Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides with Fluorinated Imines: The Expanded Scope and Mechanism Insights

Article abstract of DOI:10.1021/acs.joc.8b01743

The mechanism of the Cu(I)/(S,R_p)-PPFOMe-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with fluorinated aldimines has been studied using labeling experiments, control experiments, and linear effect experiments, which clearly ruled out the 1,3-DC/epimerization pathways and explained the unusal exo′-selective stereochemistry. This protocol allows for the preparation of a series of highly functionalized fluorinated imidazolidines in good yields with excellent stereoselectivities. Moreover, the current methods have been successfully extended to synthesize more challenging imidazolidines bearing a CF₃-containing quaternary stereogenic center via the endo-selective 1,3-DC of azomethine ylides with trifluorinated ketimine under identical reaction conditions.

Full text of DOI:10.1021/acs.joc.8b01743

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Article
Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Azomethine
Ylides with Fluorinated Imines: The Expanded Scope and Mechanism Insights
Liang Wei, Qing-Hua Li, and Chun-Jiang Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01743 • Publication Date (Web): 27 Aug 2018
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Copper(I)-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of
Azomethine Ylides with Fluorinated Imines: The Expanded Scope and
Mechanism Insights
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Liang Wei,† QingꢀHua Li,† ChunꢀJiang Wang*†,‡
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China ‡ State Key Laboratory
of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai, China 230021
Eꢀmail: cjwang@whu.edu.cn
Graphic Abstract
ABSTRACT: The mechanism of the Cu(I)/(S,Rp)ꢀPPFOMe catalyzed 1,3ꢀdipolar cycloaddition of
azomethine ylides with fluorinated aldimines has been studied using labelling experiments, control
experiments and linear effect experiments, which clearly ruled out the 1,3ꢀDC/epimerization
pathways and explained the unusal exo'ꢀselective stereochemistry. This protocol allows for the
preparation of a series of highly functionalized fluorinated imidazolidines in good yields with
excellent stereoselectivities. Moreover, the current methods have been successfully extended to
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synthesize more challenging imidazolidines bearing a CF3ꢀcontaining quaternary stereogenic center
via the endoꢀselective 1,3ꢀDC of azomethine ylides with trifluorinated ketimine under identical
reaction conditions.
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Introduction
The transitionꢀmetalꢀcatalyzed asymmetric 1,3ꢀdipolar cycloaddition (1,3ꢀDC) reactions of
azomethine ylides are one of the most efficient methods for the construction of enantiomerically
enriched heterocyclic framework.1 Various highly functionalized pyrrolidine2 and piperidine3
derivatives have been synthesized by the combination of azomethine ylides with diversified
electronꢀdeficient alkenes. The cross cycloaddition between azomethine ylides and azomethine
imines has also been disclosed by us4a and others4b affording biologically important 1,2,4ꢀtriazinane
derivatives in high enantiopurity. Nevertheless, it is surprising that limited progress has been made
so far on employing imine as dipolarophile in catalytic asymmetric 1,3ꢀDC reaction.5 We believe
this kind of 1,3ꢀDC represents a significant challenge caused by various factors including the
electronic nature of the C=N unsaturated double bond, competitive reactions and the stability of
products. Considering the importance of the potential cycloadduct of imidazolidine,6 developing a
stereoselective 1,3ꢀDC reaction with imine as dipolarophile is in highly desirable and be of great
significance.
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In 2013, we reported the first example of catalytic asymmetric exo'ꢀselective 1,3ꢀDC of
azomethine ylides with fluorinated aldimines, in which the C=N served as the efficient
dipolarophilic moiety (Scheme 1, right side).7 It is noteworthy that unusual exo'ꢀselective
cycloadducts5a,8 (2,5ꢀtransꢀconfiguration) were obtained in this reaction. Our curiosity was piqued
by the unexpected stereochemistry outcome, and therefore we engaged on a study aiming at digging
more details of this transformation. In this article, we describe the detailed mechanism investigation
on the reaction mechanism and substrate scope. Considering that several different reaction
pathways can be proposed, the experimental studies were designed to differentiate those pathways
and to gain deep insight with the transformations. Moreover, the scope of the reaction has been
extended to bulky trisubstituted fluorinated ketimine with reversed endoꢀselectivity
(2,5ꢀcisꢀconfiguration), which not only further validated the posulated mechanism, but also
provided an unprecedented entry to chiral imidazolidines bearing a CF3ꢀcontaining quaternary
stereogenic center. To our knowledge, only a few reports on constructing chiral trifluoromethylated
quaternary stereocenters have been documented despite the fact that the study on the
trifluoromethylated compounds has long been the hot topic.9,10 The current method represents the
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first example of the enantioselective preparation of imidazolidines bearing a trifluoromethylated
quaternary stereocenter,11 and we believe these compounds may exhibit some benefits to drug
discovery and are expected to find valuable applications in medicinal chemistry.
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Results and Discussion
1,3-Dipolar Cycloaddition of Imino esters and Fluorinated Aldimines
Our initial report7 of the 1,3ꢀDC reaction between imino esters 2 and fluoromethylated aldimine
1 catalyzed by 3 mol % of Cu(I)/(S,Rp)ꢀPPFOMe12 complex demonstrated that various functional
groups are tolerated in this reaction, affording 2,5ꢀtransꢀadduct 3 in high yields and excellent
diastereoꢀ/enantioselective control (Table 1, See Table S1ꢀ3 for the detail). The R group at
2ꢀposition, PMP group at 3ꢀposition, RF group at 4ꢀposition and ester group at 5ꢀposition of the
generated imidazolidine ring were controlled in an all trans relationship, corresponding to the
exo'ꢀadduct, which was further validated by the Xꢀray diffraction analysis of the enantiopure
cycloadduct 3s (Table 1) and 9 (Scheme 4) (vide infra).
a
Table 1
L
: Subsrate Scope of Cu(I)/(S,Rp)- Catalyzed 1,3-DCs of Azomethine Ylides with Fluorinated Aldimines
RF
N
RF
PPh2
Fe
PMP
PMP
Cu(MeCN)4BF4/L
1
N
(3 mol %)
Et3N, Et2O, -20 oC, 1-3 h
OMe
5
CO2R'
2
+
N
R
H
CO2R'
N
R
3
exo'-
L
(S,Rp)-
2
R = Aryl, Heteroaryl, Alkyl; RF = CF3, BrCF2, ClCF2, C2F5. C3F7, C6F13
CF3
CF3
RF
PMP
N
PMP
PMP
N
N
CO2Me
CO2R'
CO2Me
N
N
N
Aryl
Alkyl
R
H
H
H
3a-3q
, 76-95% yield
>20:1 dr, 92-97% ee
5a-5g
, 76-85% yield
10:1~>20:1 dr, 89-91% ee 10:1~>20:1 dr, 91-97% ee
3r-3x
, 76-93% yield
3s
(2R,4R,5R)-
a Each compound in Table 1 has been previously published.7
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Nonꢀfluorinated imines were further investigated for this transformation (Scheme 2, equations
1 and 2). Although no reaction occurred for nonꢀactivated imines, electronꢀdeficient imine 1g
bearing ester group worked well in this catalytic system leading to product 3w with 6:1 dr and 92%
ee for the major isomer. Isobutyraldehyde derived Nꢀtosyl imine 1h was also tolerated affording
adduct 3x with excellent dr and moderate ee. However, unidentified mixture was observed for
NꢀBoc imine 1i (Scheme 2, equation 3). Only trace amount of [3+2] cycloadduct was observed
when trifluoroacetophenone derived imine 1j was employed even with prolonged reaction time,
which probably caused by the disfavored steric congestion (Scheme 2, equation 4).
