Asymmetric Construction of Pyrrolidines Bearing a Trifluoromethylated Quaternary Stereogenic Center via CuI-Catalyzed 1,3-Dipolar Cycloaddition of Azomethine Ylides with β-CF3-β,β-Disubstituted Nitroalkenes

Article abstract of DOI:10.1002/asia.201600941

A direct and convenient method has been developed for the synthesis of optically active pyrrolidines bearing a quaternary stereogenic center containing a CF₃ group at the C-3 position of the pyrrolidine ring. The synthesis system, Cu^I/Si-FOXAP-catalyzed exo-selective 1,3-dipolar cycloaddition of azomethine ylides with β-CF₃-β,β-disubstituted nitroalkenes, provides pyrrolidines with high diastereoselectivities (up to >98:2 d.r.) and excellent enantioselectivities (up to >99.9 ee) and performs well for a broad scope of substrates under mild conditions.

Full text of DOI:10.1002/asia.201600941

CHEMISTRY
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Accepted Article
Title: Asymmetric construction of pyrrolidines bearing a trifluoromethylated Quater-
nary Stereogenic Center via Cu(I)-catalyzed 1,3-dipolar cycloaddition of β-CF3
nitroalkenes
Authors: Liwei Tang; Baojing Zhao; Li Dai; Man Zhang; Zhiming Zhou
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Chemistry - An Asian Journal
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Asymmetric Construction of Pyrrolidines Bearing a
Trifluoromethylated Quaternary Stereogenic Center via CuI-
catalyzed 1,3-Dipolar Cycloaddition of azomethine ylides with β-
CF3-β,β-disubstituted nitroalkenes
Li-Wei Tang,+[a] Bao-Jing Zhao,+[a] Li Dai,[a] Man Zhang,[a] and Zhi-Ming Zhou*[a,b]
Abstract: A direct and convenient access has been developed for
synthesis of
optical active pyrrolidines bearing a quaternary
stereogenic center containing a CF3 group at the C-3 position of the
pyrrolidine ring. The synthesis system, CuI/Si-FOXAP-catalyzed exo-
selective 1,3-dipolar cycloadditon of azomethine ylides with β-CF3-β,
β-disubstituted nitroalkenes, provides pyrrolidines with high
diastereoselectivities
(up
to
>98:2
dr)
and
excellent
enantioselectivities (up to >99.9 ee) and performs well for a broad
scope of substrates under mild conditions.
Introduction
Owing to the unique and fascinating nature of fluorine,
fluoroorganic chemistry has attracted increasing attention in
recent years. Fluorinated compounds have an growing demand
for the development and application in a wide range of important
fields such as new medicines, agrochemicals, military, textiles
and functional materials.[1] Especially, organofluorine compounds
have a remarkable record in medicinal chemistry.[2] Accordingly,
20% of pharmaceuticals and 30-40% of agrochemicals on the
market contain at least one fluorine atom.[3] The trifluoromethyl
Figure 1. Representatives of medicines and biologically active proline
derivatives bearing a trifluoromethylated or fluorinated quaternary stereocenter.
group[4] with specific properties take
a large majority of
fluorinated compounds. More specifically, many medicines or
biologically active compounds contain a trifluoromethylated or
fluorinated quaternary carbon center, including Efavirenz,
Fluorothalidomide, BMS-204352, and α-Tfm-Pro dipeptides
(Figure 1).[5]
Incorporation of trifluoromethyl groups into organic molecules
can dramatically alter many of their physical properties, including
lipophilicity, metabolic stability, especially the bioavailability;[4]
therefore, straightforward and reliable procedures for the
introduction of the trifluoromethyl groups are highly desirable.
The asymmetric synthetic methodologies has been truly
impressive in recent decades; however, the stereoselective
construction of trifluoromethylated quaternary centers is
developing relatively slowly.[6]
Trifluoromethyl group has proven to be
a
valuable
functionality in medicinal chemistry and agrochemistry, where it
is generally used to modify the physiochemical and biological
properties of target molecules. Moerover, the pyrrolidine scaffold
is a widely occurring motif in biologically active compounds. So,
we carry out our research on the preparation of pyrrolidines
bearing a trifluoromethylated quaternary stereocenter at C-3.
Although Melchiorre research group reported
a
new
organocatalytic radical-trapping strategy for the formation of
quaternary stereogenic centers in Nature very recently,[7] the
stereoselective synthesis of quaternary carbon centers is still
challenging and only limited options are available.[8] 1,3-Dipolar
cycloadditions are one of the most useful synthetic routes for the
stereoselective construction of at least one quaternary
stereocenter, containing five-membered heterocyclic rings.[9]
Overman’s group developed a catalyst system for construction of
pyrrolidines with a all-carbon quaternary stereocenter at C-4 by
using methacrylonitrile as the dipolarophiles.[10] In 2011, the
groups of Vicario and Co′rdova independently reported the
reaction of azomethine ylides derived from α-iminoacetates with
α,β-unsaturated aldehydes led to the highly enantioselective
synthesis of pyrrolidines owing a quaternary stereocenter at C-
2.[11] Deng’s group synthesis the pyrrolidines bearing quaternary
α-amino acids at the C-4.[12] Moreover, Wang and co-workers
have reported some excellent works on the preparation of
pyrrolidines bearing a quaternary stereocenter at C-2 or C-4.[13]
[a]
Dr. L. Tang, B. Zhao, L. Dai, M. Zhang, Prof. Dr. Z. Zhou
R&D Centre of Pharmaceuticals school of Chemical Engineering
and the Environment
Beijing Institute of Technology
5th zhongguancun South Street, Haidian District, Beijing(China)
E-mail: zzm@bit.edu.cn
[b]
Prof. Dr. Z. Zhou
State Key Laboratory of Explosion Science and Technology
Beijing Institute of Technology
+ The two authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Quite recently, Zhang and co-workers reported the work about
stereoselective construction of trifluoromethylated pyrrolidines
owing a quaternary stereocenter at C-3 by using β-trifluoromethyl
β, β-disubstituted enones as the dipolarophiles.[14] However, to
the best of our knowledge, β-CF3-β, β-disubstituted
nitroalkenes[15], that lead to the formation of pyrrolidines bearing
a trifluoromethylated quaternary stereocenter at C-3, have not
been explored.
Table 1. Optimization of the reaction catalytic systems[a]
.
Recently, we reported a new siloxane-substituted FOXAP
ligand(Si-FOXAP, L1) that exhibited high diastereoselectivity and
enantioselectivity in the CuII-catalyzed asymmetric 1,3-dipolar
cycloaddition of azomethine ylides with alkylidene malonates.[16]
Encouraged by this achievement, we start our work on the
preparation of pyrrolidines bearing a quaternary stereocenter at
C-3. Initially, we chose β-CF3-β,β-disubstituted nitroalkenes as
the dipolarophiles in the 1,3-dipolar cycloaddition. To our delight,
we got excellent results after optimizing the reaction conditions.
Herein, we firstly report that β-trifluoromethyl β, β-disubstituted
nitroalkenes have been used as effective dipolarophiles in the
catalytic 1,3-dipolar cycloadditions of azomethine ylides, a facile
approach to pyrrolidines bearing a trifluoromethylated quaternary
stereogenic center at the C-3 position of the pyrrolidine ring.
