Synthesis of fluorinated 3-pyrrolines and pyrroles via [3?+?2] annulation of N-aryl fluorinated imines with allenoates catalyzed by phosphine

Article abstract of DOI:10.1016/j.jfluchem.2016.12.010

A phosphine-catalyzed [3?+?2] annulation of N-aryl fluorinated imines with allenoates is reported. A series of fluorinated pyrrolines is obtained in moderate yield, which are further transformed to fluorinated pyrroles via dehydro-aromatization by DDQ in high to excellent yield. The reaction mechanism is also discussed.

Full text of DOI:10.1016/j.jfluchem.2016.12.010

Accepted Manuscript
Title: Synthesis of Fluorinated 3-Pyrrolines and Pyrroles via
[3 + 2] Annulation of N-aryl Fluorinated Imines with
Allenoates Catalyzed by Phosphine
Author: Zhentong Zhu Yuwei Guo Xiaojun Wang Fanhong
Wu Yongming Wu
PII:
S0022-1139(16)30373-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2016.12.010
FLUOR 8918
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FLUOR
Received date:
Revised date:
Accepted date:
10-10-2016
14-12-2016
19-12-2016
Please cite this article as: Zhentong Zhu, Yuwei Guo, Xiaojun Wang, Fanhong Wu,
Yongming Wu, Synthesis of Fluorinated 3-Pyrrolines and Pyrroles via [3+2] Annulation
of N-aryl Fluorinated Imines with Allenoates Catalyzed by Phosphine, Journal of
Fluorine Chemistry http://dx.doi.org/10.1016/j.jfluchem.2016.12.010
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Synthesis of Fluorinated 3-Pyrrolines and Pyrroles via [3+2] Annulation of N-aryl
Fluorinated Imines with Allenoates Catalyzed by Phosphine
Zhentong Zhua,b, Yuwei Guob,c, Xiaojun Wangb,c, Fanhong Wua,* and Yongming Wub,†
a School of Chemical and Environmental Engineering, Shanghai Institute of
Technology, 100 Haiquan Road, Shanghai 201418, China.
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, 345 Lingling Road, Shanghai 200032, China.
c Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444,
China.
* Corresponding author. Tel.: +86 21 60877230; E-mail address: wfh@sit.edu.cn
† Corresponding author. Tel.: +86 21 54925190; fax: +86 21 64166128. E-mail address:
ymwu@sioc.ac.cn
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Graphical Abstract
R1
R1
N
R1
H
DDQ (2 equiv)
toluene, 100 oC
PCy3(20 mol%)
toluene, 60 oC
+
N
CO2R2
RF
RF
N
RF
H
CO2R2
CO2R2
1
2
3
5
RF=CF3,CF2Br,CF2Cl
20-82%
87-98%
A phosphine-catalyzed [3+2] annulation of N-aryl fluorinated imines with allenoates is
reported. A series of fluorinated pyrrolines are obtained in moderate yield, which are
further transformed to fluorinated pyrroles via dehydro-aromatization by DDQ in high
to excellent yield.
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Highlights
A phosphine-catalyzed [3+2] annulation of N-aryl fluorinated imines with allenoates
is reported. A series of fluorinated pyrrolines are obtained in moderate yield.
which are further transformed to fluorinated pyrroles via dehydro-aromatization by
DDQ in high to excellent yield.
The reaction mechanism is also discussed.
3

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Abstract
A phosphine-catalyzed [3+2] annulation of N-aryl fluorinated imines with allenoates
is reported. A series of fluorinated pyrrolines are obtained in moderate yield, which are
further transformed to fluorinated pyrroles via dehydro-aromatization by DDQ in high
to excellent yield. The reaction mechanism is also discussed.
Keywords: fluorinated pyrrole; fluorinated 3-pyrroline; N-aryl fluorinated imines;
allenoates; [3+2] annulation
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1. Introduction
Pyrrolines, pyrroles and their derivatives represent an important class of heterocycles,
which are often presented in nature products and therapeutic compounds [1]. Because of
their biological properties, many of them have diverse applications such as: cholesterol
reducing and anti-inflammatory drugs, etc. [2]. It has been demonstrated that the
incorporation of fluorine or fluorinated groups into organic molecules could
dramatically alters their chemical and biological properties [3]. An indirect method
using fluorinated building blocks plays a significant role in synthesizing fluorinated
heterocycles, which has been extensively applied for the synthesis of some drugs and
inhibitors [4]. Recently, several research groups have reported methods for the synthesis
of fluorinated pyrroline and pyrroles [5-7]. For instance, Rutjes and co-workers
described a series of Ru-catalyzed ring-closing metathesis to form pyrroles and 3-
pyrrolines [5]. Liu’s group explored the silver-catalyzed intramolecular oxidative
aminofluorination of allenes [6]. Marquez and co-workers have successfully synthesized
the fluorinated 3-pyrrolines by the treatment of Grubbs 2nd generation catalyst and diene
[7]. However, the majority of these studies are too much dependent on transition-metal-
catalysis. Since Lu’s pioneer report of phosphine-catalyzed [3+2] cycloaddition of
allenoates and activated alkenes or imines[8], nucleophilic phosphine organocatalysis
has become a powerful tool for the construction of carbocycles or heterocycles. .
Particularly in heterocycles, it continues to attract great interest for researchers in
expanding its scope[9]. Herein, we report a metal-free and facile synthesis of N-aryl-2-
fluorinated-pyrrolines or pyrroles utilizing Lu’s [3+2] cycloaddition reaction.
