Development of TsDPEN based imine-containing ligands for the copper-catalysed asymmetric Kinugasa reaction

Article abstract of DOI:10.1039/d0ra03276j

A novel class of chiralN,N,Nimine-containing ligands derived from TsDPEN (N-(p-tosyl)-1,2-diphenylethylene-1,2-diamine) has been developed and applied to the copper-catalyzed asymmetric Kinugasa reaction. The copper(ii) salt proved to be an efficient catalyst precursor, and it provides an efficient way to synthesize enantioenrichedcis-β-lactam. The pathway is air-tolerant and easily manipulated, and the ligands are easy to synthesize. A working model is proposed in which the stereocontrolling step is the [2 + 2] cycloaddition between ketene and imine to explain the observed stereoselectivities.

Full text of DOI:10.1039/d0ra03276j

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Development of TsDPEN based imine-containing
ligands for the copper-catalysed asymmetric
Kinugasa reaction†
Cite this: RSC Adv., 2020, 10, 18107
*
Huakang He, Ping Deng
Chuanlong Xu,‡ Yuchen Yang,‡ Yue Wu, Feilong He,
*
and Hui Zhou
A
novel class of chiral N,N,N imine-containing ligands derived from TsDPEN (N-(p-tosyl)-1,2-
diphenylethylene-1,2-diamine) has been developed and applied to the copper-catalyzed asymmetric
Kinugasa reaction. The copper(II) salt proved to be an efficient catalyst precursor, and it provides an
efficient way to synthesize enantioenriched cis-b-lactam. The pathway is air-tolerant and easily
manipulated, and the ligands are easy to synthesize. A working model is proposed in which the
stereocontrolling step is the [2 + 2] cycloaddition between ketene and imine to explain the observed
stereoselectivities.
Received 12th April 2020
Accepted 4th May 2020
DOI: 10.1039/d0ra03276j
rsc.li/rsc-advances
reaction, such as phosphaferrocene-oxazoline,8b HETPHOX,10
Inda-bis(oxazoline),11 diamine,12 N-PINAP,13 and Prolinol-Phos-
phine.14 Enders et al. developed a method to synthesis spi-
rocyclic b-lactams through Kinugasa/Michael domino reactions
by the utilizing of copper-BOX.15 In most cases the main prod-
ucts are cis-b-lactams, except for the use of Cu-diamine by Feng
et al.12 Although progress have been achieved, the scope of
chiral ligands employed in the Kinugasa reaction is limited and
the catalytic highly enantioselective Kinugasa reaction remains
a challenge and less developed.
Chiral imino-containing ligands have emerged as a powerful
tool in asymmetric catalysis.16 Despite the great success that has
been achieved, there is still a need to develop more powerful
novel chiral ligands with imino group for asymmetric catal-
ysis.16 Chan & Li have designed two types of chiral tridentate N-
Introduction
Since the discovery of penicillin in 1928, a number of b-lactam
antibiotics have been developed.1 In addition to antibacterial
activity, b-lactam containing molecules also exhibit special
biological activities,2 such as Ezetimibe,2a dual PPARa/g ago-
nists,2b a TRPV1 antagonist,2c b-lactamic hFAAH inhibitors2d
and neuronal protective effect against brain ischemia.2e At the
same time, b-lactam compounds are also widely employed as
useful intermediates in organic synthesis.3 Therefore, consid-
erable efforts have been made in developing an efficient
synthesis method for the preparation of chiral b-lactams.4
The Kinugasa reaction, developed in 1972,5 is a simple and
direct reaction between alkynes and nitrones for the synthesis
of b-lactams in the presence of copper and a base.6 The group of
Miura reported the rst catalytic asymmetric version by using
CuI (10 mol%) and bis(oxazoline) (20 mol%) with 57% ee and
35% de in 1995.7 Fu et al. achieved the rst diastereoselective
and enantioselective catalytic Kinugasa reaction by employing
1–2.5 mol% CuCl and bis(azaferrocenes) (up to 93% ee and cis/
trans up to 95/5) in 2002.8 Tang and co-workers demonstrated
for the rst time that a copper(II) catalyst could replace the
previously performed air-sensitive copper(I) salts by using a C3-
symmetric tris(oxazoline) ligand in 2003.9 Since then, several
ligands were developed for the catalytic asymmetric Kinugasa
Chongqing Research Center for Pharmaceutical Engineering, Research Center for
Innovative Pharmaceutical and Excipient Analysis Technology, College of Pharmacy,
Chongqing Medical University, Chongqing 400016, China. E-mail: hzhou@cqmu.
edu.cn; orangedp@cqmu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra03276j
Scheme 1 Chiral imine-containing ligands derived from TsDPEN.
RSC Adv., 2020, 10, 18107–18114 | 18107
‡ These authors contributed equally.
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Table 2 Effect of the solvent on the Kinugasa reactiona
tosylated aminoimine ligands containing phenol and pyridine,
respectively (Scheme 1a, L1 and L2)17 for the addition of alkynes
to imines. Recently, we have developed a new class of chiral
polydentate N,O ligands derived from N-(p-tosyl)-1,2-
diphenylethylene-1,2-diamine (TsDPEN).18,19 Herein, we
successfully developed a novel class of chiral N,N,N imine-
containing ligands derived from TsDPEN (Scheme 1b, L3) and
applied them in Cu(II)-catalysed asymmetric Kinugasa reaction.
