Highly efficient synthesis of functionalized indolizines and indolizinones by copper-catalyzed cycloisomerizations of propargylic pyridines

Article abstract of DOI:10.1021/jo070983j

(Chemical Equation Presented) The copper-catalyzed cycloisomerizations of 2-pyridyl-substituted propargylic acetates and its derivatives are described, which offer an efficient route to C-1 oxygenated indolizines with a wide range of substituents under mild reaction conditions. The presented method could be readily applied to the synthesis of indolizinones through a cyclization/1,2- migration of tertiary propargylic alcohols.

Full text of DOI:10.1021/jo070983j

SCHEME 1
Highly Efficient Synthesis of Functionalized
Indolizines and Indolizinones by
Copper-Catalyzed Cycloisomerizations of
Propargylic Pyridines
Bin Yan, Yebing Zhou, Hao Zhang, Jingjin Chen, and
Yuanhong Liu*
their unique photophysical properties.3 Although a number of
methods are available for the synthesis of indolizines,4,5 the
development of general and efficient synthesis of functionalized
indolizines is still highly attractive.6,7 Recently, Gevorgyan et
al. reported an interesting Au-catalyzed cascade 1,2-migration/
cycloisomerization of propargylic substrates to indolizines with
various functionalities.8 The metal salts employed were sug-
gested to facilitate an alkyne-vinylidene isomerization with
concomitant 1,2-migration of H, silyl, stannyl, or germyl groups
by the formation of gold-vinylidene intermediates. We have
reported a Pd/Cu-catalyzed one-pot synthesis of 3-aminoin-
dolizines through the reactions of propargyl amines or amides
with heteroaryl bromides.9 It was found that this reaction was
strongly dependent on the presence of a base and on the solvent
employed. A suitable base may facilitate a propargyl-allenyl
isomerization to an allenic intermediate or serve as a good ligand
to stabilize the copper intermediates. On the basis of this work,
we envisioned that propargylic acetates bearing pyridine rings
may also undergo copper-catalyzed cyclization via allenic
intermediates to give indolizines (Scheme 1). In this paper, we
report the cyclization of 2-pyridyl-substituted propargylic
acetates 1 by a more convenient, economic, and efficient copper-
catalyzed approach for the synthesis of C-1 oxygenated indoliz-
ines at room temperature. The present method could be readily
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, People’s Republic of China
yhliu@mail.sioc.ac.cn
ReceiVed May 9, 2007
The copper-catalyzed cycloisomerizations of 2-pyridyl-
substituted propargylic acetates and its derivatives are
described, which offer an efficient route to C-1 oxygenated
indolizines with a wide range of substituents under mild
reaction conditions. The presented method could be readily
applied to the synthesis of indolizinones through a cycliza-
tion/1,2-migration of tertiary propargylic alcohols.
(3) (a) Taguchi, T. U.S. Patent 0015614-A1, 2001. (b) Taguchi, T. U.S.
Patent 0050476-A1, 2003.
(4) For reviews, see: (a) Uchida, T.; Matsumoto, K. Synthesis 1976,
209. (b) Behnisch, A.; Behnisch, P.; Eggenweiler, M.; Wallenhorst, T.
Indolizine. In Houben-Weyl, 1994; Vol. E6b/1, 2a, pp 323-450.
