Facile one-pot tandem synthesis of perfluoroalkylated indolizines under metal-free mild conditions

Article abstract of DOI:10.1016/j.tet.2017.01.005

A direct metal-free method for the synthesis of perfluoroalkylated indolizines by means of DIPEA-promoted tandem C[sbnd]N/C[sbnd]C bond formation was developed. Various substituted pyridines and bromoacetyl derivatives with methyl perfluoroalk-2-ynoates proceeded smoothly in this mild transformation, and the desired products were obtained in good to excellent yields under air.

Full text of DOI:10.1016/j.tet.2017.01.005

Accepted Manuscript
Facile one-pot tandem synthesis of perfluoroalkylated indolizines under metal-free
mild conditions
Dong He, Yuhong Xu, Jing Han, Hongmei Deng, Min Shao, Jie Chen, Hui Zhang,
Weiguo Cao
PII:
S0040-4020(17)30005-4
10.1016/j.tet.2017.01.005
TET 28375
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 October 2016
Revised Date: 3 January 2017
Accepted Date: 4 January 2017
Please cite this article as: He D, Xu Y, Han J, Deng H, Shao M, Chen J, Zhang H, Cao W, Facile one-
pot tandem synthesis of perfluoroalkylated indolizines under metal-free mild conditions, Tetrahedron
(2017), doi: 10.1016/j.tet.2017.01.005.
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ACCEPTED MANUSCRIPT
Facile One-pot Tandem Synthesis of PerfluoroalkylatedIndolizines under Metal-free Mild
Conditions
Dong He,a,† YuhongXu,a,† Jing Han,a HongmeiDeng,b Min Shao,b JieChen,a Hui Zhang,*a,b Weiguo
Cao*a,c,d,e

ACCEPTED MANUSCRIPT
Facile One-pot Tandem Synthesis of Perfluoroalkylated Indolizines under Metal-free Mild
Conditions
Dong He,a,† Yuhong Xu,a,† Jing Han,a Hongmei Deng,b Min Shao,b Jie Chen,a Hui Zhang,*a,b
Weiguo Cao*a,c,d,e
1

ACCEPTED MANUSCRIPT
Facile One-pot Tandem Synthesis of Perfluoroalkylated Indolizines under Metal-free Mild
Conditions
Dong He,a,† Yuhong Xu,a,† Jing Han,a Hongmei Deng,b Min Shao,b Jie Chen,a Hui Zhang,*a,b
Weiguo Cao*a,c,d,e
a Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai
200444, P. R. China
b
Laboratory for Microstructures, Instrumental Analysis and Research Center of Shanghai
University, Shanghai 200444, P. R. China
c
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, P. R. China
d Key Laboratory of Synthetic Organic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. China
e Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, P. R. China
† With equal contribution to this work
Abstract: A direct metal-free method for the synthesis of perfluoroalkylated indolizines by means
of DIPEA-promoted tandem C−N / C−C bond formation was developed. Various substituted
pyridines and bromoacetyl derivatives with methyl perfluoroalk-2-ynoates proceeded smoothly in
this mild transformation, and the desired products were obtained in good to excellent yields under
air.
Keywords: Indolizine, Perfluoroalkylated, One-pot Reaction, Metal-free, Tandem synthesis
1. Introduction
Indolizine derivatives, carrying different substituent in the nucleus ring, exhibit a wide range of
interesting biological and pharmacological properties such as anticancer, antibacterial, antifungal,
anti-cholinergic, anti-histaminic, anti-tubercular activity and cytotoxic and CNS depressant
activity, etc.1 They are also widely employed in the field of materials science such as organic
___________________________________
*Corresponding authors. Fax: +86-21-66134856; E-mail: wgcao@staff.shu.edu.cn or yehao7171@shu.edu.cn
2

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light-emitting devices (OLEDs), biological markers, and dyes.2 Thus, diverse synthetic methods to
access these molecules have been reported. Besides the direct functionalization of indolizine core,3
typical molecular constructions of indolizine have been well reviewed in the literatures.4
Especially, owing to the increasing importance of fluorine-containing heterocycles in biology,
pharmacology, and industrial application,5 synthesis of fluorine-containing indolizines became of
considerable interest to chemists.6
However, the main disadvantages of these known approaches are their limited substrate
availability, harsh reaction conditions, multi-step stage, poor regioselectivty and lower yield,
particularly for the preparation of perfluoroalkylated indolizines. Moreover, transition metals are
indispensable catalysts in some of these methods, which may require extreme care for the
purification of such biological and pharmaceutically active products due to the possible
contamination of metal residues in the target compounds.
Therefore,
a
straightforward, convenient, metal-free and regioselective route to
multiple-substituted indolizines using common chemical materials is highly attractive.
Since tandem and one-pot reactions have been widely used as a powerful tool to construct
complex molecules in organic synthetic chemistry,7 herein, we report an effective
DIPEA-promoted one-pot metal-free tandem process for the synthesis of perfluoroalkylated
indolizines from readily available pyridines, bromomethyl aryl or heteroaryl ketones and methyl
perfluoroalk-2-ynoates under mild conditions.
2. Results and Discussion
Our initial efforts were focused on the C-N / C-C reaction using pyridine 1a and
ω
-bromoacetophenone 2a with methyl 4,4,4-trifluorobut-2-ynoate 3a as the model substrates
(Table 1). It was found that the reaction became messy when the above three components were
mixed simultaneously and stirred in MeCN at 40 °C after 11 h. The reason could be attributed to
the competition between nucleophilic substitution of 1a with 2a and Michael addition of 1a with
3a.8
The reaction was thus performed in a one-pot two-step process. After the first-step reaction of
o
pyridine 1a and
ω
-bromoacetophenone 2a at 40 C in MeCN for 4 h (TLC monitored complete
conversion), methyl 4,4,4-trifluorobut-2-ynoate 3a and DIPEA were added and continued to be
o
stirred at 25 C for another 7 h. To our delight, the desired product 4a was obtained in moderate
3

