Synthesis of biindolizines through highly regioselective palladium-catalyzed C-H functionalization

Article abstract of DOI:10.1021/jo802227u

(Chemical Equation Presented) Biindolizines were synthesized under mild conditions with excellent regioselectivity in high yields through palladium-catalyzed C-H functionalization of indolizines. Synthesis of a macrocyclic compound was also achieved via intramolecular double C-H functionalization.

Full text of DOI:10.1021/jo802227u

step redox systems of theoretical and practical interests3 and
their utility in the synthesis of cyclophanes4 or as axially chiral
ligands.5
Synthesis of Biindolizines through Highly
Regioselective Palladium-Catalyzed C-H
Functionalization
Historically, construction of biindolizine systems commonly
involves the utilization of dehydrogenating agents, such as
palladium on carbon, platinum on carbon, and potassium
ferricyanide, or through an electrochemical route.6 However,
the substrate scope is rather limited under these reaction
conditions, and only electron-rich substrates work well. Re-
cently, Pd(II) salts were found to catalyze the oxidative
homocoupling reaction of benzene, thiophene, and arylpyridine
derivatives7 through a C-H functionalization.8 In addition, the
cross-coupling reactions of arenes or heteroarenes were also
achieved through double C-H functionalization process.9
However, the utility of these transformations is rather limited
mainly due to the low reactivity, poor yields and unsatisfactory
selectivity. Recently, there are significant examples reported
where a directing group has to be used for good selectivity and
yields.7b,c,9b,e-g As part of our continuing efforts to develop
efficient carbon-carbon formation processes via double C-H
functionalization,9d herein we report a palladium-catalyzed
highly regioselective oxidative coupling reaction under mild
conditions for the synthesis of biindolizines through C-H
functionalization. This represents a rare example in that excellent
yields and regioselectivity are obtained for a transition-metal-
catalyzed double C-H functionalization process without the use
of a directing group.
Ji-Bao Xia, Xue-Qiang Wang, 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 October 6, 2008
Biindolizines were synthesized under mild conditions with
excellent regioselectivity in high yields through palladium-
catalyzed C-H functionalization of indolizines. Synthesis
of a macrocyclic compound was also achieved via intramo-
lecular double C-H functionalization.
In our initial study, the oxidative coupling of the ester group
bearing indolizine 1a was performed in mesitylene at 150 °C
with 10 mol% of Pd(TFA)2, 2 equiv of Cu(OAc)2, and 2 equiv
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10.1021/jo802227u CCC: $40.75 2009 American Chemical Society
Published on Web 11/18/2008

TABLE 1. Optimization of the Homo-Coupling Reaction
Conditionsa
TABLE 2. Scope of Oxidative Homo-Coupling of Indolizinesa
entry
Pd(x mol %)
y
z
T (°C)
t
(h) conv. (%)b
1c
2
3
4
5
6
7
8
9
10
11
12
13d
Pd(TFA)2(10)
Pd(TFA)2(10)
Pd(OAc)2(10)
-
Pd(OAc)2(5)
Pd(OAc)2(2)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
2
2
2
2
2
2
2
2
2
2
1.5
1
0.2
2
2
2
2
2
2
2
2
1
-
2
2
2
150
140
140
140
140
140
60
rt
60
60
60
56
5
61
>95(93)
>95(92)
0
>95(91)
>95(74)
>95(95)
55
>95(80)
94(75)
>95(99)
49
0.33
10
0.67
35
1.5
120
0.67
7
2
36
55
60
140
77
a 0.4 mmol of 1a in solvent (2 mL). b Determined by 1H NMR, and
the number in the parentheses indicates the yield. c Reaction was carried
out in mesitylene. d O2 balloon was used.
of K2CO3. To our delight, 61% conversion was obtained after
56 h (entry 1, Table 1). The structure of the biindolizine product
2a was further confirmed by an X-ray analysis of a single
crystal.10 When DMF was used as the solvent, the reaction
proceeded faster and full conversion was obtained in 5 h (entry
2, Table 1). Interestingly, Pd(OAc)2 was found to be a better
catalyst for obtaining full conversion of 1a in a shorter reaction
time (entry 3, Table 1). Notably, the reaction did not occur in
the absence of the palladium catalyst (entry 4, Table 1). After
the examination of the catalyst loading and the reaction
temperature, we found that 5 mol% of Pd(OAc)2 gave an
excellent yield (95%) at 60 °C in 1.5 h (entries 5-8, Table 1).
It is worthy of note that a reasonable yield (74%) can be obtained
with 2 mol% of Pd(OAc)2 (entry 6, Table 1). The presence of
K2CO3 was crucial to obtain higher yield and 2 equiv of K2CO3
gave the best yield (entries 7, 9 and 10, Table 1). Examination
of the loading of oxidant revealed that 1.5 equiv of Cu(OAc)2
was sufficient to mediate the reoxidation process to give full
conversion and 99% yield (entry 11, Table 1). When a catalytic
amount of Cu(OAc)2 (0.2 equiv) in the presence of an oxygen
balloon was tested in the coupling reaction, a moderate
conversion (77%) could be obtained (entry 13, Table 1).
Under the optimized conditions as described in entry 11,
Table 1, the generality of the reaction was examined. We found
that the oxidative coupling reaction was quite general and highly
regioselective for a variety of indolizine substrates.
a 1 (0.2 M) in DMF at 60 °C with the following molar ratio: 1/
Pd(OAc)2/Cu(OAc)2/K2CO3 ) 1/0.05/1.5/2. b Reaction was carried out at
140 °C.
Various indolizine esters such as ethyl, tert-butyl, and
3-phenylpropyl esters worked well (entries 2-4, Table 2)
although tert-butyl ester 1c required a higher temperature (140
°C) for full conversion (entry 3, Table 2). Excellent yields were
obtained when substituted indolizine esters 1e-f were employed
(entries 5 and 6, Table 3). A 34% yield was obtained when 1g
was employed, probably due to the steric effect of the 2-methyl
substituent (entry 7, Table 2). Moreover, indolizine ketone and
amides 1h-k worked smoothly to give the corresponding
coupling products in good to excellent yields (entries 8-11,
Table 2). In addition to the electron-withdrawing group bearing
substrates, indolizine 1l was also tested under the optimal
conditions, and the homocoupling product 2l was obtained in
66% yield (entry 12, Table 2).
We have also explored oxidative cross-coupling reactions
between indolizine 1a and benzene (Scheme 1).11 With 10 mol%
of Pd(OAc)2 and 3 equiv of AgOAc in refluxed benzene, the
(11) For Pd-catalyzed direct arylation of indolizines, see: (a) Park, C.-H.;
Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett. 2004, 6,
1159. For mechanistic study of Pd-catalyzed direct arylation of heterocycles,
see: (b) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
10848.
(10) CCDC 687313 contains the supplementary crystallographic data for
product 2a. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data request/cif.
J. Org. Chem. Vol. 74, No. 1, 2009 457

