Iodine-mediated one-pot synthesis of C-3 acylated indolizines from pyridines, aryl methyl ketones and acrylate derivatives

Article abstract of DOI:10.1016/j.tet.2019.05.058

An I₂/CuI-promoted multi-component reaction from pyridines, aryl methyl ketones and electron deficient acrylates has been accomplished in a “one-pot” manner, which provides a straightforward and efficient access to C-3 acylated indolizines. The

Full text of DOI:10.1016/j.tet.2019.05.058

Accepted Manuscript
Iodine-mediated one-pot synthesis of C-3 acylated indolizines from pyridines, aryl
methyl ketones and acrylate derivatives
Youlai Fang, Lisheng He, Weidong Pan, Yuzhu Yang
PII:
S0040-4020(19)30620-9
https://doi.org/10.1016/j.tet.2019.05.058
TET 30379
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 March 2019
Revised Date: 19 May 2019
Accepted Date: 27 May 2019
Please cite this article as: Fang Y, He L, Pan W, Yang Y, Iodine-mediated one-pot synthesis of C-3
acylated indolizines from pyridines, aryl methyl ketones and acrylate derivatives, Tetrahedron (2019),
doi: https://doi.org/10.1016/j.tet.2019.05.058.
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Iodine-Mediated One-Pot Synthesis of C-3
Acylated Indolizines from Pyridines, Aryl
Methyl Ketones and Acrylate Derivatives
Leave this area blank for abstract info.
Youlai Fang a,b,c, Lisheng He b,c, Weidong Pan a,b,c,* and Yuzhu Yang b,c,
*
a College of Pharmacy, Guizhou University, Huaxi Avenue South, Guiyang 550025, P. R. China
b State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491
Baijin Road, Guiyang 550014, P. R. China
c The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of
Sciences, 3491 Baijin Road, Guiyang 550014, P. R. China

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Tetrahedron
journal homepage: www.elsevier.com
Iodine-Mediated One-Pot Synthesis of C-3 Acylated Indolizines from Pyridines, Aryl
Methyl Ketones and Acrylate Derivatives
Youlai Fang a, b, c Lisheng He b, c, Weidong Pan a, b, c, and Yuzhu Yang b, c,
a College of Pharmacy, Guizhou University, Huaxi Avenue South, Guiyang 550025, P. R. China
b State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, P. R. China
c The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang 550014, P. R.
China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An I2/CuI-promoted multi-component reaction from pyridines, aryl methyl ketones and
electrondeficient acrylates has been accomplished in a "one-pot" manner, which provides a
straightforward and efficient access to C-3 acylated indolizines. The key intermediate of N-
ylides is hypothesized to be generated in situ from pyridines and (hetero)aryl methyl ketones in
the presence of iodine. This method has been applied in the synthesis of two molecules with
anticonvulsant and anti-inflammatory activities.
Available online
.
Keywords:
Indolizine
One-pot
Iodine
1,3-Dipolar Cycloaddition
1. Introduction
iodine as an iodination regent for the synthesis of indolizines via
a 1,3-dipolar cycloaddition reaction of nitrogen ylides with
Indolizines are important bridgehead nitrogen heterocycles
that have received great attention due to their interesting
molecular structures featuring 10 π-delocalized electrons [1].
Indolizines exhibit a broad array of bioactivities, such as
antibacterial [2], antimycobacterial [3], antioxidant [4],
anticonvulsant [5], anti-inflammatory [5], and HIV inhibitory
activities [6]. and thus, a number of synthetic approaches have
been developed for the preparation of indolizines. The methods
for producing indolizines include the Schmidt reaction [7], the
Tschitschibabin reaction [8], 1,5-dipolar cyclizations [9], 1,3-
dipolar cyclization [10], transition metal catalyzed intramolecular
cyclization [11] and intermolecular cyclization [12]. Recently,
the syntheses of indolizines involving iodine, which serves as an
iodination reagent, have been reported. In particular, Wu and
coworkers demonstrated a two-step preparation of indolizines in
the presence of copper oxide [13]. The reaction requires a
stoichiometric amount of copper oxide and reflux conditions to
generate iodo-acetophenone for the second step, and the two
steps require different solvents. Another example was
demonstrated from Yavari and coworkers, which employed
alkynones [14]. However, the reaction requires the step by step
addition of starting materials, and the substrate scope is limited to
with onlyalkynones . Herein, we report our results of an iodine-
mediated synthesis of C-3 acylated indolizines in which pyridine
ylide was generated in situ in the presence of iodine, and this
protocol was accomplished in a one-pot manner.
2. Results and Discussion
We performed the reaction of acetophenone 1a, pyridine 2a
and methyl acrylate 3a as model substrates for optimization
(Table 1). It was found that no product was produced without the
inclusion of additional base (Table 1, entry 1). To improve the
yield of 4a, different solvents were screened, and N,N-
Dimethylformamide (DMF) was found to be the best solvent
(Table 1, entries 3-5). Increasing or decreasing the reaction
temperature caused a decrease in the yield of the product. (Table
1, entries 6-8). Attempts to increase the yield by adding various
copper salts did not deliver better results (Table 1, entries 9-13).
When replacing the copper salt with other Lewis acids, such as
Corresponding author.
E-mail: wdpan@163.com (Weidong Pan);
yangyuzhu15@126.com (Yuzhu Yang).