(5) (a) Scholtz, M. Ber. Dtsch. Chem. Ges. 1912, 45, 734. (b) Boekel-
heide, V.; Windgassen, R. J., Jr. J. Am. Chem. Soc. 1959, 81, 1456. (c)
Tschitschibabin, A. E. Ber. Dtsch. Chem. Ges. 1927, 60, 1607. (d) Hurst,
J.; Melton, T.; Wibberley, D. G. J. Chem. Soc. 1965, 2948. (e) Bora, U.;
Saikia, A.; Boruah, R. C. Org. Lett. 2003, 5, 435. (f) Miki, Y.; Hachiken,
H.; Takemura, S.; Ikeda, M. Heterocycles 1994, 22, 701. (g) Poissonnet,
G.; Theret-Bettiol, M.-H.; Dodd, R. H. J. Org. Chem. 1996, 61, 2273. (h)
Katritzky, A. R.; Qiu, G.; Yang, B.; He, H.-Y. J. Org. Chem. 1999, 64,
7618. (i) Fang, X.; Wu, Y. M.; Deng, J.; Wang, S. W. Tetrahedron 2004,
60, 5487. (j) Sasaki, T.; Kanematsu, K.; Kakehi, A.; Ito, G.; Tetrahedron
1972, 28, 4947. (k) Pohjala, E. Tetrahedron Lett. 1972, 13, 2585. (l) Nugent,
R. A.; Murphy, M. J. Org. Chem. 1987, 52, 2206. (m) Takacs, J. M.;
Weidner, J. J.; Takacs, B. E. Tetrahedron Lett. 1993, 34, 6219. (n) Kaloko,
J., Jr.; Hayford, A. Org. Lett. 2005, 7, 4305. For copper-catalyzed indolizine
formation, see: (o) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am.
Chem. Soc. 2001, 123, 2074. (p) Kim, J. T.; Gevorgyan, V. Org. Lett. 2002,
4, 4697. (q) Kim, J. T.; Butt, J.; Gevorgyan, V. J. Org. Chem. 2004, 69,
5638. (r) Kim, J. T.; Gevorgyan, V. J. Org. Chem. 2005, 70, 2054.
(6) (a) Ohsawa, A.; Abe, Y.; Igeta, H. Bull. Chem. Soc. Jpn. 1980, 53,
3273. (b) Abe, Y.; Ohsawa, A.; Igeta, H. Chem. Pharm. Bull. 1982, 30,
881.
(7) During our manuscript preparation, a platinum or InCl3-catalyzed
cyclization of pyridine propargylic pivaloate and its derivatives to indolizines
and indolizinones was been reported by Sarpong et al. The reaction usually
requires higher temperature (40-70 °C for indolizines and 100 °C for
indolizinones) with benzene as the solvent and bulky electron-rich phosphine
ligands such as 2-(di-tert-butylphosphino)biphenyl or 2-(dicyclohexylphos-
phino)biphenyl as the ligands in the case of platinum catalysis. See: Smith,
C. R.; Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169.
(8) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050.
(9) Liu, Y.; Song, Z.; Yan, B. Org. Lett. 2007, 9, 409.
Indolizines, which exhibit intriguing molecular structures
featured by an N-bridgehead bicyclic ring system, have received
much attention in recent years.1 Many of the synthetic and
natural indolizines have displayed important biological activities
which can find a variety of applications in pharmaceutical use.2
They are also useful in the field of material science owing to
(1) For reviews, see: (a) The Structure, Reactions, Synthesis, and Uses
of Heterocyclic Compounds. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vols.
1-8. (b) Flitsch, W. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol.
8, p 237. (c) Swinborne, J. H.; Klinkert, G. AdV. Heterocycl. Chem. 1978,
23, 103.
(2) For recent reviews, see: (a) Micheal, J. P. Alkaloids 2001, 55, 91.
(b) Micheal, J. P. Nat. Prod. Rep. 2002, 19, 742. (c) Nash, R. J.; Fellows,
L. E.; Dring, J. V.; Striton, C. H.; Carter, D.; Hegarty, M. P.; Bell, E. A.
Phytochemistry 1988, 27, 1403. For selected papers, see: (d) Molyneux,
R. J.; James, L. F. Science 1982, 216, 190. (e) Gubin, J.; Descamps, M.;
Chatelain, P.; Nisato, D. Eur. Pat. Appl. EP 235111, 1987; Chem. Abstr.
1988, 109, 6405b. (f) Okada, S.; Sawada, K.; Kuroda, A.; Watanabe, S.;
Tanaka, H. Eur. Pat. Appl. EP 519353, 1992; Chem. Abstr. 1993, 118,
212886y. (g) King, F. D.; Gaster, L. M.; Joiner, G. F. PCT Int. Appl. WO
9308187 1993; Chem. Abstr. 1993, 119, 160281. (h) Harrell, W. B. J.
