A facile access to fluorinated pyrrolidines via catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with methyl α- fluoroacrylate

Article abstract of DOI:10.1002/cjoc.201200765

Asymmetric 1,3-dipolar cycloaddition of methyl α-fluoroacrylate with azomethine ylides for the construction of optically active fluorinated pyrrolidines bearing one unique fluorinated quaternary and two tertiary stereogenic centers has been achieved with Cu(CH₃CN) ₄BF₄/TF-BiphamPhos complexes for the first time. This catalytic system performs well over a broad scope of substrates, providing the synthetically useful adducts in good yields and excellent diastereoselectivities and good to high enantioselectivities.

Full text of DOI:10.1002/cjoc.201200765

FULL PAPER
DOI: 10.1002/cjoc.201200765
A Facile Access to Fluorinated Pyrrolidines via Catalytic
Asymmetric 1,3-Dipolar Cycloaddition of Azomethine
Ylides with Methyl α-Fluoroacrylate
Yan, Dingcea(严定策)
Li, Qinghuab(李清华)
Wang, Chunjiang*,a,b(王春江)
a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Shanghai 230032, China
Asymmetric 1,3-dipolar cycloaddition of methyl α-fluoroacrylate with azomethine ylides for the construction of
optically active fluorinated pyrrolidines bearing one unique fluorinated quaternary and two tertiary stereogenic cen-
ters has been achieved with Cu(CH3CN)4BF4/TF-BiphamPhos complexes for the first time. This catalytic system
performs well over a broad scope of substrates, providing the synthetically useful adducts in good yields and excel-
lent diastereoselectivities and good to high enantioselectivities.
Keywords asymmetric catalysis, 1,3-dipolar cycloaddition, azomethine ylide, methyl α-fluoroacrylate, pyrrolidine
NH
Introduction
O
Organofluorine compounds are of ever increasing
importance and the chemistry of organofluorine com-
pounds is a rapidly developing area of research due to
their wide range of applications in a number of impor-
tant fields such as pharmaceuticals, agrochemicals, and
functional materials.[1] Amongst organofluorine mole-
cules, chiral fluorinated compounds containing a fluo-
rine atom bonded directly to a stereogenic center play a
unique and significant role in agricultural and medicinal
chemistry, as it often imparts enhanced biological activ-
ity, metabolic stability, binding interaction, or other de-
sirable changes in physical properties to drug mole-
cules.[2] One such example is (3S,4S)-F-DADMe-
ImmH[3] (Figure 1), the potent immucillin purine nu-
cleoside phosphorylase (PNP) inhibitor, which was ob-
tained through 1,3-dipolar cycloaddition followed by
enzymatic resolution. The fluorinated quaternary stereo-
genic carbon center on the pyrrolidine ring plays a great
role in the structure-activity relationship.
Recent decades have witnessed the great importance
of 1,3-dipolar cycloaddition in organic chemistry.[4] Es-
pecially, the catalytic asymmetric 1,3-dipolar cycloaddi-
tion of azomethine ylides to electron-deficient alkenes[5]
by using either chiral metal-based catalysts or organo-
catalysts[6] has offered a robust method to access struc-
tural motifs of chiral pyrrolidines, which presents fre-
quently in natural alkaloids and artificial molecules with
vital bioactivities. It is noteworthy that although various
NH
N
N
HO
OH
F
Figure 1 Potent immucillin purine nucleoside phosphorylase
(PNP) inhibitor F-DADMe-ImmH.
highly functionalized pyrrolidine derivatives have been
achieved, chiral fluorinated pyrrolidines have seldom
been realized via catalytic asymmetric 1,3-dipolar
cycloaddition. To the best of our knowledge, only one
example of such compounds has been reported using
chiral-auxiliary-induced 1,3-dipolar cycloaddition reac-
tion with synthetic challenging α-fluoroacrylate as the
dipolarophile.[7] Most surprisingly, commercially avail-
able methyl α-fluoroacrylate, which is expected to be a
possible dipolarophile, has seldom been employed in the
1,3-dipolar cycloaddition of azomethine ylides, and only
limited racemic examples have been reported so far.[8]
An enantioselective version of this transformation may
not only diversify the existing asymmetric 1,3-dipolar
cycloaddition of azomethine ylides but also be uniquely
valuable in the efficient construction of fluorinated pyr-
rolidines. In continuation of our interest in the field of
asymmetric construction of enantiomeric enriched pyr-
rolidine derivatives,[9] herein we reported the first cata-
lytic asymmetric 1,3-dipolar cycloaddition of azome-
*
E-mail: cjwang@whu.edu.cn; Fax: 0086-027-68754067
Received July 25, 2012; accepted September 16, 2012; published online October 30, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200765 or from the author.
