Synthesis of functionalized indolizines via copper-catalyzed annulation of 2-alkylazaarenes with α,β-unsaturated carboxylic acids

Article abstract of DOI:10.1021/ol300067h

A novel copper-catalyzed annulation of 2-alkylazaarenes with α,β-unsaturated carboxylic acids has been accomplished. This reaction featuring C-H olefination and decarboxylative amination processes provides a concise access to C-2 arylated indolizines from simple and readily available starting materials.

Full text of DOI:10.1021/ol300067h

ORGANIC
LETTERS
2012
Vol. 14, No. 4
957–959
Synthesis of Functionalized Indolizines
via Copper-Catalyzed Annulation of
2-Alkylazaarenes with r,β-Unsaturated
Carboxylic Acids
Yuzhu Yang,† Chunsong Xie,† Yongju Xie,† and Yuhong Zhang*,†,‡
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China, and
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou
730000, P. R. China
yhzhang@zju.edu.cn
Received October 29, 2011
ABSTRACT
A novel copper-catalyzed annulation of 2-alkylazaarenes with r,β-unsaturated carboxylic acids has been accomplished. This reaction featuring
CꢀH olefination and decarboxylative amination processes provides a concise access to C-2 arylated indolizines from simple and readily available
starting materials.
Indolizines represent a significant class ofnitrogen-fused
heterocylces, which are ubiquitous in many natural prod-
ucts and biologically active compounds.1 Many synthetic
and naturally occurring indolizine derivatives have found
wide applications in pharmaceuticals,2 such as in anti-
inflammatory agents,2a,b H3 receptor antagonists,2c anti-
HIV agents,2d and usage as molecular probes.2e Conse-
quently, the development of efficient especially convergent
methods for rapid construction of indolizines has stimu-
lated considerable interest. The majority of the methods
for indolizine synthesis include 1,3-dipolar cycloaddi-
tion of pyridinium N-methylides with electron-deficient
alkynes or alkenes3 and transition-metal-catalyzed intra-
molecular cycloisomerizations of pyridines with specific
C-2 functionalization.4 Recent published reports involved
a copper-catalyzed [3 þ 2] cyclization of pyridines with
alkenyldiazoacetates5 and a muticomponent approach for
the synthesis of indolizine derivatives.6 However, these
methods often suffer from limitations, such as substrate
availability and involvement of multistage synthesis. Thus
general and convenient methods for the synthesis of
indolizines from simple and readily available precursors
are still of great value.
† Zhejiang University.
(3) (a) Miki, Y.; Hachiken, H.; Takemura, S.; Ikeda, M. Heterocycles
1994, 22, 701. (b) Poissonnet, G.; Theret-Bettiol, M.-H.; Dodd, R. H.
J. Org. Chem. 1996, 61, 2273. (c) Katritzky, A. R.; Qiu, G.; Yang, B.; He,
H.-Y. J. Org. Chem. 1999, 64, 7618.
(4) (a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem.
Soc. 2001, 123, 2074. (b) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc.
2006, 128, 12050. (c) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V.
Org. Lett. 2007, 9, 3433. (d) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323. (e)
Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett.
2007, 9, 1169. (f) Yan, B.; Zhou, Y.; Zhang, H.; Chen, J.; Liu, Y. J. Org.
Chem. 2007, 72, 7783. (g) Liu, Y.; Song, Z.; Yan, B. Org. Lett. 2007, 9,
409. (h) Hardin, A. R.; Sarpong, R. Org. Lett. 2007, 9, 4547.
‡ Lanzhou University.
(1) (a) Comprehensive Heterocyclic Chemistry: The Structure, Reac-
tions, Synthesis, and Uses of Heterocyclic Compounds; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vols. 1ꢀ8. (b) Compre-
hensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon: Oxford, U.K., 1996; Vols. 1ꢀ8. (c) Micheal, J. P.
Alkaloids 2001, 55, 91. (d) Micheal, J. P. Nat. Prod. Rep. 2002, 19, 742.
(2) (a) Molyneux, R. J.; James, L. F. Science 1982, 216, 190. (b)
Oslund, R. C.; Cermak, N.; Gelb, M. H. J. Med. Chem. 2008, 51, 4708.
(c) Gupta, S. P.; Mathur, A. N.; Nagappa, A. N.; Kumar, D.; Kumaran,
S. Eur. J. Med. Chem. 2003, 38, 867. (d) Facompre, M.; Tardy, C.; Bal-
Mahieu, C.; Colson, P.; Perez, C.; Manzanares, I.; Cuevas, C.; Bailly, C.
Cancer Res. 2003, 63, 7392. (e) Kim, E.; Koh, M.; Ryu, J.; Park, S. B.
J. Am. Chem. Soc. 2008, 130, 12206.
ꢀ
ꢀ
(5) Barluenga, J.; Lonzi, G.; Riesgo, L.; Lopez, L. A.; Tomas, M.
J. Am. Chem. Soc. 2010, 132, 13200.
€
(6) Zhu, H.; Stockigt, J.; Yu, Y.; Zou, H. Org. Lett. 2011, 13, 2792.
r
10.1021/ol300067h
2012 American Chemical Society
Published on Web 02/08/2012