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yield (Table 1, entry 1). To improve the reaction yield, other solvents such as DCM, THF, EtOH,
DMF and DMSO were explored, affording much lower yields compared to MeCN (Table 1, entry
1 vs entries 2-8). The reaction temperature for the second step was also examined. At 40 °C, the
yield was increased to 69%, while a lower yield was observed at 60 or 0 oC (Table 1, entries 9-11).
Further screening of the bases showed that DIPEA uniquely facilitated the second-step cyclization
(Table 1, entry 10 vs entries 12-21). And notably, no cyclization occurred in the absence of the
base (Table 1, entry 22). Additional studies indicated that 2.0 equiv. of DIPEA was suitable and 7
h was enough for the completion of the second step (Table 1, entry 25). Ultimately, the optimal
reaction conditions were determined as 2.0 equiv. DIPEA base, MeCN solvent, 40 °C, and total 11
h for the one-pot two-step procedure under air atmosphere.
Table 1 Optimal reaction conditions screening for the second stepa
Entry
Solvent
Base (equiv)
Time (h)
4a Yield (%)b
Temperature (°C)
MeCN
THF
DIPEA (0.5)
DIPEA (0.5)
DIPEA (0.5)
DIPEA (0.5)
DIPEA (0.5)
DIPEA (0.5)
DIPEA (0.5)
DIPEA (0.5)
DIPEA (0.5)
DIPEA (0.5)
DIPEA (0.5)
Piperidine (0.5)
DBU (0.5)
25
25
25
25
25
25
25
25
0
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
7
60
50
29
32
57
16
12
33
43
69
64
24
26
47
53
36
28
19
17
1
2
DCM
3
EtOH
4
Toluene
DMSO
DMF
5
6
7
1,4-Dioxane
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
8
9
40
60
40
40
40
40
40
40
40
40
10
11
12
13
14
15
16
17
18
19
DABCO (0.5)
Et3N(0.5)
K2CO3 (0.5)
Cs2CO3 (0.5)
Al2O3 (0.5)
KF (0.5)
4

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MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
NaOH (0.5)
K3PO4 (0.5)
DIPEA (0)
40
40
40
40
40
40
40
40
40
40
7
7
12
15
0
20
21
22
23
24
25
26
27
28
29
7
DIPEA (0.1)
DIPEA (1.0)
DIPEA (2.0)
DIPEA (3.0)
DIPEA (2.0)
DIPEA (2.0)
DIPEA (2.0)
7
20
85
90
80
64
82
66
7
7
7
1
15
30
a Reaction conditions: pyridine 1a (2.0 mmol) and
ω-bromoacetophenone 2a (2.2 mmol) were
mixed and stirred in MeCN (5 mL) for 4 h in air. Then methyl 4,4,4-trifluorobut-2-ynoate 3a
b
(1.0 mmol) and base were added and continued to be stirred for additional confined time.
Isolated yields.
With the optimal conditions in hand, we first examined the scope of this reaction by varying the
ω
-bromoacetophenones. From the results, we could see that both electron-donating and
electron-withdrawing substituent on the benzene ring of -bromoacetophenones yielded the
corresponding indolizine products smoothly. No obvious steric effect was observed for
2-substituted group on the benzene ring of -bromoacetophenones in this reaction. For example,
methyl 3-(2-nitrobenzoyl)-2-(trifluoromethyl)indolizine-1-carboxylate 2f and methyl
ω
ω
3-(2-methylbenzoyl)-2-(trifluoromethyl)indolizine-1-carboxylate 2g both gave the expected
indolizines in good yields (Table 2, entries 18 and 19). In addition to this, bromomethyl heteroaryl
ketones such as
Notablely, chloromethyl aryl ketones were proved to be suitable substitutes too. And
-chloroacetophenone gave the desired products in 88% yield.
ω-bromoacetothiophene were found to be excellent substrates (Table 2, entry 6).
ω
Next, we investigated the scope of the pyridine derivatives under the optimized conditions. The
presence of an electron-donating substituent at 4-position of the pyridine ring yielded relatively
low level of indolizines (Table 2, entries 7-10). Higher yields were obtained when the pyridine
ring of 1 carried an electron-withdrawing group at the same position (Table 2, entries 13-15).
However, pyridines bearing electron-withdrawing substituents at 3-position furnished the desired
product in similar yields to those bearing electron-donating substituents (Table 2, entry 20 vs
entry 21). Notably, pyridines with the substituent at 2-position failed to give any products,
possibly due to associated steric hindrance (Table 2, entries 22 and 23).
5