2714
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2714—2720

A Facile Access to Fluorinated Pyrrolidines via Catalytic Asymmetric 1,3-Dipolar Cycloaddition
thine ylides to methyl α-fluoroacrylate affording the
fluorinated pyrrolidines in good yields with excellent
diastereoselectivity and high enantioselectivity. More-
over, another key feature of the present method is that
one unique fluorinated quaternary stereogenic cen-
ter[10,11] was generated along with the other two tertiary
stereogenic centers in the pyrrolidine moiety.
Once starting material was consumed (monitored by
TLC), the mixture was filtered through celite and the
filtrate was concentrated to dryness. The product was
purified by column chromatography to give the corre-
sponding cycloadduct, which was then directly analyzed
by HPLC on a chiralpak AD-H or a chiralpak AS-H
column to determine the enantiomeric excess.
(2R,4S,5R)-Dimethyl 5-(4-chlorophenyl)-4-fluoro-
pyrrolidine-2,4-dicarboxylate (4a): White solid, yield
Experimental
1
85%; m.p. 75—77 ℃; [α]2D5 7.6 (c 0.78, CHCl3); H
Melting points were obtained with a Yanagimoto
micro melting point apparatus and uncorrected. Optical
rotations were determined in solution of CHCl3 at 25 ℃
NMR (CDCl3, 300 MHz) δ: 7.35—7.27 (m, 4H), 4.59 (d,
J＝26.4 Hz, 1H), 4.22 (dd, J＝6.9, 9.9 Hz, 1H), 3.83 (s,
3H), 3.35 (s, 3H), 2.76—2.54 (m, 3H); 13C NMR
(CDCl3, 75 MHz) δ: 172.6, 168.4 (d, JCF＝27.8 Hz),
135.8, 133.9, 128.3, 128.2, 103.1 (d, JCF＝195.6 Hz),
70.8 (d, JCF＝28.2 Hz), 57.9, 52.3, 52.1, 39.0 (d, JCF＝
22.4 Hz); IR (film) ν: 3019, 1753, 1438, 1215, 755, 666
by using a Perkin-Elmer-241 MC polarimeter; [α]D-
Values are given in units of 10－ (°)•cm2•g . Infrared
－
1
1
spectra were measured on a Thermo Fisher Scientific
Nicolet iS10 spectrometer. H NMR spectra were re-
1
corded on a VARIAN Mercury 300 MHz or a Bruker
400 MHz spectrometer in CDCl3 with TMS as an inter-
nal standard. 13C NMR spectra were recorded on a
VARIAN Mercury 75 MHz or a Bruker 100 MHz spec-
trometer in CDCl3. Chemical shifts are reported in ppm
with the internal chloroform signal at δ 77.0 as a stan-
dard. Commercially obtained reagents were used with-
out further purification. All reactions were monitored by
TLC with silica gel-coated plates. Diastereomeric ratios
were determined from crude 1H NMR or HPLC analysis.
Enantiomeric excesses were determined by HPLC, us-
ing a chiralpak AD-H column or a chiralpak AS-H
column with hexane and i-PrOH as solvents. The race-
mic adducts were attained by using AgOAc/PPh3 as the
catalyst. The absolute configuration of (2R,4S,5R)-4a
was determined unequivocally according to the X-ray
diffraction analysis, and those of other adducts were
deduced on the basis of these results.
－
1
cm ; HRMS calcd for C14H15ClFNO4 315.0674, found
315.0669. The product was analyzed by HPLC to de-
termine the enantiomeric excess: 94% ee (chiralpak
AD-H, i-propanol/hexane, V∶V＝15∶85, flow rate 1.0
mL/min, λ＝220 nm); tr＝17.16 and 20.31 min.
(2R,4S,5R)-Dimethyl 5-(3-chlorophenyl)-4-fluoro-
pyrrolidine-2,4-dicarboxylate (4b): Colorless oil, 82%
1
yield; [α]2D5 23.5 (c 1.45, CHCl3); H NMR (CDCl3,
300 MHz) δ: 7.42 (s, 1H), 7.27—7.25 (m, 3H), 4.59 (d,
J＝26.4 Hz, 1H), 4.22 (dd, J＝6.6, 9.6 Hz, 1H), 3.84 (s,
3H), 3.37 (s, 3H), 2.67—2.54 (m, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 172.6, 168.4 (d, JCF＝28.1 Hz),
139.4, 134.2, 129.5, 128.3, 127.0, 125.0, 103.1 (d, JCF＝
192.5 Hz), 70.8 (d, JCF＝28.3 Hz), 58.0, 52.4, 52.2, 38.9
(d, JCF＝23.1 Hz); IR (film) ν: 3019, 1746, 1524, 1438,
－
1215, 928, 756, 666 cm 1; HRMS calcd for
C14H15ClFNO4 315.0674, found 315.0677. The product
was analyzed by HPLC to determine the enantiomeric
excess: 85% ee (chiralpak AS-H, i-propanol/hexane,
V∶V＝15∶85, flow rate 1.0 mL/min, λ＝220 nm); tr＝
11.48 and 12.94 min.
