DOI: 10.1002/asia.201403400
Communication
Cyclization
Intramolecular CÀN Bond Formation under Metal-free Conditions:
Synthesis of Indolizines
Junliang Wu, Wei Lin Leng, Hongze Liao, Kim Le Mai Hoang, and Xue-Wei Liu*[a]
ment without metal catalyst, which unexpectedly furnished
Abstract: Polysubstituted indolizine derivatives are con-
the desired product in good yield. With acetic anhydride as
structed via intramolecular CÀN bond formation/CÀH
the electrophilic substrate, the cyclization product 3a could be
obtained in high yield without any metal involvement in the
bond cleavage under metal-free conditions. These meth-
ods offer straightforward pathways to transform pyridyl
reaction.
chalcones into a variety of indolizines.
This reaction is very promising, as it does not involve any
transition metal catalysts or reagents commonly used for CÀH
bond activation and thus could potentially be applied to
The prominent presence of nitrogen-containing heterocycles in
numerous pharmaceuticals, agrochemicals, and biologically
active molecules has sparked considerable efforts for their syn-
thesis and functionalizations.[1] Compared to traditional proto-
cols which are based on substrate pre-activation, direct ap-
proaches toward their construction are more attractive.[2] In
this regard, transformations that employ readily available sub-
strates to provide access to multiply functionalized heterocy-
cles are highly desirable. In the last two decades, the pharma-
cological potential of indolizines and related derivatives has
become well recognized.[3] As a result, a variety of methods for
their syntheses have emerged.[4] The various synthetic routes
for indolizines can be classified mainly as the Tschirschibabin
reaction,[5] cycloaddition reactions,[6] and intramolecular cycliza-
tions.[7] Many cyclizations involve metals such as copper,[8] plat-
inum,[9] silver,[10] gold,[11] and palladium[12] as catalysts. However,
an efficient synthetic method for producing indolizines has
been continuously needed to overcome the difficult introduc-
tion of specific substituents or requirements of multistep syn-
thesis. Therefore, an alternative method allowing for various
functional group variations on the indolizine nucleus is highly
desirable to study their structural and biological activity. In line
with our continuous interest in the synthesis of heterocyclic
compounds,[13] herein, we present a cyclization reaction for the
formation of indolizines via CÀH bond cleavage of chalcones,
requiring neither metal catalyst nor synthetic oxidant.
“greener” syntheses with simple and economical reagents and
generation of minimum waste. Accordingly, we proceeded to
investigate this reaction in detail (Table 1). After initial screen-
ing of the reaction conditions, it was found that the reaction
temperature was crucial for the transformation. Only a trace
amount of product 3a was observed, with low conversion of
1a, when the reaction was carried out in acetonitrile at 808C
for 24 h (Table 1, entry 1). Notably, higher yields were obtained
when higher temperatures were used (Table 1, entries 2, 3),
with the highest yield of 93% obtained by heating the mixture
at 1108C for 10 h (Table 1, entry 3). Further studies revealed
that the efficiency of this cyclization reaction was greatly influ-
Table 1. Optimization of reaction conditions for the synthesis of 3a.[a]
Entry
Solvent
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
Hexane
THF
Toluene
Chloroform
DMF
DMSO
DMA
DCE
1,4-Dioxane
Acetic acid
80
trace
56
93
89
70
30
25
75
95
90
0
55
97 (92)
10
100
110
120
110
110
110
110
110
110
110
110
110
110
110
In a study towards the development of metal-catalyzed cycli-
zation of (E)-3-(4’’-methylphenyl)-1-(pyrid-2’-yl)prop-2-enone
(1a) via CÀH bond activation, we performed a control experi-
9
10
11
12
13
14
15
[a] Dr. J. Wu, W. L. Leng, H. Liao, K. L. Mai Hoang, Prof. Dr. X.-W. Liu
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
70
Singapore-637371 (Singapore)
Fax: (+65)6791-1961
[a] Reaction conditions: 1a (0.5 mmol), 2a (1 mL) in solvent (5 mL).
[b] Yields determined by 1H NMR specroscopy using 1,3,5-trimethoxyben-
zene as an internal standard. The number in parenthesis refers to the
yield of isolated product.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403400.
Chem. Asian J. 2015, 00, 0 – 0
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