
O
N
S
N
Et
N
Et
O
Et
O
O
F
Br
3ga 87%
3ea 75%
3fa 78%
3ha 85%
O
O
O
O
N
N
Me
Me
O
O
N
N
Me
Me
O
O
Me
Me
Me
O
3db 89%
3bb 83%
3cb 83%
3ab 81%
O
O
O
N
N
O
Bu
OMe
O
N
S
Me
N
O
Me
O
Me
F
O
3gb 88%
3eb 79%
3hb 84%
3dc 86%
N
N
N
N
Me
O
3dd 76%
3gd 78%
Scheme 2 Synthesis of indolizines catalyzed by Cu(OAc)2. Reagents and conditions: terminal alkenes 1 (0.5 mmol), 2-alkylazaarenes 2 (0.5 mmol),
Cu(OAc)2 (20 mol% to 2), solvent (4.0 mL), 80 °C, 12 h. Isolated yield of pure product based on 2 is given.
Various different 2-alkylazaarenes 2 were also found to
be suitable reaction partners with terminal alkenes 1 in this
reaction. The β-pyridine group of 2 could be ranged from
ethyl to methyl or butyl esters, all of which reacted with
terminal alkenes 1 to afford the corresponding indolizine
products in good yields (Scheme 2, entries 3ab–dc). Even 2-
alkylazaarene bearing cyano groups were well tolerated in
this transformation and offered the target products in good
yields (Scheme 2, entries 3dd and 3gd).
When 1i was used under the optimized conditions the
reaction failed to produce the expected indolizine 3ia but
gave benzophenone (4) instead (Scheme 3).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2024–2028

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air
O
O
Ph
Ph
O
Cu(Ac)2 (20 mol%)
+
N
Et
Ph
Ph
O
N
OEt
80 °C, DMSO, 12 h
Ph
1i
2a
4
Ph
3ia (not formed)
Scheme 3 Copper-catalyzed oxidative coupling–annulation of 1i and 2a
[O]
Cu(II)
Cu(I)
H+
R1
Ar
R1
R1
N
H
N
N
[O]
Ar
Cu(II)
Cu(I)
[O]
R1
R1
R1
Ar
N
N
N
H+
Ar
Ar
Scheme 4 Possible reaction mechanism
It was observed that the addition of a radical scavenger
(2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) sup-
pressed the reaction completely. The results indicated that
the radical mechanism was most likely in this reaction. On
the basis of other previous works,19 a proposed mechanism
is illustrated in Scheme 4. The reaction generate a radical
intermediate through loss of proton oxidized by copper(II),
and subsequent single-electron insertion into styrene leads
to C–C propagation, which is further oxidized by copper(II)
to a carbocation, followed by subsequent intramolecular
condensation of this β-pyridine intermediate and then oxi-
dized by air to afford the final indolizine product.
In summary, we have developed an efficient approach
to indolizine via a copper-catalyzed cross-coupling–cycliza-
tion–oxidation reaction of terminal alkenes and 2-al-
kylazaarenes under aerobic conditions in one step. Due to
the easy availability of the starting materials and potential
utilities of products, this method might be useful in organic
synthesis and medicinal chemistry. From the synthetic
point of view, this protocol represents an extremely simple,
efficient, and atom-economic way to construct substituted
indolizine in good yields with high selectivity, thus comple-
menting the method for the rapid formation of multifunc-
tional heterocycles.
search and Technology Development Program (1355004-3), State Key
Laboratory Cultivation Base for the Chemistry and Molecular Engi-
neering of Medicinal Resources, Ministry of Science and Technology
of China (CMEMR2014-A02 and CMEMR2012-A20), and Guangxi’s
Medicine Talented Persons Small Highland Foundation (1306) for fi-
nancial support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378785.
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p
p
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References and Notes
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Acknowledgment
We thank the National Natural Science Foundation of China
(21362002, 41206077, and 81260472), The Key Project of Guangxi
Department of Education (2013ZD006), and Guangxi Scientific Re-
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The reaction mixture of terminal alkenes 1 (0.5 mmol), 2-
alkylazaarenes 2 (0.5mmol), Cu(OAc)2 (20 mol%), and DMSO (2
mL) in a 10 mL round-bottom flask was stirred at 80 °C for 12 h.