General procedure for the synthesis of racemic
cycloadduct fluorinated pyrrolidine
Under argon atmosphere, PPh3 (6.6 mg, 0.0253
mmol) and AgOAc (3.8 mg, 0.023 mmol) were dis-
solved in 2 mL of DCM, and stirred at room tempera-
ture for about 0.5 h. Then, imine substrate (0.35 mmol),
Et3N (0.03 mmol) and methyl α-fluoroacrylate (0.23
mmol) were added sequentially. Once starting material
was consumed (monitored by TLC), the organic solvent
was removed and the residue was purified by column
chromatography to give the cycloadduct (60%—90%
yield), which was used as the racemic sample for HPLC
analysis.
(2R,4S,5R)-Dimethyl 5-(2-chlorophenyl)-4-fluoro-
pyrrolidine-2,4-dicarboxylate (4c): Colorless oil, 65%
1
yield; [α]2D5 －7.5 (c 1.18, CHCl3); H NMR (CDCl3,
300 MHz) δ: 7.75—7.73 (m, 1H), 7.33—7.21 (m, 3H),
5.22 (d, J＝27.0 Hz, 1H), 4.26 (dd, J＝6.0, 10.2 Hz,
1H), 3.83 (s, 3H), 3.38 (s, 3H), 2.80—2.52 (m, 3H); 13
C
NMR (CDCl3, 100 MHz) δ: 172.8, 168.1 (d, JCF＝26.9
Hz), 135.9, 133.4, 129.4, 129.1, 129.0, 126.8, 103.2 (d,
JCF＝196.7 Hz), 67.4 (d, JCF＝29.6 Hz), 57.9, 52.3, 52.3,
38.9 (d, JCF＝22.0 Hz); IR (film) ν: 3019, 1746, 1522,
－
1
General procedure for the catalytic asymmetric
1,3-dipolar cycloaddition of azomethine ylides with
methyl α-fluoroacrylate
1424, 1219, 1018, 928, 849, 771, 668 cm ; HRMS
calcd for C14H15ClFNO4 315.0674, found 315.0672. The
product was analyzed by HPLC to determine the enan-
tiomeric excess: 87% ee (chiralpak AS-H, i-propanol/
hexane, V∶V＝15∶85, flow rate 1.0 mL/min, λ＝220
nm); tr＝10.18 and 11.99 min.
Under argon atmosphere, (S)-TF-BiphamPhos 1e
(6.1 mg, 0.0076 mmol) and Cu(CH3CN)4BF4 (2.2 mg,
0.0069 mmol) were dissolved in 2 mL of DCM, and
stirred at room temperature for about 0.5 h. Then, imine
substrate (0.35 mmol), Et3N (0.03 mmol) and methyl
α-fluoroacrylate (0.23 mmol) were added sequentially.
(2R,4S,5R)-Dimethyl 5-(4-bromophenyl)-4-fluoro-
pyrrolidine-2,4-dicarboxylate (4d): White solid, 78%
1
yield; m.p. 80—82 ℃; [α]2D5 0.1 (c 1.42, CHCl3); H
Chin. J. Chem. 2012, 30, 2714—2720
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2715

Yan, Li & Wang
FULL PAPER
NMR (CDCl3, 300 MHz) δ: 7.46—7.44 (m, 2H), 7.28—
7.25 (m, 2H), 4.56 (d, J＝26.0 Hz, 1H), 4.21 (dd, J＝
7.5, 9.6 Hz, 1H), 3.82 (s, 3H), 3.34 (s, 3H), 2.80—2.48
(m, 3H); 13C NMR (CDCl3, 100 MHz) δ: 172.7, 168.5
(d, JCF＝28 Hz), 136.2, 131.3, 128.5, 122.1, 103.1 (d,
JCF＝195.5 Hz), 70.9 (d, JCF＝28 Hz), 58.0, 52.4, 52.2,
39.1 (d, JCF＝22.4 Hz); IR (film) ν: 3020, 1750, 1523,
1438, 1219, 1011, 929, 771, 666 cm ; HRMS calcd for
C14H15BrFNO4 315.0618, found 315.0617. The product
was analyzed by HPLC to determine the enantiomeric
excess: 84% ee (chiralpak AD-H, i-propanol/hexane,
V∶V＝15∶85, flow rate 1.0 mL/min, λ＝220 nm); tr＝
14.41 and 17.49 min.
determine the enantiomeric excess: 93% ee (chiralpak
AS-H, i-propanol/hexane, V∶V＝15∶85, flow rate 1.0
mL/min, λ＝220 nm); tr＝9.31 and 10.80 min.
