A facile synthesis of 3-hydroxy-3-(trifluoromethyl)-1H-pyrrol-2(3H)-ones with Br?nsted acid-catalyzed condensation-cyclization reactions of β-enamino esters and ethyl trifluoropyruvate

Article abstract of DOI:10.1016/j.tet.2014.05.052

A facile synthesis of 3-hydroxy-3-(trifluoromethyl)-1H-pyrrol-2(3H)-ones based on trifluoroacetic acid-catalyzed condensation-cyclization reactions of β-enamino esters and ethyl trifluoropyruvate is described. These reactions afford a series of α-trifluoromethylated γ-lactam compounds in good to excellent yields under mild conditions. A preliminary trial of an asymmetric catalytic version with chiral BINOL-derived phosphoric acid as enantioselective catalyst was conducted and showed promising enantioselectivity of the desired product.

Full text of DOI:10.1016/j.tet.2014.05.052

Tetrahedron 70 (2014) 4595e4601
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A facile synthesis of 3-hydroxy-3-(trifluoromethyl)-1H-pyrrol-
2(3H)-ones with Brønsted acid-catalyzed condensationecyclization
reactions of b-enamino esters and ethyl trifluoropyruvate
,
,
,
Qing-Lan Pei a c, Bao-Dong Cui a c, Wen-Yong Han a c, Zhi-Jun Wu b, Xiao-Mei Zhang a,
Wei-Cheng Yuan a
,
*
a National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
c University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthesis of 3-hydroxy-3-(trifluoromethyl)-1H-pyrrol-2(3H)-ones based on trifluoroacetic acid-
Received 9 March 2014
Received in revised form 4 May 2014
Accepted 15 May 2014
catalyzed condensationecyclization reactions of
b
-enamino esters and ethyl trifluoropyruvate is de-
-lactam compounds in good to excellent
scribed. These reactions afford a series of -trifluoromethylated
a
g
yields under mild conditions. A preliminary trial of an asymmetric catalytic version with chiral BINOL-
derived phosphoric acid as enantioselective catalyst was conducted and showed promising enantiose-
lectivity of the desired product.
Available online 21 May 2014
Keywords:
Brønsted acid
Trifluoroacetic acid
Ó 2014 Elsevier Ltd. All rights reserved.
b
-Enamino esters
Ethyl trifluoropyruvate
-Lactam compounds
g
1. Introduction
very rare.2,4 In continuation of our program on the synthesis of
various N-heterocyclic compounds,5 we have been interested in
The efficient and facile construction of promising heterocycles is
a continuing challenge for synthetic chemistry. Heterocyclic com-
pounds containing a trifluoromethyl group in particular have
emerged as attractive synthetic targets due to their applications in
various fields like pharmacy, medicine, agriculture, material sci-
ence, etc.1 Among them, 3-hydroxy-3-(trifluoromethyl)-1H-pyrrol-
2(3H)-ones 3 (Scheme 1) as one type of trifluoromethyl-containing
exploring efficient method for the synthesis of 3-hydroxy-3-(tri-
fluoromethyl)-1H-pyrrol-2(3H)-ones. We envisioned that the re-
action between b-enamino esters 1 and ethyl trifluoropyruvate 2
with appropriate catalyst could provide rapid access to 3-hydroxy-
g-lactams are important N-heterocyclic compounds in organic
synthesis, due to the potential application of the heterocyclic
structure for the synthesis of a series of drug-like molecules bearing
a trifluoromethylated quaternary carbon center,2 and the
a
-hy-
droxy-a-trifluoromethyl amide skeleton is frequently encountered
in many natural products and pharmaceuticals with significant
biologically activities.3 In this context, the development of novel
and efficient methods for the construction of 3-hydroxy-3-(tri-
fluoromethyl)-1H-pyrrol-2(3H)-one structures is therefore highly
important and desirable. However, the synthetic approaches to the
3-hydroxy-3-(trifluoromethyl)-1H-pyrrol-2(3H)-one skeletons are
* Corresponding author. E-mail addresses: yuanwc@cioc.ac.cn, yuanweicheng@
126.com (W.-C. Yuan).
Scheme 1. Design strategy for the synthesis of 3-hydroxy-3-(trifluoromethyl)-1H-
pyrrol-2(3H)-one compounds.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.052

4596
Q.-L. Pei et al. / Tetrahedron 70 (2014) 4595e4601
3-(trifluoromethyl)-1H-pyrrol-2(3H)-one compounds via a tandem
condensationecyclization pathway (Scheme 1).
(Table 1, entries 2e6). In the case of TFA, it was observed that the
expected condensationecyclization product 3a could be smoothly
obtained in 95% yield (Table 1, entry 4). We then evaluated the
effect of solvents, the survey of reaction media, such as DCE, tolu-
ene, CH3CN, and THF, revealed that the results could not be further
improved (Table 1, entries 7e10). Afterward, some polar solvents
(DMF, DMSO, and H2O) were investigated, unfortunately, almost no
product was obtained with DMF or DMSO as the reaction medium,
and the reaction did not occur in water (Table 1, entries 11e13).
Thus, the best result was achieved in CH2Cl2 (Table 1, entry 4).
Lowering the catalyst loading from 10 mol % to 5 mol % and 1 mol %
led to significant decrease in chemical yield (Table 1, entries 14 and
15). Accordingly, these studies provided the optimal reaction con-
ditions described in Table 1, entry 4.
Actually, as a building block for generating trifluoromethylated
heterocycles, ethyl trifluoropyruvate is envisioned to be an ideal
candidate. There are many examples of nucleophilic addition to
ethyl trifluoropyruvate with various nucleophiles have been re-
ported.2,4,6 Indeed, each of the reported methods results in a dif-
ferent class of CF3-containing compounds that may play as
promising biologically active motifs for pharmaceuticals and ag-
rochemicals. However, there were very few examples found in the
literature on the application of
b
-enamino esters as nucleophiles
-enamino
reacting with ethyl trifluoropyruvate,2,4 despite that
b
esters have been utilized as versatile reagents that participate in
a wide range of organic reactions.7 Herein, we report the tri-
fluoroacetic acid-catalyzed reactions between
b-enamino esters
Having a reasonable set of reaction conditions in hand, we
and ethyl trifluoropyruvate for the synthesis of functionalized 3-
hydroxy-3-(trifluoromethyl)-1H-pyrrol-2(3H)-ones via a tandem
condensationecyclization process.
