Direct Oxidative Cleavage of Multiple Csp3-H Bonds and a C-C Bond in 2-(Pyridin-2-yl)acetate Derivatives: Formal [3 + 1 + 1] Synthesis of 3-(Pyridin-2-yl)indolizine Skeletons

Article abstract of DOI:10.1021/acs.orglett.7b01492

A novel iodine-promoted oxidative cross-coupling/cyclization of 2-(pyridin-2-yl)acetate derivatives and methyl ketones via the cleavage of multiple C_sp³-H bonds has been developed, which also achieved efficient cleavage of a C-C bond in the 2-(pyridin-2-yl)acetate derivatives. This protocol represents an elegant molecular fragment assembly of diverse 3-(pyridin-2-yl)indolizines via a formal [3 + 1 + 1] annulation. Notably, the pyridine derivatives serve two pivotal roles to provide two fragments to construct 3-(pyridin-2-yl)indolizine skeletons, rather than the single role in building common indolizines.

Full text of DOI:10.1021/acs.orglett.7b01492

Letter
pubs.acs.org/OrgLett
3
Direct Oxidative Cleavage of Multiple C −H Bonds and a C−C Bond
sp
in 2‑(Pyridin-2-yl)acetate Derivatives: Formal [3 + 1 + 1] Synthesis of
3‑(Pyridin-2-yl)indolizine Skeletons
Xia Wu, Peng Zhao, Xiao Geng, Jingjing Zhang, Xingxing Gong, Yan-dong Wu, and An-xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, P. R. China
*
S Supporting Information
ABSTRACT: A novel iodine-promoted oxidative cross-coupling/cyclization of 2-(pyridin-2-yl)acetate derivatives and methyl
3
ketones via the cleavage of multiple C −H bonds has been developed, which also achieved efficient cleavage of a C−C bond in
sp
the 2-(pyridin-2-yl)acetate derivatives. This protocol represents an elegant molecular fragment assembly of diverse 3-(pyridin-2-
yl)indolizines via a formal [3 + 1 + 1] annulation. Notably, the pyridine derivatives serve two pivotal roles to provide two
fragments to construct 3-(pyridin-2-yl)indolizine skeletons, rather than the single role in building common indolizines.
he indolizine structural motif has attracted much attention
because it is frequently encountered in natural products,
Scheme 1. Direct Oxidative Annulation of α-Picoline
Derivatives
T
1
,2
synthetic pharmaceuticals, and materials chemistry. Con-
sequently, much research has focused on the synthesis of
functionalized indolizines, through either the construction or
3
,4
modification of indolizine rings.
However, 3-(pyridin-2-
yl)indolizine, a vital skeleton for building phosphoinositide 3-
kinase inhibitors, has rarely been reported. Only one example of
the direct synthesis of 3-(pyridin-2-yl)indolizine derivatives via
multistep transformation has been reported, which is protected
5
by a US patent. Therefore, the development of direct strategies
for the rapid construction of 3-(pyridin-2-yl)indolizine
skeletons, particularly green and practical oxidative cross-
coupling/annulation strategies via the cleavage of C−C and
multiple C−H bonds, is highly valuable.
The direct annulation of pyridine derivatives to prepare6
nitrogen-containing fused heterocycles is a fascinating topic
because the construction of differently functionalized hetero-
cycles with the same key core from identical or similar starting
materials potentially allows libraries for screening and
7
optimizing the lead compound to be built easily. In particular,
2
-(pyridin-2-yl)acetate derivatives have recently been used to
1
1
synthesis of indolizines (Scheme 1b). Furthermore, the
synthesis of indolizines through the annulation of aryl methyl
ketones and 2-(pyridin-2-yl)acetate derivatives has been
synthesize indolizines. Notably, iodine/peroxide, copper, and
silver-mediated oxidative cross-coupling/annulations of α-
picoline derivatives with CC or CC bonds to access
12
8
−10
described by Adimurthy (Scheme 1c). This process involves
indolizines have been well developed (Scheme 1a).
Moreover, Yan and co-workers presented an iodine-promoted
oxidative cyclization of α-picoline derivatives with differently
substituted aromatic/aliphatic enolizable aldehydes for the
Received: May 17, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the iodination of aryl methyl ketones and subsequent formation
of pyridinium ylides, resulting in an intramolecular annulation
reaction. Despite these pioneering studies, however, these
methods have mainly focused on the construction of indolizines
via intramolecular annulation of two components, and depend
on an excess of one component to improve the yield. The
direct cyclization of three components, involving 2-(pyridin-2-
yl)acetate derivatives, to build other indolizine-containing
skeletons such as 3-(pyridin-2-yl)indolizines has not been
explored, probably because the two-component cyclization is
more efficient than the three-component cyclization. Herein,
we report our progress in the oxidative cleavage of multiple
Scheme 2. Scope of Aryl Methyl Ketones and 2-(Pyridin-2-
yl)acetate Derivatives
a
3
C −H bonds in aryl methyl ketones and 2-(pyridin-2-
sp
yl)acetate derivatives and a C−C bond of 2-(pyridin-2-
yl)acetate derivatives for the convenient construction of 3-
(pyridin-2-yl)indolizine skeletons. It should be noted that this
method can avoid the use of palladium-catalyzed CO
1
3
5
insertion and multistep reactions to furnish C2-acylation of
the indolizine.