Entry
Solvent
Yieldb (%)
cis/transc
ee (cis)c (%)
Results and discussion
1
2
3
4
5
6
7
CH3CN
CH2Cl2
THF
EtOAc
DMF
97
69
77
70
68
60
74
85 : 15
84 : 16
88 : 12
84 : 16
49 : 51
87 : 13
81 : 19
82
81
66
76
74
74
73
At the outset, we investigated the Kinugasa reaction of alkyne 1a
and nitrone 2a in the presence of dicyclohexylamine as the base
in CH3CN at 0 ꢀC, evaluating various copper catalysts prepared
EtOH
Toluene
a
Reaction conditions: Cu(OAc)2 (10 mol%), L3b (10 mol%), 1a (0.2
mmol), 2a (0.22 mmol), dicyclohexylamine (1.0 equiv.), solvent (1.0
b
mL), at 0 ꢀC for 24 h. Total isolated yield of the cis- and trans-
products. c Determined by HPLC on a chiral stationary phase.
in situ from copper salts and chiral tridentate ligands L1–L3
(Fig. 1).20 Among them, Cu(OTf)2/L1 (26% yield, 87/13 cis/trans,
39% cis ee),21 CuOTf/L2 (31% yield, 95/5 cis/trans, 36% cis ee),22
Cu(OAc)2/L3b (97% yield, 85/15 cis/trans, 83% cis ee) turned out
to be the efficient combination in terms of yield, dr and enan-
tioselectivity. These results indicated that the dialkylamine
substitution in aniline obviously affected the reactivity and the
enantioselectivity. Then the substituent effect on the amino
group of L3 was examined and similar results were obtained
(72–97% yield, ꢁ85/15 cis/trans, 70–83% cis ee). Considering the
reactivity and enantioselectivity, we selected L3b for further
optimization.
Next, the inuences of different bases were studied with the
results shown in Table 1. Although the ligand contained
a tertiary amine functional group, this transformation hardly
proceeded without basic additives (Table 1, entry 1). Tertiary
amines and inorganic bases gave poor yield (Table 1, entries 3, 4
and 6). Secondary amines afforded the desired products with
better yield and enantioselectivity, and higher sterically
hindered secondary amines achieved higher diastereoselectivity
(Table 1, entries 2, 5 and 7). Dicyclohexylamine proved to be the
best base.
Fig. 1 Effect of copper salts and ligands on the asymmetric Kinugasa
reaction. Reaction conditions: copper salt (10 mol%), ligand (10 mol%),
1a (0.2 mmol), 2a (0.22 mmol), dicyclohexylamine (1.0 equiv.), CH3CN
(1.0 mL), at 0 ꢀC for 24 h. aTotal isolated yield of the cis- and trans-
products. bThe ratios of cis/trans (x/1) and the ee of the cis-products
were determined by HPLC on a chiral stationary phase. cN.R. ¼ no
reaction.
Table 1 Effect of the base on the asymmetric Kinugasa reactiona
Solvent effects were studied next, with the results summa-
rized in Table 2. Only moderate enantioselectivity could be
obtained in examined solvents other than CH2Cl2 and CH3CN
(Table 2, entries 1–7). No diastereoselectivity was observed in
DMF (Table 2, entry 5). The best yield and enantioselectivity
were obtained by CH3CN (Table 2, entry 1).
Subsequently, the reaction temperature was examined. As
shown in Table 3, both the diastereoslectivity and enantiose-
lectivity were dependent on the reaction temperature. When the
temperature was decreased from 0 to ꢂ30 ꢀC, the diaster-
eoslectivity and enantioselectivity increased (Table 3, entries 1–
Entry
Base
Yieldb (%)
cis/transc
ee (cis)c (%)
1
2
3
4
5
6
7
—
Trace
97
10
9
73
—
—
83
44
71
79
68
80
Cy2NHd
iPr2NEt
K2CO3
iPr2NH
Cy2NMee
nBu2NH
85 : 15
87 : 13
61 : 39
80 : 20
85 : 15
59 : 41
24
90
a
Reaction conditions: Cu(OAc)2 (10 mol%), L3b (10 mol%), 1a (0.2
mmol), 2a (0.22 mmol), base (1.0 equiv.), CH3CN (1.0 mL), at 0 ꢀC for 3). When the reaction temperature further decreased to ꢂ40 ꢀC,
b
c
24 h. Total isolated yield of the cis- and trans-products. Determined
by HPLC on a chiral stationary phase. Dicyclohexylamine. N,N-
Dicyclohexylmethylamine.
the reaction almost stopped by about halfway through (Table 3,
entry 4).
d
e
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Table 3 Effect of temperature on the asymmetric Kinugasa reactiona
Scheme 2 mmol-scale reaction.