Pharm. Sci. 1970, 59, 275. (i) Koya, K.; Sun, L.; Ono, M.; Ying, W.; Li,
H. PCT Int. Appl. WO 03022846, 2003.
10.1021/jo070983j CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/25/2007
J. Org. Chem. 2007, 72, 7783-7786
7783

TABLE 1. Optimization Studies for the Cu-Catalyzed
Cycloisomerization Reactions
SCHEME 2
yielda
time product (%)
entry substrate
CuX
base
solvent
THF
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
5% CuI
5% CuI
5% CuI
5% CuBr
5% CuCI
2% CuI
5% CuI
5% CuI
-
-
3 h
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
98
2.0 Et2NH THF
1.5 h
95
3
4
5
6
-
CH2Cl2 3.5 h
CH3CN 2 h
CH3CN 3 h
CH3CN 6 h
CH3CN 2 h
CH3CN 40 min
CH3CN 12 h
CH3CN 18 h
CH3CN 2 h
(>99)
(>99)
(>99)
(>99)
97
-
-
-
7
8
-
1.0 Et3N
2.0 Et3N
-
97
9
10
11
NRb
63
5% CuI
5% CuI
1.0 Et3N
82
a Isolated yields; NMR yields are given in parentheses. b NR ) no
reaction.
afford 2g in 90% yield after 1 h (Table 2, entry 5). The
appearance of a vinylic group in the substrates such as 1h and
1i did not influence the efficiency of this reaction, in which the
corresponding products 2h and 2i were formed in 86 and 83%
yields, respectively (Table 2, entries 6 and 7). An alkyne
terminus tethered with an OAc group afforded the corresponding
product 2j in 90% yield (Table 2, entry 8). Alkyne substituted
with a TMS group resulted in a complete desilylation during
the reaction, and the product 2b was obtained in 68% yield
(Table 2, entry 9). 6-Bromopyridyl-substituted substrate 1l
afforded the desired indolizine 2k in 77% yield (Table 2, entry
10). The reaction of 2-quinolyl-substituted propargyl acetate 1m
also proceeded well to give benz[e]indolizine 2l in 89% yield
(Table 2, entry 11). It is interesting to note that the reaction has
also been accomplished starting from 1n with silyl-protected
groups (OTBS-), furnishing 2m in 85% yield (Table 2, entry
12). A clean formation of a phenyl-bridged indolizine 2n was
achieved in 82% yield by using 1o as the substrate (Table 2,
entry 13). The structure of indolizines was unequivocally
confirmed by single-crystal analysis of 2l,12 and the result clearly
showed N-bridgehead bicycles.
We propose the following two possible pathways for the
formation of indolizine 2 (Scheme 2). According to path a, a
CuI-base-induced propargyl-allenyl isomerization of 1 occurs
first to form 3. Next, nucleophilic attack of pyridyl nitrogen to
the Cu-coordinated allenyl double bond results in the formation
of cation 4; this is followed by deprotonation to lead to copper-
(I)-indolizine intermediate 5. Protonolysis of 5 with loss of
Cu(I) affords the desired product 2. This mechanism is
analogous to that proposed for Cu-catalyzed cycloisomerization
of alkynyl imines into pyrroles5ï and silver-assisted cyclization
of allenyl ketones to furans.13 Alternatively, in path b,7
coordination of the triple bond in alkyne 1 to Cu(I) enhances
the electrophilicity of alkyne, and the subsequent nucleophilic
attack of the nitrogen lone pair would form the cation 6, which
undergoes deprotonation followed by demetalation to
afford 2.
applied to the synthesis of indolizinones through a cyclization/
1,2-migration of tertiary propargylic alcohols.
To test the hypothesis, the cyclization of propargyl acetates
1a and 1b, which were easily prepared in good yields from
pyridine-2-carboxaldehyde, were examined first, and the results
are summarized in Table 1. Gratifyingly, the reaction was proved
to be quite efficient with various copper catalysts. In the
presence of 5 mol % of CuI, the cyclization occurred smoothly
in THF to afford the desired indolizine 2a in 98% yield after 3
h without the use of any base (Table 1, entry 1).
