Quick access to druglike heterocycles: Facile silver-catalyzed one-pot multicomponent synthesis of aminoindolizines

Article abstract of DOI:10.1021/cc100086h

A direct and efficient approach to 1-aminoindolizines through three-component one-pot reaction of heteroaryl aldehydes, secondary amines, and terminal alkynes catalyzed by AgBF₄ has been developed. Desired products were obtained in moderate to

Full text of DOI:10.1021/cc100086h

696
J. Comb. Chem. 2010, 12, 696–699
Quick Access to Druglike Heterocycles: Facile Silver-Catalyzed
One-Pot Multicomponent Synthesis of Aminoindolizines
Yaguang Bai, Jing Zeng, Jimei Ma, Bala Kishan Gorityala, and Xue-Wei Liu*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological UniVersity, Singapore 637371, Singapore
ReceiVed May 22, 2010
A direct and efficient approach to 1-aminoindolizines through three-component one-pot reaction of heteroaryl
aldehydes, secondary amines, and terminal alkynes catalyzed by AgBF4 has been developed. Desired products
were obtained in moderate to excellent yields. Similar aminoindolizines products were afforded from
trimethylsilyl protected alkyne substrates as well. This methodology provides a rapid access to construct a
diversity-oriented library of indolizines.
Introduction
method that allows functional group variation on the target
molecule and minimizes cost to construct a combinatorial
library of indolizines. To achieve this, herein we report a
silver-catalyzed multicomponent synthesis of aminoindoliz-
ines with aldehydes, amines, and alkynes as starting materials.
Indolizines are a unique class of heterocycles. They are
characterized by a N-bridgehead heterocyclic scaffold with
an electron-rich pyrrole and an electron-poor pyridine.1
Indolizines and their partially saturated derivatives have been
widely found in natural products and synthetic pharmaceu-
ticals2 which are associated with a broad spectrum of
biological activities such as antibacterial, antiviral, anti-
inflammatory3 and central nervous system (CNS) depressant
activity.4 They also have considerable potential applications
which serve as phosphatase inhibitors,5 aromatase inhibitors,6
antioxidant reagents,7 and calcium entry blockers.8 As a
consequence, great attention has been drawn to the synthesis
of indolizine derivatives and a number of elegant synthetic
methods have been developed.9
In recent years, multicomponent coupling reactions (MCRs)
have been widely employed to develop efficient and practical
methods for the diversity-oriented synthesis of structurally
complex molecules.10 Transition metal catalyzed MCRs
involving cascade C-C and C-N bond formations have been
widely used in the synthesis of heterocycles including
indolizines.11 In 2007, a novel and efficient method for
synthesizing aminoindolizines from heteroaryl aldehydes,
secondary amines, and terminal alkynes has been reported;
however, this method involves an expensive gold catalyst,
and it mainly focuses on the variation of amino substituents
on the indolizine skeleton.1b In the past few years, we have
been interested in developing new strategies to construct
heterocyclic scaffolds with high synthetic efficiency.12
The viral enzyme neuraminidase (sialidase, NA) has
recently attracted much attention in drug development
because of its important role in pathogenesis, bacterial
nutrition, and cellular interaction.13 As part of our ongoing
effort to screen new NA inhibitors, we plan to construct a
library of aminoindolizines. In view of the dramatic bioac-
tivities of indolizines, there is still need to develop a new
Results and Discussion
Our initial effort was focused on the evaluation of silver
catalytic systems for the three-component reaction of pyri-
dine-2-carboxaldehyde, morpholine, and phenylacetylene,
and the results are summarized in Table 1. We found that
silver catalyzes this one-pot multicomponent reaction ef-
ficiently. In the presence of 50 mol % AgOTf, the reaction
proceeded smoothly in toluene, providing desired aminoin-
dolizine in 81% yield at 60 °C (Table 1, entry 1). In addition,
AgClO4, CuI, AgNO3/CuI, or Ag2O could also catalyze this
reaction but led to lower yields (Table 1, entry 2-5). Catalyst
screening confirmed that AgBF4 was the most efficient
catalyst. The reaction was completed in 3 h at 60 °C to
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
AgOTf
Ag2O
CuI
AgClO4
AgNO3/CuI
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
equiv
temp (°C)
time
3 h
12 h
12 h
12 h
12 h
3 h
3 h
5 h
24 h
45 min
45 min
yield (%)b
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.05
0.05
0.05
0.05
60
60
60
60
60
60
60
60
25
85
110
81
25
47
51
29
91
90
90
trace
89
65
9
10
11
a Unless otherwise stated, reaction was carried out with pyri-
dine-2-carboxaldehyde (1.0 mmol), morpholine (1.1 mmol), and phenyl-
acetylene (1.5 mmol). b Isolated yields.
* To whom correspondence should be addressed. E-mail: xuewei@
ntu.edu.sg. Phone: +65 6316 8901. Fax: +65 6791 1961.
10.1021/cc100086h  2010 American Chemical Society
Published on Web 07/22/2010