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2. Results and discussion
Initially, we choose the allonate 2a and N-aryl trifluoroethylimine 1a, which was
obtained by the condensation of the commercial trifluoroacetaldehyde ethyl hemiacetal
with arylamine, as the model substrates to optimize the reaction condition. A couple of
phosphines have been screened at room temperature in toluene. As shown in Table 1,
phosphines, with relatively low catalytic activity, could generate anticipative products
3a in moderate yield with incomplete conversion of 1a (Table 1, entries 1-2, 5-7). Tri(2-
furyl)phosphine couldn’t promote the forming of desired product 3a as observed in
19FNMR (Table 1, entry 8), but a small amount of by-product 4a is formed
unexpectedly. Based on Ma’s research, we suspect that it is a sequential 3+2/3+2
annulation of two equivalent allenes with imines[10]. Crystal structure of 4a
demonstrates that it is a fluorinated compound of five-membered carbon ring with an
exocyclic double bond in only one configuration and the molecular weight is the same
as the construction we speculated (S.I. Figure 1). Although application of high-
performance phosphine catalyst could result in a good conversion, but the yield is low
(Table 1, entries 3-4). Particularly in the presence of PBu3, the impurities are difficult to
separate. Based on the results mentioned above, PCy3 was found to be the best suitable
catalyst for this reaction. Studies of the effects of different temperatures for this reaction
indicated that lower temperature of the reaction resulted in good conversion but in a
relatively low yield (Table 1, entries 9-11), and high temperature was beneficial to the
reaction and more 2a is required as the temperature increases (Table 1, entries 12-13).
Changes of the reaction solvent did not have a significant effect on the yield of 3a
(Table 1, entries 14-16), use of DMF or MeCN as solvent only resulted in a plenty of
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impurities under the same condition. Therefore, the optimization conditions were
ascertained as PCy3 (20 mol%) in toluene at 60oC.
Table 1 Optimization of the conditions
Br
Br
Br
H
PR3(20 mol%)
+
HN CF3
CO2Bn
+
N
N
CO2Bn
CF3
F3C
H
CO2Bn
CO2Bn
1a
2a
3a
4a
Yield(%)b
Entry
Cat.
PCy3
PPh3
PBu3
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
1,4-dioxane
p-xylene
THF
Temp.(oC) Time Conv.(1a, %)a
3a
50
48
-
4a
12
9
1
2
3
4
5
6
7
8
9
10
11
12c
13d
14d
15d
16d
17d
18d
rt
rt
rt
rt
rt
rt
rt
rt
10
0
-10
30
60
60
60
60
60
60
24h
24h
5h
81
75
100
100
65
77
64
0
82
-
PMe2Ph
PPh2Me
PCy2Ph
PPh2Cy
P(2-furyl)3
PCy3
5h
19 trace
24h
24h
24h
24h
24h
24h
24h
5h
5h
5h
5h
5h
40
43
42
-
10
13
16
-
37
34
13
14
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
96
92
22 trace
60 14
82 trace
68 trace
67 trace
72 trace
100
100
100
100
100
100
100
MeCN
DMF
5h
5h
-
-
-
-
PCy3
a Unless otherwise mentioned, reactions were performed with N-aryl trifluoroethylimine
1a (0.2 mmol), allenoate 2a (0.22 mmol), solvent (2ml).
b Isolated yield caculated on the basis of N-aryl trifluoroethylimine.
c 1.7 equiv of 2a were used
d 2.0 equiv of 2a were used.
Following the optimized reaction conditions, the scope of this methodology was further
explored. As shown in Table 2, several substrates could be tolerated under the
optimized conditions. Electron-withdraw substituents on the benzene ring of the imine
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such as bromo, chloro, iodo and trifluoromethyl could provide 3 in moderate to high
yields (Table 2, entries 1-4). Meanwhile, electron-donating groups on the benzene ring
of the imine sharply decreased the yields and leave a plenty of imines under the reaction
system. The replacement of a fluorinated group with a chlrorodifluoromethyl group
resulted in a moderate to high yield with a prolonged reaction time (Table 2, entries 7-8).
Utilizing a bromodifluoromethyl group as the fluorinated group could only produce a
relatively low yield because of the activity of the imine and the steric hindrance of the
bromineand require more reaction time (Table 2, entries 5-6). The substrates on the
ester group of allenoates such as methyl, ethyl, and tert-butyl also proceeded in good
yield (Table 2, entries 11-13).
Table 2 Phosphine-catalyzed [3+2] annulation of fluorinated imine 1 and allenoates 2
R1
R1
H
PCy3(20 mol%)
toluene, 60oC
+
N
CO2R2
N
RF
RF
H
CO2R2
1
2
3
Entry
1
1(R1,RF)
1a(Br, CF3)
1b(Cl, CF3)
1c(I, CF3)
1d(CF3, CF3)
1e(Br, CF2Br)
1f(Br, CF2Br)
1g(Br, CF2Cl)
1h(Br, CF2Cl)
1i(Br, CF3)
2(R2)
Bn
Bn
Bn
Bn
Bn
Et
Bn
Et
t-Bu
Et
Me
Time(h)
Yield(%)a
5h
5h
5h
3a, 82
3b, 73
3c, 63
3d, 73
3e, 20
3f, 31
3g, 62
3h, 75
3i, 72
3j, 75
3k, 70
2
3
4
5h
5
24h
24h
12h
12h
5h
6b
7
8b
9b
10b
11b
1j(Br, CF3)
1k(Br, CF3)
5h
5h
a isolated yield
b 1.7 equiv of 2 were used
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3-pyrrolines can also be used as significant precursor for the synthesis of pyrroles[11].
After investigation of some conditions, the presence of DDQ in 100oC was selected as
the best condition in dehydro-aromatization of some pyrrolines 3, which offered high to
excellent yield of pyrroles 5 (Table 3, entries 1-9). The structure of 5i was confirmed by
X-ray crystal diffraction studies (Figure 1).