Entry
1
Ligand/Lewis acid
L1/ Cu(OAc)2·H2O
L1/Cu(OTf)2
Yield (%)[b]
65
dr (%) [c]
ee (%) [d]
85:15
92.8
2
73
90:10
91
3
L1/Cu(ClO4)2·6H2O
L1/Cu(CH3CN)4ClO4
L1/AgOTf
71
90:10
93
4
75
92:8
96.6
5
76
95:5
88.4
6
L1/Ni(ClO4)2·6H2O
L1/Zn(OTf)2
n.d.
n.d.
n.d.
68
-
-
7
-
-
8
L1/Sc(OTf)3
-
-
9
L2/ Cu(CH3CN)4ClO4
L3/ Cu(CH3CN)4ClO4
L4
90:10
85.8
Results and Discussion
10
11
12
13[e]
n.d.
n.d.
n.d.
67
-
-
We initially examined the reactivity of azomethine ylide 1a with β-
trifluoromethyl nitroalkene 2a in the presence of 10 mol % of the
Cu(OAc)2·H2O /L1 complex as the catalyst and 10 mol% of
K2CO3 as the base in DCM at rt. Unfortunately, no desired
product was observed. To our delight, when DIPEA(10 mol%)
was used as the base, the reaction was finished smoothly, and
afforded the expected trifluoromethylated pyrrolidine 3aa in 65%
yield with good diastereoselectivity and 92.8% ee (Table 1, Entry
1), which indicated that β-trifluoromethyl nitroalkene could be
applied in our catalytic system as dipolarophile for the efficient
construction of pyrrolidines bearing a unique trifluoromethylated
quaternary stereogenic center.
-
-
L5
-
-
L1/Cu(CH3CN)4ClO4
95:5
90.2
[a] Conditions: 1a (0.2 mmol), 2a (0.2 mmol), Lewis acid (LA) (10 mol%), chiral
ligand (L) (11 mol %), and DIPEA (10 mol%) in 2.0 mL solvent at room
temperature for 6 h, unless otherwise noted. [b] Isolated yield. [c] Determined
by 1H NMR spectroscopy. [d] Determined by chiral HPLC. [e] 5 mol % catalyst
used.
systems including ligands in hand and some central metals were
screened (Table 1, entries 1-5). We initially tested L1 with
differernt Lewis acid (10 mol%) as the catalyst system in the
reaction between glycine imino ester 1a, which is the precursor
to an azomethine ylide, and β-trifluoromethyl nitroalkene 2a in
dry DCM at room temperature for 6h (Table 1). Under all the CuII
metal salts, the product could be obtained with moderate yield,
good diastereoselectivities and high enantioselectivities (Table1,
entries 2-3). The AgOTf complex combined with L1 only affored
88.4 ee value (Table 1, entry 5). Cu(CH3CN)4ClO4 proved to be
the most efficient catalyst Lewis acid, while the reaction did not
proceed in the presence of Ni(ClO4)2·6H2O, Zn(OTf)2 and
Sc(OTf)3 (Table 1, entries 6-8). Then ligands including ionic
tagged oxazolinyl-phosphine ferrocene,[17] cinchonine-derived
thiourea and quinine-derived squaramide, were examined. L2/
Cu(CH3CN)4ClO4 system could affored 85.8 ee (Table 1, entry 9),
but disappointingly, both L4 and L5 can not catalyze the reaction
(Table 1, entries 11 and 12). Furthermore, the catalyst loading
Scheme 1. Screened ligands in this reaction
Encouraged by these promising results, several catalytic
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10.1002/asia.201600941
FULL PAPER
was then examined. However, the ee value of 3aa decreased to
90.2% when the catalyst loading was reduced to 5 mol% (Table
1, entry 13).
aldehydes, bearing electron-withdrawing and electron-donating
substituents (Table 3, entries 1-18) on the phenyl ring all
performed well, providing the corresponding exo cycloadducts in
high yields (65-86%), with excellent diastereoselectivities (>95:5
d.r.) and enantioselectivities (93->99.9% ee). The reaction
Next, we investigated the effects of the reaction conditions on
this asymmetric 1,3-dipolar cycloaddition of the azomethine ylide
1a and nitroalkene 2a with L1/Cu(CH3CN)4ClO4 as the catalytic
system, results are summarized in Table 2. The influence of
various solvents, including ionic liquid, was tested. By changing
the solvent to CH3CN, toluene or THF all decreased the ee
value (entries 1-3). And the cycloaddition reaction did not occur
Table 3. Substrate scope of various azomethine ylides 1 and β-trifluoromethyl
nitroalkene 2a.[a]
.
-
in [Emin]BF4 (entry 5). After utilizing different bases including
Et3N, pridine, and DBU, DIPEA was still the better base (entries
6-8). Meanwhile, when the reaction was performed at
equivalent base loading, the diastereo- and enantioselectivity
decreased, although with slight higher yield (entry 10).
Furthermore, when the temperature was lowered to 0 °C, both
diastereoselectivity and enantioselectivity obviously increased
(entry 9). Based on the above results, the optimal reaction
conditions for the asymmetric 1,3-dipolar cycloaddition were as
follows: 10 mol% Cu(CH3CN)4ClO4/L1 as the catalyst, CH2Cl2 as
the solvent, and 10 mol% DIPEA as the base at 0 oC.
1
a
Entry
R1
Product
Yield (%)[b]
dr (%) [c]
ee (%) [d]
1
Ph
3aa
3ba
3ca
3da
3ea
3fa
81
74
71
77
75
72
77
98:2
96:4
95:5
95:5
95:5
95:5
96:4
99.8
99.4
93.6
95.8
97.4
97.6
2
p-ClPh
p-FPh
m-CF3
p-BrPh
3
4
Table 2. Optimization of the reaction conditions[a]
.
5
6
m-BrPh
o-BrPh
7[e]
3ga
99.0
(>99.9)
8
p-OCH3Ph
p-CH3Ph
3,4-diCH3Ph
2-naphthyl
2-furyl
3ha
3ia
79
83
81
86
80
79
65
82
73
78
n.d.
78
n.d.
98:2
98:2
98:2
98:2
98:2
98:2
96:4
98:2
98:2
98:2
-
>99.9
99.8
99.6
99.4
95.8
99.6
99.0
96.8
>99.9
97
Entry
Solvent
Base
Yield (%)[b]
dr (%) [c]
ee (%) [d]
9
1
CH3CN
Toluene
THF
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Et3N
65
73
71
75
76
77
63
83
81
83
85:15
90:10
90:10
92:8
92.8
91
10
11
12
13
14
15
16
17
18
19
20
3ja
2
3ka
3la
3
93
4
EtOH
96.6
88.4
95.7
94.4
96.5
99.8
77.8
2-thienyl
m-NO2Ph
p-MeS
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ta
-
5
[Emim]BF4
95:5
6
DCM
95:5
7
DCM
Pridine
DBU
90:10
95:5
o-OMe
8
DCM
2,4-diF
9[e]
10[f]
DCM
DIPEA
DIPEA
98:2
o-OH
-
DCM
95:5
o-Me
98:2
-
>99.9
-
cyclohexyl
[a] Conditions: 1a (0.2 mmol), 2a (0.2 mmol), Cu(CH3CN)4ClO4 (10 mol%), L1
(11 mol %) in 2.0 mL solvent at room temperature for 6 h, unless otherwise
noted. [b] Isolated yield. [c] Determined by 1H NMR spectroscopy. [d]
Determined by chiral HPLC. [e] Reacted at 0oC for 8h. [f] 1 eq. base used.