evaluated the scope of the N-protected
results were shown in Table 2. Firstly, for the
b
-enamino esters and the
-aryl-N-PMP b-
b
enamino esters 1bek, it was observed that these substrates toler-
ated substitution at any position of the aromatic ring, and both
electron-withdrawing (1bef) and electron-donating (1geh) func-
tionalities were compatible. The expected 3-hydroxy-3-(tri-
fluoromethyl)-1H-pyrrol-2(3H)-ones 3beh could be smoothly
obtained in high yields (Table 2, entries 1e7). In the case of the 2-
2. Results and discussion
Our experiments began with the reaction of (Z)-methyl-3-
phenyl-3-(phenylamino)acrylate (1a) and ethyl trifluoropyruvate
(2). Reaction optimization involved variation of catalyst, solvent,
and catalyst loading and the results from these experiments were
shown in Table 1. We examined the model reaction in CH2Cl2 in the
presence of 10 mol % p-toluenesulfonic acid (TsOH) at room tem-
Table 2
Substrate scope for the tandem condensationecyclization reaction of N-protected
b-
enamino esters and ethyl trifluoropyruvatea
perature. After
8
h,
a
mixture of the desired con-
densationecyclization product 3a and condensation product 4a in
89:11 ratio was provided in 41% yield (Table 1, entry 1). However,
when the mixture of 3a and 4a was dried under vacuum at 80 ꢀC for
10 h, 4a could be completely converted to 3a, giving the final
product 3-hydroxy-3-(trifluoromethyl)-1H-pyrrol-2(3H)-one 3a in
41% yield for two steps (Table 1, entry 2). Among the Brønsted acids
that were screened, trifluoroacetic acid (TFA) gave the best result
Entry
1
1
3
Yieldb (%)
R1¼4-FC6H4 (1b)
3b
94
Table 1
2
3
4
5
6
7
8
9
R1¼4-BrC6H4 (1c)
R1¼2-ClC6H4 (1d)
R1¼3-ClC6H4 (1e)
R1¼4-ClC6H4 (1f)
R1¼4-MeC6H4 (1g)
R1¼4-MeOC6H4 (1h)
R1¼2-Naphthyl (1i)
R1¼2-Thienyl (1j)
R1¼Cyclohexyl (1k)
3c
3d
3e
3f
3g
3h
3i
96
96
94
95
88
88
91
86
90
Optimization of the reaction conditionsa
Entry
Solvent
Catalyst
Yieldb (%)
41c
41
41
95
77
56
73
90
3j
3k
10
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
Toluene
CH3CN
THF
DMF
DMSO
H2O
CH2Cl2
CH2Cl2
TsOH
TsOH
AcOH
TFA
MeSO3H
PhCO2H
TFA
TFA
TFA
TFA
TFA
11
R2¼4-FC6H4 (1l)
3l
92
12
13
14
15
16
17
18
R2¼4-BrC6H4 (1m)
R2¼4-ClC6H4 (1n)
R2¼4-MeC6H4 (1o)
R2¼2-MeOC6H4 (1p)
R2¼3-MeOC6H4 (1q)
R2¼4-MeOC6H4 (1r)
R2¼Bn (1s)
3m
3n
3o
3p
3q
3r
91
88
96
93
95
95
86
9
82
10
11
12
13
14
15
Trace
Trace
Trace
nr
TFA
TFA
TFA
TFA
3s
83d
67e
19
R3¼Et (1t)
3t
96
a
Unless otherwise noted, the reaction was firstly carried out with 1a (0.2 mmol),
2 (0.5 mmol), and catalyst (0.02 mmol) in solvent (2.0 mL) at room temperature for
8 h. The product was purified as a mixture of 3a and 4a via column chromatography
on silica gel, and then the mixture was dried under vacuum at 80 ꢀ C for 10 h to
furnish the end product 3a.
20
21
R3¼iPr (1u)
R3¼tBu (1v)
3u
3v
95
98
a
Unless otherwise noted, the reaction was firstly carried out with 1 (0.2 mmol), 2
(0.5 mmol), and TFA (0.02 mmol) in CH2Cl2 (2.0 mL) at room temperature for 8 h.
The product was purified as a mixture of the desired condensationecyclization
product 3 and the condensation product via column chromatography on silica gel
and then the mixture was dried under vacuum at 80 ꢀ C for 10 h to furnish the final
product 3.
b
Isolated yield of 3a for two steps.
Isolated yield of the mixture of 3a and 4a and the ratio 89:11 was determined by
c
1H NMR analysis.
d
TFA (5 mol %) was used.
TFA (1 mol %) was used. TFA¼trifluoroacetic acid, DCE¼1,2-dichloroethane,
e
b
Isolated yield of 3 for two steps. PMP¼p-methoxyphenyl.
nr¼no reaction.

Q.-L. Pei et al. / Tetrahedron 70 (2014) 4595e4601
4597
naphthyl derivative 1i, very high yield for the corresponding
product 3i was achieved as well (Table 2, entry 8). N-PMP
enamino ester bearing heteroaromatic -substituent was also
suitable substrate as exemplified by the preparation of 3j (Table 2,
entry 9). Notably, the less reactive aliphatic compound 1k also
structure analysis (Scheme 2).8 Furthermore, the obtained 3-
hydroxy-3-(trifluoromethyl)-1H-pyrrol-2(3H)-one product 3r
could be transformed into the densely functionalized 3-hydroxy-3-
(trifluoromethyl)pyrrolidin-2-one 5 by means of reduction with Pd/
C and hydrogen in 87% yield with 51:49 dr under mild conditions
(Scheme 2b).8
b
-
b
proved to be
densationecyclization reaction affording the product 3k in 90%
yield (Table 2, entry 10). Our subsequent efforts focused on the
phenyl-N-aryl -enamino esters 1ler. Introduction of an electron-
a competent substrate in the tandem con-
b
-
b
withdrawing or electron-donating group at the benzene ring of
the N-aryl group did not significantly affect the yield (Table 2, en-
tries 11e17). Diverse products 3ler could be smoothly obtained in
yields ranging from 88% to 96%. Nevertheless, switching the N-aryl
group to N-benzyl group was no deleterious to the reactivity and
furnished 3s in 86% yield (Table 2, entry 18). Ultimately, it was
found that the R3 group in the ester moiety had no obvious in-
fluence on the reactivity of this reaction (Table 2, entries 19e21).
Remarkably, high to excellent yields were obtained for all sub-
strates above-evaluated, demonstrating the generality and ro-
bustness of the present catalytic system.
Subsequently, the method was further extended to N-un-
protected
b-enamine ester substrates (Table 3). The electronic
property of substituents on the aryl ring of the substrates had no
obvious effect on the generation of the product. Substrates bearing
electron-donating or electron-withdrawing substituents on the
aromatic ring were all able to smoothly react with ethyl tri-
fluoropyruvate, delivering the corresponding products (Table 3,
3xea0) in very high yields. Furthermore, the 2-naphthyl substrate
1b0 and 2-thienyl 1c0 could afford the corresponding products 3b0
and 3c0 in 68% and 90% yields, respectively. Overall, the results, il-
lustrated in Tables 2 and 3, not only demonstrate that there is good
Scheme 2. Large scale experiment for the synthesis of 3r, the transformation of 3r to 5,
and the X-ray structure of 3r.