2
Tetrahedron
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CuI (0.2 equiv)
2 (4.0 equiv)
K2CO3 (8.0 equiv)
iron, zinc, or nickel, the results indicated that CuI was most
COOMe
O
I
O
effective (Table 1, entries 14-17). In addition to K2CO3, other
bases were tested under the reaction conditions, but no
improvement of yield was observed (Table 1, entries 18-24).
Decreasing or increasing the amount of CuI did not improve the
reaction (Table 1, entries 25-26). Finally, when the reaction was
performed under inert conditions, no increased yield was
obtained (Table 1, entry 27).
COOMe
N
R1
N
DMF (0.3 M), air
90 oC,16 h
4
2a
3a
1
R1
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
N
N
N
N
N
O
O
O
O
O
S
O
Table 1. Optimization of reaction conditionsa.
NC
4e, 65%
CO2Me
4c, 72%
CO2Me
4d, 63%
CO2Me
4a, 66%
4b, 71%
CO2Me
CO2Me
N
N
N
N
N
O
O
O
O
O
F3C
4f, 74%
F
Cl
Br
I
entry solvent
additive (equiv)
T (oC)
base
Yield
of 4a
(%)
N.R.
18
30
34
28
32
40
36
52
49
66
47
50
60
4j, 63%
CO2Me
4i, 72%
4g, 66%
4h, 73%
CO2Me
CO2Me
CO2Me
CO2Me
O
1
2
3
4
5
6
7
8
DMSO
DMSO
NMP
DMF
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
-
-
-
-
-
-
-
-
100
100
100
100
100
110
90
80
90
90
90
-
N
N
N
N
N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NEt3
O
O
O
O
O
S
4o, 60%
4k, 52%
4l, 57%
4m, 64%
4n, 66%
Scheme 1: Synthesis of C-3 acylated indolizines from pyridine, methyl
acrylate and different (hetero)aryl methyl ketones.
9
CuCl (0.2)
CuBr (0.2)
CuI (0.2)
Cu(OAc)2 (0.2)
CuO (0.2)
FeCl3 (0.2)
Zn(OAc)2 (0.2)
NiCl2 (0.2)
10
11
12
13
14
15
16
17
18
19
20
21c
22
23
24
25
26
27d
The substrate scope of pyridine derivatives was studied under
the optimal reaction conditions (Scheme 2). Pyridines containing
electron-withdrawing groups delivered the corresponding
products with lower yields (5a in 47% yield) than those with
electron-donating groups (5b with methoxy group in 71% yield,
5d with methyl group in 57% yield and 5f with phenyl group in
52% yield). It is noteworthy that isoquinoline as a substrate
delivers the corresponding product 5c in a 58% yield, while no
product was obtained when quinoline was subjected to the same
reaction conditions. Furthermore, 2-methylpyridine and quinoline
were employed in this reaction to examine the effect of an
occupied ortho-position. The results showed that no product was
obtained (5g, N.R.; 5h, N.R.). Pyridines with a 3,5-dimethyl
90
90
90
90
55
59
64
35
90
Zn(CF3SO3)2 (0.2) 90
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.2)
CuI (0.1)
CuI (0.4)
CuI (0.2)
90
90
90
90
90
90
90
90
90
90
DBU
30
NHEt2
TMEDA
Na2CO3
Cs2CO3
KOAc
K2CO3
K2CO3
K2CO3
N.R.
N.R.
41
20
24
51
49
66
aReaction conditions: 1a (0.6 mmol), 2a (0.6 mmol), 3a (0.3 mmol), additive
(0.2 equiv), base (8 equiv) and I2 (4.0 equiv) in 1 mL of solvent for 16 h at
90 °C. bIsolated yields. cTMEDA: N,N,N',N'-Tetramethylethylenediamine.
dUnder nitrogen atmosphere in dry DMF.
To investigate the substrate scope of acetophenone
derivatives, a series of different (hetero)aryl methyl ketones
reacted with 2a and 3a in a one-pot fashion were studied under
standard conditions (Scheme 1). The results indicated that most
of the acetophenone derivatives reacted well under the reaction
conditions. 1-(Naphthalen-1-yl)ethanone, 1-(furan-2-yl)ethanone
and 1-(thiophen-2-yl)ethanone were compatible substrates in the
reaction and delivered the corresponding products. Cyano-,
trifluoromethyl-, fluoro-, chloro-, bromo- and even iodo-
substituted indolizine derivatives could be prepared in moderate
yields by this method. Among them, CF3 group in the para
position of the phenyl ring delivered the highest yield (74%). The
steric effect was observed when substrates possessed a methyl-
substituent on the para-position, this substrate produced a
product with a 66% yield, while a methyl-substituent in the meta-
position gave a 57% yield and a methyl-substituent in the ortho-
position gave a 52% yield. Finally, acetophenones with -OMe
and -SMe at the para position of phenyl ring were also employed
in the reaction to produce the products with a 66% yield and a
60% yield, respectively.
Scheme 2: Synthesis of C-3 acylated indolizines from acetophenone, methyl
acrylate and substituted pyridines.
substituted substrate reacted well using this method for producing
the indolizine product 5e with a 68% yield.
To study the substrate scope of electron-deficient alkenes,
different substrates were employed in the reaction under optimal

