Palladium-catalyzed oxidative C-H bond and C=C double bond cleavage: C-3 acylation of indolizines with α,β-unsaturated carboxylic acids

Article abstract of DOI:10.1021/ol200025k

A novel palladium-catalyzed C-3 acylation of indolizines with α,β-unsaturated carboxylic acids via C-H bond and C=C double bond cleavage under oxidative conditions is described. The regioselectivity is assisted by the carboxylic group, and the selection of the oxidant is crucial to the reaction.

Full text of DOI:10.1021/ol200025k

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1342–1345
Palladium-Catalyzed Oxidative C-H Bond
and CdC Double Bond Cleavage:
C-3 Acylation of Indolizines with
r,β-Unsaturated Carboxylic Acids
Yuzhu Yang,† Li Chen,† Zhaoguo Zhang,*,‡ and Yuhong Zhang*,†
Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of
China, and Department of Chemistry, Shanghai Jiao Tong University, Shanghai 200240,
People’s Republic of China
zhaoguo@sjtu.edu.cn; yhzhang@zju.edu.cn
Received January 5, 2011
ABSTRACT
A novel palladium-catalyzed C-3 acylation of indolizines with r,β-unsaturated carboxylic acids via C-H bond and CdC double bond cleavage
under oxidative conditions is described. The regioselectivity is assisted by the carboxylic group, and the selection of the oxidant is crucial to the
reaction.
Transition-metal-catalyzed reactions involving C-H
bond activation have attracted increasing attention cur-
rently because they are challenging targets in organic
chemistry and capable of providing synthetically useful
transformations.1 Over the past decades, significant pro-
gress has been achieved in the transition-metal-catalyzed
activation of C-H bonds, which furnishes promising
economical alternatives to traditional organic chemistry.2
Indolizines are an attractive class of heterocycles that are
frequently found in bioactive natural products and
pharmaceuticals.3 Direct C-H bond functionalization of
indolizines including arylation,4 alkynylation,5and dimeriza-
tion6 have been reported. We previously investigated
the direct cross-coupling of indolizines and vinylarenes
employing a Pd(OAc)2/Ag2CO3 catalytic system to pre-
pare the branched R-olefin products with high regio-
selectivity.7 In our ongoing research of direct functionalizai-
tion of indolizines, we studied the reaction of indolizines
with cinamic acids expecting to obtain the linear β-olefinated
products.8 Surprisingly, it was found that the CdC double
bond of cinnamic acid experienced palladium-catalyzed
† Zhejiang University.
‡ Shanghai Jiao Tong University.
(1) (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A Acc. Chem. Res.
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Chem. Rev. 2007, 107, 174–238. (e) Li, B.-J.; Yang, S.-D.; Shi, Z.-J.
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r
10.1021/ol200025k
Published on Web 02/18/2011
2011 American Chemical Society