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Reaction Mechanism Investigations
Despite the fact that transitionꢀmetalꢀcatalyzed 1,3ꢀDCs of azomethine ylides have received
significant attention in the recent years, examples on access to exo'ꢀselective products are extremely
rare.8 Previous reports have demonstrated that cycloadducts with 2,5ꢀcis configuration were usually
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obtained in most cases no matter with endoꢀ or exoꢀselectivity controlled 1,3ꢀDCs of azomethine
ylides (Scheme 1, left side).2 With these prior observations in mind, we considered that the
2,5ꢀtrans products might formed via the epimerization of the first generated 2,5ꢀcis imidazolidine.
Give in to this view, we proposed two possible reaction pathways: the 1,3ꢀDC of azomethine ylides
with fluorinated aldimines gave the 2,5ꢀcis configured Int-I (pathway a, endoꢀselectivity) or Int-II
(pathway b, exoꢀselectivity) with the commonlyꢀobserved diastereoselectivity, then followed by the
sequential baseꢀpromoted epimerization at 2ꢀ or 5ꢀposition to deliver the final exo'ꢀselectivity
(Figure 1).
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Deuteriumꢀlabelled experiments were subsequently performed to validated the feasibility of the
proposed 1,3ꢀDC/epimerization mechanism. Deuteriumꢀlabelled Nꢀbenzylidene glycine methyl
ester 6 was employed as the precursor of azomethine ylide under the optimized reaction condition
with ether and methanol as the solvent, respectively (Scheme 3). No matter nonꢀprotic or protic
solvent was used, only 2,5ꢀtrans imidazolidine 7 with 100% deuterium ration was obtained as
single isomer in high yield and 95% ee, which revealed that no epimerization occurred at the
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2ꢀposition of the imidazolidine ring in this annulation process under the reaction conditions and
therefore ruled out the postulated reaction pathway (a) in Figure 1.
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In order to examine the possibility of the 2,5ꢀtrans cycloadduct caused by the epimerization of
the firstly formed 2,5ꢀcisꢀimidazolidine at its 5ꢀposition, the second control experiment was
designed with the
αꢀsubstituted imino ester 8 derived from (±)ꢀalanine as the precursor of
azomethine ylide. In this case, if the 2,5ꢀcisꢀimidazolidine 9 was formed as the intermediate via
reaction pathway (b), no epimerization would occur due to the generated nitrogenꢀsubstituted
quaternary stereogenic center at the 5ꢀposition (Scheme 4, the upside). Initial experiment revealed
that the reaction proceeded smoothly with 20 mol % Cu(I)/(S,Rp)ꢀPPFOMe complex catalyst
loading and the Cs2CO3 as the base because of the less reactive nature of imino ester 8, producing
the cycloadduct imidazolidine 9 as single isomer in moderate ylide with excellent
diastereoselectivity and moderate enantioselectivity (Scheme 4, the downside). The Xꢀray
crystallographic analysis validated the configuration of 9 is still in 2,5ꢀtrans configuration, which
further ruled out the possible epimerization at the 5ꢀposition of the imidazolidine ring in the
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postulated reaction pathway (b) in Figure 1.
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Scheme 4. Control experiment to investigate the possibility of epimerization at the 5-position of the imidazolidine
8
ring with rac-alanine derived
9
CF3
PMP
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N
5
CO2Me
2
N
p-Cl-C6H4
H
cis-9
Ph
Cu(I)/L
(20 mol %)
N
5-epimerization
1a, Cs2CO3
Et2O, -10 oC, 48 h
MeO2C
8
CF3
PMP
N
5
CO2Me
2
N
H
p-Cl-C6H4
trans-9
53% yield, >20:1 dr, 75%ee
(99% ee after recrystallization)
(2R,4R,5R)-9
The optically active imidazolidine derivative 3a was readily converted into other related chiral
molecules as depicted in Scheme 5.7 The pꢀTsOH mediated hydrolysis of the adduct 3a targeted the
diamine (2R,3R)ꢀ10,
a
trifluoromethylated analogue of the synthetically useful
(2R,3R)ꢀ2,3ꢀdiaminobutanoic acid13 in 81% yield with maintained enantioselectivity. Interestingly,
imidazolidine 3a could also be alternatively achieved by the condensation of pꢀchloro benzaldehyde
and enantiomerically enriched (2R,3R)ꢀ10 (Scheme 5). That the predominantly 2,5ꢀtrans isomer is
more thermodynamically stable than other epimers can thus be verified both in the asymmetric
catalytic process and the simple condensation. Diamine 10 then transformed to cyclic urea 11 using
triphosgen as the cyclization reagent under basic condition. The deprotection of the PMP group in
the presence of Ce(NH4)2(NO3)6 give corresponding hetereocycles 12 in 65% yield without any
erosion of the stereoselectivity.
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Furthermore, only asymmetric Mannich addition occurred with the consistent stereoselectivity
when glycine ketimine 13 was employed under standard reaction conditions, and no annulation
adduct was observed. The subsequent intramolecular cyclization was totally suppressed probably
due to the disfavored steric hindrance of benzophenone moiety (Scheme 6). Hydrolysis of the
adduct 14 under acid condition gave rise to the compound (2R,3R)ꢀ10, which confirmed the
stereochemistry of the Mannich addition step.
The linear effect experiment for this reaction was also examined (see SI for more details). As
shown in Figure 2, with (S,Rp)ꢀPPFOMe as the chiral ligand, we observed a clear linear effect in the
asymmetric 1,3ꢀDCs of azomethine ylide 2a with trifluoromethylated imine 1a. Such a linear
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correlation indicates that the possible active species in this Cu(I)/(S,Rp)ꢀPPFOMeꢀcatalyzed
cycloaddition reaction is a monomeric Cu(I) complex having (S,Rp)ꢀPPFOMe as a bidentate chiral
ligand [Cu(I):L = 1:1].14
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1.0
0.8
0.6
0.4
0.2
0.0
0.0
0.2
0.4
0.6
0.8
1.0
X ee% of the ligand L
Figure 2. Linear Effect for the Asymmetric 1,3ꢀDipolar Cycloaddition of Trifluoromethylated Imine 1a with
Imino Ester 2a Catalyzed by Cu(CH3CN)4BF4/(S,Rp)ꢀPPFOMe Complex.
On the basis of deuteriumꢀlabelled experiments, thermodynamic stability of the cycloadduct and
the linear correlation results, a plausible stepwise mechanism was proposed to rationalize the
observed exo'ꢀselectivity for this 1,3ꢀDC (Figure 3). The in situꢀformed azomethine ylide is
coordinated to the Cu(I) complex leading to the catalytically active species (A) based on the linear
correlation results. Initial Mannich addition of the chiral metallated azomethine ylide (A) to the Re
face (C=N) of the fluorinated imine 1a through the gauche conformation generates the zwitterionic
intermediate (B), which could be facilitated by the possible coordination interaction between the
imino group of 1a and the Cu(I) center. After the Mannich reaction, the copper atom spontaneously
switches from imino ester to NPMP for forming the sixꢀmembered chairꢀlike species (C). Before
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the subsequent intramolecular cyclization, the CꢀN single bond must rotate into the species (D)
hence the amino unit approaches the Re face of the imine moiety to give the exo'ꢀdiastereomer, in
which the substituents at 2 and 5 position of imidazolidine ring are arranged at trans configuration.