Entry T (ꢀC) Time (h) Yieldb (%) cis/trans
ee (cis)c (%)
enantioselectivities (Table 4, entries 2, 3 and 12–15). The reac-
tion conditions were also compatible with electron withdrawing
group (Table 4, entries 4 and 21). Phenylacetylene with
a strongly electron donating methoxy group had very low reac-
tivity and only trace amount of corresponding product could be
observed (Table 4, entry 5). The application of alkyl alkynes in
the system is feasible, as exemplied by the formation of
product 3e with high diastereoselectivity (99 : 1), albeit with low
enantioselectivity (12% ee). Next, effects of C-substituents of the
nitrone were investigated (Table 4, entries 7–15). Methyl group
and fused aromatic substituents had no adverse effect on the
reaction. While strong decrease in reactivity for electron with-
drawing group and heterocyclic substituents was observed
(Table 4, entries 10 and 11). The electronic character of the N-
bound aromatic groups of nitrones was also investigated (Table
4, entries 16–20). Whether electron-decient or electron-rich N-
1
2
3
4
0
24
48
48
97
>99
>99
85 : 15c
90 : 10c
82
87
ꢂ15
ꢂ30
ꢂ40
91 : 9c (10.5 : 1)d 90
48 or 72 46
92 : 8c
90
a
Reaction conditions: Cu(OAc)2 (10 mol%), L3b (10 mol%), 1a (0.2
mmol), 2a (0.22 mmol), dicyclohexylamine (1.0 equiv.), CH3CN (1.0
b
c
mL). Total isolated yield of the cis- and trans-products. Determined
by HPLC on a chiral stationary phase. d Determined by H NMR.
1
Under the established optimal reaction conditions, the
substrate scope of the cycloaddition reaction between various
alkynes and nitrones was examined next (Table 4). First,
different alkynes participated in the reaction (Table 4, entries 1–
6, 12–15, and 21). Weakly electron donating methyl group did
not pose a problem for the reaction, and the corresponding cis-
b-lactams were isolated in good yields, diastereo- and
Table 4 Substrate scope of the asymmetric Kinugasa reactiona
Entry
R1, R2, R3
T (ꢀC)
Product
cis/transb
Yield (cis)c (%)
ee (cis)d (%)
1
2
3
4
C6H5, C6H5, Ar
ꢂ30
ꢂ30
ꢂ30
0
3a
3b
3c
3d
10.5 : 1
13.1 : 1
9.6 : 1
6.2 : 1
92
93
91
74
90
88
91
88
4-Me-C6H4, C6H5, Ar
3-Me-C6H4, C6H5, Ar
4-F-C6H4, C6H5, Ar
5
6
7
8
4-MeOC6H4, C6H5, Ar
Cyclohexyl, C6H5, Ar
C6H5, 3-Me-C6H4, Ar
C6H5, 4-Me-C6H4, Ar
C6H5, 2-naphthyl, Ar
C6H5, 4-Cl-C6H4, Ar
C6H5, 2-furyl, Ar
4-Me-C6H4, 3-Me-C6H4, Ar
3-Me-C6H4, 3-Me-C6H4, Ar
4-Me-C6H4, 4-Me-C6H4, Ar
3-Me-C6H4, 4-Me-C6H4, Ar
C6H5, C6H5, C6H5
C6H5, C6H5, 4-Me-C6H4
C6H5, C6H5, 4-Cl-C6H4
C6H5, C6H5, 4-Br-C6H4
C6H5, C6H5, 4-F-C6H4
4-F-C6H4, C6H5, C6H5
0
0
Trace
3e
3f
>99 : 1
14 : 1
6.7 : 1
5.3 : 1
68
80
81
70
12
90
83
77
ꢂ30
0
3g
9
0
0
0
ꢂ30
ꢂ30
0
3h
Trace
Trace
3i
3j
3k
10
11
12
13
14
15
16
17
18
19
20
21
17.5 : 1
12.5 : 1
11 : 1
6.3 : 1
12.9 : 1
14 : 1
12.5 : 1
11.8 : 1
16.5 : 1
16.3 : 1
91
90
80
82
93
71
80
82
70
75
89
89
79
79
91
85
87
87
86
84
0
3l
ꢂ30
3m
3n
3o
3p
3q
0
0
0
0
0
3r
a
Reaction conditions: Cu(OAc)2 (10 mol%), L3b (10 mol%), 1 (0.2 mmol), 2 (0.22 mmol), dicyclohexylamine (1.0 equiv.), CH3CN (1.0 mL), at ꢂ30 ꢀC
or 0 ꢀC for 48 h. Determined by 1H NMR of the crude reaction mixture. Isolated yield of cis-product by chromatography on silica gel.
b
c
d
Determined by HPLC on a chiral stationary phase.
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Fig. 2 Structure of the Cu complex optimized by DFT and proposed working model for stereoselectivity.
aryl nitrones were found to be highly suitable substrates for this air-tolerant and easily manipulated, and the ligands are easy to
asymmetric transformation. synthesize. Further investigations are underway in our labora-
To demonstrate the utility of this method, a mmol scale tory including further geometry optimization of ligands, the
catalytic asymmetric Kinugasa reaction with 2.0 mmol 1a and detailed mechanism, and the extending of the substrate scope.
