Efficient synthesis of indolizines and new imidazo[1,2-a]pyridines via the expected cyclization of aromatic cycloimmonium ylides with electron deficient alkynes and ethyl cyanoformate

Article abstract of DOI:10.1016/j.tetlet.2013.09.033

Aromatic cycloimmonium ylides underwent smooth cyclization with electron deficient alkynes in presence of anhydrous K₂CO₃ in DMF solvent at room temperature to afford substituted indolizines. Ylides have also undergone expected cyclization with ethyl cyanoformate to produce imidazo[1,2-a]pyridines. The structures of these newly synthesized compounds have been confirmed by spectroscopic techniques and X-ray diffraction studies.

Full text of DOI:10.1016/j.tetlet.2013.09.033

Accepted Manuscript
Efficient synthesis of indolizines and new imidazo[1,2-a]pyridines via the ex‐
pected cyclization of aromatic cycloimmonium ylides with electron deficient
alkynes and ethyl cyanoformate
C. Sandeep, Basavaraj Padmashali, Rashmi S. Kulkarni
PII:
S0040-4039(13)01587-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.09.033
TETL 43533
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
30 July 2013
4 September 2013
11 September 2013
Please cite this article as: Sandeep, C., Padmashali, B., Kulkarni, R.S., Efficient synthesis of indolizines and new
imidazo[1,2-a]pyridines via the expected cyclization of aromatic cycloimmonium ylides with electron deficient
alkynes and ethyl cyanoformate, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.09.033
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Efficient synthesis of indolizines and new imidazo[1,2-a]pyridines via the
expected cyclization of aromatic cycloimmonium ylides with electron
deficient alkynes and ethyl cyanoformate
C. Sandeep a , Basavaraj Padmashali a,* and Rashmi S. Kulkarni a
a Department of Chemistry, Sahyadri Science College(Autonomous), Shimoga-577203
Karnataka, India.
A B S T R A C T
Aromatic cycloimmonium ylides underwent smooth cyclization with electron deficient
alkynes in presence of anhydrous K2CO3 in DMF solvent at room temperature to afford
substituted indolizines. Ylides have also undergone expected cyclization with ethyl
cyanoformate to produce imidazo[1,2-a]pyridines. The structures of these newly synthesized
compounds have been confirmed by spectroscopic techniques and X-ray diffraction studies.
Keywords:
Indolizines
Cycloaddition
Imidazo[1,2-a]pyridines
Alkynes
Ethylcyanoformate.
Indolizines are aromatic organic compounds containing condensed five and six- membered
rings with bridging nitrogen. They are isoelectronic with indole and represent a group of
heterocyclic compounds structurally related to purines. Indolizine skeletons with different
degrees of unsaturation are present in a wide variety of natural and unnatural azacyclic
compounds. Most of the naturally occurring indolizines have been isolated from species of
genus dendrobates (poison-arrow frogs); monomorium (ants); dendrobium (orchids);
tylophora and the leguminosae family (plants). Indolizine alkaloids display broad spectrum of
biological activities.1. Polyhydroxylated indolizine alkaloids are excellent inhibitors of
biologically important path ways. These include the binding and processing of glycoproteins,
potent glycosidase inhibitor activities, activity against AIDS and some carcinogenic cells as
well as against other important pathologies.2,3. Indolizines are the simplest pyrroloazines,
formally obtained by the condensation of a pyridine and a pyrrole ring, being isomeric to
indole. This relatively simple indolizine skeleton offers the possibility of fine tuning certain
properties by varying the number and type of substituents.4,6. Such an example is the
synthesis of highly specific chemosensors obtained by linking 7-substituted indolizines to a
cyclodextrine moiety.9. Several synthetic methods for obtaining indolizines are known, one of
1