[a] Conditions: 1a (0.2 mmol), 2a (0.2 mmol), Cu(Ch3CN)4ClO4 (10 mol%), L1
(11 mol %), and DIPEA (10 mol%) in 2.0 mL DCM at 0oC, unless otherwise
noted. [b] Isolated yield. [c] Determined by 1H NMR spectroscopy. [d]
Determined by chiral HPLC. [e] The ee values given in parenthese was
determined after simple recrystallization.
Next, the substrate scope of this 1,3-dipolar cycloaddition
was investigated under the optimized reaction conditions. As
shown in Table 3, a wide array of azomethine ylides from
appeared to be quite general with respect to the substrates
tested. As a whole, the substrates with electron-donating groups
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gave higher conversions and enantioselectivities than those with
electron-withdrawing ones. The azomethine ylides with a thienyl
moiety and methylthio moiety were also tolerated in this reaction,
and the cycloadduct was obtained with an excellent ee value,
even though the sulfur atom was potentially coordinated to the
Cu salt (Table 2, entries 13 and 15). The naphthyl derivative of
the imino ester afforded the corresponding product 3ka in 76%
yield and 99.4% ee (Table 2 entry 11). Moreover, the furan-2-
carbaldehyde-derived imino ester worked well, leading to 78%
yield of 3la with 95.8% ee (entry 12). Unfortunately, the
cyclohexyl substituted iminoester (entry 20) and the imino ester
bearing an ortho-OH-substituted groups on the aromatic ring
could not be used in the present dipolar [3+2] cycloaddition and
the racemic reaction did not occur as well (entry 18). It is
noteworthy that, such as with bromide substituents, the position
in the ring of the substrate affected the outcomes (entries 5-7).
investigated (Table 4, entry 7), two adjacent all-carbon
quaternary stereogenic centers would be generated in the
corresponding adduct. Regrettably, the reaction did not occurred
at all. Then two more substrates were investigated: just changed
the ester group of imino ester. The compounds could worked
well in this transformation, producing the corresponding 3ca in
99.4% ee, even the one with the bulky t-butyl ester did react,
yielding the product 3da with higher ee value (99.8%). These
proved that the construction of pyrrolidine with two adjacent
quaternary stereocenters is the most difficult and challenging
task.
To further evaluate the prospects of this methodology in
synthesis, a gram-scale synthesis of chiral 3ea was performed.
By treatment of 4 mmol of 1e and 4mmol of 2a, chiral 3ea was
afforded in 73% yield with >95:5 d.r. and 97.5% ee. And to
further confirm the regiochemical control of this cycloaddition and
determine the absolute configuration of the adduct, a single-
[18]
crystal X-ray diffraction study of 3ga was performed
and its
Table 4. Substrate scope of azomethine ylides 1 and various β-trifluoro-
methyl nitroalkenes 2.[a]
.
absolute configuration was determined to be exo-(2R,3R,4S,5R)
(Figure 2, upper).
Entry
R2
R3
Product
3ab
3ac
Yield (%)[b]
ee (%) [d]
>99.9
99.6
99.8
99.8
>99.9
99.8
-
1
p-BrPh
3,4-diMePh
p-ClPh
p-FPh
2-naphthyl
p-OMePh
Ph
Me
Me
Me
Me
Me
Me
Me
Et
83
79
81
76
88
85
n.r.
80
73
2
3
3ad
3ae
4
5
3af
6
3ag
3bb
3ca
7[d]
8
Ph
99.4
99.8
9
Ph
t-Bu
3da
[a] Conditions: 1 (0.2 mmol), 2 (0.2 mol), Cu(CH3CN)4ClO4 (10 mol%), and L1
(11 mol %) in DCM (2.0 mL) at 0oC for 8 h, unless otherwise noted and the
diastereomeric ratios are >98:2. [b] Isolated yield. [c] Determined by chiral
HPLC. [d] α-methyl iminoester used.
Figure 2. X-ray structure of 3ag (upper) and proposed transition state for
asymmetric induction (nether).
Then, the substrate scope of dipolarophiles was investigated
(Table 4). A series of β-trifluoromethyl nitroalkene with different
substituents were synthesized. β-Trifluoromethyl nitroalkenes
with
both
electron-withdrawing
and
electron-donating
Based on the configuration of the product, the
enantioselectivity could be rationalized by using proposed
transition state, as shown in Figure 2. It can illustrated that the
positon of the substituents on the aromatic ring of azomethine
ylides affect the result through the steric impact. This can
reasonably explain that ortho-substituted azomethine ylides led
to higher enantioselectivities than para- and meta-ones (showed
substituents underwent 1,3-dipolar cycloaddition, resulting in
good yields and excellent ee values (>99 ee, entries 1-6).
Notably, the product 3aa and 3ae got the highest ee value (>99.9
ee).
Encouraged by these results, the reaction of alanine-derived
imino ester, containing a substituent at the α-position was
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CDCl3) δ = 7.66 (s, 2H), 7.41 (d, 5H), 7.34 (d, 2H), 5.45 (d, J=7.4, 1H),
4.97 (s, 1H), 4.93 (d, J=7.4, 1H), 3.82 (s, 3H), 3.04 (br, 1H). 13C NMR
(126 MHz, CDCl3) δ = 168.18, 135.23, 134.71, 131.21, 129.61, 129.48,
128.81, 127.90, 126.22 (d, JCF=286.1), 96.65, 66.94, 66.69, 66.18 (q,
JCF=23.2), 53.17. IR (KBr) ν 1747, 1558, 1497, 1436, 1363, 1268, 1179,
1156, 1092, 1014, 814, 735, 700, 544 cm-1. HRMS Calcd. For
C19H16ClF3N2O4+H+: 429.08289, found: 429.08304. HPLC (Chiralpak OD-
H column, hexane/2-propanol = 95/5, flow rate = 0.7 mL/min) tR = 17.13
min, 18.50 min.
in Table 1). On the other hand, the substituents on the aromatic
rings of β-trifluoromethyl nitroalkenes have a limited effect on the
enantioselectivity of the reaction.