When a base such as Et2NH was added, the reaction
proceeded much faster, furnishing 2a in 95% yield within 1.5
h (Table 1, entry 2). Further studies indicated that the amine
played a role in increasing the reaction rate (Table 1, entries 7,
8, 10, and 11). Importantly, when terminal alkyne 1b10 was
reacted in CH3CN, a complete conversion of the starting material
was observed after 18 h without the amine and in 2 h with 1.0
equiv of Et3N present. Additionally, the final yield of product
was 63% without the amine and 82% with the amine present.
No reaction was observed in the absence of Cu(I) at room
temperature (Table 1, entry 9).11 On the basis of the results
shown above, we chose the following reaction conditions: 5
mol % of CuI, 1.0 equiv of Et3N in CH3CN, stirred at room
temperature for an appropriate time.
Under these conditions, a variety of propargylic compounds
bearing pyridine rings was smoothly converted into the corre-
sponding indolizines or its analogues (Table 2), which indicated
the procedure readily accommodates a wide range of function-
alities. The alkyne moiety in propargylic pyridine 1 bearing an
aromatic ring reacted very well to provide the cyclization
products in 87-97% yields within less than 15 min (Table 2,
entries 1-4). Electron-withdrawing as well as electron-donating
substituents on aromatic rings are well tolerated. The use of
t
sterically more hindered Bu-substituted 1g also proceeded to
To probe that Cu(I) could be an effective catalyst for inducing
a cyclization/1,2-shift of tertiary propargylic alcohol reported
(10) It was reported that employment of Cu(I) salts for the cyclization
of TBS-protected propargyl pyridine 2-[1-(tert-butyldimethylsilyl)prop-2-
ynyl] pyridine led to trace amount of products. See ref 8.
(11) It was found that, under solvent-free conditions, 1a can be cyclized
without copper catalyst to afford 2a in 41% yield after 8 h at high
temperature of 130 °C.
(12) See Supporting Information.
(13) Marshall, J. A.; Bartley, G. S. J. Org. Chem. 1994, 59, 7169.
7784 J. Org. Chem., Vol. 72, No. 20, 2007

TABLE 2. Copper-Catalyzed Cycloisomerizations of Propargylic Pyridines to 1,3-Disubstituted Indolizines
a Isolated yields. All of the reactions were carried out at room temperature using 5 mol % of CuI, 1 equiv of Et3N in CH3CN. b 10 mol % of CuI and 2.0
equiv of Et3N were used.
by Sarpong,7 we proceeded to examine the cyclizations of 7.
To our delight, our method showed great efficiency for the 1,2-
migration reactions. As shown in Table 3, under refluxing
conditions in CH3CN, a variety of propargylic alcohol was
successfully transferred to indolizinones 8a-f in the presence
of 5 mol % of CuI and 1 equiv of Et3N within 3 h, and the
yields ranged from 70 to 92%. According to the reported method
catalyzed by PtCl2, a higher reaction temperature (100 °C in
benzene) and longer reaction time (48-168 h) were needed.
We also investigated the reaction in the absence of a base, and
the results indicated that comparable yields of migration products
were observed (Table 3, entries 1-5); however, in some cases,
a longer reaction time was required (Table 3, entries 4
and 5).
range of substituents. Further studies to extend the scope of
synthetic utility for these Cu-catalyzed cyclizations are in
progress in our laboratory.
Experimental Section
General Procedure for the Synthesis of C-1 Oxygenated
Indolizines. To a solution of propargylic acetate 1 (0.5 mmol) in
3 mL of acetonitrile were added CuI (4.8 mg, 0.025 mmol) and
triethylamine (70 µL, 0.5 mmol) successively at room temperature.
The resulting solution was stirred at room temperature until the
reaction was completed as monitored by thin-layer chromato-
graphy. The solvent was removed by rotary evaporation, and the
residue was purified by flash chromatography on silica gel to
afford the desired products 2. Note: The color of most indolizines
2 turned from yellow to brown when exposed in air for several
hours.