Table 3 Synthesis of N-aryl pyrroles
R1
R1
DDQ (2eq)
toluene, 100oC
N
N
RF
RF
CO2R2
CO2R3
3
5
Entry
3(R1,R2,RF)
3a(Br, Bn, CF3)
3b(Cl, Bn, CF3)
3c(I, Bn, CF3)
3d(CF3, Bn, CF3)
3g(Br, Bn, CF2Cl)
3h(Br, Et, CF2Cl)
3i(Br, t-Bu, CF3)
3j(Br, Et, CF3)
Time
7h
7h
Yield(%)a
5a, 98
5b, 90
5c, 94
5d, 92
5g, 90
5h, 87
5i, 98
1
2
3
4
5
6
7
8
7h
12h
12h
7h
7h
7h
5j, 95
9
3k(Br, Me, CF3)
7h
5k, 96
a isolated yield
Figure 1 Crystal structure of 5i
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A plausible mechanism has been proposed from the Lu’s [3+2] cycloaddition reaction
and the strength of analogue products in Yu’s study [8][12]. Initially, allenoate 2a in
presence of the phosphine catalyst generates a zwitterionic intermediate A which
behaves as a 1,3-dipole and undergoes a [3+2] cycloaddition with 1a to give a
phophorus ylieded intermediate B. After a proton shift it generates another zwitterionic
C, and then eliminates the phosphine give rise to the desire product 3a.
PCy3
2a
3a
Br
CO2Bn
PCy3
N
CF3
CO2Bn
A
H
Cy3P
Br
N
C
1a
H-shift
CF3
H
Cy3P
CO2Bn
B
Scheme 1 A plausible mechanism for formation of 3a
3. Conclusion
In conclusion, we have reported a phosphine-catalyzed [3+2] annulation reaction of
fluorinated imines with electron deficient allenoates. The electron-withdraw substituents
on the benzene ring of the imines are beneficial to the annulation. Finally, an efficient
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dehydro-aromatization can be used to synthesize N-aryl pyrroles via DDQ with a high
to excellent yield.
4. Experimental
4.1 General Information
Unless otherwise stated, all reactions were run in an oven-dried Schlenk tube and
1
magnetic stirring under an atmosphere of nitrogen. H NMR spectra were recorded in
CDCl3 on an Agilent NMR 400 spectrometer (400 MHz) with TMS as internal
standard.13C NMR spectra were taken on a Bruker AM-400 (101 MHz) spectrometer or
19
an Aglilent 400 spectrometer (101 MHz). F NMR spectra were taken on an Agilent
400 spectrometer (376 MHz). IR spectra were obtained with a Nicolet AV-360
spectrophotometer. Mass spectra were recorded on Finnigan MAT-8430 mass
spectrometer. Solvents were purchased from commercial sources and purified before
used by standard procedures. TLC analysis was performed on silica gel plates, column
chromatography over silica gel (mesh 300-400) and petroleum ether/ethyl acetate or n-
hexane/dichloromethane combination were used as the eluent.
4.2 General procedure for 1 synthesis
For example the procedure for 1c synthesis: The a solution of 1-ethoxy-2,2,2-
trifluoroethanol (7.2g, 50mmol), 4-iodoaniline (9.9g, 45mmol) and catalytic amount of
p-toluene sulfonic acid (20mg) in toluene (30 mL) was added, then the mixture was
heated at 130oC and refluxed for 4h. After completion of reaction as indicated by TLC,
the mixture was concentrated in vacuo. Then vacuum distillation to provide the desire
product 1c.
4.2.1 (E)-2,2,2-trifluoro-N-(4-iodophenyl)ethan-1-imine (1c)
White solid, mp: 95-97 oC, bp: 37-39 oC, 20 pa; 1H NMR (400 MHz, CDCl3) δ 7.79 (q,
J = 3.4 Hz, 1H), 7.73 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H); 13C NMR (101 MHz,
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CDCl3) δ 147.70 (q, J = 39.1 Hz), 147.05 (s), 138.61 (s), 122.88 (s), 118.97 (q, J =
274.5 Hz), 93.91 (s); 19F NMR (376 MHz, CDCl3) δ -71.20 (d, J = 3.4 Hz); IR (film,cm-
1): ν 2912, 1665, 1589, 1479, 1359, 1281, 1139, 1006, 886, 818; HRMS (EI) calcd. For
C8H5NF3I: 298.9419; Found: 298.9422.
4.2.2 (E)-2-bromo-N-(4-bromophenyl)-2,2-difluoroethan-1-imine (1e)
o
1
Yellow liquid, bp: 40-42 C, 20 pa; H NMR (400 MHz, CDCl3) δ 7.82 (t, J = 5.2 Hz,
1H), 7.55 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ
19
151.70 (t, J = 28.7 Hz), 146.07, 132.66, 122.91, 122.38, 115.26 (t, J = 304.8 Hz); F
NMR (376 MHz, CDCl3) δ -56.47 (d, J = 5.2 Hz); IR (film,cm-1): ν 2922, 1655, 1582,
1484, 1339, 1240, 1121, 967, 861, 758; HRMS (EI) calcd. For C8H5NF2Br2: 310.8757,
Found: 310.8756.