Owing to our continued interest in the construction of
14
diverse heterocycles, we aimed to prepare 3-(pyridin-2-
yl)indolizine biheterocycle skeletons via the oxidative cleavage
3
of a C−C bond and multiple C −H bonds. We began this
sp
study by investigating acetophenone (1a), ethyl 2-(pyridin-2-
yl)acetate (2a), and iodine in dimethyl sulfoxide at 100 °C. The
biheterocyclic skeleton, ethyl 2-benzoyl-3-(pyridin-2-yl)-
indolizine-1-carboxylate (3aa), was obtained in 28% yield
(see Supporting Information (SI)) based on acetophenone.
Importantly, the reaction displayed high selectivity (Table S1,
entry 1). Even though all substrates and catalysts were added in
one pot, both pyridinium ylides and two-component cyclization
12
byproducts were not observed. Encouraged by this result, we
first examined the effect of different equivalents of 2a and found
that the best result was obtained with 1.5 equiv of 2a (Table S1,
entries 2−3). The temperature was tested between 90 and 130
°
C and found to have an important influence on the reaction
yield and rate (Table S1, entries 4−6). The reaction was further
a
Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), I (2.0 mmol), and
optimized by varying the number of equivalents of iodine
2
TfOH (1.0 mmol) in DMSO (4 mL) at 130 °C for 24 h. Isolated yield.
(
Table S1, entries 7−9). The results indicated that increasing
the equivalents of iodine to 2.0 can obtain 3aa in 54% yield
Table S1, entry8). Subsequently, a series of Brønsted and
(
naphthalene moiety (87 and 78%, 3ma and 3na). Notably,
methyl ketones containing thiophenyl, furanyl, and benzofuryl
moieties could also be applied to the 3-(pyridin-2-yl)indolizine
scaffold without any difficulties (3oa−qa, 60−81%). In
addition, methyl 2-(pyridin-2-yl)acetate 2b was also suitable
for this reaction (3ab−pb, 78−88%). As shown in Scheme 2,
methyl, nitro, chloro, and fluoro aromatic methyl ketone all
reacted with 2b smoothly affording the desired products in
moderate to good yields.
Lewis acids were screened as additives for the reaction, and the
TfOH was best in promoting the reaction. Hydrochloric acid
was detrimental to the yield, which may generate the pyridine
salt (Table S1, entries 10−15). The effect of different amounts
of TfOH on the outcome of the reaction was investigated,
revealing that the amount of TfOH had an important
discernible impact on the yields (Table S1, entries 16−18).
Finally, to our delight, changing the 1a/2a molar ratio to 1:2
increased the yield of 3aa to 83% (Table S1, entry 19).
To gain insight into the reaction mechanism, the following
experiments were performed. Acetophenone (1a, 1.0 mmol)
Having optimized the reaction conditions, we proceeded to
expand the scope of the reaction with a broad array of aryl
methyl ketone substrates (Scheme 2). A series of acetophenone
derivatives with electron-donating and -withdrawing substitu-
ents on the phenyl ring (e.g., methyl, methoxyl, ethoxyl, 3,4-
methylenedioxyl, phenyl, nitro, chloro, bromo) underwent the
desired transformation in a regiospecific fashion to deliver the
corresponding products 3aa−la in moderate to good yields
was heated with I (2.0 mmol) and TfOH (1.0 mmol) in
2
DMSO at 130 °C to give phenylglyoxal 1ab and corresponding
hydrated species 1ac in quantitative yield (Scheme 3a). α-Iodo-
ketone 1aa and hydrated species 1ac were reacted with ethyl 2-
(pyridin-2-yl)acetate 2a under the standard conditions
(Schemes 3b and 3c), giving desired product 3aa in 85% and
87% yields, respectively. These results confirmed that phenacyl
iodine (1aa) and phenylglyoxal 1ab were intermediates in this
transformation. Moreover, the reaction of hydrated species 1ac
(
69−85%). The electronic and steric properties of the aromatic
ketone substrate had very little impact on the efficiency of this
reaction. Moreover, the structure of compound 3da was further
confirmed by X-ray crystallographic analysis (see SI).
Furthermore, the phenyl ring could be replaced by a
with 2a without additional I afforded product 4a (see SI) in
2
92% yield and its structure was confirmed by X-ray crystallo-
graphic analysis (Scheme 3d). Furthermore, the reaction of
B
DOI: 10.1021/acs.orglett.7b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Control Experiments
Scheme 5. Proposed Mechanism
attack is successfully avoided. The aldehyde group of
phenylglyoxal 1ab was then activated by TfOH to obtain
activated intermediate lab′. The activated aldehyde group of
phenylglyoxal 1ab′ is then attacked by ethyl 2-(pyridin-2-
yl)acetate 2a to give intermediate A, which undergoes
dehydration to yield intermediate B. Next, another molecule
of 2a trapped intermediate B to give intermediate C via Michael
1
6
hydrated species 1ac and 2a without additional I at room
addition, which was further oxidized to yield product 5a.