Conclusions
In conclusion, we have developed the first catalytic asymmetric
synthesis of pyrrolidines bearing a unique trifluoromethylated
quaternary stereogenic center via the CuI/Si-FOXAP-catalyzed
1,3-dipolar cycloaddition of azomethine ylides with β-
trifluoromethyl β, β-disubstituted nitroalkenes. This method
provides a reliable strategy for the excellent enantioselective
(2R,3R,4S,5R)-methyl
5-(4-fluorophenyl)-4-nitro-3-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ca) : White solid. Yield =
71 %; mp 96-98 oC; ee = 93.6 %; [α]D20 = -38.9 (c = 1.2, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 7.66 (s, 2H), 7.48-7.33 (m, 5H), 7.13 (t, 2H), 5.46 (d,
J = 7.5 Hz, 1H), 4.96 (s, 1H), 4.93 (d, J = 7.0 Hz, 1H), 3.82 (s, 3H), 3.08
(br, 1H). 13C NMR (126 MHz, CDCl3) δ 168.19, 163.09 (d, JCF = 248.8 Hz),
132.03 (d, J = 2.8 Hz), 131.25, 129.45, 128.80, 128.40 (d, J = 8.3 Hz),
127.88, 126.26 (d, JCF = 286.1 Hz), 116.52, 116.35, 96.77, 77.29, 77.04,
76.78, 67.02, 66.72, 66.22 (q, JCF = 23.3 Hz), 53.16. IR (KBr) ν 1749,
1561, 1515, 1436, 1366, 1270, 1230, 1183, 1154, 1128, 820, 755, 695,
555, 510 cm-1. HRMS Calcd. For C19H16F4N2O4+H+: 413.11244, found:
413.12246. HPLC (Chiralpak OD-H column, hexane/2-propanol = 90/10,
flow rate = 1 mL/min) tR = 4.15 min, 8.93 min.
construction
of
polysubstituted
pyrrolidines
with
a
trifluoromethylated quaternary stereocenter at the C-3; the
reaction exhibited excellent diastereoselectivity, excellent
enantioselectivity and a broad substrate scope. Moreover, the
cycloaddition proceeded in the presence of only 10 mol% of base
under mild conditions. The easy availability of the substrates and
the potential bioactivity of the enantioenriched trifluoromethylated
pyrrolidine derivatives make this methodology particularly
interesting in medicinal chemistry and organofluorine chemistry.
Further investigation of this protocol towards the synthesis of
pyrrolidines with all-carbon quaternary stereocenter is underway
in our laboratory.
(2R,3R,4S,5R)-methyl
4-nitro-3-phenyl-3-(trifluoromethyl)-5-(4-
(trifluoromethyl) phenyl)pyrrolidine-2-carboxylate (exo-3da) : Colorless oil.
Yield = 77 %; ee = 95.8 %; [α]D20 = -41 (c =1, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.67 (m, 4H), 7.62-7.55 (m, 2H), 7.46-7.34 (m, 3H), 5.50 (d, J =
7.4 Hz, 1H), 5.06-4.93 (m, 2H), 3.83 (s, 3H), 3.11 (t, J = 11.8 Hz, 1H). 13
C
NMR (126 MHz, CDCl3) δ 168.13, 137.33, 131.86 (q, JCF = 32.7 Hz),
131.11, 130.03, 129.79, 129.53, 128.85, 127.89 (d, J = 1.4 Hz), 126.16 (q,
J = 3.7 Hz), 124.92 (dd, JCF = 313.4, 279.4 Hz), 123.64 (q, J = 3.7 Hz),
96.33, 66.90, 66.69, 66.11 (q, JCF = 23.3 Hz), 53.20. 19F NMR (471 MHz,
CDCl3) δ = -62.72, -66.11. IR (KBr) ν 1747, 1561, 1436, 1328, 1157, 1122,
1073, 806, 763, 699, 523 cm-1. HRMS Calcd. For C20H16F6N2O4+H+:
463.10925, found: 463.10929. HPLC (Chiralpak OD-H column, hexane /
2-propanol = 90 / 10, flow rate = 1 mL / min) tR = 7.78 min, 8.95 min.
Experimental Section
General procedure for the Cu-catalyzed [3+2] 1,3-dipolar
cycloaddition reaction.
Cu(CH3CN)4ClO4 (6.54 mg, 0.02 mmol) and Ligand 1 (0.022 mmol) were
added under argon to a 10mL Schlenk tube, containing activated 4Å MS.
The freshly distilled anhydrous DCM (1 mL) was added into the tube.
After being stirred for 30 min at room temperature, the solution was
cooled to 0 oC before the glycine imino ester 16 (0.2 mmol), nitroalkenes
17 (0.2 mmol) and DIPEA (3 μL, 0.02 mmol) were added subsequently.
The reaction mixture was stirred at 0 oC for ambient time. When the
reaction was complete as monitored by TLC, the mixture was passed
through a short column of silica gel and the diastereometric ratio
(exo/endo) was determined by the 1H NMR spectroscopic analysis of the
crude product. Then the pure adducts was purified by column
chromatography on silica gel (200-300 mesh).
(2R,3R,4S,5R)-methyl
5-(4-bromophenyl)-4-nitro-3-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ea) : Brown solid. Yield =
75 %; mp 45-47 oC; ee = 97.4 %; [α]D20 = -30.7 (c =0.8, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 7.65 (s, 2H), 7.57 (d, 2H), 7.41 (d, 3H), 7.27 (d, 2H),
5.44 (d, J = 7.3 Hz, 1H), 4.96 (s, 1H), 4.91 (s, 1H), 3.82 (s, 3H), 3.08 (s,
1H). 13C NMR (126 MHz, CDCl3) δ 168.16, 135.23, 132.58, 131.18,
129.48, 128.81, 128.16, 127.88, 126.20 (d, JCF = 286.1 Hz), 123.35, 96.59,
66.99, 66.67, 66.18 (q, JCF = 23.1 Hz), 53.18. IR (KBr) ν 1746, 1557, 1435,
1363, 1271, 1178, 1155, 1010, 811, 766, 699, 523 cm-1. HRMS Calcd.
For C19H16BrF3N2O4+H+: 473.03238, found: 473.03247. HPLC (Chiralpak
OD-H column, hexane / 2-propanol = 90 / 10, flow rate = 1 mL / min) tR
10.17 min, 11.60 min.
=
(2R,3R,4S,5R)-methyl 4-nitro-3,5-diphenyl-3-(trifluoromethyl)pyrrolidine-2-
carboxylate (exo-3aa): Yellow oil. Yield = 81 %; ee = 99.8 %; [α]D = -
20
58.7 (c = 1.6, CH2Cl2); 1H NMR (500 MHz, CDCl3): δ 7.68 (s, 2H), 7.47-
7.31 (m, 8H), 5.52 (d, J = 7.3 Hz, 1H), 4.98 (s, 1H), 4.96 (d, J = 7.4 Hz,
1H), 3.83 (s, 3H), 3.17 (br, 1H). 13C NMR (126 MHz, CDCl3) δ 168.22,
136.15, 131.38, 129.43, 129.41, 129.24, 128.77, 127.92, 126.46, 126.31
(d, JCF = 286.1 Hz), 96.88, 67.79, 66.82, 66.39 (q, JCF = 23.1 Hz), 53.13.
IR (KBr) ν 1747, 1568, 1500, 1435, 1362, 1273, 1179, 1155, 910, 730,
697, 519 cm-1. HRMS Calcd. For C19H17F3N2O4+H+: 395.12187, found:
395.12206. HPLC (Chiralpak OD-H column, hexane/2-propanol = 90/10,
flow rate = 1 mL/min) tR = 8.32 min, 9.95 min.