(2R,4S,5R)-Dimethyl 4-fluoro-5-(p-tolyl)pyrrolidine-
2,4-dicarboxylate (4h): Colorless oil, 82% yield; [α]D25
1
9.1 (c 0.20, CHCl3); H NMR (CDCl3, 300 MHz) δ:
7.26—7.11 (m, 4H), 4.56 (d, J＝26.0 Hz, 1H), 4.21—
4.17 (m, 1H), 3.83 (s, 3H), 3.32 (s, 3H), 2.81—2.53 (m,
3H), 2.32 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 172.7,
168.6, 137.9, 133.8, 128.9, 126.6, 103.5 (d, JCF＝191.1
Hz), 71.6 (d, JCF＝27.6 Hz), 58.2, 52.4, 52.2, 39.6 (d,
JCF＝22.6 Hz), 21.1; IR (film) ν: 3019, 1746, 1552,
－
1
－
1
1424, 1219, 1018, 928, 849, 771, 668 cm ; HRMS
calcd for C15H18FNO4 295.1220, found 295.1218. The
product was analyzed by HPLC to determine the enan-
tiomeric excess: 87% ee (chiralpak AS-H, i-propanol/
hexane, V∶V＝15∶85, flow rate 1.0 mL/min, λ＝220
nm); tr＝8.75 and 10.60 min.
(2R,4S,5R)-Dimethyl 4-fluoro-5-(4-fluorophenyl)-
pyrrolidine-2,4-dicarboxylate (4e): Colorless oil, 68%
1
yield; [α]2D5 －0.2 (c 1.04, CHCl3); H NMR (CDCl3,
300 MHz) δ: 7.39—7.34 (m, 2H), 7.05—6.99 (m, 2H),
4.59 (d, J＝27.0 Hz, 1H), 4.21 (dd, J＝6.9, 9.3 Hz, 1H),
3.83 (s, 3H), 3.34 (s, 3H), 2.81—2.53 (m, 3H); 13C
NMR (CDCl3, 100 MHz) δ: 172.7, 168.6, (d, JCF＝28
Hz), 162.5 (d, JCF＝245.3 Hz), 132.9, 128.6 (d, JCF＝
8.1 Hz), 115.1 (d, JCF＝21.4 Hz), 103.2 (d, JCF＝195.8
Hz), 70.9 (d, JCF＝28 Hz), 58.0, 52.4, 52.2, 39.0 (d,
JCF＝22.4 Hz); IR (film) ν: 3020, 1746, 1605, 1512,
1438, 1216, 928, 771, 668 cm－1; HRMS calcd for
C14H15F2NO4 299.0969, found 299.0967. The product
was analyzed by HPLC to determine the enantiomeric
excess: 86% ee (chiralpak AD-H, i-propanol/hexane,
V∶V＝15∶85, flow rate 1.0 mL/min, λ＝220 nm); tr＝
11.12 and 12.51 min.
(2R,4S,5R)-Dimethyl 4-fluoro-5-(m-tolyl)pyrroli-
dine-2,4-dicarboxylate (4i): Colorless oil, 77% yield;
[α]2D5 8.2 (c 0.56, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ: 7.26—7.08 (m, 4H), 4.56 (d, J＝26.0 Hz, 1H), 4.21
(dd, J＝7.2, 9.3 Hz, 1H), 3.83 (s, 3H), 3.31 (s, 3H),
2.80—2.49 (m, 3H), 2.36 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ: 172.8, 168.9 (d, JCF＝28.2 Hz), 137.9,
136.7, 128.9, 128.2, 127.4, 123.7, 103.5 (d, JCF＝195.3
Hz), 71.7 (d, JCF＝27.5 Hz), 58.2, 52.4, 52.1, 39.6 (d,
JCF＝22.5 Hz), 21.4; IR (film) ν: 2919, 1752, 1735,
－
1
1216, 770, 665 cm ; HRMS calcd for C15H18FNO4
295.1220, found 295.1221. The product was analyzed
by HPLC to determine the enantiomeric excess: 84% ee
(chiralpak AS-H, i-propanol/hexane, V∶V＝15∶85,
flow rate 1.0 mL/min, λ＝220 nm); tr＝7.95 and 9.77
min.