During the past few years, transition-metal-catalyzed
direct benzylic CꢀH functionalization of 2-alkylazaarenes
has attracted much attention.7 These reactions were sup-
posed to be initiated by the formation of metal enamide
species through the electrophilic metalation of 2-alkyla-
zaarenes. In the course of our ongoing efforts devoted
toward studying transition-metal-catalyzed CꢀH func-
tionalization,8 we discovered that, by virtue of copper
as an inexpensive catalyst, indolizine derivatives were able
to be accessed directly by annulation of 2-alkylazaarenes
and cinnamic acids featuring CꢀH olefination and
decarboxylative amination processes. This methodology
addresses many current limitations for the synthesis of
indolizines, furnishing a diverse collection of valuable C-2
arylated indolizines using readily and commercially avail-
able reagents.9
the base were employed (Table 1, entry 22). When the
reaction was conducted at a lower temperature, it pro-
ceeded with a lower yield, and a higher reaction tempera-
ture did not help increase the yield (Table 1, entry 23 and
Supporting Information). Further attempts to substitute
DMF with other solvents failed to yield better results (see
Supporting Information).
Table 1. Reaction Optimizationa
Our initial attempt started with the reaction of 2-ethyl-
pyridine and cinnamic acid at 140 °C under a N2 atmo-
sphere. Screening of the copper catalysts (Table 1, entries
1ꢀ6) revealed that Cu(OAc)2 was optimal to give the
annulation product 3a in 45% yield (Table 1, entry 6). In
contrast to other copper-catalyzed CꢀH activation
processes,10 the reaction failed to work under oxidative
reaction conditions (Table 1, entry 7 and Supporting
Information). Surprisingly, the product was isolated in
39% yield when copper bronze was employed as the
catalyst (Table 1, entry 8), and the reaction failed again
when the atmosphere was switched from N2 toO2 (Table 1,
entry 9). It was found that employing 2 equiv LiOAc as an
additive elevated the yield to51% (Table 1, entry 10), while
other additives such as NaOAc, KOAc, and LiCl were less
effective (Table 1, entries 11ꢀ13). To improve the yield, we
exploited active metal powders in the Cu(OAc)2 system to
generate in situ Cu(0) species (Table 1, entries 14ꢀ17).
Gratifyingly, adding 0.5 equiv of nickel powder increased
the yield of the product to 62% (Table 1, entry 17). No
reaction was observed in the absence of copper catalyst
(Table 1, entry 18), and the ligand (1,10-phenanthroline)
was required to obtain a higher yield (Table 1, entry 19 and
Supporting Information). It was found that, by extending
the reaction time to 36 h, the yield of the product reached
the highest yield (66%) (Table 1, entry 20). A 3 equiv
amount of2-ethylpyridinesubstratewas required toget the
best yield, and the yield decreased to 31% when 1 equiv of
2-ethylpyridine as the substrate and 2 equiv of pyridine as
time
(h)
yield
(%)b
entry
catalyst
CuI
additive
1
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
36
48
36
36
trace
11
28
23
0
2
CuCl
3
Cu(OTf)2
CuCl2
4
5
CuBr2
6
Cu(OAc)2
Cu(OAc)2
copper bronze
copper bronze
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
ꢀ
45
0
7c
8
39
0
9c
10
11
12
13
14
15
16
17
18
19d
20
21
22e
23f
LiOAc
51
29
trace
46
38
44
49
62
0
NaOAc
KOAc
LiCl
Fe powder þ LiOAc
Al powder þ LiOAc
Zn powder þ LiOAc
Ni powder þ LiOAc
Ni powder þ LiOAc
Ni powder þ LiOAc
Ni powder þ LiOAc
Ni powder þ LiOAc
Ni powder þ LiOAc
Ni powder þ LiOAc
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
35
66
65
31
58
a Reaction conditions: 2-ethylpyridine (1.5 mmol), cinnamic acid
(0.5 mmol), catalyst (0.1 mmol), 1,10-phenanthroline (0.1 mmol), additive
(0.25 mmol for reductive metal powder and 1 mmol for the other), DMF
(N,N-dimethylformamide, 1 mL), 140 °C, N2. b Isolated yield. c Under
O2. d In the absence of 1,10-phenanthroline. e 0.5 mmol of 2-ethylpyr-
idine and 1.0 mmol of pyridine were employed in the reaction. f The
reaction was performed at 160 °C.
(7) (a) Qian, B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.; Huang,
H. J. Am. Chem. Soc. 2010, 132, 3650. (b) Rueping, M.; Tolstoluzhsky,
N. Org. Lett. 2011, 13, 1095. (c) Song, G.; Su, Y.; Gong, X.; Han, K.; Li,
X. Org. Lett. 2011, 13, 1968. (d) Burton, P. M.; Morris, J. A. Org. Lett.
2010, 12, 5359. (e) Jiang, H.; Chen, H.; Wang, A.; Liu, X. Chem.
Commun. 2010, 46, 7259.
(8) (a) Yang, Y.; Cheng, K.; Zhang, Y. Org. Lett. 2009, 11, 5606. (b)
Yang, Y.; Chen, L.; Zhang, Z.; Zhang, Y. Org. Lett. 2011, 13, 1342.
(9) Direct C-2 arylation of indolizines is difficult to realize because
the CꢀH arylation of indolizines occurs on the most electron-rich C-3
position; see: (a) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek,
A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159. For the synthesis of C-2
arylated indolizines through palladium-catalyzed approaches, see:
(b) Chernyak, D.; Skontos, C.; Gevorgyan, V. Org. Lett. 2010, 12,
3242. (c) Chernyak, D.; Gevorgyan, V. Org. Lett. 2010, 12, 5558.
(10) For a recent review on copper-catalyzed CꢀH functionalizatioin
under oxidative reaction conditions, see: Wendlandt, A. E.; Suess,
A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062.
With the optimal reaction conditions in hand, we next
examined the scope of substituted 2-alkylazaarenes in this
annulation process as shown in Scheme 1. Various pyr-
idines with C-2 functional groups such as CH2CN,
CH2COOEt, CH2Ph, and n-C5H11 were compatible with
the reaction conditions, resulting in the formation of the
desired products in moderate yields (3bꢀ3e). When 2-pico-
line participated in this reaction, the corresponding prod-
uct 3f was isolated in 45% yield. 2,6-Lutidine and 2,3-
lutidine were transferred via this reaction to give the
expected indolizines with methyl substituents on C-5 and
C-8 positions respectively (3g and 3h). It is noteworthy that
958
Org. Lett., Vol. 14, No. 4, 2012