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At last, we turned to check the scope of alkynes. The reactivity of other perfluroalkylated alkynes
3 was examined. The results showed that the reactivity of 3b and 3c was lower than 3a, as they
provided lower yields of products 4 (Table 2, entry 1 vs entries 11 and 12). This result may also
be due to the steric hindrance of their longer carbon chain.
A variety of functional groups such as Br, Cl, NO2, CO2Me, Me and OMe were compatible with
this transformation, which allows further elaboration of the perfluoroalkylated indolizines.
Furthermore, as this reaction proceeded under metal-free conditions, it could be used for the
preparation of various indolizines containing heteroatom functional groups, circumventing the
problem of deactivation of the transition metal catalyst by chelation.
The structure of 4 was confirmed by 1H NMR, 19F NMR, 13C NMR, MS, HRMS, IR spectra data,
and single-crystal X-ray diffraction analysis of 4d (Fig. 1).9
Table 2 Synthesis of perfluoroalkylated indolizinesa
R1
R1
O
Br
R2
N
Y
O
R2
N
RF
CO2Me 3
MeCN
O
Br
R1
+
40 oC, 4h
Y
n
N
DIPEA, MeCN, 40 o
7 h
C
Y
MeO2C
CF3
n
R2
n
1
2
4
R1 = H, 1a;
4-Me, 1b;
Y = C ( n = 2), R2 = H, 2a;
RF = CF3, 3a;
C2F5, 3b;
4-OMe, 2b;
4-NO2, 2c;
4-Cl, 2d;
4-CO2Me, 1c;
3-Br, 1d;
n-C3F7, 3c
3-Me, 1e;
2-OMe, 1f;
2-Me, 1g
4-Me, 2e;
2-NO2, 2f;
2-Me, 2g;
Y = S (n = 1), R2 = H, 2h
Entry
R1
R2
3
Product 4
Yield of 4 (%)b
1
2
H
H
C6H5
4-OMeC6H4
4-NO2C6H4
4-ClC6H4
4-MeC6H4
2-Thienyl
4-MeC6H4
4-OMeC6H4
4-NO2C6H4
C6H5
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
4a
4b
4c
4d
4e
4f
90 (88c)
91
3
H
93
4
H
92
5
H
93
6
H
89
7
4-Me
4-Me
4-Me
4-Me
H
4g
4h
4i
82
8
88
9
80
10
11
12
4j
85
C6H5
4k
4l
80
H
C6H5
72
6

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13
14
15
16
17
18
19
20
4-CO2Me
4-CO2Me
4-CO2Me
4-CO2Me
4-CO2Me
H
C6H5
4-OMeC6H4
4-NO2C6H4
C6H5
3a
3a
3a
3c
3c
3a
3a
3a
4m
4n
4o
4p
4q
4r
4s
98
94
95
80
79
74
80
65
4-NO2C6H4
2-NO2C6H4
2-MeC6H4
C6H5
H
3-Br
4t
21
22
23
3-Me
2-OMe
2-Me
C6H5
C6H5
C6H5
3a
3a
3a
4u
4v
4w
66
0
0
a
Reaction conditions: pyridine
1
(2.0 mmol) and
ω
-bromoacetophenone or
ω
-bromoacetothiophene 2 (2.2 mmol) , were mixed and stirred in MeCN (5 mL) for 4 h. Then
methyl perfluoroalk-2-ynoate 3 (1.0 mmol) and DIPEA (2.0 mmol) were added and continued to
be stirred for another 7 h. b Isolated yields. c
-chloroacetophenone was used.
ω
Figure 1 X-ray structure of compound 4d
Based on the above experimental facts and the results of previous study,10 a plausible reaction
mechanism for the process is proposed in Scheme 1 with 1a, 2a and 3a as an example. Firstly,
nucleophilic substitution of 1a and 2a generates pyridinium salt I. Then deprotonation of I by
DIPEA gives zwitterionic intermediate II, whose negative carbon regioselectively attacks the
carbon atom adjacent to CF3 in 3a to furnish cyclized intermediate III. IV is thus generated from
III by hydrogen abstraction upon treatment of the base. The subsequent dehydrogenative
aromatization of intermediate IV in air affords the final product 4a.
7

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Scheme 1 The proposed mechanism for the transformation
3. Conclusions
We have developed a metal-free perfluoalkylated indolizine synthesis through C-N / C-C
formation of pyridines, bromomethyl aryl or heteroaryl ketones and methyl
perfluoroalk-2-ynoates using DIPEA as a base. With advantages such as readily available
starting materials, simple synthetic procedures, good to excellent yields of the products, good
regioselectivity, and mild reaction conditions, the method developed herein is expected to
serve as a promising protocol for the construction of relevant nitrogen-containing
heterocycles.
4. Experimental
4.1 General Information
8

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Reagents and solvents were purchased from commercially sources and used without further
purification. Methyl perfluoroalk-2-ynoates and
ω-bromoacetothiophene were prepared according
to the known literatures.11,12 Melting points were recorded on a WRS-1 instrument and are
1
uncorrected. H, 19F and 13C NMR spectra were recorded on a Bruker DRX- 500 MHz
spectrometer. All chemical shifts are reported in parts per million downfield (positive) of the
1
standard: C6F6 for 19F, TMS for H and 13C NMR spectra. IR spectra were obtained on an
AVATAR370 FTIR spectrometer. LR-MS (lower resolution mass spectra) and HR-MS (high
resolution mass spectra) were obtained on Agilent6230, APEXIII, Bruker Daltonics, Inc. APEXIII
7.0 TESALA FTMS, Thermo Fisher Scientific LTO FT Ultra and Ionspec 4.7 TESALA FTMS
instruments, respectively. X-ray analysis was performed on a Bruker Smart Apex2 CCD
spectrometer. Yields reported in this publication refer to isolated ones of compounds and their
purity was determined by 1H NMR.
4.2 General procedure for the synthesis of 4a-4u:
The mixture of pyridines 1 (2.0 mmol) and ω-bromoacetophenones 2 (2.2 mmol) was stirred at 40
oC in MeCN (5.0 mL) for 4 h, then methyl perfluoroalk-2-ynoates 3 (1.0 mmol) and DIPEA (2.0
mmol) were added. The mixture was stirred at the same temperature for another 7 h. The solvent
was removed under vacuum and the residue was purified by column chromatography on silica gel
by eluting with petroleum ether / ethyl acetate 45:1 to 20:1) to afford the desired products.
Methyl 3-benzoyl-2-(trifluoromethyl)indolizine-1-carboxylate 4a: white solid; yield: 90 %;
m.p.: 78.0-79.2 oC; 1H NMR (500 MHz, CDCl3) δ: 3.97 (s, 3H), 6.89-6.92 (m, 1H), 7.28-7.31 (m,
1H), 7.49-7.52 (m, 2H), 7.63-7.66 (m, 1H), 7.85-7.87 (m, 2H), 8.37-8.40 (m, 2H) ppm; 13C NMR
2
(125 MHz, CDCl3,): δ 51.7, 115.2, 118.9, 120.7 (q, JC-F = 36.6 Hz, CF3), 122.1, 122.1 (q, 1JC-F
=
268.6 Hz, CF3), 125.7, 125.8, 128.5, 128.7, 129.5, 134.1, 137.6, 138.6, 163.4, 188.3 ppm; 19F
NMR (470 MHz, CDCl3) δ: -52.5 (s, CF3) ppm. IR (KBr): υ 2925, 1723, 1639, 1514, 1226, 694
cm-1. MS (DART) m/z (%): 348.1 [(M+H)]+. HRMS (DART) calcd. for C18H12F3NO3 [(M+H)]+:
348.0841, found: 348.0842.
Methyl 3-(4-methoxybenzoyl)-2-(trifluoromethyl)indolizine-1-carboxylate 4b: white solid;
1
yield: 91%; m.p.: 129.4-130.7 °C; H NMR (500 MHz, CDCl3) δ: 3.87 (s, 3H), 3.95 (s, 3H),
6.82-6.85 (m, 1H), 6.93-6.96 (m, 2H), 7.22-7.25 (m, 1H), 7.81-7.84 (m, 2H), 8.21-8.22 (m, 1H),
9