4.2.3 (E)-N-(4-bromophenyl)-2-chloro-2,2-difluoroethan-1-imine (1g)
Colorless liquid, bp: 34-36 oC, 20 pa; 1H NMR (400 MHz, CDCl3) δ 7.85 (t, J = 4.5 Hz,
1H), 7.55 (d, J = 8.7 Hz, 2H), 7.11 (d, J = 8.6 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ
19
150.83 (t, J = 32.1 Hz), 146.28, 132.67, 122.87, 122.38, 122,17 (t, J = 290.6 Hz); F
NMR (376 MHz, CDCl3) δ -59.98 (d, J = 4.4 Hz); IR (film,cm-1): ν 2920, 1660, 1583,
1484, 1340, 1244, 1071, 984, 827, 775; HRMS (EI) calcd. For C8H5NF2ClBr: 226.9262,
Found: 266.9260.
4.3 General procedure for 3 synthesis
For example the procedure for 3a synthesis: In a nitrogen-filled box, a schlenk tube was
charged with tricyclohexylphosphine (11.2 mg, 0.04 mmol). Then toluene (2.0 mL),
imine (50.4 mg, 0.2 mmol) and 2,3-alleonate (69.6 mg, 0.4 mmol) was added
successively and stirred at 60oC for 5h. After completion of reaction as indicated by
TLC, the mixture was concentrated in vacuo. The residue was purified by column
chromatography on silica (combined solvent ethyl acetate and petrol ether as eluent to
provide the desire product 3a.
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4.3.1
benzyl
1-(4-bromophenyl)-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-
carboxylate (3a)
1
Yellow liquid; H NMR (400 MHz, CDCl3) δ 7.41-7.35 (m, 5H), 7.34 (d, J = 9.0 Hz,
2H), 7.21 (s, 1H), 6.61 (d, J = 8.9 Hz, 2H), 5.40 (p, J = 5.1 Hz, 1H), 5.32 – 5.21 (m, 2H),
13
4.46 (ddd, J = 17.3, 5.6, 1.7 Hz, 1H), 4.21 (d, J = 17.2 Hz, 1H); C NMR (101 MHz,
CDCl3) δ 161.52 (s), 144.79 (s), 143.32 (s), 135.22 (s), 132.00 (s), 129.59 (d, J = 1.6
Hz), 128.68 (s), 128.57 (s), 128.43(s), 124.98 (q, J = 286.8 Hz), 113.98 (d, J = 0.9 Hz),
110.49 (s), 67.14 (s), 64.39 (q, J = 32.3 Hz), 56.77 (s); 19F NMR (376 MHz, CDCl3) δ -
72.54 (d, J = 4.9 Hz); IR (film,cm-1): ν 2851, 1725, 1594, 1496, 1370, 1255, 1135, 1098,
808, 749; HRMS (EI) calcd. For C19H15NO2F3Br: 425.0238; Found: 425.0240.
4.3.2
benzyl
1-(4-chlorophenyl)-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-
carboxylate (3b)
Yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.41 – 7.34 (m, 5H), 7.21 (s, 1H), 7.20 (d,
J = 9.1 Hz, 2H), 6.64 (d, J = 9.0 Hz, 2H), 5.40 (p, J = 5.1 Hz, 1H), 5.31 – 5.12 (m, 2H),
13
4.45 (ddd, J = 17.3, 5.6, 1.7 Hz, 1H), 4.20 (d, J = 17.3 Hz, 1H); C NMR (101 MHz,
CDCl3) δ 161.54 (s), 144.38 (s), 143.37 (s), 135.25 (s), 129.59 (d, J = 1.6 Hz), 129.13
(s), 128.68 (s), 128.57 (s), 128.43 (s), 125.02 (q, J = 286.8 Hz), 123.33 (s), 113.49 (d, J
= 0.7 Hz), 67.13 (s), 64.45 (q, J = 32.3 Hz), 56.84 (s); 19F NMR (376 MHz, CDCl3) δ -
72.57 (d, J = 4.8 Hz); IR (film,cm-1): ν 2846, 1726, 1600, 1499, 1369, 1258, 1135,
1091, 811, 749; HRMS (EI) calcd. For C19H15NO2F3Cl: 381.0743; Found: 381.0745.
4.3.3
benzyl
1-(4-iodophenyl)-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-
carboxylate (3c)
Yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 9.0 Hz, 2H), 7.40 – 7.33 (m,
5H), 7.20 (s, 1H), 6.50 (d, J = 8.9 Hz, 2H), 5.39 (p, J = 5.1 Hz, 1H), 5.30 – 5.21 (m, 2H),
13
4.44 (ddd, J = 17.3, 5.5, 1.7 Hz, 1H), 4.19 (d, J = 17.2 Hz, 1H); C NMR (101 MHz,
CDCl3) δ 161.49 (s), 145.37 (s), 143.26 (s), 137.85 (s), 135.18 (s), 129.60 (d, J = 1.7
Hz), 128.66 (s), 128.56 (s), 128.43(s), 124.93 (q, J = 286.8 Hz), 114.58 (d, J = 0.9 Hz),
19
79.82 (s), 67.15 (s), 64.25 (q, J = 32.3 Hz), 56.65 (s); F NMR (376 MHz, CDCl3) δ -
72.52 (d, J = 5.1 Hz); IR (film,cm-1): ν 2962, 1724, 1588, 1493, 1370, 1256, 1135, 1095,
806, 750; HRMS (EI) calcd. For C19H15NO2F3I: 473.0100; Found: 473.0108.