Multicomponent Synthesis of Aminoindolizines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 697
Table 3. Silver Catalyzed Formation of Heterocycle Substituted
Table 2. Silver Catalyzed Three-Component Reactions to
Synthesize Aminoindolizinesa b
Aminoindolizinesa b
,
,
a Unless otherwise stated, reaction was carried out at 85 °C using
aldehyde (1.0 mmol), amine (1.1 mmol), and acetylene (1.5 mmol)
catalyzed by 0.05 equiv of AgBF4. b Isolated yields. c No reaction, start-
ing material recovered.
a Unless otherwise stated, reaction was carried out at 85 °C using
aldehyde (1.0 mmol), amine (1.1 mmol), and acetylene (1.5 mmol)
catalyzed by 0.05 equiv of AgBF4. b Isolated yields. c Yields obtained
by using terminal alkynes. d Yields obtained by using TMS protected
alkynes.
furnish the product in 91% yield in the presence of 50 mol
% AgBF4 (Table 1, entry 6). Lowering the catalyst loading
to 5 mol % resulted in a similar yield (Table 1, Entry 7, 8).
Interestingly, the reaction time dramatically decreased from
3 h to 45 min when the reaction temperature increased to
85 °C, and the yield of 89% was obtained. Further increase
in temperature (110 °C) and decrease in time (30 min)
resulted in poor yields (Table 1, entry 9-11). The results
were not satisfactory when dichloromethane (DCM), tet-
rahydrofuran (THF), and acetonitrile were used as solvents,
where most of the compounds decomposed in the reaction
mixture. Further investigations of the reaction conditions
revealed that toluene was the best solvent, and a catalyst
loading of 0.05 equiv could be used to afford indolizines in
good yields.
With the optimized conditions, we started to examine the
scope of this multicomponent reaction. As illustrated in Table
2, analogues of pyridine-2-carboxaldehyde were first tested
under the optimized conditions. Reactions involving 6-meth-
yl-pyridine-2-carboxaldehyde and 2-quinolinecarboxaldehyde
proceeded smoothly and gave desired products in 73% and
88% yields, respectively (Table 2, 4b, 4c). With respect to
amines, acyclic secondary amines such as dibenzylamine also
afforded corresponding indolizine in good yield (Table 2,
4d). However, a complex reaction mixture was observed
when a primary amine such as benzylamine was used.1b
Subsequently, a variety of alkynes, aldehydes, and amines
were successfully transformed into the corresponding ami-
noindolizines in good to excellent yields. As evident from
Table 2, besides simple phenylacetylene, other substituted
aryl acetylenes also served as good substitutes for this
reaction (Table 2, 4e-g). Interestingly, aryl alkynes with
electron-withdrawing substitutes furnished lower yields
(Table 2, 4g). On the other hand, alkyl alkynes gave the
corresponding indolizines in poor to moderate yields (Table
2, 4 h-j). This could be attributed to the instability of the
compounds which decomposed quickly at room tempera-
ture.14 No reaction occurred when N,N-diethylpropargyl-
amine was used. However, to our surprise, reaction with
phthalimide propargylamine furnished the corresponding
indolizine in 80% yield (Table 2, 4k-4l).