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The key intermediate C (Int-C) was studied by configuration analysis and further understood
by the reaction of azomethine ylide with trisubstituted ketamine. As shown in Figure 4, both the
OMe group and the hydrogen atom are arranged in the 1,3ꢀaxial positions of the sixꢀmembered
chairꢀlike Int-C. We envisioned that if the H atom in axial position was replaced by a more bulky
group such as CO2Et, the steric congestion between the CO2Et group of the ketimine and the OMe
group would lead to energy disfavored intermediate G, which may result in a different reaction
pathway and therefore in a change in selectivity (Figure 4).
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OMe
R'
*L
PMP
Cu
N
O
H
F3C
N
6
7
R
8
9
R = H (D, favored): MeOax and Hax
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G
R = CO2Et ( , disfavored): MeOax and CO2Etax
Figure 4. Conformation analysis based on the six-memebered chair-like intermediates.
To verify this postulate, Nꢀ(4ꢀchlorobenzylidene)ꢀglycine methyl ester 2a and trisubstituted
αꢀCF3ꢀketimine ester 1k were subjected to the standard reaction conditions, and the cycloadduct
imidazolidine 15d was obtained indeed as a single isomer with exclusive diastereoselectivity and
excellent enantioselectivity in moderate yield (Scheme 7). The relative configuration of 15d was
finally identified as 2,5ꢀcis configuration, and its absolute configuration was further confirmed by
Xꢀray structure analysis as (2S,4R,5S), which validates the above configuration analysis of the
postulated intermediates in the catalytic cycle (Figure 3 and 4).
Scheme 7. Initial test on the Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of α-CF3-ketimine ester 1g with imino ester 2a
CF3
CO2Et
PMP
N
5
CO2Me
2
N
+
CF3
exo-
selectivity
N
H
p-Br-C6H4
PMP
1k
Cu(I)/(S,Rp)-L
(5 mol %)
CO2Et
15d
2,5-trans-
Et3N, Et2O
-20 oC, 48 h
p-Br-C6H4
N
CO2Me
CF3
CO2Et
PMP
endo-
selectivity
2d
N
5
CO2Me
2
N
H
p-Br-C6H4
15d
2,5-cis-
56% yield
>20:1 dr, 96%ee
15d
(2S,4R,5S)-
Based on the experiment result, the mechanism for the Cu(I)ꢀcatalyzed endoꢀselective 1,3ꢀDC
of azomethine ylide with trisubstituted ketimine was then postulated (Figure 5). The similar
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sixꢀmembered chairꢀlike intermediate (G) leading to exo'ꢀselectivity was inhibited due to the
disfavored 1,3ꢀaxial interaction between ꢀOMe and ꢀCO2Et group and instead the cyclization step
takes place through intermediate F providing 2,5ꢀcis imidazolidine 15. The postulated catalytic
cycle is fully consistent with the observed stereochemical outcome.
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Considering the great significance of developing new methods on accessing CF3ꢀcontaining
quaternary stereocenters, we decided to extend the generality of the 1,3ꢀDCof azomethine ylides
with ketimine 1k. To improve the reaction yield, Et3N was replaced with a stronger inorganic base
Cs2CO3 and toluene was chosen to be the reaction solvent instead of ethyl ether according to the
solvent reꢀscreening. To our delight, the less reactive ketimine 1k was consumed completely based
on the TLC monitoring and the desired product was isolated in 77% yield with excellent
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stereoselectivity at ꢀ20 C with toluene as the solvent. Under the reꢀoptimized reaction conditions,
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the substrate scope with respect to the imino esters was evaluated and the results were summarized
in Table 4. Imino esters with electronꢀwithdrawing, ꢀdonating or ꢀneutral substituted phenyl group
were all well tolerated delivering the desired products in good yield and good to excellent
enantioselectivity (up to 83% yield, 96% ee, Table 2, entries 1ꢀ7). Notably, fused 2ꢀnaphthyl imine
15i and heteroaromatic substituted 2ꢀthienyl imino ester 15j gave the comparable results. (entries 8
and 9). The alkylꢀsubstituted imino esters are not viable substrates in this reaction, only trace
amount of desired products were isolated. αꢀSubstituted amino acids derived imino esters also
failed to reaction with 1k probably due to the disfavored steric hindrance.
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Conclusion
The copper(I)ꢀcatalyzed 1,3ꢀdipolar cycloaddition between azomethine ylide and fluorinated
aldimine has been studied with different tools with the goal of refining the reaction mechanism. The
elaborated control experiments successfully rule out the possible sequential 1,3ꢀDCs/epimerization
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pathways and demonstrated that the generated exo'ꢀcycloadducts are the thermodynamically stable
diastereoisomers. Combination the results of the control experiments and linear effect experiments,
we proposed that the current 1,3ꢀdipolar cycloaddition might proceeded stereospecifically in a
stepwise Mannich/cyclization process. In addition, we have applied the Cu(I)/(S,Rp)ꢀPPFOMe
catalyzed asymmetric 1,3ꢀdipolar cycloaddition to a range of disubstituted fluorinated aldimines and
trisubstituted fluorinated ketimine. This methodology provides a direct entry to biologically
important imidazolidines bearing a fluoroalkylꢀcontaining tertiary or quaternary stereogenic center
in high yield with excellent stereoselectivity, and further transformations provide useful chiral
fluorinated compounds.
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EXPERIMENTAL SECTION
1
General Information. H NMR spectra were recorded on a VARIAN Mercury 300 MHz or
Bruker 400 MHz spectrometer in CDCl3. Chemical shifts are reported in ppm with the internal TMS
signal at 0.0 ppm as a standard. The data are reported as (s = single, d = double, t = triple, q =
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quartet, m = multiple or unresolved, and brs = broad single). C NMR spectra were recorded on a
Bruker 100 MHz or 75 MHz spectrometer in CDCl3 or DMSOꢀd6. Chemical shifts are reported in
ppm with the internal chloroform signal at 77.0 ppm as a standard. Commercially available reagents
were used without further purification. All reactions were monitored by TLC with silica gelꢀcoated
plates. Diastereomeric ratios were determined from crude 1H NMR or HPLC analysis. Enantiomeric
ratios were determined by HPLC, using a chiralpak ADꢀH column, a chiralpak ASꢀH column or a
chiralcel ODꢀH column with hexane and iꢀPrOH as solvents, or determined by GC using βꢀdex 325
column. Chiral ligand (S,Rp)ꢀPPFOMe12 and fluorinated imines15 was prepared according to the
literature procedure. The racemic adducts were obtained by using AgOAc/PPh3 as the catalyst. The
absolute configuration of (2R,4R,5R)ꢀ3s, (2R,4R,5R)ꢀ9 and (2S,4R,5S)ꢀ15d was determined
unequivocally according to the Xꢀray diffraction analysis, and those of other adducts were deduced
on the basis of these results.
