Synthesis of 3-Haloindolizines by copper(ii) halide mediated direct functionalization of indolizines

Article abstract of DOI:10.1021/ol9000872

3-Haloindolizines were synthesized via Cu(II) halide mediated halogenation of indolizines. This C-H direct functionalization process occurred under mild conditions giving 3-haloindolizines in moderate to excellent yields, and the products obtained were tested under the Suzuki-Miyaura reaction providing 3-arylindolizines in high yields.

Full text of DOI:10.1021/ol9000872

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1187-1190
Synthesis of 3-Haloindolizines by
Copper(II) Halide Mediated Direct
Functionalization of Indolizines
Ji-Bao Xia and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
slyou@mail.sioc.ac.cn
Received January 15, 2009
ABSTRACT
3-Haloindolizines were synthesized via Cu(II) halide mediated halogenation of indolizines. This C-H direct functionalization process occurred
under mild conditions giving 3-haloindolizines in moderate to excellent yields, and the products obtained were tested under the Suzuki-Miyaura
reaction providing 3-arylindolizines in high yields.
Indolizines are important N-fused heterocycles broadly found
in biologically important natural products and synthetic
pharmaceuticals.1 Accordingly, synthesis and functionaliza-
tion of indolizines have attracted considerable attention over
the decades.2 The 3-haloindolizines are particularly attractive
since their analogues have been used as biologically interest-
ing compounds3 and their important role as the synthetic
intermediates for 3-substituted indolizines is also apparent.
In addition, transition-metal-catalyzed cross-coupling reac-
tions would allow the installation of carbon-carbon and
carbon-heteroatom bonds regioselectively upon the avail-
ability of 3-haloindolizines. Therefore, efforts toward the
synthesis of 3-haloindolizines have been underway for a long
time. For instance, reaction of pyridines with tetrachlorocy-
clopropene could lead to the formation of 3-chloroindolizines,
but together with problematically separable 1,3-dichloroin-
dolizines.4 The reaction of dichlorocarbene with pyridines
also led to 3-chloroindolizines but generally with low yields.5
3-Haloindolizines were also synthesized by the treatment of
indolizines with Br2/acetic acid, NOCl/acetic acid, or NCS/
acetic acid; however, a mixture of mono- and dihalosubsti-
tuted products was given in low yields.6 Despite the
significance of 3-haloindolizines and many attempts so far,
the efficient synthesis of 3-haloindolizines has not been
documented yet.
(2) For reviews, see: (a) Uchida, T.; Matsumoto, K. Synthesis 1976,
209. (b) Behnisch, A.; Behnisch, P.; Eggenweiler, M.; Wallenhorst, T.
Indolizine. In Houben-Weyl; Thieme: Stuttgart, Germany, 1994; Vol. E6b/
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G.; Leesakul, N.; Hu, H.-W.; Xu, J.-H. Eur. J. Org. Chem. 2007, 3718. (d)
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Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 9868. (f) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Org. Lett.
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S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463. (i) Hardin, A. R.; Sarpong, R.
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H.; Zhang, S.; Chimmanamada, D.; Kostik, E.; James, D.; Koya, K.; Sun,
L. Tetrahedron Lett. 2007, 48, 5739. (l) Kim, I.; Choi, J.; Won, H. K.;
Lee, G. H. Tetrahedron Lett. 2007, 48, 6863. (m) Guazzelli, G.; Settambolo,
R. Tetrahedron Lett. 2007, 48, 6034. (n) Kuznetsov, A. G.; Bush, A. A.;
Babaev, E. V. Tetrahedron 2008, 64, 749. (o) Niyomura, O.; Yamaguchi,
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Chernyak, D.; Gadamsetty, S. B.; Gevorgyan, V. Org. Lett. 2008, 10, 2307.
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Michael, J. P. Nat. Prod. Rep. 2007, 24, 191. (c) Michael, J. P. Nat. Prod.
Rep. 2008, 25, 139. For selected examples, see: (d) Molyneux, R. J.; James,
L. F. Science 1982, 216, 190. (e) Hagishita, S.; Yamada, M.; Shirahase,
K.; Okada, T.; Murakami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.;
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10.1021/ol9000872 CCC: $40.75
Published on Web 02/12/2009
2009 American Chemical Society

As part of our research program toward the development
of a C-H activation process and direct functionalization of
the indolizines,7 we report in this paper that the Cu(II) halide
mediated halogenation of indolizines affords regioselectively
3-haloindolizines. This work was inspired by the recent
findings by Yu and co-workers where a catalytic amount of
CuCl2 was found to enable the chlorination of 2-arylpyridines
in the presence of Cl2CHCHCl2 as the chlorine source.8
Recently, in our laboratory the CuCl2 alone was found to
mediate the synthesis of 3-chloroindolizines under mild
conditions for a wide range of substrates. The 3-chloroin-
dolizines were demonstrated to be suitable for synthesis of
3-arylindolizines in high yields under the Suzuki-Miyaura
reaction conditions.
Table 2. Scope of Halogenation of Indolizinesa
In our initial studies, indolizine 1a was chosen as the
model substrate to test the direct chlorination process. To
our delight, reaction of indolizine 1a with 2.0 equiv of CuCl2
in DMF at 60 °C gave 3-chloroindolizine 2a in 27% yield
with 1a being recovered in 68% yield (entry 1, Table 1).
Table 1. Optimization of the Reaction Conditionsa
CuCl2
(x equiv)
time
(h)
yieldb
(%)
entry
solvent
T (°C)
1
2.0
3.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.5
1.2
DMF
DMF
DMF
EtOH
60
60
80
60
60
60
60
40
rt
rt
rt
40
rt
rt
24
96
30
36
36
12
36
12
24
48
48
20
72
72
27 (68)
46 (38)
57 (36)
91 (7)
91
87
2 (89)
89
2
3c
4
5
6
7
8
THF
CH3CN
dioxane
CH3CN
CH3CN
CH2Cl2
Et2O
CH3CN
CH3CN
CH3CN
9
90
10
11
12
13
14
41 (50)
41 (41)
93
77
80 (8)
a 0.2 mmol of 1a in solvent (1 mL). b Isolated yield and the numbers in
the parenthesis indicate the yield of recovered 1a. c 10% yield of byproduct
was isolated.
Using 3.0 equiv of CuCl2 or performing the reaction at 80
°C, the starting material 1a could not be completely
consumed (entries 2 and 3, Table 1). Notably, 10% aldehyde
byproduct, likely formed by reacting with DMF, was isolated
when the reaction was performed at 80 °C. Several other
solvents were screened. Surprisingly, the reaction in dioxane
a 1 (0.2 M) in CH3CN at 40 °C or rt with the following molar ratio:
1/CuX2 ) 1:1.5.
(3) Rogers, B. N.; Piotrowski, D. W.; Walker, D. P.; Jacobsen, E. J.;
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afforded only trace amount of 2a (entry 7, Table 1). Reaction
in EtOH, THF, or CH3CN all afforded 2a in good yields. In
1188
Org. Lett., Vol. 11, No. 5, 2009