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8.33-8.35 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 51.6, 55.6, 102.0, 114.1, 114.9, 119.7 (q,
1
2JC-F = 36.6 Hz, CF3), 120.6, 122.2 (q, JC-F = 268.2 Hz, CF3), 122.6, 125.4, 125.5, 131.2, 132.1,
137.4, 163.5, 164.6, 186.7 ppm; 19F NMR (470 MHz, CDCl3) δ: -53.0 (s, CF3) ppm. IR (KBr): υ
2957, 2849, 1708, 1599, 1265, 1228, 639 cm-1. MS (DART) m/z (%): 378.1 [(M+H)]+. HRMS
(DART) calcd. for C19H14F3NO4 [(M+H)]+: 378.0942; found: 378.0948.
Methyl 3-(4-nitrobenzoyl)-2-(trifluoromethyl)indolizine-1-carboxylate 4c: white solid; yield:
1
93%; m.p.: 176.0-177.9 °C; H NMR (500 MHz, CDCl3) δ: δ 3.97 (s, 3H), 7.01-7.04 (m, 1H),
7.37-7.41 (m, 1H), 7.97-8.00 (m, 2H), 8.32-8.34 (m, 1H), 8.40-8.41 (d, 1H), 8.73-8.75 (d, 1H)
ppm; 13C NMR (125 MHz, CDCl3) δ: 51.9, 103.9, 116.1, 120.7, 120.8, 121.9 (q, 1JC-F = 268.8 Hz,
CF3), 122.3 (q, 2JC-F = 36.5 Hz, CF3), 123.8, 126.1, 127.0, 130.2, 138.2, 144.1, 150.5, 163.1, 186.2
ppm; 19F NMR (470 MHz, CDCl3) δ: -51.3 (s, CF3) ppm. IR (KBr): υ 3116, 1725, 1655, 1523,
1219, 1144, 536 cm-1. MS (DART) m/z (%): 393.1 [(M+H)]+. HRMS (DART) calcd. for
C18H11F3N2O5 [(M+H)]+: 393.0688; found: 393.0693.
Methyl 3-(4-chlorobenzoyl)-2-(trifluoromethyl)indolizine-1-carboxylate 4d: White solid;
yield: 92%; m.p.: 115.6-116.3 °C; 1H NMR (500 MHz, CDCl3) δ: 3.67 (s, 3H), 7.01-7.04 (m, 1H),
7.37-7.41 (m, 1H), 7.97-7.99 (m, 2H), 8.31-8.34 (m, 2H), 8.40-8.41 (d, J = 9.2 Hz, 1H), 8.73-8.75
(d, J = 7.2 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ:51.7, 102.8, 115.4, 121.0 (q, 2JC-F = 36.6
1
Hz, CF3), 121.5, 121.5, 122.1 (q, JC-F = 268.1 Hz, CF3), 125.7, 126.1, 129.1, 130.8, 137.1 137.8,
140.6, 163.3, 187.0 ppm; 19F NMR (470 MHz, CDCl3) δ: -51.3 (s, CF3) ppm. IR (KBr): υ 2956,
1697, 1648, 1514, 1226, 1139, 836, 557 cm-1. MS (DART) m/z (%): 382.0 [(M+H)]+. HRMS
(DART) calcd. for C18H11ClF3NO3 [(M+H)]+: 382.0447; found: 382.0450.
Methyl 3-(4-methylbenzoyl)-2-(trifluoromethyl)indolizine-1-carboxylate 4e: White solid;
1
yield: 93%; m.p.: 121.2-122.0 °C; H NMR (500 MHz, CDCl3) δ: 2.44 (s, 3H), 3.96 (s, 3H),
6.85-6.88 (m, 1H), 7.24-7.29 (m, 3H), 7.73-7.76 (d, J = 8.3 Hz, 2H), 8.29-8.30 (d, J = 7.2 Hz, 1H),
8.35-8.37 (d, J = 9.2 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 21.8, 51.6, 102.8, 102.2, 115.0,
120.7, 121.2 (q, 2JC-F = 36.5 Hz, CF3), 122.2 (q, 1JC-F = 267.9 Hz, CF3), 122.4, 122.4, 125.6, 125.6,
129.5, 129.7, 135.9, 137.5, 145.4, 163.5, 187.9 ppm; 19F NMR (470 MHz, CDCl3) δ: -52.8 (s,
CF3) ppm. IR (KBr): υ 2954, 2134, 1717, 1641, 1515, 1279, 1227, 557 cm-1. MS (DART) m/z
10