(2R,3R,4S,5R)-methyl
5-(3-bromophenyl)-4-nitro-3-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3fa) : White solid. Yield =
72 %; mp 95-97 oC; ee = 97.6%; [α]D20 = -37.5 (c =0.72, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 7.68 (m, 2H), 7.57 (m, 2H), 7.44 (s, 3H), 7.31-7.29 (m,
2H), 5.49 (d, J = 7.4 Hz, 1H), 4.96 (m, 2H), 3.85 (s, 3H), 3.12 (t, J = 10.8
Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 168.12, 138.44, 132.44, 131.16,
130.94, 129.77, 128.82, 128.69 (d, JCF = 201.0 Hz), 127.33, 125.09,
125.06, 123.47, 96.44, 66.87, 66.68, 66.15 (q, JCF = 23.3 Hz), 53.18. IR
(KBr) ν 1747, 1558, 1436, 1362, 1270, 1180, 1155, 998, 778, 695, 519
cm-1. HRMS Calcd. For C19H16BrF3N2O4+H+: 473.03238, found:
473.03240. HPLC (Chiralpak AD-H column, hexane / 2-propanol = 90 / 10,
flow rate = 1 mL / min) tR = 11.22 min, 14.12 min.
(2R,3R,4S,5R)-methyl
5-(4-chlorophenyl)-4-nitro-3-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ba) : Brown oil. Yield =
20
74 %; ee = 99.4 %; [α]D = -37.3 (c = 1.2, CH2Cl2); 1H NMR (500 MHz,
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(2R,3R,4S,5R)-methyl
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ga) : White solid. Yield =
77 %; mp 146-148 oC; ee = 99.0%; [α]D = -87.5 (c =0.96, CH2Cl2); 1H
5-(2-bromophenyl)-4-nitro-3-phenyl-3-
1156, 819, 761, 705, 479 cm-1. HRMS Calcd. For C23H19F3N2O4+H+:
445.13752, found: 445.13781. HPLC (Chiralpak OD-H column, hexane /
2-propanol = 90 / 10, flow rate = 1 mL / min) tR = 11.6 min, 18.30 min.
20
NMR (500 MHz, CDCl3) δ 7.68 (s, 2H), 7.64 (d, 1H), 7.55 (d, 1H), 7.48-
7.37 (m, 4H), 7.29-7.22 (m, 1H), 5.58 (d, J = 6.8 Hz, 1H), 5.49 (t, J = 7.6
Hz, 1H), 5.08 (d, J = 9.0 Hz, 1H), 3.83 (s, 3H), 3.07 (t, J = 10.0 Hz, 1H).
13C NMR (126 MHz, CDCl3) δ 168.31, 135.74, 133.82, 131.21, 130.66,
(2R,3R,4S,5S)-methyl
5-(furan-2-yl)-4-nitro-3-phenyl-3-(trifluoromethyl)
pyrrolidine-2-carboxylate (exo-3la) : Yellow oil. Yield = 80 %; ee = 95.8%;
α
= +13.7 (c =1.2, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.80-7.59 (m,
129.45, 128.70, 128.48, 128.07 (d, J = 1.5 Hz), 127.45, 126.19 (d, JCF
=
2H), 7.51-7.32 (m, 4H), 6.48-6.24 (m, 2H), 5.82 (dd, J = 192.1, 6.2 Hz,
1H), 5.38 (d, J = 4.8 Hz, 1H), 5.05-4.83 (m, 1H), 3.86 (d, J = 45.9 Hz, 3H),
3.37 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 169.44 (d, J = 388.4 Hz),
148.88 (d, J = 157.7 Hz), 143.41 (d, J = 50.1 Hz), 132.49, 131.18, 129.08
286.3 Hz), 124.74, 96.08, 66.20, 65.92, 65.88 (d, JCF = 23.3 Hz), 53.14.
IR (KBr) ν 1746, 1558, 1434, 1313, 1265, 1192, 1154, 1121, 1028, 762,
703, 517, 482 cm-1. HRMS Calcd. For C19H16BrF3N2O4+H+: 473.03238,
found: 473.03302. HPLC (Chiralpak AS-H column, hexane / 2-propanol =
90 / 10, flow rate = 1 mL / min) tR = 8.63 min, 10.67 min.
(dd, J = 71.2, 13.2 Hz), 128.12, 127.97 (d, J = 1.3 Hz), 125.56 (dd, JCF
=
286.0, 124.0 Hz), 110.79 (d, J = 14.3 Hz), 108.99 (d, J = 38.5 Hz), 94.96
(d, J = 56.3 Hz), 66.72 (s), 65.88 (dd, JCF = 86.4, 24.1 Hz), 63.09 (d, J =
295.8 Hz), 59.33 (d, J = 2.8 Hz), 53.29 (d, J = 31.8 Hz). IR (KBr) ν 1745,
1561, 1504, 1436, 1365, 1277, 1201, 1153, 1005, 910, 730, 700, 597 cm-1.
HRMS Calcd. For C17H15F3N2O5+H+: 385.10113, found: 385.10131.
HPLC (Chiralpak OD-H column, hexane / 2-propanol = 90 / 10, flow rate =
1 mL / min) tR = 4.28 min, 7.27 min.
(2R,3R,4S,5R)-methyl
5-(4-methoxyphenyl)-4-nitro-3-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ha) : Coloeless oil. Yield
= 79 %; ee = >99.9%; = -16 (c =0.6, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.67 (s, 2H), 7.45-7.34 (m, 3H), 7.31 (d, 2H), 6.94 (t, 2H), 5.46 (t,
J = 10.3 Hz, 1H), 4.95 (s, 1H), 4.89 (d, J = 7.4 Hz, 1H), 3.83-3.81 (m, 6H),
3.07 (s, 1H). 13C NMR (126 MHz, CDCl3) δ 168.27, 160.22, 131.46,
129.36, 128.75, 128.08, 127.91, 127.81, 126.35 (d, JCF = 286.2 Hz),
114.75, 96.99, 67.50, 66.78, 66.34 (q, JCF = 23.0 Hz), 55.38, 53.10. IR
(KBr) ν 1747, 1558, 1517, 1437, 1364, 1251, 1178, 1155, 1030, 1028,
829, 735, 701, 550, 521 cm-1. HRMS Calcd. For C20H19F3N2O5+H+:
425.13243, found: 425.13267. HPLC (Chiralpak AS-H column, hexane /
2-propanol = 95 / 5, flow rate = 1 mL / min) tR = 14.83 min, 17.07 min.
(2R,3R,4S,5S)-methyl
4-nitro-3-phenyl-5-(thiophen-2-yl)-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ma) : Yellow solid. Yield
o
= 79 %; mp 92-94 C; ee = 99.6%; α = -35 (c =0.4, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 7.66 (s, 2H), 7.44-7.34 (m, 4H), 7.12 (d, 1H), 7.04 (t,
1H), 5.56 (d, J = 7.2 Hz, 1H), 5.19 (s, 1H), 4.96 (s, 1H), 3.82 (s, 3H), 3.15
(s, 1H). 13C NMR (126 MHz, CDCl3) δ 167.91, 138.72, 131.14, 129.47,
128.80, 127.92 (d, J = 1.5 Hz), 127.45, 126.28, 126.13 (d, JCF = 286.1 Hz),
125.80, 97.13, 66.73, 66.35 (dd, JCF = 46.5, 23.3 Hz), 63.74, 53.18. IR
(KBr) ν 1746, 1559, 1436, 1360, 1276, 1179, 1156, 972, 762, 699, 518
cm-1. HRMS Calcd. For C17H15F3N2O4S+H+: 401.07829, found: 401.07833.