2.2 mmol 2a in the presence of 10 mol% chiral copper complex
proceeded smoothly and 3a was isolated with comparably high
yield and stereoselectivity (Scheme 2).
Experimental section
The research of Kinugasa reaction mechanism has been an
active research area.23 Recently, Hein's group reported an
improved mechanism based on the analysis of multiple
byproducts and detailed kinetic analysis.23a According to the
modied mechanism, the stereocontrolling step is the [2 + 2]
cycloaddition between ketene and imine, which are generated
by reductive elimination and protonation from the initial [3 + 2]
cycloaddition intermediate between nitrone and s-Cu acetylide.
Based on this research and the geometry of Cu complex opti-
mized by DFT,24 a working model to explain the observed ster-
eoselectivities is proposed in Fig. 2. The ketene combined with
the tert-amine forming a zwitterionic enolate (phenyl away
from N is favourable for the steric repulsion) and the imine
coordinated to the Cu in a suitable position by avoiding the
steric repulsion of n-butyl group on nitrogen.25
General
The solvents were dried by molecular sieve for more than 72 h
before use. Other commercial reagents were used as purchased.
NMR (Bruker 600 MHz) spectra were recorded in the deuterated
solvents as stated, using residual non-deuterated solvent as
internal standard. High resolution mass spectra were recorded
with a Bruker Solari XFT-ICR-MS system. The enantiomeric
excess (ee) was determined by HPLC (Shimadzu LC-16) analysis
using the corresponding commercial chiral column as stated in
the experimental procedures at 23 ꢀC with UV detector (254 nm).
Optical rotations were measured on a commercial polarimeter
(Rudolph Autopol I) and are reported as follows: [a]TD (c ¼ g/100
mL, solvent). The diastereomeric ratios of the b-lactams were
determined by integration of 1H NMR spectra (the coupling
constant for C3/C4 vicinal protons is 4.5–6 Hz for cis isomers and
2–2.5 Hz for trans isomers).8a The absolute conguration of 3a, 3e
and 3m was determined by the comparison of the HPLC reten-
tion time and optical rotations with the literature data.8a,12 The
absolute conguration of 3b–3d, 3f–3l and 3n–3r was determined
by analogy.
Conclusions
In summary, we have successfully employed the novel chiral
N,N,N imine-containing ligands derived from TsDPEN in the
catalytic enantioselective Kinugasa reaction. It provides an
efficient way to synthesize cis-b-lactam in good to excellent
yields (up to 93%) and with good to excellent diastereo- and
enantioselectivities (dr up to 17.5 : 1, ee up to 91%). This new
protocol for the Kinugasa reaction is not effective for aliphatic
General preparation procedure of ligands
L1 and L2 are known compounds.17
1
L1. Yellow solid, H NMR (600 MHz, CDCl3) d 12.66 (s, 1H),
alkynes and phenylacetylenes with a strongly electron donating 8.16 (s, 1H), 7.41 (d, J ¼ 8.0 Hz, 2H), 7.34–7.31 (m, 1H), 7.19–7.07
group. A working model is proposed in which the stereo- (m, 9H), 7.00–6.95 (m, 3H), 6.90–6.83 (m, 3H), 5.32 (d, J ¼
controlling step is the [2 + 2] cycloaddition between ketene and 7.4 Hz, 1H), 4.76 (t, J ¼ 6.7 Hz, 1H), 4.56 (d, J ¼ 5.9 Hz, 1H), 2.30
imine to explain the observed stereoselectivities. The N,N-dia- (s, 3H).
lkylamine substitution is an unprecedented modication on the
TsDPEN based imine containing ligand scaffold. The pathway is 4.5 Hz, 1H), 8.00 (d, J ¼ 7.7 Hz, 1H), 7.85–7.83 (m, 1H), 7.62 (d, J
L2. Yellow solid, 1H NMR (600 MHz, CDCl3) d 8.60 (d, J ¼
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¼ 8.2 Hz, 2H), 7.32–7.30 (m, 1H), 7.22–7.16 (m, 10H), 6.99 (d, J ¼ 129.1, 128.3, 128.25, 128.20, 128.1, 128.0, 127.9, 127.7, 127.6,
7.1 Hz, 1H), 5.94 (s, 1H), 4.64 (d, J ¼ 6.6 Hz, 1H), 4.32 (d, J ¼ 127.3, 127.2, 127.08, 127.06, 126.9, 126.8, 124.2, 122.9, 122.8,
6.6 Hz, 1H), 2.43 (s, 3H).
121.7. ESI-HRMS calcd for C36H44N3O2S+ [M + H]+: 582.3149,
General preparation procedure of L3. To a solution of o-u- found 582.3140.
