Asymmetric construction of trifluoromethylated pyrrolidines via Cu(i)-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with 4,4,4-trifluorocrotonates

Article abstract of DOI:10.1039/c1cc14295j

Trifluoromethylated pyrrolidines have been synthesized via catalytic asymmetric 1,3-dipolar cycloaddition with excellent stereoselectivity for the first time. Epimerization of the endo-pyrrolidines obtained from cis-4,4,4-trifluorocrotonate into the exo-p

Full text of DOI:10.1039/c1cc14295j

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COMMUNICATION
Asymmetric construction of trifluoromethylated pyrrolidines via
Cu(I)-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with
4,4,4-trifluorocrotonatesw
a
a
Qing-Hua Li,z Min-Chao Tong,z Jun Li,a Hai-Yan Taoa and Chun-Jiang Wang*ab
Received 16th July 2011, Accepted 25th August 2011
DOI: 10.1039/c1cc14295j
Trifluoromethylated pyrrolidines have been synthesized via catalytic
asymmetric 1,3-dipolar cycloaddition with excellent stereoselectivity
for the first time. Epimerization of the endo-pyrrolidines obtained
from cis-4,4,4-trifluorocrotonate into the exo-pyrrolidines was also
revealed.
were successfully achieved via 1,3-dipolar cycloaddition of
trans-trifluorocrotonate with azomethine ylides in the presence
of stoichiometric amounts of AgOAc.6 Subsequently, the initial
attempt to access the optically active trifluoromethylated pyrro-
lidines was reported by the same group employing a chiral
azomethine ylide through a chiral-auxiliary-induced 1,3-dipolar
cycloaddition reaction.7 Nevertheless, quite limited progress
has been made in the directly catalytic asymmetric approach to
access those compounds. Therefore, the development of a
catalytic method for the straightforward synthesis of enantio-
enriched pyrrolidines bearing the trifluoromethyl group is in
high demand. Herein, we communicated the first catalytic
asymmetric synthesis of trifluoromethylated pyrrolidines via
1,3-dipolar cycloaddition of azomethine ylides to trans- and
cis-trifluorocrotonates with high yield, excellent diastereo- and
enantioselectivity. Epimerization of the kinetically favored
endo-pyrrolidines into the thermodynamically favored exo-
pyrrolidines was also revealed.
The chemistry of organofluorine compounds is a rapidly
developing area of research due to their wide range of applications
in a number of important fields such as drug discovery and
materials science.1 Amongst organofluorine molecules, chiral
trifluoromethylated compounds play a unique and significant
role in agricultural and medicinal chemistry, as they often
impart enhanced biological activity, metabolic stability, binding
interaction, or other desirable changes in physical properties
to drug molecules.2 As a consequence, extensive studies have
been conducted on the exploitation of the efficient methods for
the asymmetric synthesis of such compounds.2 In recent years, the
catalytic asymmetric 1,3-dipolar cycloaddition of azomethine
ylides to electron-deficient alkenes3 has proven to be the
diversity-oriented synthesis (DOS)4 for biologically active
pyrrolidine derivatives bearing multiple stereogenic centers in
good yields and moderate to high enantio-/diastereoselectivities.
Although various electron-deficient alkenes have been applied
as dipolarophiles for this transformation, most of them are
limited to maleates, fumarates, maleimides, acrylates, nitroalkenes
and vinyl phenyl sulfones.3 However, the easily available
trans-trifluorocrotonate, which was used as starting building
blocks in the synthesis of many fluorine-containing compounds,5
has seldom been employed as dipolarophiles in the asymmetric
1,3-dipolar cycloaddition of azomethine ylides. To the best of
our knowledge, only limited racemic examples have been
reported involving trans-trifluorocrotonate as the dipolarophile
so far.6 For example, Bonnet-Delpon and co-workers addressed
that highly endo-selective trifluoromethylated pyrrolidines
Our initial studies began with the reaction of trans-ethyl
trifluorocrotonate (1a) with N-benzylidene glycine methyl
ester (2a) in the presence of 10 mol% AgOAc/PPh3 and
15 mol% Et3N to probe the possibility of employing catalytic
amounts of the metal complex as the catalyst. To our delight,
the AgOAc/PPh3 complex exhibited high catalytic efficiency,
and the reaction was finished in less than 5 h at room tempera-
ture affording the highly endo-selective trifluoromethylated
pyrrolidine (3aa) in 88% yield (Scheme 1), which is comparable
with the result achieved by using stoichiometric amounts of
AgOAc.6
Encouraged by this promising result, we then conducted the
asymmetric reaction to evaluate the enantioselectivity using
several commercially available chiral ligands such as Monophos
(L1) and BINAP (L2), both of which exhibited excellent
results in the catalytic asymmetric 1,3-dipolar cycloaddition
a College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, China. E-mail: cjwang@whu.edu.cn;
Fax: +86-27-68754067
b Shanghai Institute of Organic Chemistry, 354 Fenglin Road,
Shanghai 200032, China
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 827404 and 827405. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/c1cc14295j
z Q.-H. Li and M.-C. Tong made equal contribution to this work.