HPLC (Chiralpak AS-H column, hexane / 2-propanol = 90 / 10, flow rate =
1 mL / min) tR = 8.92 min, 9.92 min.
(2R,3R,4S,5R)-methyl
4-nitro-3-phenyl-5-(p-tolyl)-3-
(trifluoromethyl)pyrrolidine-2-carboxylate (exo-3ia) : White solid. Yield =
o
83 %; mp 58-60 C; ee = 99.8%; = -37.8 (c =0.9, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 7.73 (s, 2H), 7.38 (d, 3H), 7.33 (d, 2H), 7.13 (d, 2H),
5.97 (d, J = 5.9 Hz, 1H), 5.45 (s, 1H), 5.36 (d, J = 5.7 Hz, 1H), 3.92 (s,
3H), 3.20 (s, 1H), 2.31 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 171.31,
138.47, 133.11, 132.64, 129.32, 129.20, 128.76, 128.18, 126.68, 125.27
(d, JCF = 285.8 Hz), 97.23, 65.63 (q, JCF = 24.6 Hz), 64.60, 63.85, 53.39,
21.17. IR (KBr) ν 1738, 1562, 1435, 1302, 1240, 1175, 1156, 1023, 760,
700, 548 cm-1. HRMS Calcd. For C20H19F3N2O4+H+: 409.13752, found:
409.13790. HPLC (Chiralpak OD-H column, hexane / 2-propanol = 90 / 10,
flow rate = 0.7 mL / min) tR = 10.17 min, 11.28 min.
(2R,3R,4S,5R)-methyl
4-nitro-5-(3-nitrophenyl)-3-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3na) : Yellow solid. Yield =
o
65 %; mp 175-177 C; ee = 99.0%; α = +21.4 (c =0.6, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 8.34 (s, 1H), 8.08 (m, 1H), 7.74 (d, 1H), 7.66 (s, 1H),
7.44 (t, 1H), 7.36–7.28 (m, 1H), 6.00 (d, J = 6.3 Hz, 1H), 5.41 (s, 1H),
5.39 (s, 1H), 3.88 (s, 1H), 3.44 (s, 1H). 13C NMR (126 MHz, CDCl3) δ
170.79, 148.36, 139.19, 132.92, 131.76, 129.52 (d, J = 8.6 Hz), 128.88,
(2R,3R,4S,5R)-methyl
5-(3,4-dimethylphenyl)-4-nitro-3-phenyl-3-
128.19, 125.17 (d, JCF = 286.0 Hz), 123.75, 122.32, 96.98, 65.64 (d, JCF =
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ja) : White solid. Yield =
24.8 Hz), 64.39, 62.84 (d, J = 2.3 Hz), 53.61, 29.71. IR (KBr) ν 1740,
1563, 1526, 1345, 1245, 1205, 1160, 931, 762, 734, 698, 681, 515 cm-1.
HRMS Calcd. For C19H16F3N3O6+H+: 440.10694, found: 440.10700.
HPLC (Chiralpak AS-H column, hexane / 2-propanol = 95 / 5, flow rate =
0.7 mL / min) tR = 52.0 min, 56.2 min.
o
1
81 %; mp 100-102 C; ee = 99.6%; = -29.4 (c =0.84, CH2Cl2); H NMR
(500 MHz, CDCl3) δ 7.67 (s, 2H), 7.45-7.38 (m, 3H), 7.18 (d, 1H), 7.14-
7.07 (m, 2H), 5.49 (d, J = 7.4 Hz, 1H), 4.95 (s, 1H), 4.88 (d, J = 7.2 Hz,
1H), 3.82 (s, 3H), 3.13 (br, 1H), 2.29 (s, 3H), 2.28 (s, 3H). 13C NMR (126
MHz, CDCl3) δ 168.28, 137.83, 137.78, 133.49, 131.48, 130.53, 129.35,
128.74, 127.93, 127.70, 126.34 (d, JCF = 286.2 Hz), 123.66, 96.97, 67.75,
66.82, 66.43 (d, JCF = 23.0 Hz), 53.09, 19.88, 19.52. IR (KBr) ν 1747,
1558, 1436, 1362, 1271, 1179, 1155, 822, 765, 702, 573, 438 cm-1.
HRMS Calcd. For C21H21F3N2O4+H+: 423.15317, found: 423.15354.
HPLC (Chiralpak OD-H column, hexane / 2-propanol = 90 / 10, flow rate =
1 mL / min) tR = 7.38 min, 8.60 min.
(2R,3R,4S,5R)-methyl
5-(4-(methylthio)phenyl)-4-nitro-3-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3oa) : Yellow oil. Yield =
82 %; ee = 96.8%; = -16.7 (c =0.86, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ = 7.69 (s, 2H), 7.50-7.37 (m, 3H), 7.36-7.30 (m, 4H), 5.49 (d,
J=7.4, 1H), 4.98 (s, 1H), 4.93 (d, J=7.4, 1H), 3.84 (s, 3H), 3.08 (s, 1H),
2.52 (s, 3H). 13C NMR (126 MHz, CDCl3) δ = 168.20, 140.23, 132.60,
131.32, 129.40, 128.76, 127.89, 126.98, 126.91, 126.27 (d, JCF=286.1),
96.79, 67.38, 66.73, 66.29 (q, JCF=23.2), 53.13, 15.52. IR (KBr) ν 1746,
1557, 1500, 1435, 1363, 1268, 1178, 1155, 1093, 1015, 811, 766, 699,
545 cm-1. HRMS Calcd. For C20H19F3N2O4S+H+: 441.10959, found:
441.10966. HPLC (Chiralpak OD-H column, hexane / 2-propanol = 90 / 10,
flow rate = 1 mL / min) tR = 14.03 min, 17.18 min.
(2R,3R,4S,5R)-methyl
5-(naphthalen-2-yl)-4-nitro-3-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ka) : White solid. Yield =
o
86 %; mp 147-148 C; ee = 99.4%; = -19 (c =0.9, CH2Cl2); 1H NMR
(500 MHz, CDCl3) δ 7.93 (d, 1H), 7.87 (m, 3H), 7.71 (m, 2H), 7.55 (m, 2H),
7.48 (d, 1H), 7.45-7.41 (m, 3H), 5.62 (d, J = 7.4 Hz, 1H), 5.13 (dd, J =
11.4, 7.7 Hz, 1H), 5.05 (d, J = 12.0 Hz, 1H), 3.85 (s, 3H), 3.30 (t, J = 12.7
Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 168.29, 133.46, 133.35, 133.23,
131.38, 129.56, 129.42, 128.79, 128.15, 127.96, 127.78, 126.89, 126.32
(2R,3R,4S,5R)-methyl
5-(2-methoxyphenyl)-4-nitro-3-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3pa) : Brown solid. Yield =
73 %; ee = >99.9%; = -88.5 (c =0.8, CH2Cl2); 1H NMR (500 MHz,
(d, JCF= 286.2 Hz), 125.98, 123.48, 96.82, 67.92, 66.81, 66.41 (q, JCF
=
23.0 Hz), 53.16. IR (KBr) ν 2924, 1748, 1559, 1436, 1356, 1273, 1180,
CDCl3) δ = 7.67 (s, 2H), 7.44-7.33 (m, 4H), 7.31 (d, 1H), 7.00 (t, 1H), 6.94
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(d, 1H), 5.62 (d, J = 7.4, 1H), 5.04 (d, J = 5.7, 1H), 4.98 (s, 1H), 3.83 (s,
3H), 3.81 (s, 3H), 3.77 (br, 1H). 13C NMR (126 MHz, CDCl3) δ = 168.41,
157.15, 131.57, 131.24, 130.28, 130.13, 129.25, 128.56, 128.04, 126.28
423.15350. HPLC (Chiralpak AD-H column, hexane / 2-propanol = 90 / 10,
flow rate = 1 mL / min), tR = 7.72min, 10.62 min.