orobenzaldehyde (10 mmol) and a secondary-amine (20 mmol)
L3c. White solid, (mixture of E- and Z-, E/Z ¼ 14.3/1), 1H NMR
in 20 mL DMF was added K2CO3 (20 mmol), and the mixture (600 MHz, CDCl3) d 8.10 (E, s, 1H), 7.88 (E, d, J ¼ 7.7 Hz, 1H),
ꢀ
was stirred under a N2 atmosphere at 75 C until the reaction 7.60 (Z, d, J ¼ 7.8 Hz, 0.15H), 7.46 (Z, d, J ¼ 7.5 Hz, 0.17H), 7.31–
proceed completely detected by TLC. The reaction mixture was 7.25 (E + Z, m, 3H), 7.23–7.09 (E + Z, m, 10H), 6.9–6.8 (E + Z, m,
ltered, the ltrate was diluted with CH2Cl2 (50 mL) and washed 3.1H), 6.73 (E + Z, d, J ¼ 8.3 Hz, 1H), 6.19 (E + Z, s, 1.06H), 4.83
with saturated sodium bicarbonate solution (20 mL ꢃ 3). The (E, q, J ¼ 3.2 Hz, 1H), 4.69 (Z, d, J ¼ 5.8 Hz, 0.07H), 4.47 (E, d, J ¼
organic layers were dried (Na2SO4), and puried through 3.2 Hz, 1H), 4.32 (Z, d, J ¼ 5.8 Hz, 0.07H), 2.80–2.76 (E + Z, m,
column chromatography (petroleum ether/ether, 10 : 1) on 4H), 2.37 (Z, s, 0.24H), 2.29 (E, s, 3H), 1.69–1.64 (E + Z, m,
silica gel to obtain a crude product. The crude product was 4.19H). 13C NMR (150 MHz, CDCl3) d E: 163.2, 150.4, 142.3,
dissolved in the mixture of petroleum ether/ether (v/v 10 : 1) 141.0, 140.2, 137.3, 131.3, 129.2, 129.1, 128.3, 128.0, 127.06,
and acidied to pH 2 with 1 M HCl. The resulting mixture was 127.04, 126.98, 126.90, 126.7, 124.1, 118.9, 114.9, 78.7, 63.6,
extracted twice with water, and the aqueous layer was basied to 52.6, 25.3, 21.4. ESI-HRMS calcd for C32H34N3O2S+ [M + H]+:
pH 9 with 1 M NaOH and extracted with CH2Cl2. The 524.2366, found 524.2358.
dichloromethane layers were dried and the solvents were
L3d. White solid, (mixture of E- and Z-, E/Z ¼ 3.7/1), 1H NMR
removed in vacuo to afford 4. To a solution of 4 (1.2 mmol) in (600 MHz, CDCl3) d 8.13 (E, s, 1H), 8.02 (E, d, J ¼ 7.7 Hz, 1H),
30 mL ethanol was added 5 (1.2 mmol) and the mixture was 7.66 (Z, d, J ¼ 7.6 Hz, 0.57H), 7.58 (Z, d, J ¼ 7.8 Hz, 0.58H), 7.42
stirred at 75 ꢀC under a N2 atmosphere until the reaction (E + Z, t, J ¼ 7.6 Hz, 0.61H), 7.32–7.31 (E + Z, m, 3.49H), 7.25–7.23
proceed completely detected by TLC. The EtOH was removed in (E + Z, m, 1.87H), 7.18–7.05 (E + Z, m, 12H), 6.92–6.90 (E + Z, m,
vacuo to give L3.
3.14H), 6.20–6.19 (E + Z, m, 1.24H), 4.91 (Z, d, J ¼ 3.4, 0.27H),
4.84–4.83 (E, m, 1H), 4.53 (Z, s, 0.27H), 4.48 (E, d, J ¼ 3.5 Hz,
1H), 2.59–2.57 (E + Z, m, 2H), 2.49–2.46 (E + Z, m, 2H), 2.29 (Z, s,
0.9H), 2.26 (E, s, 3H), 1.37–1.30 (E + Z, m, 6H). 13C NMR (150
MHz, CDCl3) d E: 162.0, 154.5, 142.2, 140.9, 140.0, 131.6, 78.5,
63.6, 54.5, 26.0, 23.9, 21.3; Z: 162.0, 152.9, 143.3, 141.1, 139.8,
137.7, 135.6, 134.8, 133.2, 75.0, 70.7, 68.4, 26.7, 26.1, 24.3, 21.4;
E + Z: 129.1, 129.02, 128.98, 128.95, 128.5, 128.45, 128.43,
128.29, 128.26, 128.15, 128.07, 128.04, 127.95, 127.7, 127.5,
127.2, 127.1, 127.0, 127.95, 126.7, 126.6, 126.2, 125.2, 124.1,
122.3, 120.3, 118.6. ESI-HRMS calcd for C33H36N3O2S+ [M + H]+:
538.2523, found 538.2518.