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(%): 362.1 [(M+H)]+. HRMS (DART) calcd. for C19H14F3NO3 [(M+H)]+: 362.0994; found:
362.0999.
Methyl 3-(thiophene-3-carbonyl)-2-(trifluoromethyl)indolizine-1-carboxylate 4f: white solid;
yield: 89 %; m.p.: 102.4-103.9 °C; 1H NMR (500 MHz, CDCl3) δ: 3.97 (s, 3H), 6.88-6.91 (m, 1H),
7.14-7.16 (m, 1H), 7.27-7.29 (m, 1H), 7.53-7.54 (m, 1H), 7.81-7.82 (m, 1H), 8.31-8.32 (m, 1H),
8.35-8.37 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3,): δ 51.7, 102.3, 115.1, 119.9 (q, 2JC-F = 36.5
Hz, CF3), 120.7, 122.3 (q, 1JC-F = 268.6 Hz, CF3), 123.4, 125.5, 125.8, 128.5, 135.7, 136.4, 137.4,
145.3, 163.4, 179.9 ppm; 19F NMR (470 MHz, CDCl3) δ: -52.6 (s, CF3) ppm. IR (KBr): υ 2923,
1698, 1636, 1517, 1238, 1135, 727 cm-1. MS (ESI) m/z (%): 354 [(M+H)]+. HRMS (TOF) calcd.
for C16H10F3NO3S [(M+H)]+: 354.0367, found: 354.0413.
Methyl 7-methyl-3-(4-methylbenzoyl)-2-(trifluoromethyl)indolizine-1-carboxylate 4g: white
1
solid; yield: 82%; m.p.: 133.8.4-134.1 °C; H NMR (500 MHz, CDCl3) δ: 2.41 (s, 3H), 2.42 (s,
3H), 3.94 (s, 3H), 6.69-6.70 (d, J = 7.1 Hz, 1H), 7.26-7.27 (d, J = 7.9 Hz, 2H), 7.72-7.74 (d, J =
7.9 Hz, 2H), 8.12 (s, 1H), 8.23-8.24 (d, J = 7.2 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 21.5,
2
1
21.8, 51.5, 100.9, 117.7, 118.7 120.3 (q, JC-F = 36.5 Hz, CF3), 121.9, 121.5, 122.2 (q, JC-F
=
268.3 Hz, CF3), 125.1, 129.4, 129.7, 136.2, 137.2 138.1, 145.2, 163.7, 187.9 ppm; 19F NMR (470
MHz, CDCl3) δ: -52.6 (s, CF3) ppm. IR (KBr): υ 2960, 1710, 1648, 1512, 1228, 1144, 786 cm-1.
MS (DART) m/z (%): 376.1 [(M+H)]+. HRMS (DART) calcd. for C20H16F3NO3 [(M+H)]+:
376.1150; found: 376.1155.
Methyl 3-(4-methoxybenzoyl)-7-methyl-2-(trifluoromethyl)indolizine-1-carboxylate 4h: white
solid; yield: 88%; m.p.: 142.0-143.2 °C; 1H NMR (500 MHz, CDCl3) δ: 2.38 (s, 3H), 3.85 (s, 3H),
3.93 (s, 3H), 6.65-6.67 (m, 1H), 6.91-6.93 (m, 2H), 7.97-7.81 (m, 2H), 8.09-8.14 (m, 2H) ppm;
13C NMR (125 MHz, CDCl3) δ: 21.4, 51.4, 55.5, 100.6, 114.0, 117.6, 118.7, 119.7 (q, 2JC-F = 36.4
Hz, CF3), 122.0, 122.3 (q, 1JC-F = 268.1 Hz, CF3), 124.9, 129.4, 131.4, 132.0, 137.0, 137.9, 163.7,
164.5, 186.7 ppm; 19F NMR (470 MHz, CDCl3) δ: -52.9 (s, CF3) ppm. IR (KBr): υ 2955, 1705,
1651, 1599, 1510, 1263, 1147, 615 cm-1. MS (DART) m/z (%): 392.1 [M+H]+. HRMS (DART)
calcd. for C20H16F3NO4 [(M+H)]+: 392.1099; found: 392.1104.
11