Scheme 1. Scope of the Synthesis of Indolizines: Substituents on
2-Alkylazaarenesa
Scheme 2. Scope of the Synthesis of Indolizines: Substituents on
R,β-Unsaturated Carboxylic Acidsa
a Reaction conditions: 2-alkylazaarene (1.5 mmol), cinnamic acid
(0.5 mmol), Cu(OAc)2 (0.1 mmol), 1,10-phenanthroline (0.1 mmol),
nickel powder (0.25 mmol), LiOAc (1 mmol), DMF (1 mL), 140 °C, N2,
36 h. Isolated yield.
2-methyl quinoline and 1-methyl isoquinoline also reacted
with cinnamic acid to afford the annulation products 3i
and 3j in moderate yields.
a Reaction conditions: 2-ethylpyridine (1.5 mmol), substituted R,
β-unsaturated carboxylic acid (0.5 mmol), Cu(OAc)2 (0.1 mmol), 1,
10-phenanthroline (0.1 mmol), nickel powder (0.25 mmol), LiOAc
(1 mmol), DMF (1 mL), 140 °C, N2, 36 h. Isolated yield.
We next examined the scope of substituted R,β-unsatu-
rated carboxylic acids in this annulation process as shown
in Scheme 2. It was found that a variety of substituted
cinnamic acids can be converted to the desired products in
modest yields, showing good functional group tolerance of
both electron-withdrawing substituents (F, Cl, CF3, and
NO2) and electron-donating substituents (OMe and Me).
The ability to incorporate halogen substituents (F and Cl,
3kꢀ3o) and a nitro group (3q) into the product makes this
process possess potential for further synthetic transforma-
tions. As for substitution patterns, ortho-substituted cin-
namic acid delivereda relatively lower yield compared with
its meta- or para-analogues probably due to the steric
hindrance (3s, 3t, and 3u). Moreover, we were delighted
to find that naphthyl- and heteroaryl-substituted R,
β-unsaturated carboxylic acids were tolerated in this pro-
cess, providing the corresponding indolizine derivatives
(3vꢀ3x). But alkyl-substituted R,β-unsaturated carboxylic
acid such as crotonic acid failed in the reaction to give the
desired product 3y.
not need oxidants. In addition, powder XRD analyses of
the precipitates after the reaction revealed that a typical
Cu(0) diffraction pattern was presented, illustrating that
Cu(0) species may be involved in this reaction. Further
research is required to elucidate the detailed mechaism.
In summary, we have developed a novel and convenient
copper-catalyzed direct synthesis of indolizines from read-
ily available 2-alkylazaarenes and R,β-unsaturated car-
boxylic acid. This new reaction can tolerate a broad
variety of substituents, leading to C-2 arylated indolizines.
Acknowledgment. Funding from the National Basic
Research Program of China (No. 2011CB936003) and
Natural Science Foundation of China (No. 21072169) is
acknowledged.
Although the mechanistic details are not clear at present,
some experiments have been done to verify the catalytic
pathways (see Supporting Information). GC analyses of
the gases captured during the reaction confirmed the
release of CO2 and H2, indicating this process involves
decarboxylation and the dehydrogenative coupling does
Supporting Information Available. Experimental pro-
cedure and characterization of all compounds. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
959