L3a. White solid, (mixture of E- and Z-, E/Z ¼ 5.6/1), 1H NMR
(600 MHz, CDCl3) d 8.14 (E, s, 1H), 7.97 (E, d, J ¼ 7.4 Hz, 1H),
7.91 (Z, d, J ¼ 7.5 Hz, 0.18H), 7.56 (Z, d, J ¼ 8.0 Hz, 0.37H), 7.51
(Z, d, J ¼ 7.5 Hz, 0.38H), 7.32–7.29 (E + Z, m, 3.96H), 7.19–7.00 (E
+ Z, m, 11.37H), 6.91–6.89 (E + Z, m, 3.12H), 6.19 (E, d, J ¼
7.0 Hz, 1H) 4.84 (E, q, J ¼ 3.3 Hz, 1H), 4.77 (Z, d, J ¼ 5.2 Hz,
0.18H), 4.51 (E, d, J ¼ 3.4 Hz, 1H), 4.26 (Z, d, J ¼ 5.3 Hz, 0.18H),
2.35 (E, s, 6H), 2.32 (Z, s, 0.71H), 2.25 (E, s, 3H), 2.23 (Z, s,
0.20H). 13C NMR (150 MHz, CDCl3) d E: 162.1, 154.1, 142.2,
140.9, 140.0, 137.2, 131.5, 129.0, 121.9, 117.8, 78.5, 63.6, 45.0,
21.3; Z: 162.1, 152.5, 143.4, 140.02, 139.4, 135.5, 133.4, 129.2,
124.0, 120.2, 75.2, 71.6, 68.5, 45.4, 21.4.; E + Z: 128.27, 128.22,
127.98, 127.95, 127.84, 127.5, 127.4, 127.03, 127.02, 126.90,
126.89, 126.7, 126.5. ESI-HRMS calcd for C30H32N3O2S+ [M +
H]+: 498.2210, found 498.2200.
General procedure for the asymmetric Kinugasa reaction
The mixture of Cu(OAc)2 (0.02 mmol, 10 mol%) and L3b
(0.02 mmol, 10 mol%) was stirring in CH3CN (0.5 mL) under air
atmosphere at 35 ꢀC for 1 h. Then, dicyclohexylamine (0.2
mmol) and alkyne 1 (0.2 mmol) were sequentially added, and
the test tube was rinsed with CH3CN (0.2 mL), aer stirring at
room temperature for 10 minutes, the mixture was cooled to
ꢂ30 ꢀC or 0 ꢀC. Aer stirring for 10 min at ꢂ30 ꢀC or 0 ꢀC,
nitrone 2 (0.22 mmol) and CH3CN (0.3 mL) were added. The
mixture was further stirred at ꢂ30 ꢀC or 0 ꢀC for the time
indicated in Table 4. The resulting solution was puried by
column chromatography (petroleum ether/AcOEt) on silica gel
to afford the products.
(3S,4S)-1-(4-Carboethoxyphenyl)-3,4-diphenyl-2-azetidinone
(3a). White solid, 68.3 mg, 92% yield (cis), 90% ee. [a]2D0 ¼ ꢂ11.3
(c 0.80, CHCl3). The ee was determined by HPLC analysis using
a CHIRALPAK IA column, hexane/2-propanol 90/10, ow rate ¼
1.0 mL minꢂ1, 254 nm, cis: tr ¼ 14.6 min (3S4S, major) and tr ¼
15.9 min (3R4R, minor); trans: tr ¼ 17.5 min and tr ¼ 18.3 min
(ref. 12: CHIRALPAK IA column, hexane/2-propanol 90/10, ow
rate ¼ 1.0 mL minꢂ1, cis: tr ¼ 17.5 min, tr ¼ 18.9 min; trans: tr ¼
L3b. White solid, (mixture of E- and Z-, E/Z ¼ 9.1/1), 1H NMR
(600 MHz, CDCl3) d 8.27 (E, s, 1H), 8.03 (E, d, J ¼ 7.3 Hz, 1H),
7.65 (Z, d, J ¼ 7.9 Hz, 0.23H), 7.42 (Z, d, J ¼ 7.6 Hz, 0.25H), 7.34–
7.33 (E + Z, m, 3H), 7.17–7.00 (E + Z, m, 12H), 6.93 (E, d, J ¼
7.9 Hz, 2H), 6.28, (Z, s, 0.11H), 6.20 (E, d, J ¼ 6.5 Hz, 1H), 4.82 (E,
q, J ¼ 3.5 Hz, 1H), 4.64 (Z, d, J ¼ 6.4 Hz, 0.11H), 4.51 (E, d, J ¼
3.7 Hz, 1H), 4.28 (Z, d, J ¼ 6.4 Hz, 0.11H), 3.00–2.95 (Z, m,
0.49H), 2.73–2.64 (E, m, 4H), 2.28 (E, s, 3H), 2.27 (Z, s, 0.16H),
1.20–1.15 (E, m, 4H), 1.03–0.96 (E, m, 4H), 0.71 (E, t, J ¼ 7.4 Hz,
6H). 13C NMR (150 MHz, CDCl3) d E: 162.5, 152.5, 142.3, 141.1,
140.0, 137.4, 131.2, 78.0, 63.7, 54.2, 29.0, 21.4, 20.3, 13.9; Z:
162.5, 150.0, 143.5, 139.6, 139.2, 137.3, 130.7, 75.8, 71.9, 68.5,
54.6, 31.6, 29.4, 22.6, 21.5, 20.6, 20.3, 14.1, 14.0; E + Z: 129.3,
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22.1 min (3S4R), tr ¼ 23.6 min (3R4S)). The ee was also deter- 7.2 Hz, 3H), 1.18–1.10 (m, 4H), 0.76–0.66 (m, 2H). 13C NMR (150
mined by HPLC analysis using a Chiralcel OD-H column, MHz, CDCl3) d 167.8, 166.1, 141.1, 137.2, 134.6, 130.8, 129.0,
hexane/2-propanol 95/5, ow rate ¼ 1.0 mL minꢂ1, cis: tr ¼ 128.7, 128.6, 125.3, 124.9, 116.6, 115.9, 62.9, 60.8, 60.7, 60.7,
25.3 min (3S4S, major) and tr ¼ 35.8 min (3R4R, minor); trans: tr 58.6, 34.9, 31.1, 30.7, 29.7, 29.7, 26.1, 25.5, 25.4, 14.3.