We also tried to develop a catalytic asymmetric version for the
tandem condensationecyclization process. The reaction of b-en-
amine ester 1s and ethyl trifluoropyruvate (2) was selected as
a model to illustrate the possibility of the catalytic asymmetric
process (Scheme 3). Gratifyingly, in the presence of 20 mol % chiral
BINOL-derived phosphoric acid A,9 the expected tandem con-
densationecyclization process proceeded smoothly under the
standard reaction conditions, and afforded product 3s in 95% yield
with 59% ee.10 The absolute configuration of 3s was not determined
at the moment and the exploration of more effective chiral
Brønsted acids is undergoing.
substrate scope for the reaction of
b-enamine esters with ethyl
trifluoropyruvate (2) using trifluoroacetic acid as catalyst, providing
access to a range of 3-hydroxy-3-(trifluoromethyl)-1H-pyrrol-
2(3H)-ones in high to excellent yields, but also show that the fea-
ture of N-protected or N-unprotected in the substrates has no
deleterious to the reactivity.
Table 3
Substrate scope for the tandem condensationecyclization reaction of N-unprotected
b
-enamino esters and ethyl trifluoropyruvatea
Scheme 3. A preliminary attempt on the catalytic asymmetric reaction of
ester and ethyl trifluoropyruvate.
b-enamine
3. Conclusion
In summary, we have developed a facile method for the syn-
thesis of 3-hydroxy-3-(trifluoromethyl)-1H-pyrrol-2(3H)-ones
with trifluoroacetic acid-catalyzed the reactions of
ters and ethyl trifluoropyruvate. Using this protocol, a series of
functionalized -trifluoromethylated -lactam compounds are able
b-enamino es-
a
g
to be smoothly obtained in good to excellent yields via a tandem
condensationecyclization process. The potential utilities of the
protocol also had been demonstrated by a large scale experiment
and further transformation of the product. Additionally, a pre-
liminary trial of an asymmetric catalytic version with chiral BINOL-
derived phosphoric acid as enantioselective catalyst was conducted
and afforded the desired product in excellent yield with moderate
enantioselectivity.
To test the practicality of the current method for the synthesis of
3-hydroxy-3-(trifluoromethyl)-1H-pyrrol-2(3H)-ones, reaction of
compound 1r with ethyl trifluoropyruvate (2) was performed on
a large scale under the standard reaction conditions. The reaction
proceeded smoothly to provide 3r in high to 92% yield (Scheme 2a).
The structure of product 3r has been confirmed by X-ray crystal

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Q.-L. Pei et al. / Tetrahedron 70 (2014) 4595e4601
4. Experimental section
(d, J¼8.4 Hz, 2H), 5.00e4.89 (br, 1H), 3.73 (s, 3H), 3.62 (s, 3H); 13C
NMR (75 MHz, CDCl3)
d
51.8, 51.9, 55.3, 76.5 (q, J¼31.5 Hz,1C), 105.3,
4.1. General
105.4, 114.3, 122.8 (q, J¼286.9 Hz, 0.5C), 122.9 (q, J¼286.3 Hz, 0.5C),
124.6, 124.7, 126.5, 126.6, 127.9, 128.2, 128.7, 129.4, 129.5, 130.5,
131.3, 131.4, 132.1, 133.1, 157.5, 157.9, 159.6, 162.8, 163.1, 170.0, 170.2;
HRMS (ESI) calcd for C20H15ClF3NNaO5 [MþNa]þ: 464.0483, found:
464.0489.
Reagents were purchased from commercial sources and were
used as received unless mentioned otherwise. Reactions were
monitored by TLC. 1H NMR and 13C NMR (300 and 75 MHz,
respectively) spectra were recorded in CDCl3. 1H NMR chemical
shifts are reported in parts per million (ppm) relative to tetrame-
thylsilane (TMS) with the solvent resonance employed as the
internal standard. Data are reported as follows: chemical shift,
multiplicity (s¼singlet, br s¼broad singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet), coupling constants (Hz) and integration.
13C NMR chemical shifts are reported in parts per million (ppm)
from tetramethylsilane (TMS) with the solvent resonance as the
internal standard. Melting points were recorded on a Buchi Melting
Point B-545.
4.2.5. Methyl 2-(3-chlorophenyl)-4-hydroxy-1-(4-methoxyphenyl)-
5-oxo-4-(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
(3e). Yellow solid, 94% yield; mp 126.8e127.9 ꢀC; 1H NMR
(300 MHz, CDCl3)
(d, J¼7.8 Hz, 1H), 6.88 (d, J¼9.0 Hz, 2H), 6.77 (d, J¼9.0 Hz, 2H), 5.09
(br s, 1H), 3.74 (s, 3H), 3.65 (s, 3H); 13C NMR (75 MHz, CDCl3)
51.9,
d
7.33 (d, J¼7.8 Hz, 1H), 7.26e7.19 (m, 2H), 7.04
d
55.4, 76.6 (q, J¼31.3 Hz, 1C), 104.0, 114.5, 122.8 (q, J¼286.6 Hz, 1C),
124.8, 127.2, 128.8, 129.3, 129.4, 130.6, 133.9, 158.5, 159.5, 163.2,
169.9; HRMS (ESI) calcd for C20H15ClF3NNaO5 [MþNa]þ: 464.0483,
found: 464.0479.
4.2. General procedure for the synthesis of 3-hydroxy-3-(tri-
fluoromethyl)-1H-pyrrol-2(3H)-ones
4.2.6. Methyl 2-(4-chlorophenyl)-4-hydroxy-1-(4-methoxyphenyl)-
5-oxo-4-(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
(3f). Yellow solid, 95% yield; mp 134.1e135.8 ꢀC; 1H NMR
To a test tube equipped with a magnetic stirring bar were
sequentially added 1 (0.20 mmol), TFA solution (c¼0.01 M, 2 mL
CH2Cl2), and ethyl trifluoropyruvate (0.5 mmol). Then the mixture
was stirred for indicated time at room temperature. After com-
pletion of the reaction, as monitored by TLC, the solvent was
removed under reduced pressure, and the residue was subjected to
flash chromatography on silica gel (petroleum ether/ethyl
acetate¼5:1) to give the mixture of the corresponding product.
After that the mixture was dried in vacuum at 100 ꢀC for 10 h to
afford the single product 3.