ACCEPTED MANUSCRIPT
Methyl 7-methyl-3-(4-nitrobenzoyl)-2-(trifluoromethyl)indolizine-1-carboxylate 4i: white
1
solid; yield: 80%; H NMR (500 MHz, CDCl3) δ: 2.46 (s, 3H), 3.95 (s, 3H), 6.85-6.87 (m, 1H),
7.94-7.96 (d, J = 8.6 Hz, 2H), 8.16 (s, 1H), 8.29-8.31 (d, J = 8.6 Hz, 2H), 8.68-8.70 (d, J = 7.2 Hz,
1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 21.5, 51.8, 102.7, 118.8, 118.9, 120.3, 121.9 (q, 1JC-F
=
2
268.8 Hz, CF3), 122.6 (q, JC-F = 36.5 Hz, CF3), 123.7, 125.6, 130.1, 138.8, 144.5, 150.4, 163.3,
186.0 ppm; 19F NMR (470 MHz, CDCl3) δ: -51.1 (s, CF3) ppm. IR (KBr): υ 2921, 2354, 1709,
1666, 1528, 1383, 1220, 577 cm-1. MS (DART) m/z (%): 407.1 [(M+H)]+. HRMS (DART) calcd.
for C19H13F3N2O5 [(M+H)]+: 407.0844; found: 407.0849.
Methyl 3-benzoyl-7-methyl-2-(trifluoromethyl)indolizine-1-carboxylate 4j: white solid; yield:
1
85%; m.p.: 110.2-111.4 °C; H NMR (500 MHz, CDCl3) δ: 2.43 (s, 3H), 3.95 (s, 3H), 6.72-6.74
(m, 1H), 7.46-7.49 (m, 2H), 7.60-7.63 (m, 1H), 7.82-7.84 (m, 2H), 8.13 (s, 1H) 8.33-8.34 (d, J =
7.2 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 21.5, 51.6, 101.2, 117.9, 118.8, 120.9 (q, 2JC-F
=
1
36.4 Hz, CF3), 121.6, 122.2 (q, JC-F = 268.1 Hz, CF3), 125.2, 128.7, 129.5, 133.9, 137.4, 138.2,
138.8, 163.6, 188.3 ppm; 19F NMR (470 MHz, CDCl3) δ: -52.4 (s, CF3) ppm. IR (KBr): υ 2952,
1693, 1638, 1511, 1219, 1147, 698 cm-1. MS (DART) m/z (%): 362.1 [(M+H)]+. HRMS (DART)
calcd. for C19H14F3NO3 [(M+H)]+: 362.0994; found: 362.0999.
Methyl 3-benzoyl-2-(pentafluoroethyl)indolizine-1-carboxylate 4k: white solid; yield: 80%;
m.p.: 88.5-88.8 °C; 1H NMR (500 MHz, CDCl3) δ: 3.93 (s, 3H), 6.74-6.78 (m, 1H), 7.16-7.20 (m,
1H), 7.45-7.48 (m, 2H), 7.61-7.64 (m, 1H), 7.74-7.77 (m, 3H), 8.33-8.35 (m, 1H) ppm; 13C NMR
(125 MHz, CDCl3) δ: 51.5, 103.0, 113.0 (m, CF2), 114.8, 116.7 (t, 2JC-F = 26.8 Hz, CF2), 119.1 (qt,
2
1JC-F = 286.0 Hz, JC-F = 38.2 Hz, CF3), 120.9, 124.5, 124.7, 129.0, 129.6, 134.7, 137.0, 137.2,
163.4, 188.8 ppm; 19F NMR (470 MHz, CDCl3) δ: -101.1 (s, CF2), -81.7 (s, CF3) ppm. IR (KBr): υ
2957, 1695, 1665, 1515, 1236, 1191, 742 cm-1. MS (DART) m/z (%): 398.1 [(M+H)]+. HRMS
(DART) calcd. for C19H12F5NO3 [(M+H)]+: 398.0804; found: 398.0626.
Methyl 3-benzoyl-2-(heptafluoropropyl)indolizine-1-carboxylate 4l: white solid; yield: 72%;
1
m.p.: 101.2-102.6 °C; H NMR (500 MHz, CDCl3) δ: 3.92 (s, 3H), 6.75-6.77 (m, 1H), 7.17-7.20
(m, 1H), 7.45-7.48 (m, 2H), 7.61-7.64 (m, 1H), 7.70-7.72 d, J = 7.2, 1H), 7.76-7.77 (d, J = 7.6,
2H), 8.36-8.38(d, J = 9.4, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 51.4, 103.2, 109.0 (m, CF2),
114.8, 115.2 (m, CF3), 116.3 (m, CF2), 119.2 (t, 2JC-F = 34.1 Hz, CF2), 120.5, 121.0, 124.4, 124.7,
12