2
temperature afforded intermediate 5a (detected by HRMS). 5a
was not separated due to the difficulty in controlling the E/Z
selectivity. Iodine was then added to the reaction and the sealed
tube was moved to an oil bath at 130 °C, affording product 3aa
in 87% yield (Scheme 3e). The result indicated that 5a was a
key intermediate in this transformation and implied that ester
groups are necessary for annulation process. This control
experiment further implied that cleavage of C−C bonds of 2-
Product 5a could then be iodinated to obtain intermediate D in
the presence of molecular iodine. Finally, annulation,
aromatization, and deesterification furnish the desired
product 3aa. Moreover, the product 4a could be obtained in
1
6
the absence of I
from 5a via intramolecular cyclization and
2
deesterification.
In summary, we have demonstrated a novel approach to the
synthesis of 3-(pyridin-2-yl)indolizine derivatives, using a C−C
and multiple Csp −H bonds cleavage strategy, with concurrent
3
(
pyridin-2-yl)acetate derivatives occurred after the cyclization.
Next, a 13C-labeling experiment was also conducted under
C2-acylation of indolizine. In this unique iodine/TfOH
copromoted oxidative annulation process, a 2-(pyridin-2-
yl)acetate derivative plays two vital roles to construct 3-
(pyridin-2-yl)indolizine skeletons, rather than common in-
dolizines. Moreover, the protocol is facile and provides an
efficient route to complex 3-(pyridin-2-yl)indolizine derivatives.
A reasonable mechanism is proposed, which could promote the
discovery of new methodologies through iodine/TfOH
1
3
the optimized conditions using acetophenone-β- C as the
substrate, which could give the expected product (3aa′) in 80%
yield (Scheme 4). This experimental result confirmed that
methyl ketones provided one carbon to form the indolizine
ring.
Scheme 4. 13C Labeling Experiment
3
sp
copromoted cleavage of C−C and multiple C −H bonds.
Research on this is currently underway in our laboratory.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01492.
Based on the experimental results described above, as well as
15
the results of previous reports, a mechanism for this I2-
promoted oxidative cross-coupling/annulation process was
proposed, as shown in Scheme 5. Acetophenone 1a was
converted to phenylglyoxal 1ab with released HI and DMS via
an iodination/Kornblum oxidation sequence. Remarkably, the
generation of pyridinium ylides 2aa via rapid nucleophilic
Experimental procedures, product characterizations,
1
13
crystallographic data, and copies of the H and
C
NMR spectra (PDF)
Crystallographic data for 3da (CIF)
Crystallographic data for 4a (CIF)
C
DOI: 10.1021/acs.orglett.7b01492
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
7) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell
AUTHOR INFORMATION
Corresponding Author
■
*
Science: Oxford, U.K., 2000; chapter 25. (b) Crawley, M. L., Trost, B.
M., Eds. Applications of Transition Metal Catalysis in Drug Discovery and
Development: An Industrial Perspective; John Wiley & Sons: Hoboken,
NJ, 2012. (c) Lamb, E. Top 200 Drugs of 2008. Pharmacy Times, 2009.
E-mail: chwuax@mail.ccnu.edu.cn.
ORCID
(8) (a) Liu, R. R.; Hong, J. J.; Lu, C. J.; Xu, M.; Gao, J. R.; Jia, Y. X.
An-xin Wu: 0000-0001-7673-210X
Notes
Org. Lett. 2015, 17, 3050. (b) Xiang, L. K.; Zhang, F. M.; Chen, B. H.;
Pang, X. B.; Yang, X. D.; Huang, G. S.; Yan, R. L. RSC Adv. 2015, 5,
2
9424. (c) Liu, J. L.; Liang, Y.; Wang, H. S.; Pan, Y. M. Synlett 2015,
6, 2024. (d) Reddy, N. N. K.; Mohan, D. C.; Adimurthy, S.
The authors declare no competing financial interest.
2
Tetrahedron Lett. 2016, 57, 1074. (e) Li, H. X.; Li, X. M.; Yu, Y.; Li, J.
J.; Liu, Y.; Li, H.; Wang, W. Org. Lett. 2017, 19, 2010.
ACKNOWLEDGMENTS
■
(9) (a) Tang, S.; Liu, K.; Long, Y.; Qi, X. T.; Lan, Y.; Lei, A. W.
This work was supported by the National Natural Science
Foundation of China (Grants 21472056 and 21602070). We
also thank Dr. Chuanqi Zhou, Hebei University, for analytical
support. This work was supported by “The Fundamental
Research Funds for the Central Universities” (CCNU15ZX002
and CCNU16A05002). This work was also supported by the
Chem. Commun. 2015, 51, 8769. (b) Tang, S.; Liu, K.; Long, Y.; Gao,
X. L.; Gao, M.; Lei, A. W. Org. Lett. 2015, 17, 2404. (c) Tan, X. C.;
Liang, Y.; Bao, F. P.; Wang, H. S.; Pan, Y. M. Tetrahedron 2014, 70,
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