(2R,4S,5R)-Dimethyl 4-fluoro-5-(4-(trifluoromethyl)-
phenyl)pyrrolidine-2,4-dicarboxylate (4f): Colorless oil,
1
63% yield; [α]2D5 －1.6 (c 0.48, CHCl3); H NMR
(CDCl3, 300 MHz) δ: 7.65—7.52 (m, 4H), 4.67 (d, J＝
26.0 Hz, 1H), 4.25 (dd, J＝6.3, 9.3 Hz, 1H), 3.84 (s,
3H), 3.30 (s, 3H), 2.82—2.51 (m, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 172.6, 168.4 (d, JCF＝28.1 Hz),
141.4, 130.4 (q, JCF＝32.2 Hz), 127.3, 125.1 (q, JCF＝
3.6 Hz), 123.9 (q, JCF＝270.3 Hz), 103.1 (d, JCF＝196
Hz), 71.0 (d, JCF＝28.1 Hz), 58.1, 52.5, 52.2, 39.1 (d,
JCF＝22.3 Hz); IR (film) ν: 3019, 1747, 1523, 1423,
(2R,4S,5R)-Dimethyl 4-fluoro-5-(o-tolyl)pyrrolidine-
2,4-dicarboxylate (4j): Colorless oil, 75% yield; [α]D25
1
5.0 (c 0.30, CHCl3); H NMR (CDCl3, 300 MHz) δ:
7.26—7.22 (m, 2H), 7.14—7.11 (m, 2H), 4.57 (d, J＝
26.4 Hz, 1H), 4.24—4.18 (m, 1H), 3.83 (s, 3H), 3.32 (s,
3H), 2.81—2.46 (m, 3H), 2.32 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 172.9, 168.9 (d, JCF＝30.8 Hz),
137.9, 133.8, 133.8, 129.0, 126.6, 103.5 (d, JCF＝195.1
Hz), 71.6 (d, JCF＝27.7 Hz), 58.2, 52.4, 52.2, 39.6 (d,
JCF＝22.5 Hz), 21.1; IR (film) ν: 3019, 1757, 1512,
－
1
1325, 1211, 928, 787, 751, 668 cm . The product was
analyzed by HPLC to determine the enantiomeric ex-
cess: 84% ee (chiralpak AD-H, i-propanol/hexane＝
15/85, flow rate 1.0 mL/min, λ＝220 nm); tr＝9.26 and
11.69 min.
－
1
1425, 1215, 1028, 928, 757, 668 cm ; HRMS calcd for
C15H18FNO4 295.1220, found 295.1223. The product
was analyzed by HPLC to determine the enantiomeric
excess: 90% ee (chiralpak AS-H, i-propanol/hexane,
V∶V＝15∶85, flow rate 1.0 mL/min, λ＝220 nm); tr＝
8.74 and 10.53 min.
(2R,4S,5R)-Dimethyl 4-fluoro-5-phenylpyrrolidine-
2,4-dicarboxylate (4g): White solid, 79% yield; m.p.
70—72 ℃; [α]2D5 9.1 (c 0.93, CHCl3); 1H NMR
(CDCl3, 300 MHz) δ: 7.36—7.26 (m, 5H), 4.61 (d, J＝
26.0 Hz, 1H), 4.26—4.20 (m, 1H), 3.84 (s, 3H), 3.29 (s,
3H), 2.77—2.55 (m, 3H); 13C NMR (CDCl3, 100 MHz)
δ: 172.9, 168.7 (d, JCF＝28.2 Hz), 137.0, 136.9, 128.2,
126.7, 103.4 (d, JCF＝195.1 Hz), 71.6 (d, JCF＝27.6 Hz),
58.1, 52.4, 52.1, 39.4 (d, JCF＝22.5 Hz); IR (film) ν:
3019, 1746, 1602, 1521, 1425, 1218, 1019, 928, 767,
699 cm－1; HRMS calcd for C14H16FNO4 281.1063,
found 281.1059. The product was analyzed by HPLC to
(2R,4S,5R)-Dimethyl 4-fluoro-5-(naphthalen-1-yl)-
pyrrolidine-2,4-dicarboxylate (4k): Colorless oil, 78%
yield; [α]2D5 －97.7 (c 0.7 2, CHCl3); 1H NMR (CDCl3,
300 MHz) δ: 8.12—8.09 (m, 1H), 7.91—7.77 (m, 3H),
7.54—7.46 (m, 3H), 5.52 (d, J＝27.0 Hz, 1H), 4.33 (dd,
J＝6.6, 11.1 Hz, 1H), 3.86 (s, 3H), 2.90—2.59 (m, 6H);
13C NMR (CDCl3, 100 MHz) δ: 172.8, 168.5 (d, JCF＝
27.4 Hz), 133.4, 131.0, 128.6, 128.5, 126.1, 125.6,
2716
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2714—2720

A Facile Access to Fluorinated Pyrrolidines via Catalytic Asymmetric 1,3-Dipolar Cycloaddition
125.2, 124.9, 123.1, 123.0, 103.6 (d, JCF＝195.3 Hz),
67.1 (d, JCF＝28.1 Hz), 58.0, 52.4, 51.8, 39.4 (d, JCF＝
Table 1 Screening studies of the asymmetric 1,3-dipolar
cycloaddition of imino ester 3a with methyl α-fluoroacrylate 2
22.3 Hz); IR (film) ν: 3019, 1745, 1522, 1425, 1217,
－
1018, 849, 771, 669 cm 1; HRMS calcd for
F
[M]/L (3 mol%)
N
CO2Me
p-Cl-C6H4
+
C18H18FNO4 331.1220, found 331.1218. The product
was analyzed by HPLC to determine the enantiomeric
excess: 90% ee (chiralpak AS-H, i-propanol/hexane,
V∶V＝15∶85, flow rate 1.0 mL/min, λ＝220 nm); tr＝
11.57 and 15.78 min.