Scheme 1 AgOAc/PPh3-catalyzed 1,3-dipolar cycloaddition of imino
ester 2a with trans-4,4,4-trifluorocrotonate 1a.
c
11110 Chem. Commun., 2011, 47, 11110–11112
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Table 1 Screening studies of the catalytic asymmetric 1,3-dipolar
cycloaddition of imino ester 2a with trans-4,4,4-trifluorocrotonates 1a
the ester functional group of 1 was also investigated to further
improve the enantioselectivity. Replacing the ethyl group of
trans-trifluorocrotonate with the bulky tert-butyl ester (1b)
led to 93% ee without loss of diastereoselectivity (Table 1,
entry 18).
Having established the optimal reaction conditions, we then
investigated a series of representative imino esters 2 derived from
glycinate to test the substrate scope. As shown in Table 2, a
wide array of imino esters derived from aromatic aldehyde
reacted smoothly with trans-4,4,4-trifluorocrotonate 1b affording
the desired endo-adducts in excellent diastereoselectivities and
good enantioselectivities (Table 2, entries 1–10). It appears that
the position and the electronic property of the substituents on
the aromatic rings have very limited effect on the enantio-
selectivities. It is noteworthy that comparable results were still
achieved for the sterically hindered ortho-substituted imino esters
2c, 2f and 2h in terms of selectivity and reactivity (Table 2,
entries 3, 6 and 8). Additionally, the heteroaryl substituted
imino ester 2k was also tolerated in this transformation
leading to 90% yield and 88% ee9 (Table 2, entry 11). Imino
ester 2l derived from (ꢁ)-alanine also worked well affording
the desired endo-3bl bearing a quaternary stereogenic center10
with 94% ee (Table 2, entry 12).
Entry
L
[M]
Solvent
R
T/1C Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
L1 AgOAc DCM
L1 CuBF4 DCM
L2 AgOAc DCM
L2 CuBF4 DCM
L3 AgOAc DCM
L3 CuBF4 DCM
L4 CuBF4 DCM
L5 CuBF4 DCM
L6 CuBF4 DCM
L7 CuBF4 DCM
L7 CuBF4 THF
L7 CuBF4 EtOAc Et (1a)
L7 CuBF4 MeCN Et (1a)
L7 CuBF4 PhMe Et (1a)
L7 CuBF4 DCM
L7 CuBF4 DCM
L7 CuBF4 DCM
L7 CuBF4 DCM
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
Et (1a)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
85
78
54
35
85
88
85
37
70
85
85
35
80
Trace
85
3
6
50
60
10
23
59
35
63
78
59
50
35
—
83
86
85
93
9
10
11
12
13
14
15d
16e
17f
18
Et (1a)
Et (1a)
Et (1a)
t-Bu (1b) ꢀ20 85
ꢀ20 82
ꢀ40 45
Having succeeded in the asymmetric 1,3-dipolar cycloaddition
of imino ester with trans-4,4,4-trifluorocrotonate, we then
investigated the behavior of cis-trifluorocrotonate under the
optimized reaction conditions (Table 3). Reaction of cis-4,4,4-
ethyl trifluorocrotonate11 1c with glycine-derived imino esters
bearing electron-neutral, electron-deficient and electron-rich
groups on the aryl ring delivered the expected endo-adducts 4
in good yield with excellent diastereo- and enantioselectivity
(98–99% ee) (Table 3, entries 1–3). For the (ꢁ)-alanine derived
imino ester, 89% ee was also achieved for the desired cyclo-
adduct 4cl (Table 3, entry 4).
a
All reactions were carried out with 0.23 mmol of 1 and 0.35 mmol of
b
2a in 2 mL solvent for 0.5–1 h. CuBF4 = Cu(CH3CN)4BF4. Isolated
c
yield. Ee and 498 : 2 dr was determined by chiral HPLC analysis.