(d, JCF = 286.1), 123.21, 121.03, 110.85, 95.18, 66.62, 66.24 (q, JCF
=
(2R,3R,4S,5R)-methyl
3-(4-chlorophenyl)-4-nitro-5-phenyl-3-
23.4), 65.13, 54.96, 52.98. IR (KBr) ν 1743, 1561, 1500, 1438, 1281,
1215, 1160, 1137, 1086, 821, 750, 723, 569, 524 cm-1. HRMS Calcd. For
C20H19F3N2O5+H+: 425.13243, found: 425.13293. HPLC (Chiralpak AS-H
column, hexane / 2-propanol = 90 / 10, flow rate = 1 mL / min), major
enantiomer tR = 18.28 min.
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ad) : Brown solid. Yield =
o
1
81 %; mp 102-103 C, ee = 99.8%; = -47.3 (c =0.9, CH2Cl2); H NMR
(500 MHz, CDCl3) δ 7.62 (d, 2H), 7.53-7.33 (m, 7H), 5.50 (d, J = 7.3 Hz,
1H), 4.95 (d, J = 7.3 Hz, 1H), 4.92 (s, 1H), 3.83 (s, 3H), 2.86 (br, 1H). 13
C
NMR (126 MHz, CDCl3) δ 167.82, 135.82 (d, J = 10.2 Hz), 129.73, 129.47,
129.39, 129.37, 129.35, 129.03, 126.40, 126.04 (d, JCF = 286.2 Hz), 96.69,
67.77, 66.64, 65.89 (q, JCF = 23.5 Hz), 53.25. IR (KBr) ν 1748, 1558, 1500,
1435, 1361, 1277, 1219, 1179, 1157, 1100, 1014, 970, 938, 877, 829,
755, 696, 526 cm-1. HRMS Calcd. For C19H16ClF3N2O4+H+: 429.08289,
found: 429.08295. HPLC (Chiralpak AD-H column, hexane / 2-propanol =
90 / 10, flow rate = 1 mL / min), tR = 11.07 min, 12.37min.
(2R,3R,4S,5R)-methyl
5-(2,4-difluorophenyl)-4-nitro-3-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3qa) : White solid. Yield =
o
1
78 %; mp 98-99 C; ee = 97%; = -71.1 (c =0.9, CH2Cl2); H NMR (500
MHz, CDCl3) δ = 7.68 (s, 2H), 7.55–7.38 (m, 4H), 6.96 (m, 8.3, 2H), 5.56
(d, J=7.4, 1H), 5.15 (s, 1H), 5.00 (d, J = 4.6, 1H), 3.84 (s, 3H), 3.30 (s,
1H). 13C NMR (126 MHz, CDCl3) δ 168.07, 163.22 (dd, JCF = 293.0, 12.2
Hz), 161.22 (dd, JCF = 291.4, 12.2 Hz), 131.15 (s), 129.58, 129.47, 128.77,
127.92, 126.16 (d, J CF= 286.2 Hz), 119.09 (dd, JCCF = 13.2, 3.6 Hz),
112.32 (dd, JCCF = 21.4, 3.3 Hz), 104.90 (t, JCCF = 25.6 Hz), 95.53, 66.68,
65.96 (q, JCF = 23.4 Hz), 62.07, 53.12. 19F NMR (471 MHz, CDCl3) δ -
66.09 (d, J = 3.2 Hz), -107.66 (d, J = 7.7 Hz), -112.02 (s). IR (KBr) ν 1745,
1621, 1563, 1501, 1454, 1267, 1181, 1162, 1121, 962, 859, 818, 766,
703, 613, 512 cm-1. HRMS Calcd. For C19H15F5N2O4+H+: 431.10302,
found: 431.10305. HPLC (Chiralpak OD-H column, hexane / 2-propanol =
90 / 10, flow rate = 1 mL / min), tR = 8.68 min, 10.07min.
(2R,3R,4S,5R)-methyl
3-(4-fluorophenyl)-4-nitro-5-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ae) : Brown oil. Yield =
76 %; ee = 99.8%; = -54.9 (c =1.1, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.68 (m, 2H), 7.54-7.32 (m, 5H), 7.10 (t, 2H), 5.50 (d, J = 7.3 Hz,
1H), 4.94 (d, 2H), 3.84 (s, 3H), 3.02 (br, 1H). 13C NMR (126 MHz, CDCl3)
δ 167.98, 163.02 (d, JCF = 250.8 Hz), 135.97, 130.09 (d, J = 6.8 Hz),
129.46, 129.31, 127.11 (d, J = 3.4 Hz), 127.08 (dd, JCF = 273.1, 234.9 Hz),
126.41, 115.87 (d, J = 21.6 Hz), 96.81, 67.86, 66.77, 65.91 (q, JCF = 23.2
Hz), 53.22. IR (KBr) ν 1748, 1610, 1558, 1517, 1437, 1273, 1219, 1157,
938, 878, 838, 822, 756, 697, 539 cm-1. HRMS Calcd. For
C19H16F4N2O4+H+: 413.11244, found: 413.11247. HPLC (Chiralpak AD-H
column, hexane / 2-propanol = 90 / 10, flow rate = 1 mL / min), tR = 10.12
min, 12.45min.
(2R,3R,4S,5R)-methyl
4-nitro-3-phenyl-5-(o-tolyl)-3-
(trifluoromethyl)pyrrolidine-2-carboxylate (exo-3sa) : White solid. Yield =
78 %; ee = >99.9%; = -48.4 (c =0.9, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.71 (m, 2H), 7.49-7.40 (m, 4H), 7.37-7.29 (m, 2H), 7.25 (d, 1H),
5.68 (d, J = 7.7 Hz, 1H), 5.25 (d, J = 7.7 Hz, 1H), 5.02 (s, 1H), 3.83 (s,
3H), 2.84 (br, 1H), 2.42 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 168.13,
137.49, 134.03, 131.40, 131.34, 129.40, 129.12, 128.76, 127.91 (d, J =
1.6 Hz), 127.18, 126.48 (q, JCF = 286.1 Hz), 124.72, 96.21, 67.07, 66.40
(q, JCF = 23.0 Hz), 63.80, 53.09, 29.72, 19.41. IR (KBr) ν 1745, 1558,
1499, 1437, 1359, 1269, 1224, 1179, 1154, 752, 698, 541 cm-1. HRMS
Calcd. For C20H19F3N2O4+H+: 409.13752, found: 409.13796. HPLC
(Chiralpak OD-H column, hexane / 2-propanol = 95 / 5, flow rate = 1 mL /
min), major enantiomer tR = 8.42 min.