(300 MHz, CDCl3)
(d, J¼9.0 Hz, 2H), 6.79 (d, J¼9.0 Hz, 2H), 5.09 (s, 1H), 3.77 (s, 3H),
3.68 (s, 3H); 13C NMR (75 MHz, CDCl3)
51.9, 55.4, 76.6
d
7.29 (d, J¼8.4 Hz, 2H), 7.16 (d, J¼8.4 Hz, 2H), 6.88
d
(q, J¼31.5 Hz,1C),103.7, 114.5, 122.9 (q, J¼286.6 Hz,1C),124.9,126.0,
128.3, 128.8, 130.6, 136.8, 159.0, 159.4, 163.3, 169.9; HRMS (ESI)
calcd for C20H15ClF3NaO5 [MþNa]þ: 464.0483, found: 464.0485.
4.2.7. Methyl 4-hydroxy-1-(4-methoxyphenyl)-5-oxo-2-(p-tolyl)-4-
(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
(3g). Colorless oil, 88% yield; 1H NMR (300 MHz, CDCl3)
d 7.07
4.2.1. Methyl 4-hydroxy-5-oxo-1,2-diphenyl-4-(trifluoromethyl)-4,5-
dihydro-1H-pyrrole-3-carboxylate (3a). White solid, 95% yield; mp
(s, 4H), 6.86 (d, J¼9.0 Hz, 2H), 6.75 (d, J¼9.0 Hz, 2H), 5.16 (br s, 1H),
3.73 (s, 3H), 3.64 (s, 3H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3)
126.5e128.0 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.39e7.20 (m, 8H),
6.98e6.96 (m, 2H), 5.18 (br s, 1H), 3.65 (s, 3H); 13C NMR (75 MHz,
CDCl3)
d
21.5, 51.7, 55.3, 76.6 (q, J¼31.3 Hz, 1C), 103.0, 114.3, 123.0
(q, J¼286.5 Hz, 1C), 124.5, 125.3, 128.5, 128.8, 129.1, 140.9, 159.2,
160.5, 163.7, 170.2; HRMS (ESI) calcd for C21H18F3NNaO5 [MþNa]þ:
444.1029, found: 444.1024.
d
51.7, 76.4 (q, J¼38.3 Hz, 1C), 103.7, 123.0 (q, J¼286.7 Hz, 1C),
127.5, 127.6, 127.9, 128.5, 129.1, 129.2, 130.5, 132.7, 159.9, 163.6,
169.7; HRMS (ESI) calcd for C19H14F3NNaO4 [MþNa]þ: 400.0767,
found: 400.0750.
4.2.8. Methyl
fluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (3h). Colorless
oil, 88% yield; 1H NMR (300 MHz, CDCl3)
4-hydroxy-1,2-bis(4-methoxyphenyl)-5-oxo-4-(tri-
4.2.2. Methyl 2-(4-fluorophenyl)-4-hydroxy-1-(4-methoxyphenyl)-
5-oxo-4-(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
(3b). White solid, 94% yield; mp 155.3e157.1 ꢀC; 1H NMR (300 MHz,
d
7.13 (d, J¼8.7 Hz, 2H),
6.87 (d, J¼9.0 Hz, 2H), 6.77 (d, J¼8.7 Hz, 2H), 6.76 (d, J¼9.0 Hz, 2H),
5.19 (s, 1H), 3.78 (s, 3H), 3.74 (s, 3H), 3.66 (s, 3H); 13C NMR (75 MHz,
CDCl3)
d
7.23e7.18 (m, 2H), 7.01e6.95 (m, 2H), 6.86 (d, J¼9.0 Hz, 2H),
CDCl3)
d
51.7, 55.2, 55.3, 76.7 (q, J¼31.2 Hz, 1C), 102.5, 113.2, 114.3,
6.76 (d, J¼9.0 Hz, 2H), 5.13 (s, 1H), 3.73 (s, 3H), 3.65 (s, 3H); 13C NMR
119.3, 123.0 (q, J¼286.6 Hz, 1C), 125.4, 128.7, 131.2, 159.2, 160.2,
161.1, 163.7, 170.2; HRMS (ESI) calcd for C21H18F3NNaO6 [MþNa]þ:
460.0978, found: 460.0957.
(75 MHz, CDCl3)
d
51.8, 55.3, 76.6 (q, Jꢁ31.3 Hz, 1C), 103.5, 114.4,
115.3 (d, J¼22.0 Hz, 1C), 122.9 (q, J¼286.5 Hz, 1C), 123.6 (d, J¼3.5 Hz,
1C), 125.0, 128.8, 131.5 (d, J¼8.7 Hz, 1C), 159.3, 159.4, 163.4, 163.6
(d, J¼250.7 Hz, 1C), 170.0; HRMS (ESI) calcd for C20H15F4NNaO5
[MþNa]þ: 448.0779, found: 448.0770.
4.2.9. Methyl 4-hydroxy-1-(4-methoxyphenyl)-2-(naphthalen-2-yl)-
5-oxo-4-(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
(3i). Red solid, 91% yield; mp 138.7e140.1 ꢀC; 1H NMR (300 MHz,
4.2.3. Methyl 2-(4-bromophenyl)-4-hydroxy-1-(4-methoxyphenyl)-
5-oxo-4-(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
(3c). White solid, 96% yield; mp 154.1e155.7 ꢀC; 1H NMR
CDCl3) d 7.82e7.79 (m, 3H), 7.74e7.71 (m, 1H), 7.57e7.49 (m, 2H),
7.20 (d, J¼8.4 Hz, 1H), 6.92 (d, J¼8.7 Hz, 2H), 6.69 (d, J¼8.7 Hz, 2H),
5.25 (br s, 1H), 3.66 (s, 3H), 3.59 (s, 3H); 13C NMR (75 MHz, CDCl3)
(300 MHz, CDCl3)
(d, J¼8.7 Hz, 2H), 6.76 (d, J¼8.7 Hz, 2H), 5.29 (br, 1H), 3.74 (s, 3H),
3.65 (s, 3H); 13C NMR (75 MHz, CDCl3)
51.9, 55.3, 76.6 (q,
J¼31.2 Hz, 1C), 103.7, 114.5, 122.8 (q, J¼286.5 Hz, 1C), 124.8, 125.2,
126.5, 128.7, 130.7, 131.2, 159.1, 159.4, 163.3, 169.9; HRMS (ESI) calcd
for C20H15BrF3NNaO5 [MþNa]þ: 507.9978, found: 507.9964.
d
7.43 (d, J¼8.1 Hz, 2H), 7.08 (d, J¼8.1 Hz, 2H), 6.86
d
51.8, 55.2, 76.7 (q, J¼31.3 Hz,1C), 103.5,114.3, 123.0 (q, J¼286.3 Hz,
1C), 124.9, 125.2, 125.3, 126.8, 127.6, 127.7, 128.5, 128.7, 130.1, 131.9,
133.6, 159.2, 160.2, 163.7, 170.2; HRMS (ESI) calcd for
C
d
24H18F3NNaO5 [MþNa]þ: 480.1029, found: 480.1032.