ACCEPTED MANUSCRIPT
129.1, 129.7, 134.7, 136.9, 137.3, 163.4, 188.8 ppm; 19F NMR (470 MHz, CDCl3) δ: -122.1 (t, J =
7.6, CF2), -98.3 (m, CF2), -80.5 (t, J = 10.3 Hz, CF3) ppm. IR (KBr): υ 2922, 1711, 1665, 1511,
1261, 1227, 742 cm-1. MS (DART) m/z (%): 448.1 [(M+H)]+. HRMS (DART) calcd. for
C20H12F7NO3 [(M+H)]+: 448.0772; found: 448.0778.
Dimethyl 3-benzoyl-2-(trifluoromethyl)indolizine-1,7-dicarboxylate 4m: white solid; yield:
1
98%; m.p.: 145.6-146.2 °C; H NMR (500 MHz, CDCl3) δ: 3.95 (s, 3H), 3.97 (s, 3H), 7.37-7.39
(m, 1H), 7.46-7.49 (m, 2H), 7.61-7.64 (m, 1H), 7.80-7.82 (m, 2H), 8.26-8.28 (m, 1H), 8.98-8.99
(m, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 52.0, 52.7, 105.9, 113.9, 121.2 (q, 2JC-F = 37.1 Hz,
1
CF3), 121.8 (q, JC-F = 268.6 Hz, CF3), 123.4, 123.5, 125.0, 125.2, 126.7, 128.9, 129.5, 134.5,
135.7, 137.9 162.7, 164.9, 187.9 ppm; 19F NMR (470 MHz, CDCl3) δ: -52.93 (s, CF3) ppm; IR
(KBr): υ 2958, 1725, 1648, 1509, 1448, 1316, 1217, 1445, 662 cm-1; MS (DART) m/z (%): 406.1
[(M+H)]+. HRMS (DART) calcd. for C20H14F3NO5 [(M+H)]+: 406.0891; found: 406.0897.
Dimethyl 3-(4-methoxybenzoyl)-2-(trifluoromethyl)indolizine-1,7-dicarboxylate 4n: white
solid; yield: 94%; m.p.: 161.7-162.1 °C; 1H NMR (500 MHz, CDCl3) δ: 3.86 (s, 3H), 3.95 (s, 3H),
3.98 (s, 3H), 6.93-6.95 (d, J = 8.9 Hz, 2H), 7.34-7.36 (m, 1H), 7.79-7.81 (d, J = 8.8 Hz, 2H),
8.13-8.15 (d, J = 7.5 Hz, 1H), 9.00 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 51.9, 52.7, 55.6,
105.5, 113.7, 114.3, 120.4 (q, 2JC-F = 36.7 Hz, CF3), 121.9 (q, 1JC-F = 268.6 Hz, CF3), 123.5, 124.0,
125.0, 126.4, 130.5, 132.2, 135.5, 162.9, 164.9, 165.0, 186.2 ppm; 19F NMR (470 MHz, CDCl3) δ:
-53.4 (s, CF3) ppm. IR (KBr): υ 2958, 1724, 1599, 1507, 1259, 1217, 1171, 616 cm-1. MS (DART)
m/z (%): 436.1 [(M+H)]+. HRMS (DART) calcd. for C21H16F3NO6[(M+H)]+: 436.0996; found:
436.1002.
Dimethyl 3-(4-nitrobenzoyl)-2-(trifluoromethyl)indolizine-1,7-dicarboxylate 4o: white solid;
1
yield: 95%; m.p.: 132.0-133.6 °C; H NMR (500 MHz, CDCl3) δ: 3.99 (s, 3H), 4.00 (s, 3H),
7.51-7.53 (m, 1H), 7.97-8.00 (m, 2H), 8.32-8.34 (m, 2H), 8.60-8.62 (m, 1H), 9.03-9.04 (m, 1H)
1
ppm; 13C NMR (125 MHz, CDCl3) δ: 52.2, 52.9, 106.9, 114.8, 121.6 (q, JC-F = 268.9 Hz, CF3),
2
122.0, 122.7 (q, JC-F = 36.9 Hz, CF3), 123.2, 123.9, 125.6, 127.8, 130.2, 136.5, 143.3, 150.7,
162.5, 164.7, 186.1 ppm; 19F NMR (470 MHz, CDCl3) δ: -51.7 (s, CF3) ppm. IR (KBr): υ 2957,
1727, 1639, 1529, 1310, 1218, 564 cm-1. MS (ESI) m/z (%): 473.3 [(M+H)]+. HRMS (ESI) calcd.
for C20H12F3N2O7[(M+H)]+: 473.0582; found: 473.0567.
13

ACCEPTED MANUSCRIPT
Dimethyl 3-benzoyl-2-(heptafluoropropyl)indolizine-1,7-dicarboxylate 4p: white solid; yield:
80%; m.p.: 111.10-112.6 °C; 1H NMR (500 MHz, CDCl3) δ: 3.94 (s, 3H), 3.95 (s, 3H), 7.29-7.31
(m, 1H), 7.46-7.49 (t, J = 7.7 Hz, 2H), 7.63-7.66 (t, J = 7.1 Hz, 1H), 7.70-7.76 (m, 3H), 9.04 (s,
1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 51.8, 52.7, 107.0, 111.0 (m, CF2), 113.7, 114.9 (m,
CF2), 118.0 (m, CF3), 117.4 (t, 2JC-F = 27.7 Hz, CF2), 123.9, 124.0, 125.8, 125.8, 125.9, 129.2,
129.6, 135.0, 135.4, 136.5, 162.9, 165.0, 188.1 ppm; 19F NMR (470 MHz, CDCl3) δ: -122.2 (t, J =
8.7 Hz, CF2), -98.7 (m, CF2), -80.5 (t, J = 9.8 Hz, CF3) ppm. IR (KBr): υ 2959, 1729, 1658, 1448,
1243, 1110, 558 cm-1. MS (ESI) m/z (%): 528.1 [(M+H)]+. HRMS (ESI) calcd. for
C22H13F7NO5[(M+H)]+: 528.0664; found: 528.0652.
Dimethyl 3-(4-nitrobenzoyl)-2-(heptafluoropropyl)indolizine-1,7-dicarboxylate 4q: white
1
solid; yield: 79%; m.p.: 152.7-153.9 °C; H NMR (500 MHz,CDCl3) δ: 3.95(s, 3H), 3.95(s, 3H),
7.37-7.39 (m, 1H), 7.85-7.86 (d, J = 7.2 Hz, 1H), 7.92-7.94 (d, J = 8.7 Hz, 2H), 8.30-8.31 (d, J =
8.7 Hz, 2H), 9.04(s, 1H) ppm; 13C NMR (125 MHz, CDCl3) δ: 51.9, 52.8, 107.6, 114.3, 115.9 (m,
CF2), 116.7 (m, CF2), 108.8 (m, CF3), 118.1 (t, 2JC-F = 27.5 Hz, CF2), 123.9, 124.1, 124.2, 126.5,
130.5, 136.0, 141.4, 151.1, 162.6, 164.7, 187.0 ppm;19F NMR (470 MHz, CDCl3) δ: -122.1 (t, J =
9.0 Hz, CF2), -98.2 (m, CF2), -80.5 (t, J = 10.1 Hz, CF3) ppm; IR (KBr): υ 2956, 1726, 1697, 1527,
1348, 1218, 743 cm-1. MS (ESI) m/z (%): 573.1 [(M+H)]+. HRMS (ESI) calcd. for C22H12F7N2O7
[(M+H)]+: 573.0513; found: 573.0503.
Methyl 3-(2-nitrobenzoyl)-2-(trifluoromethyl)indolizine-1-carboxylate 4r: yellow solid; yield:
1
74 %; m.p.: 178.0-178.8 °C; H NMR (500 MHz, CDCl3) δ: 3.95 (s, 3H), 6.99-7.02 (m, 1H),
7.35-7.38 (m, 1H), 7.67-7.70 (m, 1H), 8.12-8.14 (m, 1H), 8.37-8.39 (m, 1H), 8.43-8.45 (m, 1H),
8.63-8.64 (m, 1H), 8.67-8.69 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3,): δ 52.1, 116.8, 120.2,
121.6 (q, 1JC-F = 269.2 Hz, CF3), 122.5 (q, 2JC-F =37.2 Hz, CF3), 124.6, 127.5, 127.7, 130.6, 131.9,
133.4, 136.5, 138.0, 147.9, 163.3, 184.2 ppm; 19F NMR (470 MHz, CDCl3) δ: -51.5 (s, CF3) ppm.
IR (KBr): υ 2919, 1720, 1640, 1514, 1214, 702 cm-1. MS (ESI) m/z (%): 393.1 [(M+H)]+. HRMS
(TOF) calcd. for C18H11F3N2O5 [(M+H)]+: 393.0705, found: 393.0696.
Methyl 3-(2-methylbenzoyl)-2-(trifluoromethyl)indolizine-1-carboxylate 4s: white solid;
1
yield: 80 %; m.p.: 119.2-120.0 °C; H NMR (500 MHz, CDCl3) δ: 2.58 (s, 3H), 3.94 (s, 3H),
6.92-6.95 (m, 1H), 7.17-7.20 (m, 1H), 7.29-7.30 (m, 1H), 7.30-7.31 (m, 1H), 7.31-7.33 (m, 1H),
14