cleavage in the presence of 2 equiv of K2CrO4, which led to
the formation of C-3 acylated indolizines. Notably, the
reaction was switched to annulation when BQ (1,4-
benzoquinone) was used as the oxidant in the presence of
2 equiv of KOAc, affording the annulation product via a
decarboxylation process.9
The reaction rate was drastically decreased in a nitrogen
atmosphere (Table 1, entry 6). It should be noted that
the small amount of byproducts (the annulation pro-
duct and the gem-selective alkenylation product) were
always observed in these reactions, which had a delete-
rious effect on the yield of acylation product 3a. No
reaction was observed in the absence of palladium
catalyst (Table 1, entry 7).
Table 1. Screening of the Reaction Conditionsa
After the study of reaction conditions, we found that a
small amount of water was crucial for switching the
reaction to the single acylation product. It was found that
the addition of 10 equiv of H2O to the reaction system led
to the formation of sole acylated product in 58% yield
(Table 1, entries 8-10). Again, the yield was reduced in a
nitrogen atmosphere(Table1, entry 11), showing oxygenis
needed to improve the reaction. Among the palladium
catalysts investigated, PdCl2 was clearly the best choice
(entries 12 and 13). Further investigation of reaction
solvents led us to establish the optimized reaction condi-
tions as follows: 10 mol % of PdCl2, 2 equiv of K2CrO4, 10
equiv of H2O, DMF as solvent under O2 at 60 °C for 12 h.
Under the optimized reaction conditions, different R,β-
unsaturated carboxylic acids were examined, and the
results are presented in Table 2. Both aryl- and alkyl-
substituted R,β-unsaturated carboxylic acids showed good
reactivity. The cinnamic acids with electron-withdrawing
groups in the aryl ring reacted smoothly to give the
acylated indolizines in high efficiency (Table 2, entries
1-3). It is noteworthy that the presence of a C-X bond
(X = F, Cl, and Br) in the cinnamic acids (2b, 2c, and 2d)
did not alter the reaction pathway, and the produced halo-
containingindolizine derivativescould befurtherfunction-
alized to construct more complicated structures. Ortho-
substituted cinnamic acid delivered lower yield compared
with its meta- or para-analogues due to the steric hindrance
(entries 4-6). Electron-donating substituent (OMe) at the
para-position of the phenyl ring made the product in 50%
yield (entry 7). When (E)-3-(naphthalen-1-yl)acrylic acid
was employed, the corresponding product3iwas formedin
lower yield (entry 8), possibly due to the steric effect.
Importantly, alkyl-substituted R, β-unsaturated carboxylic
acids participated in the reaction well to afford the corre-
sponding products (entries 9 and 10).
entry
catalyst
oxidant
atmosphere
yieldb (%)
1c
2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Cu(OAc)2
KMnO4
K2S2O8
K2Cr2O7
K2CrO4
K2CrO4
K2CrO4
K2CrO4
K2CrO4
K2CrO4
K2CrO4
K2CrO4
K2CrO4
air
air
air
air
air
N2
air
O2
O2
O2
N2
air
air
25
0
14
44
52
18
0
3
4
5
6
7
8d
9e
10f
11e
12
13
PdCl2
41
58
36
32
27
0
PdCl2
PdCl2
PdCl2
Pd(OAc)2
Pd(PPh3)4
a Reaction conditions: indolizines (0.4 mmol), cinnamic acids (0.6
mmol), palladium catalyst (0.04 mmol), and oxidant (0.8 mmol) were
mixed in 1 mL of DMF at 60 °C for 12 h. b Isolated yield of 3a. c 1 equiv of
KOAc was added. d 5 equiv of H2O was added. e 10 equiv of H2O was
added. f 15 equiv of H2O was added.
Initially, we examined the reaction of 1a and cinnamic
acid (2a) in the presence of 10 mol % of PdCl2, 2 equiv of
Cu(OAc)2, and 1 equiv of KOAc at 60 °C for 12 h in the
air (Table 1, entry 1). Unprecedently, we isolated the
acylated product 3a in 25% yield, while the desired
linear alkenylation product was not found. Considering
the acylated product might come from the oxidation of
in situ formed alkene, we employed KMnO4 as the
oxidant, but there were no products (Table 1, entry 2).
By the use of K2S2O8, we isolated the acylated product
in 14% yield (Table 1, entry 3). To our delight, the use of
K2Cr2O7 as the oxidant obviously improved the reac-
tion (Table 1, entry 4); the yield was further increased to
52% when K2CrO4 was employed (Table 1, entry 5).
The substituent effects of the indolizine on this reaction
were studied using cinnamic acid (2a) to react with various
indolizines (Figure 1). The indolizines bearing electron-
withdrawing groups such as COOR and CN on both the
C-1 and C-2 positions provided 48-61% yields (3l-p).
7-Methylindolizine-1-carbonitrile was also compatible
with the reaction conditions, giving the desired product
3q in 45% yield.
The annulation product observed in Table 1 is an
important member in the family of cyclazines due to its
novel structural properties.10 It might be formed via dual
C-H functionalization and decarboxylative coupling in
our Pd-catalytic system.11 Therefore, we optimized the
(8) For recent applications of using R, β-unsaturated carboxylic acids
on cross-coupling reactions, see: (a) Yamashita, M.; Hirano, K.; Satoh,
T.; Miura, M. Org. Lett. 2010, 12, 592–595. (b) Wang, Z.; Ding, Q.; He,
X.; Wu, J. Org. Biomol. Chem. 2009, 7, 863–865. (c) Yamashita, M.;
Hirano, K.; Satoh, T.; Miura, M. Chem. Lett. 2010, 39, 68–69.
(9) For recent examples of decarboxylative coupling on C-C bond-
forming reactions, see: (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science
2006, 313, 662–664. (b) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am.
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Liang, Y.-M.; Li, C.-J. Angew. Chem., Int. Ed. 2009, 48, 792–795. (e)
Shang, R.; Yang, Z.-W.; Wang, Y.; Zhang, S.-L.; Liu, L. J. Am. Chem.
Soc. 2010, 132, 14391–14393. (f) Wang, C.; Piel, I.; Glorius, F. J. Am.
Chem. Soc. 2009, 131, 4194–4195. (g) Cornella, J.; Lu, P.; Larrosa, I.
Org. Lett. 2009, 11, 5506–5509.
(10) Liang, F.; Hu, J.; Zhang, L.; Hu, Y.; Hu, H. J. Heterocycl. Chem.
2001, 38, 853–857 and references cited therein.
Org. Lett., Vol. 13, No. 6, 2011
1343