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Procedure for the Synthesis of ketimine 1k. This compound is prepared according to reported
procedure15c: To a solution of the iminophosphorane (5 mmol) in dry toluene (20 mL) was added
dropwise the trifluorinated keto ester (5 mmol), and the reaction mixture was stirred at 80 °C for 18
h. Then the reaction mixture was cooled to room temperature, and the solvents were eliminated
under reduced pressure. Et2O (20 mL) was added and the reaction mixture cooled to 0 °C. The
white precipitate was filtered through a pad of Celite and washed with cold Et2O (3 × 10 mL). The
filtrate was concentrated under reduced pressure and purified by flash column chromatography.
General Procedure for the Synthesis of Racemic Cycloadducts. Under argon atmosphere,
PPh3 (6.6 mg, 0.025 mmol) and AgOAc (3.8 mg, 0.023 mmol) were dissolved in 2 mL of DCM, and
stirred at room temperature for about 0.5 h. Then, imine substrate (0.35 mmol), base (0.03 mmol)
and imines (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 cycloaddition product, which was used as the racemic sample for the HPLC analysis.
General Procedure for Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides with
Aldimines. Under argon atmosphere, (S,Rp)ꢀPPFOMe (3.3 mg, 0.0077 mmol) and Cu(CH3CN)4BF4
(2.2 mg, 0.007 mmol) were dissolved in 2 mL of ethyl ether, and stirred at room temperature for
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about 0.5 h. After imino ester (0.35 mmol) was added, the mixture was dropped to ꢀ20 C. Then,
Aldimine (0.23 mmol) and Et3N (0.03 mmol) were added sequentially. Once starting material was
consumed (monitored by TLC), the mixture was filtered through celite and the filtrate was
concentrated to dryness. The residue was purified by column chromatography to give the
corresponding cycloaddition product, which was then directly analyzed by HPLC analysis to
determine the enantiomeric excess.
(2
R
,4
R,5R
)-5-ethyl
4-methyl
2-(4-chlorophenyl)-1-(4-methoxyphenyl)imidazo-lidine-4,5-dicarboxylate (3y). The title
compound was prepared according to the general procedure as described above in 87% yield (83.8
mg). d.r. = 6:1; [α]25D = +15.4 (c 0.59, CHCl3); 1H NMR (CDCl3, TMS, 400 MHz) δ 7.61 (d, J = 8.4
Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 6.74 (d, J = 9.2 Hz, 2H), 6.45 (d, J = 9.2 Hz, 2H), 5.50 (s, 1H),
4.50 (d, J = 2.8 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.26 (d, J = 2.8 Hz, 1H), 3.78 (s, 3H), 3.70 (s,
13
3H), 1.36 (t, J = 7.2 Hz, 3H); C NMR (CDCl3, TMS, 100 MHz) δ 172.4, 170.9, 152.6, 139.3,
138.6, 134.3, 128.9, 128.6, 114.7, 114.5, 79.2, 66.4, 63.0, 61.8, 55.6, 52.8, 14.2; IR (KBr) ν 2927,
2337, 1743, 1513, 1445, 1247, 1209, 1037, 816cmꢀ1. HRMS (ESI+) m/z: ([M+H]+) Calcd. For
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C21H24ClN2O5: 419.1361, found: 419.1368. The product was analyzed by HPLC to determine the
enantiomeric excess: 92% ee (Chiralpak ADꢀH, iꢀpropanol/hexane = 30/70, flow rate 1.0 mL/min, λ
= 220 nm); tr = 10.07 and 19.09 min.
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(2
R
,4
R,5
S)-methyl
2-(4-chlorophenyl)-5-isopropyl-1-tosylimidazolidine-4-car-boxylate
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(3z). The title compound was prepared according to the general procedure as described above in 92%
yield (92.5 mg). [α]25D = ꢀ7.7 (c 0.45, CHCl3); 1H NMR (CDCl3, TMS, 400 MHz) δ 7.72 (d, J = 8.4
Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.36ꢀ7.29 (m, 4H), 5.80 (s, 1H), 3.65ꢀ3.61 (m, 2H), 3.57 (s, 3H),
2.46 (s, 3H), 1.48ꢀ1.44 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H); 13C NMR
(CDCl3, TMS, 100 MHz) δ 172.7, 144.3, 138.1, 134.8, 134.0, 130.0, 128.5, 128.4, 128.0, 77.9, 69.8,
63.2, 52.5, 33.7, 21.6, 20.4, 18.8; IR (KBr) ν 2927, 2332, 1741, 1597, 1489, 1349, 1163, 1089, 1014,
755, 665 cmꢀ1. HRMS (ESI+) m/z: ([M+H]+) Calcd. For C21H26ClN2O4S: 437.1290, found:
437.1296. The product was analyzed by HPLC to determine the enantiomeric excess: 56% ee
(Chiralpak ASꢀH, iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 220 nm); tr = 16.52 and
23.51 min.
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General Procedure for Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides with
Fluorinated Ketimine 1k. Under argon atmosphere, (S,Rp)ꢀPPFOMe (3.3 mg, 0.0077 mmol) and
Cu(CH3CN)4BF4 (2.2 mg, 0.007 mmol) were dissolved in 2 mL of toluene, and stirred at room
temperature for about 0.5 h. After imino ester (0.35 mmol) was added, the mixture was dropped to
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ꢀ20 C. Then, fluorinated imine 1k (0.23 mmol) and Cs2CO3 (0.03 mmol) were added sequentially.
Once starting material was consumed (monitored by TLC), the mixture was filtered through celite
and the filtrate was concentrated to dryness. The residue was purified by column chromatography to
give the corresponding cycloaddition product, which was then directly analyzed by HPLC analysis
to determine the enantiomeric excess.
(2
S,4
R
,5
S)-5-ethyl
4-methyl
2-(4-chlorophenyl)-1-(4-methoxyphenyl)-5-(trifluoromethyl)imidazolidine-4,5-dicarboxylate
(15a). The title compound was prepared according to the general procedure as described above in
77% yield (86.1 mg); [α]25D = ꢀ99.4 (c 1.06, CHCl3); 1H NMR (CDCl3, TMS, 300 MHz) δ 7.48 (d,
J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 8.7 Hz, 2H), 5.66 (d,
J = 12.0 Hz, 1H), 4.48ꢀ4.32 (m, 3H), 3.81 (s, 3H), 3.87 (s, 3H), 2.93 (dd, J1 = J2 = 12.0 Hz, 1H),
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1.42 (t, J = 7.2 Hz, 3H); C NMR (CDCl3, TMS, 100 MHz) δ 168.4, 167.8, 155.6, 136.3, 134.7,
134.1, 129.1, 128.9, 124.7 (q, J = 289.4 Hz), 123.8, 113.9, 79.8, 75.3 (q, J = 26.0 Hz), 66.6, 62.8,
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55.1, 53.0, 14.0; IR (KBr) ν 2950, 2424, 1745, 1710, 1515, 1468, 1421, 1215, 1135, 1037, 929, 664,
626 cmꢀ1. HRMS (ESI+) m/z: ([M+H]+) Calcd. For C22H24ClF3N2O5: 487.1242, found: 487.1249.