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4.3.4 benzyl 2-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-2,5-dihydro-1H-pyrrole-
3-carboxylate (3d)
Yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.7 Hz, 2H), 7.41 – 7.34 (m,
5H), 7.22 (s, 1H), 6.76 (d, J = 8.6 Hz, 2H), 5.48 (p, J = 5.0 Hz, 1H), 5.31 – 5.22 (m,
13
2H), 4.49 (dd, J = 17.0, 5.0 Hz, 1H), 4.28 (d, J = 17.1 Hz, 1H); C NMR (101 MHz,
CDCl3) δ 161.37 (s), 147.99 (s), 143.02 (s), 135.12 (s), 129.63 (d, J = 1.5 Hz), 128.66
(s), 128.58 (s), 128.43 (s), 126.60 (q, J = 3.8 Hz), 124.87 (q, J = 286.6 Hz), 124.65 (q, J
= 270.3 Hz), 120.26 (q, J = 32.8 Hz), 111.89 (d, J = 0.9 Hz), 67.21 (s), 64.18 (q, J =
32.5 Hz), 56.53 (s); 19F NMR (376 MHz, CDCl3) δ -61.30 (s), -72.46 (d, J = 4.9 Hz); IR
(film,cm-1): ν 2855, 1727, 1617, 1529, 1333, 1255, 1136, 1070, 846, 749; HRMS (EI)
calcd. For C20H15NO2F6: 415.1007; Found: 415.1002.
4.3.5 benzyl 2-(bromodifluoromethyl)-1-(4-bromophenyl)-2,5-dihydro-1H-pyrrole-3-
carboxylate (3e)
Yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.39 – 7.34 (m, 5H), 7.33 (d, J = 9.1 Hz,
2H), 7.23 (s, 1H), 6.63 (d, J = 7.9 Hz, 2H), 5.39 (s, 1H), 5.28 – 5.22 (m, 2H), 4.54 (ddd,
13
J = 17.3, 5.3, 1.4 Hz, 1H), 4.16 (d, J = 17.4 Hz, 1H); C NMR (101 MHz, CDCl3) δ
161.66 (s), 144.75 (s), 143.51 (s), 135.19 (s), 131.92 (s), 131.03 (t, J = 303.5 Hz),
130.91 (d, J = 3.9 Hz), 128.64 (s), 128.53 (s), 128.41 (s), 114.24 (s), 110.62 (s), 69.07
19
(dd, J = 29.5, 27.5 Hz), 67.12 (s), 57.28 (s); F NMR (376 MHz, CDCl3) δ -46.69 (dd,
J = 162.8, 2.6 Hz), -47.68 (d, J = 162.8 Hz); IR (film,cm-1): ν 2921, 1724, 1593, 1494,
1367, 1247, 1100, 1010, 809, 753; HRMS (EI) calcd. For C19H15NO2F2Br2: 484.9438;
Found: 484.9445.
4.3.6 ethyl 2-(bromodifluoromethyl)-1-(4-bromophenyl)-2,5-dihydro-1H-pyrrole-3-
carboxylate (3f)
White solid, mp: 95-97 oC; 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 9.1 Hz, 2H), 7.19
(s, 1H), 6.65 (d, J = 7.9 Hz, 2H), 5.38 (t, J = 3.9 Hz, 1H), 4.54 (ddd, J = 17.2, 5.3, 1.3
13
Hz, 1H), 4.34 – 4.21 (m, 2H), 4.17 (d, J = 17.2 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); C
NMR (101 MHz, CDCl3) δ 161.79 (s), 144.75 (s), 142.81 (s), 131.93 (s), 131.81 (d, J =
5.7 Hz), 127.08 (t, J = 320.8 Hz), 114.33 (d, J = 2.5 Hz), 110.69 (s), 70.38 (dd, J = 28.3,
14

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19
24.2 Hz), 61.36 (s), 57.50 (s), 14.13 (s); F NMR (376 MHz, CDCl3) δ -46.61 (dd, J =
162.6, 2.4 Hz), -47.73 (d, J = 162.6 Hz); IR (film,cm-1): ν 2989,1715, 1590, 1492, 1367,
1249, 1113, 999, 806, 759; HRMS (EI) calcd. For C14H13NO2F2Br2: 422.9281; Found:
422.9276.
4.3.7 benzyl 1-(4-bromophenyl)-2-(chlorodifluoromethyl)-2,5-dihydro-1H-pyrrole-3-
carboxylate (3g)
Yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.34 (m, 5H), 7.32 (d, J = 9.1 Hz,
2H), 7.21 (s, 1H), 6.63 (d, J = 8.7 Hz, 2H), 5.52 (s, 1H), 5.29 – 5.21 (m, 2H), 4.49 (ddd,
13
J = 17.3, 5.4, 1.6 Hz, 1H), 4.17 (d, J = 17.3 Hz, 1H); C NMR (101 MHz, CDCl3) δ
161.67 (s), 144.76 (s), 143.51 (s), 135.20 (s), 131.94 (s), 131.02 (dd, J = 307.9, 299.2
Hz), 130.92 (d, J = 1.0 Hz), 128.65 (s), 128.55 (s), 128.43 (s), 114.24 (d, J = 1.0 Hz),
19
110.64 (s), 69.09 (dd, J = 29.5, 27.6 Hz), 67.13 (s), 57.29 (s); F NMR (376 MHz,
CDCl3) δ -54.65 (dd, J = 164.9, 3.1 Hz), -55.17 (dd, J = 164.8, 2.2 Hz), -55.17 (dd, J =
164.8, 2.2 Hz); IR (film,cm-1): ν 2918, 1724, 1594, 1495, 1368, 1247, 1100, 1021, 809,
755; HRMS (EI) calcd. For C19H15NO2F2ClBr: 440.9943; Found: 440.9939.