In 3 h. In 5 h. In 10 h.
d
e
f
reaction.3 Ag(I) or Cu(I)/Monophos complexes showed poor
enantio-selectivity for this transformation although the catalytic
activity and diastereoselectivity were satisfied (Table 1, entries
1 and 2). Combined with Ag(I) or Cu(I) salts the bisphosphine
ligand BINAP exhibited a little better asymmetric induction
but with relatively low conversion (Table 1, entries 3 and 4).
Then, a series of TF-BiphamPhos ligands8 developed in this
laboratory were next screened in order to identify a more
efficient catalyst system. In general, copper salts gave better
enantioselectivity than silver salts, and the adduct 3aa was
achieved with good yield (88%), excellent diastereoselectivity
(498 : 2) and moderate enantioselectivity (23%) when using
the Cu(CH3CN)4BF4/L3 complex as the catalyst (Table 1,
entry 6). Further ligands survey revealed that ligand L7
bearing two bromine at the 3,30-position of the TF-BIPHAM
backbone was the most promising, and provided endo-3aa as
the sole product in 85% yield and 78% ee (Table 1, entry 10).
The solvent effect was also studied, CH2Cl2 was revealed to be
the best solvent in terms of the yield and enantioselectivity
while PhMe was not suitable for this reaction (Table 1, entries
10–14). Reducing the reaction temperature from rt to 0 1C and
ꢀ20 1C led to completed reaction with 83% and 86% ee,
respectively (Table 1, entries 15 and 16). Further lowering
the temperature had detrimental effect on the reactivity and
enantioselectivity (Table 1, entry 17). Finally, the effect of
Table 2 Substrate scope of Cu(I)/L7-catalyzed asymmetric 1,3-dipolar
cycloaddition of various imino esters 2 with trans-tert-butyl 4,4,4-
trifluorocrotonate 1ba
Entry
R1
R2
3
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph (2a)
H
H
H
H
H
H
H
H
H
H
H
Me
3ba
3bb
3bc
3bd
3be
3bf
3bg
3bh
3bi
82
72
87
88
88
74
76
85
80
83
90
65
93
92
93
90
99
95
94
94
91
92
88
94
p-Me-Ph (2b)
o-Me-Ph (2c)
m-Me-Ph (2d)
p-MeO-Ph (2e)
o-MeO-Ph (2f)
p-Cl-Ph (2g)
o-Cl-Ph (2h)
m-Cl-Ph (2i)
p-Br-Ph (3j)
2-furyl (2k)
Ph (2l)
9
10
11
12d
3bj
3bk
3bl
a
All reactions were carried out with 0.23 mmol of 1 and 0.35 mmol of
b
2a in 2 mL solvent for 0.5–1 h. CuBF4 = Cu(CH3CN)4BF4. Isolated
c
yield. Ee and 498 : 2 dr was determined by chiral HPLC analysis.
Room temperature, 10 h.
d
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11110–11112 11111

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Table 3 Cu(I)/(S)-L7-catalyzed asymmetric 1,3-dipolar cycloaddition
of imino esters 2 with cis-ethyl 4,4,4-trifluorocrotonate 1ca
dipolarophile, cannot be prepared directly via 1,3-dipolar
cycloaddition even in the racemic version.6
In summary, we have developed the first catalytic asymmetric
synthesis of trifluoromethylated pyrrolidines via Cu(I)-catalyzed
1,3-dipolar cycloaddition of azomethine ylides with trans and
cis-4,4,4-trifluorocrotonates. This catalytic system exhibited
high reactivity, excellent diastereoselectivity, good enantio-
selectivity and broad substrate scope. Highly efficient epimeri-
zation of the kinetically favored endo-pyrrolidines from
cis-4,4,4-trifluorocrotonate into the thermodynamically favored
exo-pyrrolidines was also revealed. The ready availability of
the starting materials and the great importance of the chiral
trifluoromethyl compounds make the current methodology
particularly interesting in synthetic chemistry. Further investi-
gations of the scope and synthetic application of this methodology
are underway.