the most versatile being N-ylide 1,3-dipolar cycloadditions.7,8. These have been successfully
applied for the synthesis of a number of substituted indolizines and offer the advantages of a
few reaction steps and simple work-up. Furthermore, the method has recently been
reconsidered as a one-pot multicomponent process.10,11.
A careful look at the indolizine framework would logically suggest that one step or one-pot
simultaneous tandem construction of the N-C bond and C-C bond on to six- membered
nitrogen heterocycles (piperidine/pyridine), in an appropriately organized manner, using a
suitable reagent would lead to the formation of the desired azabicyclo(4,3,0)nonane frame
work.12,13.
Typical molecular constructions of indolizines fall in to three classes.
a. Condensation reactions of a 2-alkylpyridine with acid anhydrides (Scholta reaction)14 or α-
haloketones (Tschitschibabin reaction).15.
b. Reaction of an α-unsubstituted pyridine with a three- carbon fragment such as an acyl or
aryl substituted allyl halides or esters16 and methyl propiolates.17.
18
c. Reaction of pyridinium N-methylides generated from pyridinium salts under K2CO3,
,
pyridine and carbenes19 or N-trimethyl silyl methyl pyridinium triflates under fluoride ion.20
with acetylenes or reaction of pyridinium N-methyllides with ethylene in the presence of an
oxidant.21. The third route has been utilized for the synthesis of indolizines (Scheme 1) in the
present investigation. Acetylenes bearing one electron withdrawing group and one electron
donating group is an additional factor.
N-Heterocyclic ylides were prepared by stirring substituted pyridines with substituted
phenacyl bromides separately in the presence of acetone at room temperature. The solids
were filtered and dried under vacuum and used as such. The ylides obtained were up to 96-
99% yield. Anticipated indolizines have been prepared by the 1,3-dipolar cycloaddition
reaction of N-haterocyclic ylides with electron deficient alkynes in the presence of anhydrous
K2CO3 and DMF as a solvent. The reaction time has been drastically reduced to just 30
minutes with constant stirring. The completion of reaction was monitored by TLC. The
solvent was removed by distillation under reduced pressure and the reaction mixture was
diluted with ethyl acetate. The organic layer was washed with water, brine and dried with
anhydrous sodium sulphate purified by column chromatography using 60-120 mesh silica gel
and hexane-ethylacetate as a solvent.
2

Scheme 1. a) Acetone, rt; b) K2CO3, DMF, rt, 30 mins.
Table 1
Synthesis of pyridinium bromides (1a-l) and indolizine derivatives (2a-t).
Yield
Yield
(%)
70
66
60
63
65
60
55
Comp
R1
Comp R1
R2
(%)
99.0
98.3
98.5
98.8
99.1
98.18
97.4
97.6
1a
1b
1c
1d
1e
1f
4-H
4-F
2-Cl
2-Cl
2-Cl
2-Cl
2-NO2
2-NO2
2-NO2
H
2a
2b
2c
2d
2e
2f
CH3
C2H5
COOC2H5
H
CH3
C2H5
4-Cl
4-Br
4-CN
4-CH3
2-Cl
1g
2g
1h
2-NO2
2-NO2
COOC2H5
64
2h
1i
1j
1k
1l
3-NO2
96.8
3-NO2
3-NO2
3-NO2
3-NO2
3-OCH3
3-OCH3
3-OCH3
3-OCH3
3,5-CF3
3,5-CF3
3,5-CF3
3,5-CF3
H
CH3
C2H5
COOC2H5
H
77
71
64
70
69
64
60
75
70
70
66
61
2i
2j
2k
2l
2m
2n
2o
2p
2q
2r
2s
2t
3-OCH3 98.3
2,5-CF3 96.7
4-OCH3 97.2
CH3
C2H5
COOC2H5
H
CH3
C2H5
COOC2H5
In continuation of our research work, we tried to make use of N-pyridyl ylides for the
construction of other heterocyclic moieties. We decided to test the 1,3-dipolar addition of
aromatic cycloimmonium ylides to electron deficient nitriles.
3