The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (Chiralpak ASꢀH,
iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 220 nm); tr = 6.65 and 8.40 min.
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(2S,4R,5S)-5-ethyl 4-methyl 2-(3-chlorophenyl)-1-(4-methoxyphenyl)-5-(trifluoromethyl)
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imidazolidine-4,5-dicarboxylate (15b). The title compound was prepared according to the general
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procedure as described above in 79% yield (88.4 mg); [α]25 = ꢀ92.3 (c 1.46, CHCl3); H NMR
D
(CDCl3, TMS, 300 MHz) δ 7.56 (s, 1H), 7.43ꢀ7.41 (m, 1H), 7.23ꢀ7.21 (m, 2H), 6.79 (d, J = 8.7 Hz,
2H), 6.65 (d, J = 8.7 Hz, 2H), 5.65 (d, J = 11.7 Hz, 1H), 4.48ꢀ4.34 (m, 3H), 3.80 (s, 3H), 3.67 (s,
3H), 2.96 (dd, J1 = J2 = 12.3 Hz, 1H), 1.45 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, TMS, 100 MHz) δ
168.3, 167.7, 155.6, 140.0, 134.5, 133.9, 129.9, 129.2, 127.8, 126.0, 124.6 (q, J = 288.8 Hz), 123.7,
113.9, 79.8, 75.3 (q, J = 25.5 Hz), 66.6, 62.8, 55.0, 53.0, 13.9; IR (KBr) ν 2947, 2420, 1743, 1707,
1512, 1458, 1421, 1225, 1130, 1032, 933, 668, 625 cmꢀ1. HRMS (ESI+) m/z: ([M+H]+) Calcd. For
C22H23ClF3N2O5: 487.1242, found: 487.1251. The product was analyzed by HPLC to determine the
enantiomeric excess: 83% ee (Chiralpak ASꢀH, iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ
= 220 nm); tr = 6.20 and 10.23 min.
(2S,4R,5S)-5-ethyl 4-methyl 2-(2-chlorophenyl)-1-(4-methoxyphenyl)-5-(trifluoromethyl)
imidazolidine-4,5-dicarboxylate (15c). The title compound was prepared according to the general
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procedure as described above in 62% yield (69.3 mg); [α]25 = ꢀ182.5 (c 0.90, CHCl3); H NMR
D
(CDCl3, TMS, 300 MHz) δ 7.78 (m, 1H), 7.30ꢀ7.29 (m, 1H), 7.18ꢀ7.16 (m, 2H), 6.78 (d, J = 8.7 Hz,
2H), 6.64 (d, J = 8.7 Hz, 2H), 6.18 (d, J = 11.7 Hz, 1H), 4.52 (d, J = 12.9 Hz, 1H), 4.39ꢀ4.35 (m,
2H), 3.78 (s, 3H), 3.63 (s, 3H), 2.90 (dd, J1 = J2 = 12.3 Hz, 1H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR
(CDCl3, TMS, 100 MHz) δ 168.3, 167.8, 155.3, 135.0, 134.4, 134.2, 130.0, 129.4, 128.5, 127.6,
124.7 (q, J = 289.1 Hz), 123.0, 113.9, 75.8, 75.1 (q, J = 25.3 Hz), 66.8, 62.8, 55.0, 53.0, 13.9; IR
(KBr) ν 2957, 2418, 1739, 1714, 1517, 1463, 1425, 1230, 1038, 936, 659, 618 cmꢀ1. HRMS (ESI+)
m/z: ([M+H]+) Calcd. For C22H23ClF3N2O5: 487.1242, found: 487.1248. The product was analyzed
by HPLC to determine the enantiomeric excess: 94% ee (Chiralpak ADꢀH, iꢀpropanol/hexane =
10/90, flow rate 1.0 mL/min, λ = 220 nm); tr = 6.73 and 7.64 min.
(2S,4R,5S)-5-ethyl 4-methyl 2-(4-bromophenyl)-1-(4-methoxyphenyl)-5-(trifluoromethyl)
imidazolidine-4,5-dicarboxylate (15d). The title compound was prepared according to the general
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procedure as described above in 75% yield (91.5 mg); [α]25 = ꢀ84.3 (c 1.48, CHCl3); H NMR
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(CDCl3, TMS, 300 MHz) δ 7.41 (m, 4H), 6.78 (d, J = 8.7 Hz, 2H), 6.64 (d, J = 8.7 Hz, 2H), 5.65 (d,
J = 12.0 Hz, 1H), 4.48ꢀ4.34 (m, 3H), 3.79 (s, 3H), 3.66 (s, 3H), 2.94 (dd, J1 = J2 = 12.0 Hz, 1H),
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1.41 (t, J = 7.2 Hz, 3H); C NMR (CDCl3, TMS, 100 MHz) δ 168.3, 167.7, 155.5, 136.8, 134.0,
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131.8, 129.4, 124.7 (q, J = 289.1 Hz), 123.7, 122.9, 113.8, 79.7, 75.3 (q, J = 24.9 Hz), 66.5, 62.7,
55.0, 52.9, 13.9; IR (KBr) ν 2948, 2433, 1745, 1722, 1560, 1517, 1473, 1422, 1235, 1037, 927, 679,
622 cmꢀ1. HRMS (ESI+) m/z: ([M+H]+) Calcd. For C22H23BrF3N2O5: 531.0742, found: 531.0732.
The product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (Chiralpak ASꢀH,
iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 220 nm); tr = 7.18 and 9.01 min.
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(2
S,4
R
,5
S)-5-ethyl
4-methyl
1-(4-methoxyphenyl)-2-phenyl-5-(trifluoromethyl)
imidazolidine-4,5-dicarboxylate (15e). The title compound was prepared according to the general
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procedure as described above in 68% yield (70.7 mg); [α]25 = ꢀ100.6 (c 1.30, CHCl3); H NMR
D
(CDCl3, TMS, 300 MHz) δ 7.54ꢀ7.52 (m, 2H), 7.29ꢀ7.26 (m, 3H), 6.79 (d, J = 8.7 Hz, 2H), 6.62 (d,
J = 8.7 Hz, 2H), 5.68 (d, J = 11.7 Hz, 1H), 4.50ꢀ4.35 (m, 3H), 3.80 (s, 3H), 3.65 (s, 3H), 2.99 (dd,
J1 = J2 = 12.3 Hz, 1H), 1.43 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, TMS, 100 MHz) δ 168.4, 167.9,
155.3, 137.7, 134.4, 128.9, 128.6, 127.7, 124.8 (q, J = 289.4 Hz), 123.7, 113.8, 80.4, 75.3 (q, J =
25.3 Hz), 66.7, 62.7, 55.0, 53.0, 14.0; IR (KBr) ν 2944, 2401, 1745, 1718, 1523, 1507, 1428, 1219,
1027, 935, 679, 616 cmꢀ1. HRMS (ESI+) m/z: ([M+H]+) Calcd. For C22H24F3N2O5: 453.1632, found:
453.1632. The product was analyzed by HPLC to determine the enantiomeric excess: 95% ee
(Chiralpak ASꢀH, iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 220 nm); tr = 6.47 and 8.52
min.