4.3.8 ethyl 1-(4-bromophenyl)-2-(chlorodifluoromethyl)-2,5-dihydro-1H-pyrrole-3-
carboxylate (3h)
1
Yellow solid, mp: 69-70oC; H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 9.0 Hz, 2H),
7.17 (s, 1H), 6.64 (d, J = 8.7 Hz, 2H), 5.50 (s, 1H), 4.49 (ddd, J = 17.2, 5.3, 1.5 Hz, 1H),
4.32 – 4.22 (m, 2H), 4.18 (d, J = 17.2 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 161.86 (s), 144.83 (s), 142.77 (s), 131.92 (s), 131.26 (d, J = 3.6 Hz),
131.07 (t, J = 304.5 Hz), 114.24 (s), 110.57 (s), 69.11 (dd, J = 29.6, 27.2 Hz), 61.34 (s),
19
57.27 (s), 14.12 (s); F NMR (376 MHz, CDCl3) δ -54.61 (dd, J = 164.7, 2.9 Hz), -
55.20 (d, J = 164.7 Hz); IR (film,cm-1): ν 2982, 1725, 1593, 1495, 1368, 1250,
1101,1019, 809, 758; HRMS (EI) calcd. For C14H13NO2F2ClBr: 378.9786; Found:
378.9782.
4.3.9
tert-butyl
1-(4-bromophenyl)-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-
15

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carboxylate (3i)
1
Yellow liquid; H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 9.0 Hz, 2H), 7.06 (s, 1H),
6.59 (d, J = 8.8 Hz, 2H), 5.33 – 5.24 (m, 1H), 4.41 (ddd, J = 16.9, 5.5, 1.5 Hz, 1H), 4.16
(d, J = 16.8 Hz, 1H), 1.51 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 160.94 (s), 144.93 (s),
141.41 (s), 131.94 (s), 131.44 (d, J = 1.5 Hz), 126.44 (t, J = 286.8 Hz), 113.90 (d, J =
0.9 Hz), 110.29 (s), 82.26 (s), 64.55 (q, J = 32.1 Hz), 56.61 (s), 27.95 (s); 19F NMR (376
MHz, CDCl3) δ -72.31 (d, J = 5.2 Hz); IR (film,cm-1): ν 2980, 1719, 1595, 1496, 1368,
1255, 1166, 1099, 809, 756; HRMS (EI) calcd. For C16H17NO2F3Br: 391.0395; Found:
391.0398.
4.3.10
ethyl
1-(4-bromophenyl)-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-
carboxylate (3j)
1
Yellow liquid; H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 9.0 Hz, 2H), 7.15 (s, 1H),
6.60 (d, J = 8.8 Hz, 2H), 5.41 – 5.33 (m, 1H), 4.44 (ddd, J = 17.1, 5.5, 1.4 Hz, 1H), 4.33
– 4.23 (m, 2H), 4.19 (d, J = 17.1 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 161.68 (s), 144.84 (s), 142.51 (s), 131.98 (s), 129.96 (d, J = 1.7 Hz), 124.95 (q,
J = 286.7 Hz), 113.95 (d, J = 1.0 Hz), 110.43 (s), 64.41 (q, J = 32.2 Hz), 61.33 (s),
56.74 (s), 14.10 (s); 19F NMR (376 MHz, CDCl3) δ -72.60 (d, J = 5.1 Hz); IR (film,cm-
1): ν 2983, 1725, 1594, 1496, 1370, 1253, 1135, 1017, 808, 751; HRMS (EI) calcd. For
C14H13NO2F3Br: 363.0082; Found: 363.0074.
4.3.11
methyl
1-(4-bromophenyl)-2-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-3-
carboxylate (3k)
1
Yellow solid, mp: 77-78oC; H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 9.1 Hz, 2H),
7.16 (s, 1H), 6.60 (d, J = 8.9 Hz, 2H), 5.38 (p, J = 5.2 Hz, 1H), 4.44 (ddd, J = 17.2, 5.6,
13
1.7 Hz, 1H), 4.19 (d, J = 17.2 Hz, 1H), 3.81 (s, 3H); C NMR (101 MHz, CDCl3) δ
162.10 (s), 144.79 (s), 142.85 (s), 131.98 (s), 129.54 (d, J = 1.7 Hz), 124.91 (q, J =
286.6 Hz), 113.94 (d, J = 0.9 Hz), 110.45 (s), 64.37 (q, J = 32.3 Hz), 56.75 (s), 52.23 (s);
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19F NMR (376 MHz, CDCl3) δ -72.72 (d, J = 5.0 Hz); IR (film,cm-1): ν 2921, 1727,
1595, 1496, 1362, 1251, 1163, 1099, 982, 847, 813, 752; HRMS (EI) calcd. For
C13H11NO2F3Br: 348.9925; Found: 348.9928.
4.3.12
dibenzyl
(S)-1-((R)-1-((4-bromophenyl)amino)-2,2,2-trifluoroethyl)-2-
methylenecyclopen -t-3-ene-1,3-dicarboxylate (4a)
Yellow solid, mp: 122-124oC ; 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.24 (m, 7H), 7.19
(d, J = 8.7 Hz, 2H), 7.14 – 7.06 (m, 3H), 6.50 (d, J = 8.7 Hz, 2H), 6.15 (s, 1H), 5.49 (s,
1H), 5.21 (q, J = 12.4 Hz, 2H), 5.05 (d, J = 11.9 Hz, 1H), 4.91 (d, J = 11.9 Hz, 1H),
4.59 (td, J = 14.1, 7.0 Hz, 1H), 3.98 (d, J = 10.9 Hz, 1H), 3.49 (dd, J = 19.9, 1.8 Hz,
1H), 2.86 (dd, J = 19.9, 2.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 170.67 (s), 162.67
(s), 146.90 (s), 145.18 (s), 144.84 (s), 135.71 (s), 134.61 (s), 133.78 (s), 132.10 (s),
131.79 (s), 128.63 (s), 128.61 (s), 128.34 (s), 128.23 (s), 127.75 (s), 125.34 (q, J = 286.9
Hz), 115.58 (s), 112.85 (s), 111.29 (s), 68.34 (s), 66.38 (s), 60.52 (q, J = 26.9 Hz), 58.72
19
(s), 35.83 (s); F NMR (376 MHz, CDCl3) δ -67.01 (d, J = 7.1 Hz); IR (film,cm-1): ν
3389, 3033, 1723, 1594, 1490, 1343, 1240,1174, 908, 814, 749; HRMS (EI) calcd. For
C30H25NO4F3Br: 599.0919, Found: 599.0914.