particular, good yields could be obtained in CH3CN even at
40 °C or room temperature (entries 8 and 9, Table 1). After
testing the amount of CuCl2, we found that the reaction with
1.5 equiv of CuCl2 in CH3CN at 40 °C gave the best result
(93% yield, entry 12, Table 1).
Scheme 1
.
Plausible Mechanism of the Chlorination of
Indolizine 1f
Under the optimized conditions as described in entry 12,
Table 1, the generality of the reaction was examined.
Chlorination of indolizine esters 1b-f gave moderate yields
due to byproduct formation (entries 2-6, Table 2; also see
Figure 1). Excellent yields were obtained when 2-substituted
decided to test their synthesis from 3-chloroindolizines under
the Suzuki-Miyaura conditions. This will be a simple
demonstration of the utility of these 3-chloroindolizines. With
the above 3-chloroindolizines in hand, we have screened the
Suzuki-Miyaura conditions using phenyl boronic acid.
Figure 1. ORTEP representation of 4f.
Table 3. Cross-Coupling of 3-Chloroindolizines with Phenyl
Boronic Acida
indolizines 1g, 1h, 1j, and 1k were employed (entries 7, 8 and
10, 11, Table 2). 6-Methoxycarbonyl-substituted indolizine 1i
was well tolerated and gave good yield (entry 9, Table 2).
Chlorination of indolizine ketone 1l afforded product in 77%
yield at room temperature (entry 12, Table 2). Nitrile, amide,
and Weinreb amide groups were tolerated, and chlorination of
substrates 1m-q gave their corresponding 3-chloroindolizines
in moderate to good yields (entries 13-17, Table 2). However,
reaction of indolizine 1r with CuCl2 did not give any desired
product, presumably due to the instability of indolizine 1r under
the reaction conditions. In addition, bromination of indolizines
1g and 1n was tested under similar conditions using 1.5 equiv
of CuBr2, and the corresponding 3-bromoindolizines 2r and 2s
were obtained in moderate yields (58 and 62% yield, entries
19 and 20, Table 2).
During the chlorination of 1f, the byproduct was isolated
in 32% yield and its structure was disclosed as a monochlo-
ride dimeric product 4f, which was further confirmed by an
X-ray analysis (eq 1 and Figure 1).9 With the formation of
the side product, a plausible mechanism was proposed for
this chlorination process, as depicted in Scheme 1.10 In-
dolizine 1f reacts with CuCl2 by an electron-transfer giving
the radical cation 5. Compound 5 takes a chloride from CuCl2
resulting in cation intermediate 6, which loses a proton to
give chlorinated product 2f. In addition, indolizine 1f can
react with 6 giving 7 by a Friedel-Crafts reaction. Com-
pound 7 loses a proton giving 8, which can be oxidized to
4f under the reaction conditions.
a 2 (0.2 M) in toluene at 100 °C with the following molar ratio:
2/PhB(OH)2/PdCl2(SPhos)2/K3PO4 ) 1:1.5:0.02:2.
Since the 3-arylindoliznes are biologically important
compounds11 and of great synthetic importance,2,12 we
Org. Lett., Vol. 11, No. 5, 2009
1189

Interestingly, PdCl2(SPhos)2 was found to be an efficient
catalyst.13 As shown in Table 3, in the presence of 2 mol %
of PdCl2(SPhos)2, various 3-chloroindolizines underwent
smoothly the coupling with phenylboronic acid, affording
3-phenylindolizines in excellent yields. It was worthy of note
that the reaction could tolerate various functional groups such
as CO2Me, COMe, CN, and CONHMe on indolizines (entries
6-8, Table 3).
In summary, we have found that the CuCl2 alone efficiently
mediated the synthesis of 3-chloroindolizines under mild
conditions for a wide range of substrates. The utility of
3-chloroindolizines have been demonstrated in the synthesis
of 3-arylindolizines under the Suzuki-Miyaura reaction
conditions.
Acknowledgment. We thank the National Natural Science
Foundation of China, National Basic Research Program of
China (973 Program 2009CB825300), the Chinese Academy
of Sciences, and the Science and Technology Commission
of Shanghai Municipality (07pj14106, 07JC14063) for
generous financial support.
Supporting Information Available: Experimental pro-
cedures, characterization of the products, and the crystal-
lographic data of compound 4f. This material is available
free of charge via the Internet at http://pubs.acs.org.
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