conditions (Table 2). The result was that most of the electron
di-tert-butyl fumarate resulted with a products 6h and 6i in 63%
yield and 61% yield, respectively (Table 2, entries 9-10). When
the substrates were aliphatic unsaturated aldehydes or chalcones,
the yield decreased under standard reaction conditions b(Table 2,
entries 11-15). When butane-1,4-diyl diacrylate was subjected to
the properly tuned condition, product 6o, containing two
indolizine scaffolds, was isolated in a 63% yield (Table 2, entry
16).
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deficient alkenes reacted and gave the corresponding products ef
Furthermore ficiently. Ethyl acrylate, acrylonitrile, butyl acrylate
and tert-butyl acrylate were used in this reaction and delivered
the corresponding products 6a-6d (Table 2, entries 1-4). It is
noteworthy that both E- and Z-dimethyl fumarate reacted well in
the optimal conditions to deliver the same product 6g in moderate
yields (Table 2, entries 7-8). Furthermore, diethyl fumarate and
Table 2. Synthesis of C-3 acylated indolizines from acetophenone, pyridine, and different electron deficient alkenes.
Entry
Alkene
Product
Yield(%)
Entry
Alkene
Product
Yield(%)
1
74
9
63
6a
6h
2
62
10
61
6b
CO2nBu
6i
N
CO2nBu
3
70
11
35
O
6c
CO2 Bu
6j
t
N
4
68
12
30
O
6k
6d
O
Ph
Ph
N
5
70
13
38
O
6l
6e

4
Tetrahedron
ACCEPTED MANUSCRIPT
O
O
6
50
14
34
6f
6m
CO2Me
CO2Me
N
7
58
15
37
O
6g
6n
CO2Me
CO2Me
N
8
54
16
63a
O
6g
6o
a Reaction conditions: 1a (1.2 mmol), 2a (1.2 mmol), 3 (0.3 mmol), CuI (0.12 mmol), I2 (2.4 mmol), K2CO3 (4.8 mmol), DMF (1.0 mL), air, 90 oC, 16 h.
intermediate C in the presence of base delivers intermediate D,
which undergoes 1,3-dipolar cycloaddition with methyl acrylate
to form intermediate E, followed by further dehydrogenative
aromatization in the presence of iodine to form the product
indolizine.
To further prove the potential of this method, We utilized this
protocol for the synthesis of two biologically active compounds
(7a and 7b) (Scheme 3) [5]. When electron-deficient alkynes,
such as methyl propiolate, dimethyl but-2-ynedioate, and 1,3-
diphenylprop-2-yn-1-one, were subjected to this reaction under
optimal conditions, no product was detected (Scheme 4). Possible
explanation could be that the side reaction of iodine with alkynes
which consumed the alkynes. After the reaction employing
alkynes, we have detected the complete consumption of alkynes,
while no expected product was found.
Scheme 3: Synthesis of anti-convulsant and anti-inflammatory indolizines.
Scheme 5: A plausible mechanism of the multiple-component reaction.
3. Conclusion
A one-pot method for the synthesis of multisubstituted
indolizines was developed from acetophenones, pyridines and
electron deficient alkenes. The substrate scope of this method
was broad, since various (hetero)aryl methyl ketones, pyridines,
and electron deficient alkenes were successfully applied using
this protocol. We have also utilized the methodology to
synthesize two biologically active compounds, which may attract
the interests of many medicinal chemists. Further exploration and
application of this methodology are currently ongoing in our
laboratory.
Scheme 4: Reactions with electron-deficient alkynes under optimal conditions.
Based on previous reports [13, 14] and the above results, a
plausible mechanism of this reaction is proposed in Scheme 5.
Initial complexation of acetophenone and CuI forms intermediate
A, which undergoes deprotonation to give intermediate B.
Addition of iodine to intermediate B which reacts with pyridine
generates pyridine ylide intermediate C in situ. Deprotonation of