4.4 General procedure for 5 synthesis
For example the procedure for 5a synthesis: In a nitrogen-filled box, a schlenk tube was
charged with 3a (42.5 mg, 0.1 mmol) and DDQ (45.4mg, 0.2mmol) in toluene (2.0 mL).
The reaction mixture was stirred at 100oC for 7h. After completion of reaction as
indicated by TLC, the mixture was concentrated in vacuo. The residue was purified by
column chromatography on silica (combined solvent ethyl acetate and petrol ether as
eluent) to provide the desire product 5a.
4.4.1 benzyl 1-(4-bromophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate (5a)
17

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Yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.5 Hz, 2H), 7.47 – 7.30 (m,
5H), 7.21 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 2.9 Hz, 1H), 6.74 (d, J = 3.0 Hz, 1H), 5.33 (s,
2H); 13C NMR (101 MHz, CDCl3) δ 162.67 (s), 138.19 (s), 135.86 (s), 132.41 (s),
128.53 (s),128.24 (s), 128.20 (s), 127.74 (d, J = 0.5 Hz), 126.12 (d, J = 1.2 Hz), 123.11
(s), 122.75 (q, J= 38.9 Hz), 120.20 (q, J= 270.3 Hz), 119.59 (q, J = 1.6 Hz), 112.32 (s),
66.68 (s); 19F NMR (376 MHz, CDCl3) δ -53.16 (s); IR (film, cm-1): ν 3034, 2956, 1728,
1554, 1495, 1455, 1265, 1188, 1130, 1016, 834, 787; HRMS (EI) calcd. For
C19H13NO2F3Br: 423.0082; Found: 423.0086.
4.4.2 benzyl 1-(4-chlorophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate (5b)
Yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.8 Hz, 2H), 7.42 – 7.29 (m,
5H), 7.25 (d, J = 8.9 Hz, 2H), 6.76 (d, J = 3.0 Hz, 1H), 6.73 (d, J = 3.0 Hz, 1H), 5.32 (s,
2H); 13C NMR (101 MHz, CDCl3) δ 162.68 (s), 137.66 (s), 135.85 (s), 135.12 (s),
129.40 (s), 128.51 (s), 128.22 (s), 128.18 (s), 127.45 (d, J = 0.8 Hz), 126.14 (d, J = 1.3
Hz), 122.80 (dd, J = 77.6, 38.9 Hz), 120.18 (q, J = 270.0 Hz), 119.54 (d, J = 2.0 Hz),
112.27 (s), 66.67 (s); 19F NMR (376 MHz, CDCl3) δ -53.16 (s); IR (film, cm-1): ν 3034,
2959, 1727, 1553,1499, 1435, 1264, 1188, 1130, 1018, 837, 743; HRMS (EI) calcd. For
C19H13NO2F3Cl: 379.0587; Found: 379.0595.
4.4.3 benzyl 1-(4-iodophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate (5c)
Yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.7 Hz, 2H), 7.49 – 7.27 (m,
5H), 7.06 (d, J = 8.5 Hz, 2H), 6.75 (d, J = 3.0 Hz, 1H), 6.72 (d, J = 3.0 Hz, 1H), 5.32 (s,
2H); 13C NMR (101MHz, CDCl3) δ 162.67 (s), 138.90 (s), 138.39 (s), 135.84 (s),
128.52 (s), 128.23 (s), 128.18 (s), 127.89 (d, J = 0.9 Hz), 126.05 (d, J = 1.4 Hz), 122.70
(q, J = 39.0 Hz), 120.17 (q, J = 270.0 Hz), 119.61 (d, J = 2.0 Hz), 112.33 (s), 94.55 (s),
66.68 (s); 19F NMR (376 MHz, CDCl3) δ -53.11 (s); IR(film,cm-1): ν 3033, 2946, 1726,
1553, 1493, 1436, 1264, 1187, 1130, 1013, 830, 743; HRMS (EI) calcd. For
C19H13NO2F3I: 470.9943, Found:470.9944.
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4.4.4
benzyl
2-(trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-pyrrole-3-
carboxylate (5d)
Yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.6
Hz, 2H), 7.43 – 7.29 (m, 5H), 6.79 (d, J = 3.0 Hz, 1H), 6.77 (d, J = 3.0 Hz, 1H), 5.33 (s,
13
2H); C NMR (101MHz, CDCl3) δ 162.58 (s), 142.08 (s), 135.78 (s), 131.28 (q, J =
33.2 Hz), 128.53 (s), 128.25 (s), 128.22 (s), 126.62 (d, J = 0.8 Hz), 126.47 (q, J = 3.7
Hz), 126.03 (s), 123.49 (q, J = 272.5 Hz), 122.79 (q, J = 39.0 Hz), 120.14 (q, J = 270.0
Hz), 120.02 (d, J = 2.0 Hz), 112.58 (s), 66.75 (s); 19F NMR (376 MHz, CDCl3) δ -53.00
(s), -62.71 (s); IR(film,cm-1): ν 3036, 2960, 1728, 1522, 1481, 1437, 1266, 1189, 1130,
1064, 851, 746; HRMS (EI) calcd. For C20H13NO2F6: 413.0850, Found: 413.0854.