MeO2C
Et3N (15 mol%)
3a
2
F
MeO2C
CO2Me
p-Cl-C6H4
N
H
(2R,4S,5R)-Dimethyl 4-fluoro-5-(furan-2-yl)pyrroli-
dine-2,4-dicarboxylate (4l): Colorless oil, 68% yield;
4a
1
[α]2D5 15.65 (c 1.34, CHCl3); H NMR (CDCl3, 400
Entry L
[M]
AgOAc
Solvent T/℃t/min Yieldb/% eec/%
MHz) δ: 7.36—7.27 (m, 1H), 6.37—6.33 (m, 2H), 4.63
(d, J＝22.0 Hz, 1H), 4.19—4.15 (m, 1H), 3.82 (s, 3H),
3.57 (s, 3H), 2.79—2.53 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ: 172.9, 168.3 (d, JCF＝27.3 Hz), 150.2,
142.6, 110.5, 108.4, 102.5 (d, JCF＝195.4 Hz), 66.0 (d,
JCF＝29.7 Hz), 58.3, 52.7, 52.5, 39.1 (d, JCF＝22.1 Hz);
IR (film) ν: 3012, 1740, 1500, 1430, 1055, 875, 788,
680 cm－1; HRMS calcd for C12H14FNO5 271.0856,
found 271.0861. The product was analyzed by HPLC to
determine the enantiomeric excess: 71% ee (chiralpak
AD-H, i-propanol/hexane, V∶V＝15∶85, flow rate 1.0
mL/min, λ＝254 nm); tr＝9.72 and 10.73 min.
1
2
3
4
5
6
7
8
9
1a
DCM r.t. 12
80
81
70
79
81
83
81
63
68
81
85
33
84
65
28
45
87
75
65
71
73
94
1a Cu(CH3CN)4BF4 DCM r.t. 12
1b Cu(CH3CN)4BF4 DCM r.t. 12
1c Cu(CH3CN)4BF4 DCM r.t. 12
1d Cu(CH3CN)4BF4 DCM r.t. 12
1e Cu(CH3CN)4BF4 DCM r.t. 12
1e Cu(CH3CN)4BF4 THF r.t. 12
1e Cu(CH3CN)4BF4 Ether r.t. 12
1e Cu(CH3CN)4BF4 EtOAc r.t. 12
10 1e Cu(CH3CN)4BF4 PhMe r.t. 12
11 1e Cu(CH3CN)4BF4 DCM －20 24
a All reactions were carried out with 0.23 mmol of 2 and 0.35
mmol of 3a in 2 mL of solvent. b Isolated yield. c Determined by
HPLC analysis.
Absolute configuration determination of cycloadduct
(2R,4S,5R)-4a
Crystal data for (2R,4S,5R)-4a: C14H15ClFNO4, Mr＝
315.72, T＝293 K, monoclinic, space group P2(1), a＝
8.0809(15) Å, b＝7.9705(14) Å, c＝23.140(4) Å, V＝
1477.4(5) Å3, Z＝4, 4818 unique reflections, final R1＝
0.0364 and wR2＝0.0887 for 4239 observed [I＞2σ(I)]
reflections, Flack χ＝0.0106(11). CCDC 893074 con-
tains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB21EZ, UK; fax: (＋44) 1223-336-
033; or deposit@ccdc.cam.ac.uk).