(2
S,4
R
,5
S)-5-ethyl
4-methyl
1-(4-methoxyphenyl)-2-(p-tolyl)-5-(trifluoromethyl)
imidazolidine-4,5-dicarboxylate (15f). The title compound was prepared according to the general
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procedure as described above in 77% yield (82.6 mg); [α]25 = ꢀ103.0 (c 1.42, CHCl3); H NMR
D
(CDCl3, TMS, 300 MHz) δ 7.41 (d, J = 7.5 Hz, 2H), 7.08 (d, J = 7.5 Hz, 2H), 6.78 (d, J = 8.7 Hz,
2H), 6.62 (d, J = 8.7 Hz, 2H), 5.65 (d, J = 11.7 Hz, 1H), 4.48ꢀ4.34 (m, 3H), 3.79 (s, 3H), 3.65 (s,
3H), 2.97 (dd, J1 = J2 = 12.3 Hz, 1H), 2.27 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, TMS,
100 MHz) δ 168.5, 168.0, 155.3, 138.2, 137.7, 134.5, 129.7, 128.5, 128.4, 124.8 (q, J = 289.3 Hz),
124.7, 123.7, 113.8, 80.5, 75.4 (q, J = 25.1 Hz), 66.7, 62.7, 55.1, 53.0, 21.4, 14.0; IR (KBr) ν 2955,
2421, 1748, 1730, 1516, 1507, 1458, 1225, 1028, 935, 669, 619 cmꢀ1. HRMS (ESI+) m/z: ([M+H]+)
Calcd. For C23H26F3N2O5: 467.1788, found: 467.1793. The product was analyzed by HPLC to
determine the enantiomeric excess: 96% ee (Chiralpak ASꢀH, iꢀpropanol/hexane = 10/90, flow rate
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1.0 mL/min, λ = 220 nm); tr = 6.05 and 7.66 min.
(2 ,4 ,5 )-5-ethyl 4-methyl 1-(4-methoxyphenyl)-2-(o-tolyl)-5-(trifluoromethyl)
S
R S
5
6
imidazolidine-4,5-dicarboxylate (15g). The title compound was prepared according to the general
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procedure as described above in 75% yield (80.4 mg); [α]25 = ꢀ132.9 (c 1.28, CHCl3); H NMR
D
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(CDCl3, TMS, 300 MHz) δ 7.63 (d, J = 7.2 Hz, 1H), 7.11ꢀ7.09 (m, 3H), 6.72 (d, J = 8.7 Hz, 2H),
6.63 (d, J = 8.7 Hz, 2H), 5.90 (d, J = 11.7 Hz, 1H), 4.51ꢀ4.30 (m, 3H), 3.80 (s, 3H), 3.66 (s, 3H),
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2.91ꢀ2.83 (m, 1H), 2.51 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H); C NMR (CDCl3, TMS, 100 MHz) δ
168.5, 168.0, 155.2, 136.8, 135.5, 134.7, 130.3, 128.4, 126.6, 124.8 (q, J = 291.3 Hz), 123.1, 113.8,
76.3, 75.1 (q, J = 25.7 Hz), 66.8, 62.7, 55.1, 53.0, 18.9, 14.0; IR (KBr) ν 2932, 2433, 2401, 1741,
1723, 1523, 1510, 1422, 1215, 1036, 930, 671, 628 cmꢀ1. HRMS (ESI+) m/z: ([M+H]+) Calcd. For
C23H26F3N2O5: 467.1788, found: 467.1791. The product was analyzed by HPLC to determine the
enantiomeric excess: 95% ee (Chiralpak ADꢀH, iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ
= 220 nm); tr = 6.64 and 7.64 min.
(2S,4R,5S)-5-ethyl 4-methyl 1-(4-methoxyphenyl)-2-(naphthalen-2-yl)-5-(trifluoromethyl)
imidazolidine-4,5-dicarboxylate (15h). The title compound was prepared according to the general
procedure as described above in 83% yield (95.9 mg); [α]25 = ꢀ109.4 (c 1.56, CHCl3); H NMR
1
D
(CDCl3, TMS, 300 MHz) δ 7.98 (s, 1H), 7.78ꢀ7.69 (m, 4H), 7.44ꢀ7.41 (m, 2H), 6.86 (d, J = 8.7 Hz,
2H), 6.58 (d, J = 8.7 Hz, 2H), 5.86 (d, J = 11.7 Hz, 1H), 4.56ꢀ4.37 (m, 3H), 3.79 (s, 3H), 3.57 (s,
3H), 3.12 (dd, J1 = J2 = 12.3 Hz, 1H), 1.46 (d, J = 7.2 Hz, 1H); 13C NMR (CDCl3, TMS, 100 MHz)
δ 168.5, 167.9, 155.4, 135.2, 134.3, 133.6, 133.0, 128.7, 128.0, 127.6, 126.3, 126.1, 124.8 (q, J =
289.7 Hz), 124.4, 123.8, 113.8, 80.6, 75.5 (q, J = 25.5 Hz), 66.7, 62.7, 55.0, 53.0, 14.0; IR (KBr) ν
2952, 2430, 2410, 1748, 1713, 1517, 1502, 1424, 1362, 1211, 1040, 925, 673, 626 cmꢀ1. HRMS
(ESI+) m/z: ([M+H]+) Calcd. For C26H26F3N2O5: 503.1788, found: 503.1788. The product was
analyzed by HPLC to determine the enantiomeric excess: 92% ee (Chiralpak ASꢀH,
iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 220 nm); tr = 8.46 and 11.78 min.
(2S,4R,5S)-5-ethyl 4-methyl 1-(4-methoxyphenyl)-2-(thiophen-2-yl)-5-(trifluoromethyl)
imidazolidine-4,5-dicarboxylate (15i). The title compound was prepared according to the general
procedure as described above in 52% yield (54.8 mg); [α]25 = ꢀ110.2 (c 0.32, CHCl3); H NMR
1
D
(CDCl3, TMS, 300 MHz) δ 7.18 (m, 2H), 6.87ꢀ6.85 (m, 3H), 6.67 (d, J = 8.4 Hz, 2H), 5.99 (d, J =
11.7 Hz, 1H), 4.48ꢀ4.31 (m, 3H), 3.79 (s, 3H), 3.67 (s, 3H), 3.15 (dd, J1 = J2 = 12.3 Hz, 1H), 1.42 (d,
13
J = 7.2 Hz, 1H); C NMR (CDCl3, TMS, 100 MHz) δ 168.2, 167.5, 155.9, 141.8, 134.1, 127.5,
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126.5, 126.4, 124.5 (q, J = 289.3 Hz), 124.4, 113.8, 76.0, 75.0 (q, J = 25.3 Hz), 66.1, 62.6, 55.0,
53.0, 13.9; IR (KBr) ν 2938, 2428, 2405, 1742, 1712, 1574, 1513, 1432, 1220, 1039, 925, 665, 621
cmꢀ1. HRMS (ESI+) m/z: ([M+H]+) Calcd. For C20H22F3N2O5S: 459.1196, found: 459.1199. The
product was analyzed by HPLC to determine the enantiomeric excess: 96% ee (Chiralpak ASꢀH,
iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 220 nm); tr = 7.71 and 11.42 min.