¼ 12.8 min and tr ¼ 16.3 min (ref. 8a: Chiralcel OD, hexane/2-
(3S,4S)-1-(4-Carboethoxyphenyl)-4-(3-methylphenyl)-3-phenyl-2-
propanol 95/5, ow rate ¼ 1.0 mL minꢂ1, cis: tr ¼ 19.8 min azetidinone (3f). White solid, 61.7 mg, 80% yield (cis), 90% ee.
(3S4S), tr ¼ 38.6 min (3R4R)). 1H NMR (600 MHz, CDCl3) d 7.97 [a]D20 ¼ ꢂ11.5 (c 0.93, CHCl3). The ee was determined by HPLC
(d, J ¼ 8.7 Hz, 2H), 7.44 (d, J ¼ 8.7 Hz, 2H), 7.11–7.03 (m, 10H), analysis using a Chiralcel OD-H column, hexane/2-propanol 90/10,
5.50 (d, J ¼ 6.2 Hz, 1H), 5.05 (d, J ¼ 6.3 Hz, 1H), 4.35–4.31 (m, ow rate ¼ 0.8 mL minꢂ1, tr ¼ 15.4 min (major) and tr ¼ 20.0 min
2H), 1.35 (t, J ¼ 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) d 166.0, (minor). 1H NMR (600 MHz, CDCl3) d 7.97 (d, J ¼ 8.5 Hz, 2H), 7.44
165.9, 141.2, 133.8, 131.7, 130.9, 128.8, 128.3, 128.2, 128.1, (d, J ¼ 8.5 Hz, 2H), 7.10–7.04 (m, 5H), 6.98 (t, J ¼ 7.8 Hz, 1H), 6.89
127.3, 127.1, 125.9, 116.7, 60.9, 60.6, 60.5, 14.3.
(d, J ¼ 7.6 Hz, 1H), 6.83 (d, J ¼ 6.3 Hz, 2H), 5.45 (d, J ¼ 6.2 Hz, 1H),
(3S,4S)-1-(4-Carboethoxyphenyl)-3-(4-methylphenyl)-4-phenyl-2- 5.03 (d, J ¼ 6.2 Hz, 1H), 4.33 (q, J ¼ 7.1 Hz, 2H), 3.14 (s, 3H), 1.35 (t,
azetidinone (3b). White solid, 71.7 mg, 93% yield (cis), 88% ee. J ¼ 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) d 166.04, 166.00, 141.3,
[a]2D0 ¼ ꢂ12.1 (c 0.72, CHCl3). The ee was determined by HPLC 138.0, 134.0, 131.8, 130.8, 128.9, 128.8, 128.2, 128.1, 127.7, 125.8,
analysis using a CHIRALPAK IA column, hexane/2-propanol 90/10, 124.2, 116.7, 60.9, 60.6, 60.5, 21.2, 14.3. ESI-HRMS calcd for
ow rate ¼ 1.0 mL minꢂ1, tr ¼ 13.6 min (major) and tr ¼ 17.7 min C25H24NO3+ [M + H]+: 386.1751, found 386.1725.
(minor). 1H NMR (600 MHz, CDCl3) d 7.97 (d, J ¼ 8.5 Hz, 2H), 7.43
(3S,4S)-1-(4-Carboethoxyphenyl)-4-(4-methylphenyl)-3-phenyl-2-
(d, J ¼ 8.5 Hz, 2H), 7.13–7.11 (m, 3H), 7.05–7.04 (m, 2H), 6.93–6.88 azetidinone (3g). White solid, 62.4 mg, 81% yield (cis), 83% ee.
(m, 4H), 5.48 (d, J ¼ 6.2 Hz, 1H), 5.02 (d, J ¼ 6.2 Hz, 1H), 4.35–4.32 [a]2D0 ¼ ꢂ18.3 (c 0.9, CHCl3). The ee was determined by HPLC
(m, 2H), 2.17 (s, 3H), 1.36 (t, J ¼ 7.1 Hz, 3H). 13C NMR (150 MHz, analysis using a Chiralcel OD-H column, hexane/2-propanol 90/10,
CDCl3) d 166.3, 166.0, 141.2, 137.0, 133.9, 130.9, 128.9, 128.7, 128.5, ow rate ¼ 1 mL minꢂ1, tr ¼ 12.6 min (major) and tr ¼ 17.4 min
128.4, 128.1, 127.1, 125.8, 116.7, 60.9, 60.6, 60.4, 21.1, 14.3.