4.4.5 benzyl 1-(4-bromophenyl)-2-(chlorodifluoromethyl)-1H-pyrrole-3-carboxylate
(5g)
Yellow liquid; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.7 Hz, 2H), 7.46 – 7.29 (m,
5H), 7.24 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 3.0 Hz, 1H), 6.67 (d, J = 3.0 Hz, 1H), 5.32 (s,
13
2H); C NMR (101 MHz, CDCl3) δ 162.72 (s), 138.31 (d, J = 1.4 Hz), 135.83 (s),
132.30 (s), 128.49 (s), 128.31 (s), 128.23 (t, J = 34.8 Hz), 128.17 (s), 128.15 (t, J = 1.1
Hz), 125.82 (s), 123.12 (s), 121.13 (t, J = 289.2 Hz), 117.80 (t, J = 1.9 Hz), 112.21 (s),
66.65 (s); 19F NMR (376 MHz, CDCl3) δ -41.54 (s); IR (film,cm-1): ν 3071, 2924, 1719,
1552, 1493, 1435, 1261, 1177, 1099, 1027, 883, 742; HRMS (EI) calcd. For
C19H13NO2F2ClBr: 438.9786, Found: 438.9782.
4.4.6 ethyl 1-(4-bromophenyl)-2-(chlorodifluoromethyl)-1H-pyrrole-3-carboxylate (5h)
Yellow solid, mp: 128-129 oC; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.7 Hz, 2H),
7.24 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 2.9 Hz, 1H), 6.67 (d, J = 3.0 Hz, 1H), 4.33 (q, J =
7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.08 (s), 138.38
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(s), 132.28 (s), 128.15 (s), 127.56 (t, J = 31.0 Hz), 125.79 (s), 123.05 (s), 121.21 (t, J =
19
287.7 Hz), 118.33 (s), 112.00 (s), 60.89 (s), 14.10 (s); F NMR (376 MHz, CDCl3) δ -
41.34 (s); IR (film,cm-1): ν 2961, 2854, 1728, 1549, 1494, 1461, 1260, 1178, 1095, 1016,
881, 800; HRMS (EI) calcd. For C14H11NO2F2ClBr: 376.9630, Found: 377.9636.
4.4.7 tert-butyl 1-(4-bromophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate (5i)
Yellow solid, mp: 70-72 oC; 1H NMR (400 MHz, CDCl3) 7.57 (d, J = 8.7 Hz, 2H), 7.19
(d, J = 8.6 Hz, 2H), 6.70 (d, J = 2.9 Hz, 1H), 6.68 (d, J = 2.9 Hz, 1H), 1.55 (s, 9H); 13C
NMR (101 MHz, CDCl3) δ 162.47 (s), 138.41 (s), 132.35 (s), 127.69 (s), 125.86 (s),
122.87 (s), 122.07 (s), 122.00 (q, J = 2.1 Hz), 120.33 (q, J = 269.7 Hz), 112.10 (s),
19
81.49 (s), 27.99 (s); F NMR (376 MHz, CDCl3) δ -52.72 (s);IR (film,cm-1): ν 3130,
2918, 1685, 1542, 1496, 1435, 1277, 1200, 1147, 1015, 833, 753; HRMS (EI) calcd.
For C16H15NO2F3Br: 389.0238, Found: 389.0237.
4.4.8 ethyl 1-(4-bromophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate (5j)
Yellow solid, mp: 105-107 oC; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.7 Hz, 2H),
7.20 (d, J = 8.6 Hz, 2H), 6.74 – 6.71 (m, 2H), 4.32 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 7.1
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.00 (d, J = 0.6 Hz), 138.24 (s), 132.36 (s),
127.73 (d, J = 0.9 Hz), 126.03 (d, J = 1.4 Hz), 123.02(s), 122.45 (q, J = 38.0 Hz),
19
120.20 (q, J = 269.9 Hz), 120.09 (q, J = 2.0 Hz), 112.09 (s), 60.89 (s), 14.08 (s); F
NMR (376 MHz, CDCl3) δ -53.14 (d, J = 3.1 Hz); IR (film,cm-1): ν 3128, 2991, 1721,
1561, 1494, 1434, 1248, 1188, 1127, 1037, 838, 755; HRMS (EI) calcd. For
C14H11NO2F3Br: 360.9925, Found: 360.9919.
4.4.9 methyl 1-(4-bromophenyl)-2-(trifluoromethyl)-1H-pyrrole-3-carboxylate (5k)
20

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o
1
Yellow solid, mp: 62-64 C; H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.7 Hz, 2H),
13
7.20 (d, J = 8.6 Hz, 2H), 6.72 (dd, J = 6.5, 3.0 Hz, 2H), 3.86 (s, 2H); C NMR (101
MHz, CDCl3) δ 163.35 (s), 138.18 (s), 132.38 (s), 127.73 (s), 126.08 (d, J = 1.4 Hz),
123.07 (s), 122.63 (q, J = 38.8 Hz), 120.15 (q, J = 269.8 Hz), 119.55 (q, J = 1.8 Hz),
112.10 (s), 51.96 (s); 19F NMR (376 MHz, CDCl3) δ -53.36 (s); IR (film,cm-1): ν 3130,
2951, 1724, 1555, 1494, 1434, 1250, 1200, 1131, 1030, 860, 750; HRMS (EI) calcd.
For C13H9NO2F3Br: 346.9769, Found: 346.9761.
Acknowledgements
This work was supported by the National Basic Research Program of China
(2012CB821600) and the National Natural Science Foundation of China (No.
21172239).
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