698 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Bai et al.
Scheme 1. Proposed Catalytic Cycle for the Silver Catalyzed Three-Component Reaction
The efficiency of this reaction prompted us to employ
heterocycle substituted alkynes to synthesize a variety of
3-heterocycle substituted aminoindolizines (Table 3). We
envisioned that these novel structures may present potential
utilities in pharmacological areas. However, the yields of
reactions using heterocycle alkynes as substrates varied
according to the positions of the heteroatom and the
functionalities on heterocycles. First, we checked the reac-
tions of 2-ethynylpyridine and 2-ethynylquinoline, and it was
found that the desired indolizines were rapidly formed in
good to excellent yields (Table 3, 5a, 5h). In contrast, the
reaction involving 4-ethynylpyridine was intriguing and
resulted in poor yield (Table 3, 5b). In addition, use of
3-ethynylpyridine could not give any product after refluxing
for 12 h (Table 3, 5c). When methyl and octyl substituted
3-ethynylpyridine were used, the reactions proceeded well,
and high yields were achieved (Table 3, 5d, 5g). 3-Ethy-
nylquinoline, 4-ethnylisoquinoline and 5-ethnylquinoline
could be recognized as substituted pyridines, which reacted
well to generate the corresponding indolizines in high yields
(Table 3, 5i-k).
Interestingly, trimethylsilyl (TMS) protected alkynes also
tolerated these reaction conditions and yielded the same
products as those of terminal alkynes (Table 3, 5a, 5b, 5e,
5g, 5h, 5k, and 5i). Since both terminal alkyne and TMS
protected alkyne generated the same alkynyl silver interme-
diate in the presence of silver salts,15 we believe that these
two types of reactions should have proceed through the same
mechanism (Scheme 1). Thus, in situ generated alkynyl silver
reacts with the activated imonium to afford N-substituted
propargylic pyridine, which undergoes cyclization and
deprotonation subsequently to generate indolizines. As all
the heterocycle substituted TMS acetylenes could be easily
synthesized from TMS acetylene and iodine or bromine
substituted heterocycles via Sonogashira reaction developed
by Thorand and Krause,16 this method serves as a more rapid
and direct approach to construct indolizines.
Conclusion
In conclusion, we have reported the synthesis of
functionalized aminoindolizines with the aid of one-pot
three-component reaction catalyzed by a cheap and easily
available catalyst AgBF4. A library of 22 aminoindolizines
has been prepared promptly. Furthermore, we also found
that both TMS protected alkynes and terminal alkynes
were well tolerated in this reaction to give the same
products. Further efforts are currently underway to expand
the library and also to evaluate the biological activity of
these novel compounds.
Experimental Section
General Procedure for the Synthesis of 1-Aminoin-
dolizines: Synthesis of 1-Morpholin-4-yl-3-phenyl-indoliz-
ine (4a). To a solution of AgBF4 (9.5 mg, 0.05 mmol) in
toluene (1.0 mL) were added pyridine-2-carboxaldehyde
(95 µL, 1.0 mmol), phenyl acetylene (130 µL, 1.2 mmol),
and morpholine (86 µL, 1.0 mmol) successively. The
resulting mixture was stirred at 85 °C until the reaction
was completed as monitored by thin-layer chromatogra-
phy. The mixture was then diluted with dichloromethane
(5 mL) and washed with water (2 × 5 mL). The aqueous
phase was extracted with dichloromethane (3 × 5 mL).
The combined organic phase was washed with saturated
aqueous NaCl, dried over anhydrous Na2SO4, filtered and
concentrated under vacuum. The residue was purified by
flash chromatography on aluminum oxide to afford target
1
product 4a (243.5 mg, 89%) as a yellow oil. H NMR
(300 MHz, C6D6, Me4Si) 2.87 (t, J ) 1.5 Hz, 4H), 3.75
(t, J ) 1.5 Hz, 4H), 6.01-6.06 (m, 1H), 6.35 (dd, J )

Multicomponent Synthesis of Aminoindolizines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 699
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Acknowledgment. Financial supports from Nanyang
Technological University (RG50/08) and the Ministry of
Health, Singapore (NMRC, H1N1R/001/2009) are grate-
fully acknowledged. Y.B. is thankful for the grant from
Nanyang Technological University under the Undergradu-
ate Research Experience on Campus (URECA) programme.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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CC100086H