To our delight, the reaction was finished smoothly in
less than 12 h with AgOAc/(S)-TF-BiphamPhos (L) as
the catalyst and Et3N as base in dichloromethane at
room temperature, yielding the expected fluorinated
pyrrolidine 4a in 80% yield with excellent diastereose-
lectivity (dr＞98∶2) and 33% ee (Table 1, Entry 1),
which indicated that methyl α-substituted fluoroacrylate
could be applied in our catalytic system as dipolaro-
philes for the efficient construction of fluorinated pyr-
rolidines bearing a unique fluorinated quaternary
stereogenic center. Switching the metal precursor from
AgOAc into Cu(CH3CN)4BF4 witnessed the great en-
hancement of the enantiomeric excess from 33% to 84%
(Table 1, Entry 2). Encouraged by these promising re-
sults, Cu(CH3CN)4BF4 was chosen as the metal precur-
sor for further ligand and solvent screening and the rep-
resentative results are tabulated in Table 1. Inferior
asymmetric inductions were observed when the phenyl
group on the phosphorus atom of TF-BiphamPhos (1a)
was replaced by bulkier xylyl group (1b) or cyclohexyl
group (1d) although the diastereoselectivities were still
kept at the similar level (Table 1, Entries 3 and 5).
Much lower enantioselectivity was delivered by chiral
ligand TF-BiphamPhos (1c) bearing the electron-with-
drawing 3,5-bis(trifluoromethyl)phenyl groups on the
phosphorus atom (Table 1, Entry 4). Further ligand tun-
ing revealed that TF-BiphamPhos (1e) with two bro-
mine at the 3,3'-position of TF-BIPHAM backbone[12]
was the most effective chiral ligand and provided 4a in
Results and Discussion
Initially, we examined the reaction of commercially
available methyl α-fluoroacrylate (2) and N-(4-chloro-
benzylidene)-glycine methyl ester (3a) in the presence
of chiral TF-BiphamPhos (Figure 2) and metal salts to
establish the optimal reaction condition.
CF3
R2
1a: R1 = Ph, R2 = H;
1b: R1 = 3,5-bis(methyl)phenyl, R2 = H;
1c: R1 = 3,5-bis(trifluoromethyl)phenyl, R2 = H;
1d: R1 = Cy, R2 = H;
1e: R1 = Ph, R2 = Br
F3C
F3C
NH2
NHPR1
2
R2
CF3
(S)-TF-BiphamPhos
Figure 2 Structure of chiral ligand TF-BiphamPhos.
Chin. J. Chem. 2012, 30, 2714—2720
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2717

Yan, Li & Wang
FULL PAPER
83% yield with excellent diastereoselectivity (＞98∶2)
and 87% ee (Table 1, Entry 6). A study of reaction with
Cu(CH3CN)4BF4/(S)-1e in various solvents identified
CH2Cl2 was the best solvent in terms of the yield and
enantioselectivity (Table 1, Entries 7—10). Examina-
tion of various organic and inorganic bases such as
DBU, TMG, DMAP, and K2CO3 disclosed that Et3N
was the optimal base. Reducing the temperature to
－20 ℃ in DCM led to full conversion with exclusive
diastereoselectivity and 94% ee within 24 h (Table 1,
Entry 11), but further lowering the temperature could
not improve the enantioselectivity.
sterically hindered ortho-chloro-substituted imino ester
3c, ortho-methyl-substituted imino ester 3j and
1-naphthylaldehyde derived imino ester 3k is notewor-
thy (Table 2, Entries 3, 10 and 11). Additionally, the
heteroaryl substituted imino ester 3l derived from
2-furylaldehyde also works in this transformation lead-
ing to 68% yield and 71% ee (Table 2, Entry 12). How-
ever, no cycloaddition was observed when alkyl substi-
tuted imino ester was tested under the same reaction
conditions. The absolute configuration of 4a achieved
by Cu(CH3CN)4BF4/(S)-TF-BiphamPhos 1e was un-
equivocally determined as (2R,4S,5R) by X-ray diffrac-
tion analysis (Figure 3). Those of other adducts were
deduced on the basis of these results.
Table 2 Substrate scope of Cu(I)/1e-catalyzed asymmetric
1,3-dipolar cycloaddition of imino esters 3 with methyl α-fluoro-
acrylate 2
F
Cu(I)/1e (3 mol%)
+
R
N
CO2Me
MeO2C
Et3N (15 mol%),
-20 oC, 24 - 30 h
3
2
F
MeO2C
R
CO2Me
N
H
4
Entry
1
R
Product
Yieldb/% eec/%
p-Cl-C6H4 (3a)
m-Cl-C6H4 (3b)
o-Cl-C6H4 (3c)
p-Br-C6H4 (3d)
p-F-C6H4 (3e)
p-CF3-C6H4 (3f)
Ph (3g)
4a
4b
4c
4d
4e
4f
85
82
65
78
68
63
79
82
77
75
78
68
94
85
87
84
86
84
93
88
84
90
90
71
Figure 3 X-ray crystallographic structure of (2R,4S,5R)-4a.