In summary, we have developed a Cu-catalyzed cycloisomer-
ization or cyclization/1,2-migration of propargylic pyridines
under mild reaction conditions, which provided an efficient route
to C-1 oxygenated indolizines and indolizinones with a wide
Acetic Acid 3-Butylindolizin-1-yl Ester (2a). Flash column
chromatography on silica gel (ethyl acetate/petroleum ether 1:10)
J. Org. Chem, Vol. 72, No. 20, 2007 7785

TABLE 3. Copper-Catalyzed Cyclization/1,2-Migration of Tertiary
Propargylic Alcohols
1.12-1.24 (m, 2H), 1.35-1.45 (m, 2H), 1.86 (s, 3H), 2.30 (t, J )
7.5 Hz, 2H), 6.07-6.12 (m, 1H), 6.32-6.37 (m, 1H), 6.80 (s, 1H),
7.08 (d, J ) 7.5 Hz, 1H), 7.30-7.34 (m, 1H); 13C NMR (C6D6,
Me4Si) δ 14.0, 20.4, 22.8, 25.5, 29.4, 105.3, 110.0, 114.5, 116.5,
121.1, 121.3, 121.7, 127.3, 168.3; IR (neat) 2957, 1748, 1556, 1212,
1081, 731 cm-1; HRMS (EI) calcd for C14H17NO2 231.1259, found
231.1259.
A Typical Procedure for the Synthesis of 3,8a-Diphenyl-8aH-
indolizin-1-one (8a). To a solution of 1,3-diphenyl-1-(pyridin-2-
yl)prop-2-yn-1-ol 7a (143 mg, 0.5 mmol) in 3 mL of acetonitrile
were added CuI (4.8 mg, 0.025 mmol) and triethylamine (70 µL,
0.5 mmol) successively at room temperature. The resulting solution
was stirred at refluxing temperature until the reaction was completed
as monitored by NMR (2 h) (the reactions of other substrates were
monitored by GC). The solvent was removed by rotary evaporation,
and the residue was purified by flash chromatography on silica gel
(ethyl acetate/petroleum ether 1:4) to afford the product 8a in 76%
1
isolated yield as a deep yellow solid: mp 120-122 °C; H NMR
(C6D6, Me4Si) δ 4.92 (t, J ) 6.6 Hz, 1H), 5.08 (s, 1H), 5.67 (dd,
J ) 9.3 Hz, J ) 5.4 Hz, 1H), 6.31 (d, J ) 7.2 Hz, 1H), 6.43 (d, J
) 9.0 Hz, 1H), 6.96-7.11 (m, 6H), 7.21 (t, J ) 7.8 Hz, 2H), 7.71
(d, J ) 7.8 Hz, 2H); 13C NMR (C6D6, Me4Si) δ 72.1, 99.9, 108.9,
122.8, 122.8, 124.6, 125.0, 128.0, 128.1, 128.8, 129.0, 129.7, 130.8,
141.5, 173.9, 199.9; IR (KBr) 3059, 1684, 1541, 1385, 761, 697
cm-1
285.1164.
; HRMS (EI) calcd for C20H15NO 285.1154, found
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant Nos. 20121202, 20423001,
20732058), Chinese Academy of Science and the Major State
BasicResearchDevelopmentProgram(GrantNo.2006CB806105)
for financial support.
a Isolated yields. Unless noted, all of the reactions were carried out at
refluxing temperature using 5 mol % of CuI, 1 equiv of Et3N in CH3CN.
b The reactions were done in the absence of Et3N, and the results of these
reactions (reaction time and the yields of the products) are listed in the
parentheses.
Supporting Information Available: Experimental details and
spectroscopic characterization of all new compounds and CIF file
giving crystallographic data of 2l. This material is available free
of charge via the Internet at http://pubs.acs.org.
afforded the title product in 97% isolated yield as a light
yellow liquid: 1H NMR (C6D6, Me4Si) δ 0.78 (t, J ) 7.2 Hz, 3H),
JO070983J
7786 J. Org. Chem., Vol. 72, No. 20, 2007