Table 2. Reactions of Indolizine 1a with Different R, β-Unsat-
urated Carboxylic Acidsa
Figure 1. Acylation of various indolizines with cinnamic acid
under the optimized reaction conditions.
Scheme 1. Annulations of Indolizine with R,β-Unsaturated
Carboxylic Acids
the para-position of the phenyl ring gave higher yield than
the electron-withdrawing group (46% of 4b and 59% of 4c,
respectively). (E)-3-(Naphthalen-1-yl)acrylic acid showed
a relatively lower reactivity to give 4d in 45% yield. The
crotonic acid 2j participated in the reaction to give the
annulation product 4e in 39% yield.
Control experiments were performed to verify the cata-
lytic pathways (Scheme 2). When indolizine 1a was treated
with methyl cinnamate (Y = Me) or potassium cinnamate
(Y = K) under identical conditions, no desired C-3 acyla-
tion product was detected. Moreover, using gem-selective
alkenylation product 5 as the starting material, we failed to
get the acylation product or the annulation product. These
results may rule out the possibility of Fujiwara-type oxi-
dative vinylation followed by chromium-mediated carbon-
carbon double-bond cleavage.12 Instead, the COOH group
could play an important role in this reaction.
On the basis of previous studies13 and our experimental
results, a plausible mechanism for the reactions is illu-
strated in Scheme 3. The electrophilic palladation first
a Reaction conditions: 1a (0.4 mmol), 2 (0.6 mmol), PdCl2 (0.04
mmol), K2CrO4 (0.8 mmol), H2O (4 mmol) were dissolved in 1 mL of
DMF under O2 balloon at 60 °C for 12 h. b Isolated yield.
(11) Other reported annulation reactions include the following. (a) 2-
Phenylbenzoic acids by palladium catalysis: Wang, C.; Rakshit, S.;
Glorius, F. J. Am. Chem. Soc. 2010, 132, 14006–14008. (b) Arylboronic
acids by rhodium catalysis: Fukutani, F.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2009, 11, 5198–5201. (c) Benzoic acids by iridium catalysis:
Ueura, K.; Satoh, T.; Miura, M. J. Org. Chem. 2007, 72, 5362–5367. (d)
Heteroaromatic acids by palladium catalysis: Yamashita, M.; Hirano,
K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 2337–2340.
reaction conditions intensely, and the annulation product
4a was finally successfully isolated in 52% yield in the
presence of 10 mol % of Pd(OAc)2, 1 equiv of BQ, and
2 equiv of KOAc under O2 atmosphere (Scheme 1). The
effect of the substitution on the aryl ring was also exam-
ined. The electron-donating substituent such as -OMe at
(12) (a) Fujiwara, Y.; Noritani, I.; Danno, S.; Asano, R.; Teranishi,
S. J. Am. Chem. Soc. 1969, 91, 7166–7169. (b) Jia, C.; Kitamura, T.;
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1344
Org. Lett., Vol. 13, No. 6, 2011

Scheme 2. Control Experiments
Scheme 3. Plausible Mechanism
occurs preferentially at the C-3 position of indolizine5 to
form the intermediate A, which undergoes the migratory
insertion to produce the intermediate B. In the presence of
K2CrO4, the oxidation of the tertiary hydrogen bond
occurs to form intermediate C,14 and the subsequent
reductive elimination generates the intermediate D. The
rapid transformation from C to D might indicate that a
small amount of water is necessary for the high yield of
acylation product3 and thus suppressesthe formation of4.
The further oxidation scission of D by K2CrO4 gives the
acylation product, and Pd(0) is oxidized to Pd(II).15
In the reactions employing BQ as the oxidant, the inter-
mediate B undergoes β-H elimination to form E, which is
scavenged by BQ/KOAc to form intermediate F. The
subsequent palladation gives the intermediate G, which
undergoes decarboxylation and reductive elimination11a to
form annulated product 4. The resulting Pd(0) species is
oxidized by BQ to regenerate Pd(II). In the absence of base,
the decarboxylation and reductive elimination of intermedi-
ate E afford the gem-selective alkenylation product 5 (eq 1).
alternative for C-3 acylated indolizine derivatives. The pro-
minent role of the COOH group in this reaction has been
disclosed: it may act as a removable group or a coupling
partner under properly tuned oxidative conditions, affording
an annulation product or an alkenylation product.
Acknowledgment. Funding from National Basic Re-
search Program of China (No. 2011CB936003) and Nat-
ural Science Foundation of China (Nos. 20872126 and
2107216) is acknowledged.
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.
In conclusion, we have developed a novel palladium-
catalyzed C-3 acylation of indolizines via C-H bond and
CdC double bond cleavage. This reaction provides an
(14) Wiberg, K. G.; Foster, G. J. Am. Chem. Soc. 1961, 83, 423–429.
(15) (a) Chang, Y. W.; Westheimer, F. H. J. Am. Chem. Soc. 1960, 82,
1401–1405. (b) Rocek, J.; Westheimer, F. H. J. Am. Chem. Soc. 1962, 84,
2241–2246. (c) Walker, B. H. J. Am. Chem. Soc. 1967, 89, 1098–1103.
(13) (a) Goossen, L. J.; Rodriguez, N.; Goossen, K. Angew. Chem.,
Int. Ed. 2008, 47, 3100–3120. (b) Satoh, T.; Miura, M. Synthesis 2010,
3395–3409.
Org. Lett., Vol. 13, No. 6, 2011
1345