2
This asymmetric 1,3-dipolar cycloaddition reaction
can be explained through the proposed transition state as
illustrated in Figure 4. The in situ-formed azomethine
ylide is coordinated to the metallic center and oriented
preferentially to form a tetracoordinated transition
state,[13] followed by cycloaddition with methyl
α-fluoroacrylate from Si face (C＝N) of the azomethine
ylide to give the adduct in (2R,4S,5R)-configuration,
which is compatible with the experimental results. The
carbonyl group of methyl α-fluoroacrylate could coor-
dinate with the Cu(I) center, which can stabilize the
negatively charged oxygen atom in the proposed transi-
tion state.[14] It could not rule out the possible hydrogen
bonds interaction between the carbonyl group and the
NH2 group of the chiral ligand, which also facilitate
stabilizing the proposed transition state.[15] Nevertheless,
the real catalytic mechanism still needs further investi-
gation.
3
4
5
6
7
4g
4h
4i
8
p-Me-C6H4 (3h)
m-Me-C6H4 (3i)
o-Me-C6H4 (3j)
1-Naphthyl (3k)
2-Furyl (3l)
9
10
11
12
4j
4k
4l
aAll reactions were carried out with 0.23 mmol of 2 and 0.35
mmol of 3 in 2 mL of DCM. Isolated yield. Determined by
b
c
HPLC analysis.
In the presence of 3 mol% of Cu(CH3CN)4BF4/1e,
and 15 mol% Et3N in CH2Cl2, 1,3-dipolar cycloaddition
of a series of representative imino esters 3 derived from
glycinate with methyl α-fluoroacrylate 2 was investi-
gated to test the generality of the reaction. As shown in
Table 2, imino esters bearing electron deficient (Table 2,
Entries 1—6), electron-neutral (Table 2, Entries 7 and
11), and electron-rich groups (Table 2, Entries 8—10)
on the aryl rings reacted with methyl α-fluoroacrylate 2
smoothly affording the corresponding cycloadducts (4a
—4k) exclusively in good yields (63%—85%) and good
enantioselectivities (84%—94%). The substitution pat-
tern and electronic property of the phenyl ring have lit-
tle effect on the enantioselectivity. The consistently ex-
cellent diastereo-/enantioselectivity obtained with the
CF3
F
MeO2C
Ph
P
OMe
-
4
N
H
5
2
F3C
F3C
CO2Me
O
N
Cu+
H
N
H
+
N
(2R,4S,5R)-fluorinated
pyrrolidine
H
O
CF3
Ph
F
MeO
(S)-TF-BiphamPhos
Figure 4 Proposed transition state.
2718
www.cjc.wiley-vch.de
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2714—2720

A Facile Access to Fluorinated Pyrrolidines via Catalytic Asymmetric 1,3-Dipolar Cycloaddition
J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2010, 111, 455;
Conclusions
(j) Georgii, G. F. In Advances in Heterocyclic Chemistry, Vol. 86,
Ed.: Katritzky, A. R., Elsevier, Amsterdam, 2004, pp. 129—224; for
recent special issues on organofluorine chemistry, see: (k) Adv.
Synth. Catal. 2010, 352, 2677.
In summary, we have successfully developed the
first example of facile access to the enantiomerically
enriched fluorinated pyrrolidine derivatives via catalytic
asymmetric 1,3-dipolar cycloaddition of azomthine
ylides to methyl α-fluoroacrylate under mild condition.
The highly efficient Cu(CH3CN)4BF4/TF-BiphamPhos
catalytic system exhibited excellent performance, pro-
viding pyrrolidine derivatives containing one unique
fluorinated quaternary and two tertiary stereogenic cen-
ter in good yields, excellent diastereoselectivity
(＞98∶2) and good to high enantioselectivity (71%—
94% ee). The ready availability of the starting materials
and the great importance of the enantiomerically en-
riched fluorinated compounds make the current meth-
odology particularly interesting in synthetic chemistry.
Efforts are currently underway to elucidate the mecha-
nistic details and the scope and limitations of this reac-
tion, and the results will be reported in due course.
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Acknowledgement
This work was supported by the 973 Program (No.
2011CB808600), the National Natural Science Founda-
tion of China (No. 21172176), the Program for New
Century Excellent Talents in University (No.
NCET-10-0649), the Program for Changjiang Scholars
and Innovative Research Team in University of the
Ministry of Education (No. IRT1030), the Fundamental
Research Funds for the Central Universities (No.
2012203020204), and Large-scale Instrument and
Equipment Sharing Foundation of Wuhan University.
We thank Prof. Li, Hua in Wuhan University for solving
the crystal structure.
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Chin. J. Chem. 2012, 30, 2714—2720