3. Danac, R.; Matarneh, C. M.A.; Shova, S.; Daniloaia, T.; Balan,
4. Experimental section
ACCEPTED MANUSCRIPT
M.; Mangalagiu, I.I. Bioorg Med Chem. 2015, 23, 2318-2327.
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Hegazi, B. Arch. Pharm. Chem. Life Sci. 2006, 339, 133-140.
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Zhang, L. Mol. Divers. 2013, 17, 221-243.
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Soc. 2009, 131, 17746-17747.
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2623.
Melting points were measured in a WRX-4 melting point
apparatus purchased from Shanghai YICE Instrumental
1
Company; H and 13C NMR spectra were recorded at 400 (500,
600) and 100 (125, 150) MHz, respectively using CDCl3 as the
solvent. (INOVA 400 MHz NMR Spectrometer, WNMR-I 500
MHz NMR Spectrometer, Bruker Avance NEO 600 MHz NMR
Spectrometer) HRMS data were recorded on an agilent 6540
mass spectrometer with electro spray ionization and TOF mass
analyzer. All column chromatography was performed using silica
gel (200-300 microns). Unless otherwise noted, commercially
available chemicals were used as received.
9. Basavaiah, D.; Devendar, B.; Lenin, D.V.; Satyanarayana, T.
Synlett 2009, 3, 411-416.
10. (a) Zhang, X.; Lu, G.-P.; Xu, Z.-B.; Cai, C. ACS Sustain Chem.
Eng. 2017, 5, 9279-9285; (b) Brioche, J.; Meyer, C.; Cossy, J.
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Y.; Wu, X.-Y.; Tong, X. Org. Lett. 2015, 17, 5376-5379.
11. For indolizine synthesis from metal catalyzed intramolecular
cylcization approach, see: (a) Seregin, I. V.; Gevorgyan, V. J. Am.
Chem. Soc. 2006, 128, 12050-12051; (b) Smith, C. R.; Bunnelle,
E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169-1171;
(c) Zhang, L.; Li, X.; Liu, Y.; Zhang, D. Chem. Commun. 2015,
51, 6633-6636; (d) Oh, K. H.; Kim, S. M.; Park, S. Y.; Park, J. K.
Org. Lett. 2016, 18, 2204-2207.
12. For indolizine synthesis from metal catalyzed intermolecular
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López, L. A.; Tomás, M. J. Am. Chem. Soc. 2010, 132, 13200-
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Org. Chem. 2017, 82, 11304-11309; (e) Yang, Y.; Wu, T.; Fang,
Y. Synlett, 2018, 29, 1909-1913.
General Procedure for the Product:
A test tube was loaded with acetophenone (1a, 0.6 mmol, 72.1
mg), pyridine (2a, 0.6 mmol, 47.5 mg), methyl acrylate (3a, 0.3
mmol, 25.8 mg), K2CO3 (2.4 mmol, 331.7 mg) , I2 (1.2 mmol,
304.6 mg), CuI (0.06 mmol, 11.4 mg) and 1 mL DMF. The
reaction mixture was stirred at 90 °C for 16 h. After completion
of the reaction, the reaction mixture was diluted with EtOAc, and
washed with 10% Na2S2O3 solution (50 mL). Then, the mixture
was extracted with EtOAc (20 mL×3), and the combined organic
layers were dried over Na2SO4, filtered, and concentrated in
vacuo. The remaining crude product was then purified through
column chromatography using silica gel (EtOAc/petroleum ether
= 1/10) to produce 4a as a yellow solid with a 66% yield.
13. Cai, Q.; Zhu, Y.-P.; Gao, Y.; Sun, J.-J.; Wu, A.-X. Can. J. Chem.
2013, 91, 414-419.
Acknowledgments
14. Yavari, I.; Sheykhahmadi, J.; Naeimabadi, M.; Halvagar, M. R.
Mol Divers. 2017, 21, 1-8.
Financial support from the Natural Science Foundation of
Guizhou Province (QKHJC[2017]1117, QKHJC[2018]1109,
QKHPTRC[2017]5718) and the West Light Foundation of The
Chinese Academy of Sciences is acknowledged.
Supplementary Material
Supporting Information File 1:
References
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