4.2.10. Methyl 4-hydroxy-5-oxo-1-phenyl-2-(thiophen-2-yl)-4-(tri-
fluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (3j). White
solid, 86% yield; mp 138.3e138.9 ꢀC; 1H NMR (300 MHz, CDCl3)
4.2.4. Methyl 2-(2-chlorophenyl)-4-hydroxy-1-(4-methoxyphenyl)-
5-oxo-4-(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
(3d). White solid, 96% yield; mp 127.9e128.8 ꢀC; 1H NMR
d
7.49e7.47 (m, 1H), 7.26e7.25 (m, 1H), 6.99e6.94 (m, 3H), 6.82
(d, J¼9.0 Hz, 2H), 5.24 (s, 1H), 3.77 (s, 3H), 3.74 (s, 3H); 13C NMR
(300 MHz, CDCl3)
d
7.38e7.11 (m, 4H), 7.01e6.97 (m, 2H), 6.75
(75 MHz, CDCl3)
d
51.9, 55.4, 76.6 (q, J¼31.2 Hz, 1C), 103.5, 114.5,

Q.-L. Pei et al. / Tetrahedron 70 (2014) 4595e4601
4599
122.9 (q, J¼286.7 Hz, 1C), 125.3, 126.5, 126.6, 129.1, 131.2, 133.8,
153.1, 159.7, 163.5, 169.7; HRMS (ESI) calcd for C18H14F3NO5S
[MþNa]þ: 436.0437, found: 436.0425.
solid, 95% yield; mp 141.6e142.9 ꢀC; 1H NMR (300 MHz, CDCl3)
7.37e7.20 (m, 5H), 7.13e7.10 (m, 1H), 6.78e6.77 (m, 1H),
6.54e6.47 (m, 2H), 5.18 (s, 1H), 3.64 (s, 3H), 3.63 (s, 3H); 13C NMR
(75 MHz, CDCl3)
114.5,119.7, 122.9 (q, J¼286.5 Hz,1C),127.6,127.9,129.1, 129.7, 130.6,
133.6, 159.8, 163.5, 169.6; HRMS (ESI) calcd for C20H16F3NNaO5
[MþNa]þ: 430.0873, found: 430.0872.
d
d
51.8, 55.3, 76.8 (q, J¼31.5 Hz, 1C), 103.6, 113.1,
4.2.11. Methyl 2-cyclohexyl-4-hydroxy-1-(4-methoxyphenyl)-5-oxo-
4-(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
(3k). Colorless oil, 90% yield; 1H NMR (300 MHz, CDCl3)
d 7.07 (br s,
2H), 6.98 (d, J¼9.0 Hz, 2H), 4.90 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H),
2.90 (br, 1H), 1.69e1.59 (m, 8H), 1.07e1.01 (m, 2H); 13C NMR
4.2.18. Methyl 4-hydroxy-1-(4-methoxyphenyl)-5-oxo-2-phenyl-4-
(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (3r). White
solid, 95% yield; mp 148.8e149.9 ꢀC; 1H NMR (300 MHz, CDCl3)
(75 MHz, CDCl3)
d 25.2, 26.1, 28.1, 28.9, 38.3, 51.7, 55.5, 76.1
(q, J¼30.9 Hz,1C),101.6,114.9,123.0 (q, J¼286.8 Hz,1C),125.8,129.7,
160.4, 163.7, 168.1, 171.0; HRMS (ESI) calcd for C20H22F3NNaO5
[MþNa]þ: 436.1342, found: 436.1348.
d
7.35e7.28 (m, 3H), 7.20e7.17 (m, 2H), 6.88e6.84 (m, 2H),
6.75e6.72 (m, 2H), 5.11 (s, 1H), 3.72 (s, 3H), 3.63 (s, 3H); 13C NMR
(75 MHz, CDCl3)
d
51.6, 55.3, 76.7 (q, J¼31.3 Hz, 1C), 103.4, 114.3,
4.2.12. Methyl 1-(4-fluorophenyl)-4-hydroxy-5-oxo-2-phenyl-4-(tri-
123.0 (q, J¼286.6 Hz, 1C), 125.2, 127.7, 127.8, 128.8, 129.1, 130.4,
159.3, 160.2, 163.6, 170.1; HRMS (ESI) calcd for C20H16F3NNaO5
[MþNa]þ: 430.0873, found: 430.0879.
fluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
solid, 92% yield; mp 122.5e123.9 ꢀC; 1H NMR (300 MHz, CDCl3)
7.40e7.26 (m, 3H), 7.20e7.17 (m, 2H), 6.95e6.92(m, 4H), 5.19 (s,1H),
3.63 (s, 3H); 13C NMR (75 MHz, CDCl3)
(3l). White
d
d
51.8, 76.7 (q, J¼31.3 Hz, 1C),
4.2.19. Methyl
fluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
solid, 86% yield; mp 122.8e123.7 ꢀC; 1H NMR (300 MHz, CDCl3)
7.50e7.45 (m, 1H), 7.40e7.35 (m, 2H), 7.20e7.15 (m, 3H), 7.11e7.09
1-benzyl-4-hydroxy-5-oxo-2-phenyl-4-(tri-
103.8, 116.2 (d, J¼22.9 Hz, 1C), 122.9 (q, J¼286.7 Hz, 1C), 127.4, 128.0,
128.6 (d, J¼3.4Hz,1C),129.1,129.4(d, J¼13.5Hz,1C),130.7,159.5,161.9
(d, J¼248.0 Hz,1C),163.5,169.8; HRMS (ESI) calcd for C19H13F4NNaO4
[MþNa]þ: 418.0673, found: 418.0667.
(3s). White
d
(m, 2H), 6.80e6.77 (m, 2H), 4.97 (s, 1H), 4.71 (d, J¼15.3 Hz,1H), 4.40
(d, J¼15.3 Hz,1H), 3.54 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 44.6, 51.5,
4.2.13. Methyl
1-(4-bromophenyl)-4-hydroxy-5-oxo-2-phenyl-4-
76.5 (q, J¼31.4 Hz, 1C), 104.2, 122.9 (q, J¼286.2 Hz, 1C), 127.2, 127.8,
127.9, 128.2, 128.5, 130.5, 135.3, 160.4, 163.3, 171.0; HRMS (ESI) calcd
for C20H16F3NNaO4 [MþNa]þ: 414.0924, found: 414.0903.
(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (3m). Light
yellow solid, 91% yield; mp 186.1e187.8 ꢀC; 1H NMR (300 MHz,
CDCl3)
d
7.42e7.29 (m, 5H), 7.20e7.18 (m, 2H), 6.83 (d, J¼8.7 Hz,
51.9, 77.0
2H), 5.17 (s, 1H), 3.64 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
4.2.20. Ethyl 4-hydroxy-5-oxo-1,2-diphenyl-4-(trifluoromethyl)-4,5-
dihydro-1H-pyrrole-3-carboxylate (3t). White solid, 96% yield; mp
(q, J¼37.8 Hz, 1C), 104.1, 122.5, 122.9 (q, J¼286.6 Hz, 1C), 127.3, 128.1,
128.9,129.2,130.8,131.7, 132.3, 159.2, 163.5, 169.5; HRMS (ESI) calcd
for C19H13BrF3NNaO4 [MþNa]þ: 477.9872, found: 477.9858.