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(2R,3R)-methyl 2-amino-4,4,4-trifluoro-3-((4-methoxyphenyl)amino)butanoate (10). 3a
(207 mg, 0.5 mmol) was dissolved in 3 mL of methanol at room temperature followed by the
addition of TsOH.H2O (380 mg, 2 mmol). The reaction mixture was stirred until starting material
was consumed (monitored by TLC) and neutralized the mixture by Na2CO3. Then the mixture was
partitioned between ethyl acetate and water, then the organic layer was washed with brine, dried
over MgSO4, and concentrated in vacuo then the organic solvent was removed and the residue was
purified by column chromatography to give compound 10 in 81% yield (118.3 mg). [α]25 = ꢀ41.2
D
(c 0.73, CHCl3); 1H NMR (CDCl3, TMS, 300 MHz) δ 6.76 (d, J = 8.7 Hz, 2H), 6.66 (d, J = 8.7 Hz,
2H), 4.54ꢀ4.51 (m, 1H), 4.43ꢀ4.36 (m, 1H), 4.12 (s, 1H), 3.73 (s, 3H), 3.59 (s, 3H), 1.78 (brs, 2H);
13C NMR (CDCl3, TMS, 100 MHz) δ 171.7, 153.1, 139.9, 125.6 (q, J = 283.1 Hz), 116.0, 114.7,
58.4 (q, J = 27.9 Hz), 55.6, 52.7, 52.6; IR (KBr) ν 3368, 2951, 1746, 1516, 1453, 1218, 1035, 929,
669 cmꢀ1. The product was analyzed by HPLC to determine the enantiomeric excess: 97% ee
(Chiralpak ASꢀH, iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 220 nm); tr = 11.07 and
20.46 min.
(4R,5R)-methyl
1-(4-methoxyphenyl)-2-oxo-5-(trifluoromethyl)imidazolidine-4-Carboxylate (11). To a solution
of 10 (100 mg, 0.34 mmol) and triethylamine (141 µL, 1.02 mmol) in dry CH2Cl2(15.0 mL) under
nitrogen at 0 °C was added a solution of triphosgene (100 mg, 0.34 mmol) in dry CH2Cl2 dropwise.
The reaction mixture was warmed to room temperature and stirred until the starting material was
consumed completely as indicated by TLC.Then the reaction was quenched and purified by column
chromatography to give the cyclic urea 11 in 85% yield (92.0 mg). [α]25D = +18.8 (c 0.16, CHCl3);
1H NMR (CDCl3, TMS, 300 MHz) δ 7.24 (d, J = 9.0 Hz, 2H), 6.92 (d, J = 9.0 Hz, 2H), 5.85 (s, 1H),
4.91ꢀ4.88 (m, 1H), 4.33 (d, J = 2.4 Hz, 1H), 3.89 (s, 3H), 3.81 (s, 3H); 13C NMR (CDCl3, TMS, 75
MHz) δ 169.7, 158.9, 158.2, 129.3, 126.9, 123.8 (q, J = 281.5 Hz), 114.3, 61.1 (q, J = 32.4 Hz),
55.3, 53.3, 52.0; IR (KBr) ν 2917, 2846, 2335, 1722, 1515, 1423, 1241, 1166cmꢀ1. HRMS (ESI+)
m/z: ([M+H]+) Calcd. For C13H14F3N2O4: 319.0897, found: 319.0900. The product was analyzed by
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HPLC to determine the enantiomeric excess: 97% ee (Chiralpak ADꢀH, iꢀpropanol/hexane = 40/60,
flow rate 1.0 mL/min, λ = 220 nm); tr = 14.87 and 16.88 min.
(4R,5R)-methyl 2-oxo-5-(trifluoromethyl)imidazolidine-4-carboxylate (12). To a solution of
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11 (92 mg, 0.29 mmol) in dry acetonitrile (2.0 mL) was added dropwise a solution of CAN (477 mg,
0.87 mmol) in H2O (1.0 mL) at 0 °C. The reaction was completed immediately and quenched by the
addition of saturated NH4Cl aqueous solution. The phases were separated and the aqueous phase
was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and
concentrated under vacuum. The residue was purified by chromatography to give 12 as a white
soild (40.0 mg, 65%). [α]25D = ꢀ35.0 (c 0.20, CHCl3); 1H NMR (CDCl3, TMS, 300 MHz) δ 6.92 (s,
1H), 6.41 (s, 1H), 4.46 (m, 1H), 4.33 (d, J = 3.2 Hz, 1H), 3.85 (s, 3H); 13C NMR (DMSOꢀd6, TMS,
100 MHz) δ 170.7, 161.1, 124.7 (q, J = 279.4 Hz), 55.2 (q, J = 32.2 Hz), 53.4, 52.9; IR (KBr) ν
3243, 2922, 2360, 2341, 1724, 1443, 1240, 1176, 1145cmꢀ1. HRMS (ESI+) m/z: ([M+Na]+) Calcd.
For C6H7F3N2O3Na: 235.0296, found: 235.0301. The product was analyzed by GC to determine the
enantiomeric excess: 97% ee (βꢀdex 325 column, 30 m x 0.25 mm x 0.25 ꢀm, column temperature:
170 oC, carrier gas: N2, 1 mL/min); tr = 9.84 and 14.29 min.
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Methyl
(2R,4R,5R)-1-(4-methoxyphenyl)-2-phenyl-5-(trifluoromethyl)imidazolidine-4-carboxylate-2-d
(7). Under argon atmosphere, (S,Rp)ꢀPPFOMe (3.3 mg, 0.0077 mmol) and Cu(CH3CN)4BF4 (2.2 mg,
0.007 mmol) were dissolved in 2 mL of ether or methanol, and stirred at room temperature for about
0.5 h. After deuteriumꢀlabelled Nꢀbenzylidene glycine methyl ester 6 (0.35 mmol) was added, the
mixture was dropped to ꢀ20 oC. Then, fluorinated imine 1a (0.23 mmol) and Et3N (0.03 mmol) was
added sequentially. Once starting material was consumed (monitored by TLC), the mixture was
filtered through celite and the filtrate was concentrated to dryness. The residue was purified by
column chromatography to give the cycloaddition product 7, which was then directly analyzed by
HPLC analysis to determine the enantiomeric excess. In Et2O: 80.6 mg, 92%; In MeOH: 78.9 mg,
90%. [α]25D = ꢀ37.3 (c 0.71, CHCl3); 1H NMR (CDCl3, TMS, 400 MHz) δ 7.54 (d, J = 7.6 Hz, 2H),
7.39ꢀ7.35 (m, 3H), 6.74 (d, J = 9.2 Hz, 2H), 6.69 (d, J = 9.2 Hz, 2H), 4.63 (q, J = 6.8 Hz, 1H), 4.31
(s, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 2.69 (brs, 1H); 13C NMR (CDCl3, TMS, 100 MHz) δ 170.5,
153.8, 139.8, 138.9, 128.94, 128.88, 126.6, 125.9 (q, J = 280.9 Hz), 117.0, 114.5, 81.4 (t, J = 23.3
Hz), 65.5 (q, J = 30.6 Hz), 60.6, 55.4, 52.9; IR (KBr) ν 3365, 2951, 2845, 1755, 1515, 1420, 1362,
1243, 1136, 1030, 930, 823, 699 cmꢀ1. HRMS (ESI+) m/z: ([M+H]+) Calcd. For C19H19DF3N2O3:
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382.1483, found: 382.1477. The product was analyzed by HPLC to determine the enantiomeric
excess: 95% ee (Chiralpak ASꢀH, iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 220 nm); tr
= 7.66 and 10.95 min.