ACCEPTED MANUSCRIPT
7.41-7.44 (m, 1H), 8.33-8.35 (m, 1H), 8.65-8.67 (m, 1H) ppm; 13C NMR (125 MHz, CDCl3,): δ
2
1
20.7, 51.8, 115.6, 118.9, 121.3 (q, JC-F = 36.7 Hz, CF3), 122.1 (q, JC-F = 268.7 Hz, CF3), 125.6,
126.1, 126.2, 130.8, 131.9, 132.5, 137.6, 138.9, 139.5, 163.6, 189.8 ppm; 19F NMR (470 MHz,
CDCl3) δ: -52.6 (s, CF3) ppm. IR (KBr): υ 2922, 1720, 1637, 1510, 1220, 745 cm-1. MS (ESI) m/z
(%): 362.1 [(M+H)]+. HRMS (TOF) calcd. for C19H14F3NO3 [(M+H)]+: 362.1005, found:
362.0999.
Methyl 3-benzoyl-6-bromo-2-(trifluoromethyl)indolizine-1-carboxylate 4t: white solid; yield:
1
65 %; m.p.: 128.0-129.2 °C; H NMR (500 MHz, CDCl3) δ: 3.97 (s, 3H), 6.70-6.73 (m, 1H),
7.40-7.41 (m, 1H), 7.47-7.50 (m, 2H), 7.62-7.65 (m, 1H), 7.79-7.81 (m, 2H), 8.59-8.61 (m, 1H)
2
ppm; 13C NMR (125 MHz, CDCl3,): δ 53.1, 108.9, 112.6, 114.6, 120.7 (q, JC-F = 36.6 Hz, CF3),
1
122.0 (q, JC-F = 268.8 Hz, CF3), 125.4, 128.3, 128.7, 129.7, 130.8, 134.1, 138.7, 138.6, 164.8,
187.5 ppm; 19F NMR (470 MHz, CDCl3) δ: -52.2 (s, CF3) ppm. IR (KBr): υ 2927, 1726, 1639,
1505, 1241, 696 cm-1. MS (ESI) m/z (%): 425.0 [(M+H)]+. HRMS (TOF) calcd. for
C18H11F3NBrO3 [(M+H)]+: 425.9957, found: 425.9951.
Methyl 3-benzoyl-6-methyl-2-(trifluoromethyl)indolizine-1-carboxylate 4u: white solid; yield:
66 %; m.p.: 112.2-113.1 °C; 1H NMR (500 MHz, CDCl3) δ: 2.26 (s, 3H), 3.93 (s, 3H), 6.75-6.78
(m, 1H), 7.11-7.13 (m, 1H), 7.58-7.63 (m, 2H), 7.80-7.82 (m, 2H), 7.24-7.25 (m, 1H), 8.48-8.49
(m, 1H) ppm; 13C NMR (125 MHz, CDCl3,): δ 19.8, 51.6, 114.9, 119.1, 120.6 (q, 2JC-F = 36.4 Hz,
1
CF3), 122.3 (q, JC-F = 268.6 Hz, CF3), 123.2, 124.1, 125.4, 125.5, 128.6, 128.8, 129.5, 133.7,
134.1, 136.5, 139.1, 165.4, 187.8 ppm; 19F NMR (470 MHz, CDCl3) δ: -52.4 (s, CF3) ppm. IR
(KBr): υ 2921, 1731, 1638, 1505, 1245, 694 cm-1. MS (ESI) m/z (%): 362.1 [(M+H)]+. HRMS
(TOF) calcd. for C19H14F3NO3 [(M+H)]+: 362.1010, found: 362.1004.
Acknowledgementsc
The authors are grateful to the National Natural Science Foundation of China (Grant Nos.
21672138, 21542005, 21272152), Yang Fan Program of Science and Technology Commission of
Shanghai Municipality (Grant No. 15YF1404200) and Shanghai Municipal Education
Commission (Peak Discipline Construction Program) for their financial support.
15

ACCEPTED MANUSCRIPT
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