104.0e105.4 ꢀC; 1H NMR (300 MHz, CDCl3)
d 7.37e7.19 (m, 8H),
6.98e6.95 (m, 2H), 5.31 (br s, 1H), 4.16e4.05 (m, 2H), 1.01
(t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 13.6, 61.0, 76.9
4.2.14. Methyl 1-(4-chlorophenyl)-4-hydroxy-5-oxo-2-phenyl-4-(tri-
(q, J¼39.9 Hz, 1C),103.9,123.0 (q, J¼286.5 Hz,1C), 127.5, 127.7, 127.8,
128.5,129.1,129.2,130.4,132.6,159.6,163.3,169.8; HRMS (ESI) calcd
for C20H16F3NNaO4 [MþNa]þ: 414.0924, found: 414.0916.
fluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
(3n). Yellow
solid, 88% yield; mp 161.6e163.3 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.43e7.39 (m, 1H), 7.35e7.31 (m, 2H), 7.28e7.20 (m, 4H), 6.91 (d,
J¼8.7Hz, 2H), 5.19(s,1H),3.66(s, 3H);13CNMR(75MHz,CDCl3)
d
51.9,
4.2.21. iso-Propyl
4-hydroxy-5-oxo-1,2-diphenyl-4-(tri-
76.8 (q, J¼31.0 Hz, 1C), 103.9, 122.8 (q, J¼286.7 Hz, 1C), 127.3, 128.1,
128.7, 129.1, 129.3, 130.8, 131.1, 134.4, 159.3, 163.5, 169.6; HRMS (ESI)
calcd for C19H13ClF3NNaO4 [MþNa]þ: 434.0377, found: 434.0380.
fluoromethyl)-4, 5-dihydro-1H-pyrrole-3-carboxylate (3u). White
solid, 95% yield; mp 110.2e111.6 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.37e7.18 (m, 8H), 6.98e6.95 (m, 2H), 5.34 (s, 1H), 5.03e4.95
(m, 1H), 1.12 (d, J¼6.3 Hz, 3H), 0.94 (d, J¼6.3 Hz, 3H); 13C NMR
4.2.15. Methyl
fluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
solid, 96% yield; mp 160.8e161.7 ꢀC; 1H NMR (300 MHz, CDCl3)
4-hydroxy-5-oxo-2-phenyl-1-(p-tolyl)-4-(tri-
(75 MHz, CDCl3)
d
21.2, 21.6, 69.0, 76.9 (q, J¼31.7 Hz,1C),104.5,123.1
(3o). White
(q, J¼286.4 Hz, 1C), 127.6, 127.7, 128.0, 128.4, 129.0, 129.3, 130.3,
132.9, 159.2, 162.9, 169.7; HRMS (ESI) calcd for C21H18F3NNaO4
[MþNa]þ: 428.1080, found: 428.1088.
d
7.35e7.25 (m, 3H), 7.21e7.18 (m, 2H), 7.03 (d, J¼8.1 Hz, 2H), 6.83
(d, J¼8.1 Hz, 2H), 5.16 (br s, 1H), 3.62 (s, 3H), 2.25 (s, 3H); 13C NMR
(75 MHz, CDCl3)
d
21.0, 51.7, 76.7 (q, J¼31.1 Hz, 1C), 103.5, 123.0 (q,
4.2.22. tert-Butyl 4-hydroxy-5-oxo-1,2-diphenyl-4-(trifluoromethyl)-
4,5-dihydro-1H-pyrrole-3-carboxylate (3v). White foam, 98% yield;
J¼286.5 Hz, 1C), 127.3, 127.7, 127.8, 129.1, 129.7, 130.0, 130.4, 138.6,
160.1, 163.6, 169.9; HRMS (ESI) calcd for C20H16F3NNaO4 [MþNa]þ:
414.0924, found: 414.0924.
mp 126.4e127.8 ꢀC; 1H NMR (300 MHz, CDCl3)
d
7.32e7.17 (m, 8H),
6.96e6.94 (m, 2H), 5.48 (br s, 1H),1.25 (s, 9H); 13C NMR (75 MHz,
CDCl3)
d
27.8, 76.9 (q, J¼31.2 Hz, 1C), 82.8, 105.3, 123.1
4.2.16. Methyl 4-hydroxy-1-(2-methoxyphenyl)-5-oxo-2-phenyl-4-
(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate
(3p). Yellow solid, 93% yield; mp 160.1e161.4 ꢀC; 1H NMR
(q, J¼286.4 Hz, 1C), 127.6, 127.8, 128.2, 128.4, 129.0, 129.2, 130.1,
132.9, 158.3, 163.0, 169.8; HRMS (ESI) calcd for C22H20F3NNaO4
[MþNa]þ: 442.1237, found: 442.1231.
(300 MHz, DMSO-d6)
4H), 7.18e7.16 (m, 2H), 7.11e7.08 (m,1H), 6.94e6.85 (m, 2H), 3.60 (s,
3H), 3.49 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
50.9, 55.6, 55.7,
d 7.79 (s, 0.4H), 7.60 (s, 0.6H), 7.30e7.23 (m,
4.2.23. Methyl 4-hydroxy-5-oxo-2-phenyl-4-(trifluoromethyl)-4,5-
dihydro-1H-pyrrole-3-carboxylate (3w). White solid, 81% yield;
d
76.6 (q, J¼30.8 Hz, 1C), 105.0, 105.3, 112.1, 112.2, 120.3, 120.5, 121.6,
121.7, 123.0 (q, J¼285.1 Hz, 0.5C), 123.2 (q, J¼286.1 Hz, 0.5C), 127.4,
127.5, 128.2, 128.3, 128.7, 128.8, 129.7, 129.8, 130.1, 130.2, 130.7,
130.9, 154.9, 155.0, 160.2, 160.4, 161.8, 161.9, 171.3, 171.9; HRMS (ESI)
calcd for C20H16F3NNaO5 [MþNa]þ: 430.0873, found: 430.0870.
mp 124.8e125.1 ꢀC; 1H NMR (300 MHz, CDCl3)
d
8.19 (br s, 1H),
7.61e7.47 (m, 5H), 5.03 (s, 1H), 3.71 (s, 3H); 13C NMR (75 MHz,
CDCl3)
51.8, 77.5 (q, J¼31.8 Hz, 1C), 102.3, 122.8 (q, J¼286.4 Hz, 1C),
d
125.0, 127.9, 128.6, 132.0, 156.4, 163.5, 171.1; HRMS (ESI) calcd for
C
13H10F3NNaO4 [MþNa]þ: 324.0454, found: 324.0442.