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(2R,4R,5R)-methyl 2-(4-chlorophenyl)-1-(4-methoxyphenyl)-4-methyl-5-(trifluoromethyl)
9
imidazolidine-4-carboxylate (9). Under argon atmosphere, (S,Rp)ꢀPPFOMe (21.8 mg, 0.051 mmol)
and Cu(CH3CN)4BF4 (14.5 mg, 0.046 mmol) were dissolved in 2 mL of ether or methanol, and
stirred at room temperature for about 0.5 h. After (±)ꢀalanine-derived imino ester 8 (78.8 mg, 0.35
10
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o
mmol) was added, the mixture was dropped to ꢀ10 C. Then, fluorinated imine 1a (46.7 mg, 0.23
mmol) and Cs2CO3 (22.8 mg, 0.07 mmol) was added sequentially. Once starting material was
consumed (monitored by TLC), the mixture was filtered through celite and the filtrate was
concentrated to dryness. The residue was purified by column chromatography to give the
cycloaddition product 9, which was then directly analyzed by HPLC analysis to determine the
enantiomeric excess. 52.2 mg, 53%. [α]25 = ꢀ86.0 (c 0.13, CHCl3); 1H NMR (CDCl3, TMS, 400
D
MHz) δ 7.46 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 9.2 Hz, 2H), 6.58 (d, J = 9.2
13
Hz, 2H), 5.21 (s, 1H), 4.88 (q, J = 7.6 Hz, 1H), 3.74 (s, 3H), 3.71 (s, 3H), 1.64 (s, 3H); C NMR
(CDCl3, TMS, 100 MHz) δ 173.1, 153.5, 139.6, 137.7, 134.6, 129.2, 128.0, 125.7 (q, J = 282.1 Hz),
115.9, 114.6, 79.2, 67.8, 65.8 (q, J = 29.0 Hz), 55.5, 53.4, 18.9; IR (KBr) ν 3318, 2945, 2420, 1741,
1515, 1470, 1423, 1210, 1134, 1026, 929, 849, 788, 670 cmꢀ1. HRMS (ESI+) m/z: ([M+H]+) Calcd.
For C20H21ClF3N2O3: 429.1187, found: 429.1179. The product was analyzed by HPLC to determine
the enantiomeric excess: 75% ee for the cycloadduct and 99% ee was achieved after simple
recrystallization (Chiralpak ASꢀH, iꢀpropanol/hexane = 5/95, flow rate 1.0 mL/min, λ = 220 nm); tr
= 7.24 and 13.67 min.
(2
R,3R)-methyl
2-((diphenylmethylene)amino)-4,4,4-trifluoro-3-((4-methoxy-phenyl)amino)butanoate
(14).
Under argon atmosphere, (S,Rp)ꢀPPFOMe (3.3 mg, 0.0077 mmol) and Cu(CH3CN)4BF4 (2.2 mg,
0.007 mmol) were dissolved in 2 mL of ether, and stirred at room temperature for about 0.5 h. After
glycine ethyl ester benzophenone Schiff Base 13 (0.35 mmol) was added, the mixture was dropped
o
to ꢀ20 C. Then, fluorinated imine 1a (0.23 mmol) and Et3N (0.03 mmol) was added sequentially.
Once starting material was consumed (monitored by TLC), the mixture was filtered through celite
and the filtrate was concentrated to dryness. The residue was purified by column chromatography to
give the product 14, which was then directly analyzed by HPLC analysis to determine the
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enantiomeric excess. In order to determine the relative and absolute configuration of the
corresponding Mannich adduct, compound 14 was hydrolyzed to compound 10 as below: 14 (78 mg,
0.19 mmol) was dissolved in 3 mL of methanol at room temperature followed by the addition of
TsOH.H2O (144 mg, 0.76 mmol). The reaction mixture was stirred until starting material was
consumed (monitored by TLC) and then neutralized the mixture with Na2CO3. Then the mixture
was partitioned between ethyl acetate and water, then the organic layer was washed with brine,
dried over MgSO4, and concentrated in vacuo then the organic solvent was removed and the residue
was purified by column chromatography to give compound 10 in 75% yield without loss of the
diastereoꢀ/enantiomeric excess. 86 mg, 82% yield. [α]25D = +10.3 (c 0.61, CHCl3); 1H NMR (CDCl3,
TMS, 400 MHz) δ 7.69ꢀ7.67 (m, 2H), 7.46ꢀ7.36 (m, 6H), 7.16ꢀ7.14 (m, 2H), 6.78ꢀ6.75 (m, 4H),
5.02 (d, J = 9.6 Hz, 1H), 4.57 (q, J = 7.6 Hz, 1H), 4.53 (s, 1H), 3.75 (s, 3H), 3.55 (s, 3H); 13C NMR
(CDCl3, TMS, 100 MHz) δ 173.4, 169.3, 153.0, 140.2, 139.0, 135.9, 130.9, 129.0, 128.7, 128.2,
127.3, 125.3 (q, J = 283.3 Hz), 115.9, 114.7, 63.9, 59.4 (q, J = 28.5 Hz), 55.6, 52.7; IR (KBr) ν
2927, 2354, 1744, 1512, 1446, 1238, 1125, 1025, 916, 695, 665 cmꢀ1. HRMS (ESI+) m/z: ([M+H]+)
Calcd. For C25H24F3N2O3: 457.1726, found: 457.1734. The product was analyzed by HPLC to
determine the enantiomeric excess: 88% ee (Chiralpak ADꢀH, iꢀpropanol/hexane = 5/95, flow rate
1.0 mL/min, λ = 220 nm); tr = 10.58 and 16.20 min.
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General procedure for the synthesis of 3a from 10 and p-chloro benzaldehyde: A solution of
enantiomerically enriched compound 10 (117 mg, 0.4 mmol, 97% ee) and pꢀchlorobenzaldehyde
(84 mg, 0.6 mmol) was stirred at room temperature. The reaction mixture was stirred until starting
material was consumed (monitored by TLC), then the organic solvent was removed and the residue
was purified by column chromatography to give compound 3a in 68% yield. The product was
analyzed by HPLC to determine the enantiomeric excess: 97% ee (Chiralpak ADꢀH,
iꢀpropanol/hexane = 10/90, flow rate 1.0 mL/min, λ = 220 nm); tr = 9.75 and 11.05 min.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge via the Internet at
http://pubs.acs.org.
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Table S1ꢀS3, Data characterization for 3a-x and 5a-g, Figure S1ꢀS3, Crystallographic data for 3s, 9,
15d, copies of NMR spectra and HPLC spectra supplied as the Supporting Information.
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AUTHOR INFORMATION
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Corresponding Author
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cjwang@whu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by NSFC (21525207, 21772147), China Postdoctoral Science Foundation
funded project (2017M620331), and the Fundamental Research Funds for the Central Universities.
The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also
appreciated. The authors thank all referees for their helpful comments and suggestions.
REFERENCES
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Am. Chem. Soc. 2014, 136, 8685. (c) Teng, H.ꢀL.; Yao, L.; Wang, C.ꢀJ., Cu(I)ꢀCatalyzed Regioꢀ and
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