SCHEME 1. Oxidative Cross-Coupling Reaction between
Indolizine 1a and Benzene
mechanism and development of an efficient oxidative cross-
coupling catalytic system are currently underway.
Experimental Section
General Procedure for the Oxidative Coupling Reaction.
Indolizine 1a (70.1 mg, 0.4 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol),
Cu(OAc)2 (109.0 mg, 0.6 mmol) and K2CO3 (110.6 mg, 0.8 mmol)
were weighed under ambient conditions and added to a dry flask.
Then DMF (2 mL) was added through a syringe and the mixture
was stirred at 60 °C for 2 h. After the reaction was complete
(disappearance of 1a was monitored by TLC), the mixture was
cooled to room temperature, filtered through a pad of celite, and
the celite was washed with CH2Cl2 (60 mL). The filtrate was
concentrated under reduced pressure. The crude product was
dissolved in Et2O (30 mL), washed with water (2 × 30 mL), brine
(30 mL), and then dried over Na2SO4. The solvent was evaporated
under reduced pressure, and the residue was subjected to flash
column chromatography with ethyl acetate/petroleum ether (1:10)
as eluent to obtain the desired product 2a (68.9 mg, 99% yield).
IR (film) 2920, 1683, 1510, 1235, 1051, 782, 743 cm-1; 1H NMR
(300 MHz, CDCl3) δ 3.94 (s, 6H), 6.74 (dd, J ) 6.6, 7.2 Hz, 2H),
7.17 (dd, J ) 8.7, 6.9 Hz, 2H), 7.47 (s, 2H), 7.83 (d, J ) 7.2 Hz,
2H), 8.31 (d, J ) 8.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 51.0,
104.0, 113.1, 114.6, 118.6, 120.0, 123.2, 123.8, 136.5, 165.0; MS
(EI) m/z 348 (100) [M]+; Anal. calcd for C20H16N2O4: C, 68.96;
H, 4.63; N, 8.04. Found: C, 68.98; H, 4.97; N, 7.91. mp: 213-215
°C.
SCHEME 2. Construction of Cyclophanes by
Intramolecular Oxidative Coupling Reactions
oxidative cross-coupling product 3 was isolated in 26% yield
along with homocoupling product 2a in 33% yield.
To demonstrate the utility of the current reaction, we then
examined the suitability of the methodology for the synthesis
of bridged macrobiindolizines, an important type of cyclophanes.
Under similar conditions, intramolecular oxidative coupling
products 5a and 5b were obtained in 38% yield and 23% yield,
respectively (Scheme 2). Synthesis of macrocyclic compounds
is rare through transition-metal-catalyzed C-H functionalization,
and recently, White and co-workers reported a macrolacton-
ization via Pd-catalyzed allylic C-H functionalization.12
In conclusion, we have developed a palladium-catalyzed
highly regioselective oxidative homocoupling reaction to syn-
thesize biindolizines through C-H functionalization of indoliz-
ines. The reaction features high efficiency of the catalyst, broad
substrate scope, excellent regioselectivity and high yield in the
absence of a directing group. Further investigation of the reaction
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 proce-
dures, characterization of the products, and the crystallographic
data of compound 2a. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Fraunhoffer, K. J.; Prabagaran, N.; Sirois, L. E.; White, M. C. J. Am.
Chem. Soc. 2006, 128, 9032.
JO802227U
458 J. Org. Chem. Vol. 74, No. 1, 2009