4.2.17. Methyl 4-hydroxy-1-(3-methoxyphenyl)-5-oxo-2-phenyl-4-
(trifluoromethyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (3q). White
4.2.24. Methyl 4-hydroxy-5-oxo-2-(p-tolyl)-4-(trifluoromethyl)-4,5-
dihydro-1H-pyrrole-3-carboxylate (3x). White solid, 80% yield; mp

4600
Q.-L. Pei et al. / Tetrahedron 70 (2014) 4595e4601
168.0e169.1 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
11.09 (br s, 1H),
0.4H), 5.69 (d, J¼6.6 Hz, 0.6H), 5.08 (br s, 0.4H), 4.94 (br s, 0.6H),
3.78 (s, 1.7H), 3.72e3.70 (m, 3.4H), 3.45 (d, J¼6.6 Hz, 0.6H), 3.27
(s, 1.3H); 13C NMR (75 MHz, CDCl3)
51.7, 51.8. 53.0, 54.5, 55.2, 55.3,
7.41 (d, J¼8.1 Hz, 2H), 7.34 (s, 1H), 7.29 (d, J¼8.1 Hz, 2H), 3.52 (s, 3H),
2.37 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d
21.1, 50.9, 77.3
d
(q, J¼30.4 Hz,1C),102.6,123.2 (q, J¼285.0 Hz,1C),126.0,128.7,141.2,
157.5, 162.6, 173.3; HRMS (ESI) calcd for C14H12F3NNaO4 [MþNa]þ:
338.0611, found: 338.0601.
61.9, 62.5, 76.6 (q, J¼31.3 Hz, 0.4C), 78.5 (q, J¼31.5 Hz, 0.6C), 113.9,
114.1, 122.6 (q, J¼282.6 Hz, 0.4C), 123.3 (q, J¼283.4 Hz, 0.6C), 124.6,
125.3, 126.8, 128.0, 128.1, 128.3, 128.5, 128.7, 129.1, 133.2, 137.5,
157.4, 157.9, 166.2, 166.4, 167.8, 168.3; HRMS (ESI) calcd for
4.2.25. Methyl 4-hydroxy-2-(4-methoxyphenyl)-5-oxo-4-(trifluoro
methyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (3y). White solid,
C
20H18F3NNaO5 [MþNa]þ: 432.1029, found: 432.1015.
93% yield; mp 165.5e167.0 ꢀC; 1H NMR (300 MHz, DMSO-d6)
d
11.04
(br s, 1H), 7.51 (d, J¼8.7 Hz, 2H), 7.27 (s, 1H), 7.03 (d, J¼8.7 Hz, 2H),
3.82 (s, 3H), 3.55 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
50.8, 55.5,
4.4. Procedure for the catalytic asymmetric reaction of b-
enamine ester and ethyl trifluoropyruvate
d
77.4 (q, J¼30.4 Hz, 1C), 101.8, 113.6, 120.8, 123.3 (q, J¼285.0 Hz, 1C),
130.7,157.2, 161.5,162.8,173.3; HRMS (ESI) calcd for C14H12F3NNaO5
[MþNa]þ: 354.0560, found: 354.0559.
To a test tube equipped with a magnetic stirring bar were se-
quentially added 1s (0.20 mmol), A (20 mol %), CH2Cl2 (2 mL), and 2
(0.5 mmol). The mixture was stirred at room temperature for 7 h,
concentrated, and the residue was subjected to flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate¼5:1) to give the
mixture of the corresponding product. Then the mixture was dried
4.2.26. Methyl
methyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (3z). White solid,
84% yield; mp 180.1e181.2 ꢀC; 1H NMR (300 MHz, DMSO-d6)
11.21
(br s, 1H), 7.71 (d, J¼8.4 Hz, 2H), 7.46 (d, J¼8.4 Hz, 2H), 7.41 (s, 1H),
3.53 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
2-(4-bromophenyl)-4-hydroxy-5-oxo-4-(trifluoro
in vacuum at 100 ꢀC for 10 h to afford the chiral product 3s as
d
20
a white solid in 95% yield, 59% ee. [
a
]
ꢁ2.6 (c 0.72, EtOH); chiral
D
d
51.0, 77.3 (q, J¼30.5 Hz,
HPLC condition: Daicel Chiralpak AD-H, hexanes/i-PrOH¼70:30,
flow rate¼1.0 mL/min, UV¼254 nm, tR¼5.77 min (minor) and
tR¼6.35 min (major).
1C), 103.7, 123.1 (q, J¼284.9 Hz, 1C), 124.6, 128.2, 130.8, 131.3, 156.7,
162.3, 173.2; HRMS (ESI) calcd for C13H9BrF3NNaO4 [MþNa]þ:
401.9559, found: 401.9549.
Acknowledgements
4.2.27. Methyl
methyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (3a0). White solid,
94% yield; mp 133.7e135.0 ꢀC; 1H NMR (300 MHz, DMSO-d6)
11.13
(br s, 1H), 7.60e7.57 (m, 1H), 7.51e7.47 (m, 1H), 7.45e7.36 (m, 3H),
3.43 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
1C), 106.0, 123.1 (q, J¼285.1 Hz, 1C), 127.3, 129.5, 129.8, 131.4, 131.7,
156.0, 161.5, 173.2; HRMS (ESI) calcd for C13H9ClF3NNaO4 [MþNa]þ:
358.0064, found: 358.0061.
2-(2-chlorophenyl)-4-hydroxy-5-oxo-4-(trifluoro
We are grateful for financial support from the National Natural
Science Foundation of China (No. 21372217), and Sichuan Youth
Science and Technology Foundation (No. 2011JQ0046
and 2013JQ0021).
d
d
50.9, 76.8 (q, J¼30.8 Hz,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.05.052.
4.2.28. Methyl
methyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (3b0). White solid,
68% yield; mp 109.1e110.8 ꢀC; 1H NMR (300 MHz, DMSO-d6)
11.25
(br s, 1H), 8.16 (s, 1H), 8.07e7.99 (m, 3H), 7.67e7.55 (m, 3H), 7.41 (br
s, 1H), 3.53 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
50.9, 77.4 (q,
J¼30.4 Hz, 1C), 103.5, 123.2 (q, J¼284.9 Hz, 1C), 125.6, 126.6, 126.9,
127.5, 127.7, 127.9, 128.7, 132.0, 133.8, 157.8, 162.5, 173.3; HRMS (ESI)
calcd for C17H12F3NNaO4 [MþNa]þ: 374.0611, found: 374.0600.