Upon completion, the reaction mixture was diluted with H2O
(30 mL) and extracted with EtOAc (3 × 30 mL). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, and filtered. The solvent was removed under vacuum.
The residue was purified by flash column chromatography to
afford indolizines 3.
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Ethyl 3-Phenylindolizine-1-carboxylate (3aa)
Yellow solid (106 mg, 0.4 mmol, 80%); mp 61–62 °C. 1H NMR
(500 MHz, CDCl3): δ = 8.18–8.23 (m, 2 H), 7.40–7.48 (m, 4 H),
7.34 (m, 1 H), 7.31–7.23 (s, 1 H), 6.98–7.01 (m, 1 H), 6.61–6.64
(m, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 1.35 (t, J = 7.1 Hz, 3 H). 13C NMR
(125 MHz, CDCl3): δ = 165.1, 136.4, 131.3, 129.1, 128.6, 128.0,
126.4, 123.4, 122.3, 120.2, 116.1, 112.6, 104.2, 59.6, 14.7. ESI-
HRMS: m/z calcd for C17H15NO2: 265.11028; found: 265.10894.
Ethyl 3-(4-Bromophenyl)indolizine-1-carboxylate (3fa)
Yellow solid (134 mg, 0.39 mmol, 78%); mp 88–89 °C. 1H NMR
(500 MHz, CDCl3): δ = 8.20–8.15 (m, 2 H), 7.55 (d, J = 8.4 Hz, 2
H), 7.34 (d, J = 8.4 Hz, 2 H), 7.22 (s, 1 H), 7.02–7.00 (m, 1 H), 6.65
(t, J = 6.8 Hz, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 1.34 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 164.9, 136.5, 132.3, 130.1, 130.0,
125.1, 123.1, 122.4, 121.9, 120.3, 116.4, 112.9, 104.5, 59.7, 14.7.
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Lett. 2011, 13, 2792.
ESI-HRMS: m/z calcd for
C17H14BrNO2: 343.02079 and
345.01874; found: 343.01908 and 345.01690.
Ethyl 3-(4-Methoxyphenyl)indolizine-1-carboxylate (3da)
Yellow solid (133 mg, 0.45 mmol, 90%); mp 112–113 °C. 1H
NMR (500 MHz, CDCl3): δ = 8.18–8.15 (m, 1 H), 8.13–8.11 (m, 1
H), 7.38–7.35 (m, 2 H), 7.16 (s, 1 H), 6.98–6.93 (m, 3 H), 6.60 (dt,
J = 6.8, 1.2 Hz, 1 H), 4.30 (q, J = 7.1 Hz, 2 H), 3.79 (s, 3 H), 1.34 (t,
J = 7.1 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 165.1, 159.4,
136.0, 130.1, 126.2, 123.6, 123.3, 122.0, 120.1, 115.6, 114.5,
(15) Barluenga, J.; Lonzi, G.; Riesgo, L.; Lopez, L. A.; Tomas, M. J. Am.
Chem. Soc. 2010, 132, 13200.
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(b) Wang, X.; Li, S.-Y.; Pan, Y.-M.; Wang, H.; Liang, H.; Chen, Z.;
Qin, X. Org. Lett. 2014, 16, 580. (c) Yang, Y.; Cheng, K.; Zhang, Y.
Org. Lett. 2009, 11, 5606. (d) Xia, J.-B.; You, S.-L. Org. Lett. 2009,
11, 1187. (e) Wu, Q.; Zhao, D.; Qin, X.; Lan, J.; You, J. Chem.
Commun. 2011, 47, 9188. (f) Xia, J.-B.; Wang, X.-Q.; You, S.-L. J.
112.4, 103.9, 59.5, 55.4, 14.7. ESI-HRMS: m/z calcd for C18H17
-
NO3: 295.12084; found: 295.11933.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2024–2028