In this regard, N-pyridyl ylides were treated with ethyl cyanoformate in the presence
of triethylamine base using THF as a solvent with constant stirring at room temperature
(Scheme 2 and 3). Interestingly, the expected formation of imidazo[1,2-a]pyridine was
observed after stirring for 3-4 h. It was possible to isolate twenty three imidazo[1,2-
a]pyridine derivatives and this would be a new method for the synthesis of imidazole ring
fused with indolizine moiety. But the formation of imidazo[1,2-a]pyridines was not observed
when N-pyridyl ylides were stirred with other nitriles such as cyanogen bromide, benzonitrile
and benzoylcyanide possibly because of less positive charge on carbon of cyano group and
stereochemistry. The formation of the imidazo[1,2-a]pyridine was confirmed by
spectroscopic techniques. The position of nitrogen in imidazo[1,2-a]pyridine that is 1-
position or 2- position was confirmed by single crystal X-ray diffraction studies of 4-methoxy
imidazo[1,2-a]pyridine derivative. 3-Acetyl-pyridiniumbromides 4a-k on addition to
ethylcyanoformate produced ethyl-6-acetyl-3-(3-methoxybenzoyl)imidazo[1,2-a]pyridine-2-
carboxylate 5a-k and minor quantities-. (below 5%) of ethyl-8-acetyl-3-(3-
methoxybenzoyl)imidazo[1,2-a]pyridine-2-carboxylates which are not isolated. Single crystal
X-ray diffraction structure has been shown in Figure 1.
Fig
1
Single crystal X-ray crystallographic study of ethyl-7-acetyl-3-(4-
methoxybenzoyl)imidazo[1,2-a]pyridine-2-carboxylate (3l).
All the imidazo[1,2-a]pyridines have been purified by column chromatography and
recrystallized using appropriate solvents. The structures of all the synthesized compounds
1
have been confirmed by various spectroscopic techniques such as LC-MS, H-NMR, IR,
along with elemental analysis and x-ray studies.
4

Scheme 2. a) TEA, THF, rt, 2-5h.
Table 2
Synthesis of 7-acetyl- imidazo[1,2-a]pyridine derivatives (3a-l).
Comp
3a
3b
3c
3d
R1
4-H
Yield (%) Comp
R1
2-Cl
2-NO2
3-NO2
3-OCH3 60
3,5-CF3 65
4-OCH3 52
Yield (%)
64
60
63
66
67
69
65
69
66
3g
3h
3i
3j
3k
3l
4-F
4-Cl
4-Br
4-CN
4-CH3
3e
3f
Scheme 3. a) Acetone, rt, b) TEA, THF, rt, 2-5h.
Table 3
Synthesis of pyridinium bromides (4a-k) and 6-acetyl- imidazo[1,2-a]pyridine derivatives
(5a-k).
Comp R1
Yield(%) Comp R1
Yield(%)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-H
4-Cl
4-Br
4-CN
4-CH3
2-Cl
2-NO2
3-NO2
99.2
98
4-H
4-Cl
4-Br
57
55
54
50
48
59
53
57
5a
5b
5c
5d
5e
5f
5g
5h
5i
98.5
98.9
97.5
97.3
97.9
97.1
4-CN
4-CH3
2-Cl
2-NO2
3-NO2
4-OCH3 61
4-F 50
3-OCH3 46
4-OCH3 98
4-F
3-OCH3 98.5
4j
4k
97.6
5j
5k
5

All the synthesized compounds have been purified by column chromatography and
recrystallized with ethyl acetate. The structures have been confirmed by spectroscopic
techniques like IR, 1H-NMR, LC-MS, elemental analysis and x-ray studies.
Proposed mechanism for synthesis of substituted indolizines and substituted new
imidazo[1,2-a]pyridines.
The research work is focused on the efficient synthesis of indolizines with drastically reduced
time of reaction. It has also made an observation on new method of synthesis of imidazo[1,2-
a]pyridines. The reactions performed are eco-friendly as they are carried out at room
temperature. The publication of these facts would be of significant use for the scientific
community.
Acknowledgement
We are thankful to the Principal, Sahyadri Science College, Shimoga, for providing
laboratory facilities.
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7