Entry R1 (2)
R2
4
Yieldb (%) drc
eec (%)
99
1
Ph (2a)
H
H
H
4ca 87
4cb 82
4cg 78
96 : 4
2
p-MeO-Ph (2b)
o-Cl-Ph (2g)
Ph (2l)
498 : 2 98
96 : 4 99
498 : 2 89
3
4d
Me 4cl 83
a
All reactions were carried out with 0.23 mmol of 1 and 0.35 mmol of
b
2a in 2 mL solvent for 0.5–1 h. CuBF4 = Cu(CH3CN)4BF4. Isolated
c
yield. Ee and dr 498 : 2 dr was determined by chiral HPLC analysis.
Room temperature, 10 h.
d
This work is supported by the NSFC (20972117), NCET-
10-0649, IRT1030, 973 program (2011CB808600), and the
Fundamental Research Funds for the Central Universities.
Interestingly, we found that endo-adducts 4cb and 4cg from
cis-ethyl 4,4,4-trifluorocrotonate 1c were readily epimerized to
exo-5cb and 5cg without loss of enantio- and diastereomeric
excess when stirred with a stoichiometric amount of DBU in
DCM at room temperature (Scheme 2). To determine the
relative and absolute configuration of cycloadduct 4cg and its
epimer 5cg, the derived amides 6cg and 7cg were synthesized
via a simple benzoylation protocol. X-Ray analysis of the two
crystals revealed (2R,3S,4R,5S) and (2R,3S,4S,5S)-configuration
for 6cg and 7cg, respectively, and therefore also for the
corresponding moieties in endo-4cg and exo-5cg (Scheme 2).y
From these experimental results, we proposed that with
cis-ethyl 4,4,4-trifluorocrotonate as the dipolarophile 3,4-cis-
substituted endo-4 was kinetically favored, and the epimerized
3,4-trans-substituted exo-5 was the thermodynamic product.
Cycloadduct endo-3bg obtained from trans-trifluorocrotonate
was also tested under the same conditions, however, no
epimerization occurred probably because the two substituents
on positions 3 and 4 of the corresponding pyrrolidine ring in
3bg have already been oriented in thermodynamically favored
trans geometry. It must be noted that the epimerized pyrroli-
dines 5cb and 5cg, which correspond to the exo-cycloadducts
when employing trans-ethyl 4,4,4-trifluorocrotonate as the
Notes and references
y For (2R,3S,4R,5S)-6cg: C23H21ClF3NO5, Mr = 483.86, T = 293 K,
orthorhombic, space group P212121, a = 8.6745(12), b = 13.3919(18),
c = 19.262(3) A, V = 2237.6(5) A3, Z = 4, 12 954 reflections
measured, 3670 unique (Rint = 0.0353) which were used in all
calculations. The final wR2 = 0.0845(all data), Flack w = 0.08(7).
For (2R,3S,4S,5S)-7cg: C23H21ClF3NO5, Mr = 483.86, T = 293 K,
orthorhombic, space group P212121,
a = 14.7950(17), b =
15.6582(17), c = 20.390(2) A, V = 4723.6(9) A3, Z = 8, 26 602
reflections measured, 6467 unique (Rint = 0.0422) which were used
in all calculations. The final wR2 = 0.0945 (all data), Flack
w = ꢀ0.02(6). CCDC 827404 (6cg), CCDC 827405 (7cg).
1 Fluorine in Medicinal Chemistry and Chemical Biology, ed.
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9 No cycloaddition was observed when an alkyl substituted imino
ester was tested under the same reaction conditions.
10 For recent reviews, see: Quaternary Stereocenters Challenges and
Solutions for Organic Synthesis, ed. J. Christoffers and A. Baro,
Wiley-VCH, Weinheim, 2005.
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Scheme 2 Epimerization of cycloadducts 4cb and 4cg and X-ray
structures of the corresponding benzoylated 6cg and 7cg.
c
11112 Chem. Commun., 2011, 47, 11110–11112
This journal is The Royal Society of Chemistry 2011