(2R,3R,4S,5R)-methyl
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3af) : Yellow oil. Yield =
88 %; ee = >99.9%; = -41.6 (c =1.6, CH2Cl2); 1H NMR (500 MHz,
3-(naphthalen-2-yl)-4-nitro-5-phenyl-3-
CDCl3) δ 8.31 (s, 1H), 7.95-7.89 (m, 1H), 7.86 (t, 2H), 7.64 (d, 1H), 7.55
(m, 2H), 7.51-7.35 (m, 5H), 5.62 (d, J = 7.4 Hz, 1H), 5.15 (s, 1H), 5.03 (d,
J = 7.4 Hz, 1H), 3.84 (s, 3H), 3.07 (br, 1H). 13C NMR (126 MHz, CDCl3) δ
168.27, 136.13, 133.04, 132.79, 129.45, 129.29, 128.66, 128.60, 128.47,
127.79 (d, JCF = 256.4 Hz), 127.47, 126.51, 125.29, 124.40, 96.86, 67.86,
67.06, 66.56 (q, JCF = 23.2 Hz), 53.17. IR (KBr) ν 1747, 1557, 1517, 1435,
1361, 1273, 1179, 1154, 1124, 815, 697, 541, 476 cm-1. HRMS Calcd.
For C23H19F3N2O4+H+: 445.13752, found: 445.13751. HPLC (Chiralpak
OD-H column, hexane / 2-propanol = 98 / 2, flow rate = 0.7 mL / min),
major enantiomer tR = 23.22 min.
(2R,3R,4S,5R)-methyl
3-(4-bromophenyl)-4-nitro-5-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ab) : Brown solid. Yield =
o
83 %; mp 116-118 C; ee = >99.9%; = -38.75 (c =1.6, CH2Cl2); 1H
NMR (500 MHz, CDCl3) δ 7.62-7.49 (m, 5H), 7.50-7.33 (m, 6H), 5.49 (d, J
= 7.3 Hz, 1H), 4.93 (m, 2H), 3.83 (s, 3H), 3.17 (t, J = 10.3 Hz, 1H). 13C
NMR (126 MHz, CDCl3) δ 167.92, 135.94, 132.01, 130.40, 129.65, 129.47,
129.33, 127.96 (dd, JCF = 223.8, 38.7 Hz), 126.41, 124.16, 96.76, 67.88,
66.70, 66.01 (q, JCF = 23.0 Hz), 53.23. IR (KBr) ν 1750, 1553, 1498, 1310,
1280, 1168, 1140, 1086, 980, 937, 843, 764, 747, 693, 553, 522 cm-1.
HRMS Calcd. For C19H16BrF3N2O4+H+: 473.03238, found: 473.03232.
HPLC (Chiralpak AD-H column, hexane / 2-propanol = 90 / 10, flow rate =
1 mL / min), major enantiomer tR = 14.22 min.
(2R,3R,4S,5R)-methyl
3-(4-methoxyphenyl)-4-nitro-5-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ag) : Brown oil. Yield =
85 %; ee = 99.8%; = -52.7 (c =1.6, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.51 (d, 2H), 7.33 (m, 5H), 6.83 (d, 2H), 5.40 (d, J = 7.5 Hz, 1H),
4.86 (d, 2H), 3.73 (s, 3H), 3.72 (s, 3H), 2.92 (br, 1H). 13C NMR (126 MHz,
CDCl3) δ 168.27, 160.03, 136.18, 129.40, 129.31 (d, J = 1.1 Hz), 129.21,
127.04, 126.45, 126.40 (q, JCF = 286.0 Hz), 122.89, 96.80, 67.63, 66.72,
65.98 (q, JCF = 23.2 Hz), 55.21, 53.09. IR (KBr) ν 1747, 1613, 1558, 1519,
1458, 1436, 1361, 1262, 1193, 1154, 1130, 1031, 970, 879, 832, 756,
698, 542 cm-1. HRMS Calcd. For C20H19F3N2O5+H+: 425.13243, found:
425.13261. HPLC (Chiralpak AS-H column, hexane / 2-propanol = 90 / 10,
flow rate = 1 mL / min), tR = 10.52 min, 15.93min.
(2R,3R,4S,5R)-methyl
3-(3,4-dimethylphenyl)-4-nitro-5-phenyl-3-
(trifluoromethyl) pyrrolidine-2-carboxylate (exo-3ac) : Brown oil. Yield =
79 %; ee = 99.6%; = -66.2 (c =1.3, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.43 – 7.23 (m, 7H), 7.07 (d, J = 8.0 Hz, 1H), 5.40 (d, J = 7.5 Hz,
1H), 4.88 (d, J = 4.4 Hz, 2H), 3.73 (s, 3H), 2.94 (s, 1H), 2.20 (s, 3H), 2.17
(s, 3H). 13C NMR (126 MHz, CDCl3) δ 168.35, 138.09, 136.95, 136.25,
129.95, 129.39, 129.18, 128.59, 127.56, 127.16 (d, J = 462.4 Hz), 126.49,
96.83, 67.58, 66.84, 66.17 (q, J = 23.0 Hz), 53.05, 29.72, 20.14, 19.40. IR
(KBr) ν 1746, 1558, 1435, 1360, 1322, 1272, 1159, 1127, 981, 843, 819,
757, 697 cm-1. HRMS Calcd. For C21H21F3N2O4+H+: 423.15317, found:
(2R,3R,4S,5R)-ethyl 4-nitro-3,5-diphenyl-3-(trifluoromethyl)pyrrolidine-2-
carboxylate (exo-3ca) : Brown oil. Yield = 80 %; ee = 99.4%; = -56.2
(c =1.2, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.71 (m, 2H), 7.52-7.32 (m,
8H), 5.54 (d, J = 7.3 Hz, 1H), 5.05-4.89 (m, 2H), 4.41-4.20 (m, 2H), 3.04
(br, 1H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3) δ 167.62,
136.17, 131.47, 129.40, 129.36, 129.21, 128.67, 128.00 (d, J = 1.5 Hz),
126.45, 126.31 (q, JCF = 286.1 Hz), 96.92, 67.89, 66.83, 66.42 (q, JCF
=
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Chemistry - An Asian Journal
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23.1 Hz), 62.47, 13.80. IR (KBr) ν 1742, 1558, 1501, 1450, 1363, 1270,
1221, 1179, 1155, 1132, 1015, 973, 877, 821, 754, 697, 519 cm-1. HRMS
Calcd. For C20H19F3N2O4+H+: 409.13752, found: 409.13773. HPLC
(Chiralpak AS-H column, hexane / 2-propanol = 90 / 10, flow rate = 1 mL /
min), tR = 5.98 min, 7.65 min.
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437.16882, found: 437.16902. HPLC (Chiralpak AD-H column, hexane /
2-propanol = 90 / 10, flow rate = 1 mL / min), tR = 6.38 min, 11.60 min.
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Acknowledgements ((optional))
Acknowledgements Text.
Keywords: trifluoromethyl • quaternary stereogenic center •
cycloaddition • ferrocenyloxazolinylphosphines • pyrrolidine
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