22. Preparation of 4-acetyl-1-(2-oxo-2-p-tolylethyl)pyridiniumbromide 1f. To a stirred
solution of 4-acetylpyridine 1g (0.0082 mol) in dry acetone (5 mL), was added 1.75 g (0.0082
mol) of 4-methylphenacylbromide and stirred at room temperature for 5 h. Solids formed
were separated out, filtered and dried under vacuum to afford 2.7 g (98.18 % yield) of 4-
acetyl-1-(2-oxo-2-p-tolylethyl)pyridiniumbromide. Similarly, other compounds of the series
1a-l were prepared.
Preparation of ethyl 7-acetyl-2-methyl-3-(3-nitrobenzoyl)indolizine-1-carboxylate 2j. To
a stirred solution of 4-acetyl-1-(2-oxo-2-p-tolylethyl)pyridiniumbromide 0.5 g (0.0013 mol),
in dry DMF, was added ethyl but-2-ynoate 0.169 g (0.00151 mol), K2CO3 0.416 g (0.0030
mol). It was stirred at room temperature for 30 min. Completion of reaction was monitored
by TLC. After completion, reaction mass was evaporated under reduced pressure and diluted
with ethyl acetate. Organic layer was washed with water, brine and dried with sodium
sulphate. The crude compound was purified by column chromatography using a mixture of
ethylacetate/hexane (1:5) to afford 0.38 g (71 % yield) of ethyl 7-acetyl-2-methyl-3-(3-
nitrobenzoyl)indolizine-1-carboxylate. Similarly, other compounds of the series 2a-ar were
prepared.
Preparation of 3-acetyl-1-(2-(4-cyanophenyl)-2-oxoethyl)pyridinium bromide 4d. To a
stirred solution of 3-acetyl pyridine 1 g (0.0082 mol) in dry acetone (5 mL), was added 1.75 g
(0.0082 mol) of 4-cyano phenacylbromide, stirred at room temperature for five hours. Solids
were separated out, filtered and dried under vacuum to afford 2.82 g (98.9 % yield) of 3-
acetyl-1-(2-(4-cyanophenyl)-2-oxoethyl)pyridiniumbromide. Similarly, other compounds of
the series 4a-k were prepared.
Preparation of ethyl-7-acetyl-3-(4-methylbenzoyl)imidazo[1,2-a]pyridine-2-carboxylate
3l. A mixture of 4-acetyl-1-(2-(4-methoxyphenyl)-2-oxoethyl)pyridiniumbromide 0.5 g
(0.0014 mol), in dry THF(5 mL) and ethylcyanoformate 0.156 g (0.0015 mol) was stirred in
presence of triethylamine 0.322 g (0.0031 mol) for 5 hours at room temperature. Completion
of reaction was monitored by TLC. The reaction mixture was evaporated under reduced
pressure and diluted with ethyl acetate. Organic layer was washed with water, brine and dried
with sodium sulphate. The crude compound was purified by column chromatography using a
mixture of ethylacetate/hexane (1:3) to afford 0.273 g (52% yield) of ethyl-7-acetyl-3-(4-
methoxybenzoyl)imidazo[1,2-a]pyridine-2-carboxylate. Similarly, other compounds of the
series 3a-l were prepared.
Preparation
of
ethyl
6-acetyl-3-(3-methoxybenzoyl)imidazo[1,2-a]pyridine-2-
carboxylate 5k. To
a
stirred solution of 3-acetyl-1-(2-(3-methoxyphenyl)-2-
oxoethyl)pyridiniumbromide 0.5 g (0.0014 mol), in dry THF(5 mL), was added
ethylcyanoformate 0.156 g (0.0015 mol) and triethylamine 0.322 g (0.0031 mol). It was
stirred it at room temperature for 5 hours. Completion of reaction was monitored by TLC.
The reaction mass was evaporated under reduced pressure and diluted with ethyl acetate.
Organic layer was washed with water, brine and dried with sodium sulphate. The crude
compound was purified by column chromatography using a mixture of ethylacetate/hexane
(1:3) to afford 0.243 g (46% yield) of ethyl-6-acetyl-3-(3-methoxybenzoyl)imidazo[1,2-
a]pyridine-2-carboxylate Similarly, other compounds of the series 5a-k were prepared
8

*Graphical Abstract (for review)
Efficient Synthesis of Indolizines and New Imidazo[1,2-a]pyridines via the
Expected Cyclization of Aromatic Cycloimmonium Ylides with Electron
Deficient Alkynes and Ethyl cyanoformate