4-hydroxy-2-(naphthalen-2-yl)-5-oxo-4-(trifluoro
d
References and notes
d
1. For reviews, see: (a) Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27; (b) Ma, J.-A.;
Cahard, D. Chem. Rev. 2004, 104, 6119; (c) Kirk, K. L. J. Fluorine Chem. 2006, 127,
1013; (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320; (e) Shibata, N.; Mizuta, S.; Kawai, H. Tetrahedron: Asymmetry
2008, 19, 2633; (f) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1; (g) Lam, Y.-h.;
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Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455.
4.2.29. Methyl
4-hydroxy-5-oxo-2-(thiophen-2-yl)-4-(trifluoro
2. Ogawa, S.; Iida, N.; Tokunaga, E.; Shiro, M.; Shibata, N. Chem.dEur. J. 2010, 16,
7090.
methyl)-4,5-dihydro-1H-pyrrole-3-carboxylate (3c0). White solid,
90% yield; mp 163.4e164.9 ꢀC; 1H NMR (300 MHz, DMSO-d6)
3. For examples, see: (a) Grant, T. L.; Ohnmacht, C. J.; Howe, B. B. Trends Pharmacol.
Sci. 1994, 15, 402; (b) Pirotte, B.; Fontaine, J.; Lebrun, P. Curr. Med. Chem. 1995, 2,
573; (c) Empfield, J. R.; Mayhugh, D.; Ohnmacht, C. J.; Frank, C. A.; Grant, T.; Li, J.
Bioorg. Med. Chem. Lett. 1997, 7, 775; (d) Prakash, G. K. S.; Mandal, M.;
Schweizer, S.; Petasis, N. A.; Olah, G. A. Org. Lett. 2000, 2, 3173; (e) Liang, P.-H.;
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P.; Bolego, C.; Cignarella, A.; Puglisi, L. Eur. J. Pharmacol. 2005, 516, 71; (g)
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House, D.; Loiseau, R.; Nisbet, L.; Pacquet, F.; Skone, P. A.; Shanahan, S. E.; Tape,
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d
11.26 (br s, 1H), 8.03 (d, J¼5.1 Hz, 1H), 7.91e7.89 (m, 1H), 7.31 (s,
1H), 7.24 (t, J¼5.1 Hz,1H), 3.67 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d
51.2, 77.2 (q, J¼30.4 Hz, 1C), 100.7, 123.2 (q, J¼285.2 Hz, 1C), 127.3,
128.6, 133.9, 134.9, 149.3, 163.1, 172.7; HRMS (ESI) calcd for
C
11H8F3NNaO4S [MþNa]þ: 330.0018, found: 330.0009.
4.3. The procedure for the transformation of 3r to 5
A solution of 3r (1 mmol) in anhydrous methanol (30 mL) was
treated with palladium (20 wt % on charcoal) under a hydrogen
atmosphere. The reaction mixture was stirred for 12 h at room
temperature. After completion of the reaction, as determined by
TLC, the mixture was filtered through Celite, concentrated, and the
residue was purified by column chromatography (EtOAc/
hexane¼5:1) to obtain 5.
4. (a) Shibata, N.; Fujimoto, H.; Mizuta, S.; Ogawa, S.; Ishiuchi, Y.; Nakamura, S.;
Toru, T. Synlett 2006, 3484; (b) Loop, I.; Skarpos, H.; Kalinovich, N.; Kazakova,
€
O.; Lork, E.; Roschenthaler, G.-V. J. Fluorine Chem. 2010, 131, 389; (c) Sibgatulin,
D. A.; Kostyuk, A. N.; Volochnyuk, D. M.; Rusanov, E. B.; Chernega, A. N. J.
Fluorine Chem. 2010, 131, 234.
4.3.1. Methyl
(trifluoromethyl)pyrrolidine-3-carboxylate (5). White foam, 87%
yield; mp 71.5e72.8 ꢀC; 1H NMR (300 MHz, CDCl3)
7.30e7.16
(m, 6H), 7.10e7.08 (m, 1H), 6.78e6.73 (m, 2H), 5.75 (d, J¼6.6 Hz,
4-hydroxy-1-(4-methoxyphenyl)-5-oxo-2-phenyl-4-
5. For selected examples from our group, see: (a) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.;
Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 2896; (b) Chen, W.-B.;
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3132; (c) Chen, W.-B.; Wu, Z.-J.; Hu, J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org.
d

Q.-L. Pei et al. / Tetrahedron 70 (2014) 4595e4601
4601
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Z.-J.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2012, 14, 490; (f) Liao, Y.-H.; Liu, X.-L.;
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Liao, Y.-H.; Wu, Z.-J.; Han, W.-Y.; Zhang, X.-M.; Yuan, W.-C. Chem.dEur. J. 2012,
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7. For selected examples, see: (a) Cimarelli, C.; Palmieri, G. J. Org. Chem. 1996, 61,
5557; (b) Suri, M.; Jousseaume, T.; Neumann, J. J.; Glorius, F. Green Chem. 2012,
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Lin, W.-Q.; Yuan, W.-C.; Zhang, X.-M. Chem.dEur. J. 2008, 14, 9864; (g) Yan, R.-
L.; Luo, J.; Wang, C.-X.; Ma, C.-W.; Huang, G.-S.; Liang, Y.-M. J. Org. Chem. 2010,
75, 5395; (h) Neumann, J. J.; Suri, M.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49,
7790; (i) Hou, G.; Li, W.; Ma, M.; Zhang, X.; Zhang, X. J. Am. Chem. Soc. 2010, 132,
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€
€
6. For selected examples, see: (a) Zhuang, W.; Gathergood, N.; Hazell, R. G.;
Jørgensen, K. A. J. Org. Chem. 2001, 66, 1009; (b) Bøevig, A.; Gothelf, K. V.;
Jørgensen, K. A. Chem.dEur. J. 2002, 8, 5652; (c) Lyle, M. P. A.; Draper, N. D.;
€ €
Wilson, P. D. Org. Lett. 2005, 7, 901; (d) Torok, B.; Abid, M.; London, G.; Esquibel,
€ €
J.; Torok, M.; Mhadgut, S. C.; Yan, P.; Prakash, G. K. S. Angew. Chem., Int. Ed. 2005,
8. For details, see Supplementary data.
44, 3086; (e) Zhuang, W.; Poulsen, T. B.; Jørgensen, K. A. Org. Biomol. Chem.
2005, 3, 3284; (f) Mikami, K.; Kakuno, H.; Aikawa, K. Angew. Chem., Int. Ed.
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C. F., III. J. Org. Chem. 2006, 71, 3822; (h) Ogawa, S.; Shibata, N.; Inagaki, J.;
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K.; Yang, Y.; Zhao, J.; Yin, C.; Lin, L.; Liu, X.; Feng, X. Chem.dEur. J. 2010, 16, 9969.
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10. For the enantiomeric excess analysis of chiral 3s, see Supplementary data.