(minor). 1H NMR (600 MHz, CDCl3) d 7.96 (d, J ¼ 8.8 Hz, 2H), 7.43
(3S,4S)-1-(4-Carboethoxyphenyl)-3-(3-methylphenyl)-4-phenyl-2- (d, J ¼ 8.6 Hz, 2H), 7.11–7.05 (m, 5H), 6.93–6.90 (m, 4H), 5.46 (d, J
azetidinone (3c). White solid, 70.2 mg, 91% yield (cis), 91% ee. ¼ 6.2 Hz, 1H), 5.03 (d, J ¼ 6.2 Hz, 1H), 4.35–4.31 (m, 2H), 2.18 (s,
[a]D20 ¼ ꢂ11.4 (c 0.69, CHCl3). The ee was determined by HPLC 3H), 1.35 (t, J ¼ 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) d 166.1,
analysis using a CHIRALPAK IA column, hexane/2-propanol 90/10, 166.0, 141.2, 137.9, 131.9, 130.8, 130.7, 129.1, 128.8, 128.2, 127.3,
ow rate ¼ 1.0 mL minꢂ1, tr ¼ 12.4 min (major) and tr ¼ 13.6 min 127.0, 125.8, 116.8, 60.8, 60.5, 60.5, 21.1, 14.3.
(minor). 1H NMR (600 MHz, CDCl3) d 7.97 (d, J ¼ 8.5 Hz, 2H), 7.44
(3S,4S)-1-(4-Carboethoxyphenyl)-4-(2-naphthyl)-3-phenyl-2-
(d, J ¼ 8.5 Hz, 2H), 7.12–6.95 (m, 6H), 6.86–6.80 (m, 3H), 5.49 (d, azetidinone (3h). Light yellow solid, 59 mg, 70% yield (cis), 77%
J ¼ 6.2 Hz, 1H), 5.02 (d, J ¼ 6.2 Hz, 1H), 4.36–4.32 (m, 2H), 2.16 (s, ee. [a]2D0 ¼ ꢂ25.5 (c 0.53, CHCl3). The ee was determined by HPLC
3H), 1.36 (t, J ¼ 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) d 166.1, analysis using a CHIRALPAK IA column, hexane/2-propanol 90/10,
166.0, 141.2, 137.7, 133.9, 131.5, 130.9, 129.5, 128.3, 128.1, 128.03, ow rate ¼ 1.0 mL minꢂ1, tr ¼ 18.11 min (major) and tr ¼
128.00, 127.1, 125.9, 125.8, 116.7, 60.9, 60.6, 60.6, 21.2, 14.3.
21.51 min (minor). 1H NMR (600 MHz, CDCl3) d 7.95 (d, J ¼ 8.8 Hz,
2H), 7.69–7.62 (m, 3H), 7.54 (d, J ¼ 8.7 Hz, 1H), 7.47 (d, J ¼ 8.8 Hz,
(3S,4S)-1-(4-Carboethoxyphenyl)-3-(4-uorophenyl)-4-phenyl-2-
azetidinone (3d). White solid, 57.6 mg, 74% yield (cis), 88% ee. 2H), 7.43–7.38 (m, 2H), 7.10–6.95 (m, 6H), 5.65 (d, J ¼ 6.2 Hz, 1H),
[a]2D0 ¼ ꢂ5.6 (c 0.3, CHCl3). The ee was determined by HPLC 5.13 (d, J ¼ 6.2 Hz, 1H), 4.34–4.30 (m, 2H), 1.34 (t, J ¼ 7.1 Hz, 3H).
analysis using a CHIRALPAK IA column, hexane/2-propanol 85/15, 13C NMR (150 MHz, CDCl3) d 166.04, 165.96, 141.3, 132.9, 132.9,
ow rate ¼ 1.0 mL minꢂ1, tr ¼ 16.7 min (major) and tr ¼ 14.3 min 131.6, 131.6, 130.9, 128.7, 128.2, 128.2, 127.8, 127.7, 127.4, 126.7,
(minor). 1H NMR (600 MHz, CDCl3) d 7.98 (d, J ¼ 8.7 Hz, 2H), 7.43 126.3, 126.3, 125.9, 124.2, 116.7, 60.9, 60.8, 60.7, 14.3.
(d, J ¼ 8.7 Hz, 2H), 7.14–7.13 (m, 3H), 7.03–7.01 (m, 4H), 6.80–6.77
(3S,4S)-1-(4-Carboethoxyphenyl)-3-(4-methylphenyl)-4-(3-
(m, 2H), 5.50 (d, J ¼ 6.2 Hz, 2H), 5.03 (d, J ¼ 6.2 Hz, 1H), 4.36–4.32 methylphenyl)-2-azetidinone (3i). White solid, 72.7 mg, 91%
(m, 2H), 1.36 (t, J ¼ 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) yield (cis), 89% ee. [a]2D0 ¼ ꢂ16.0 (c 1.09, CHCl3). The ee was
d 166.0, 165.7, 162.8, 161.1, 141.1, 133.7, 130.9, 130.5, 130.4, determined by HPLC analysis using a Chiralcel OD-H column,
128.51, 128.3, 127.0, 126.0, 116.8, 115.3, 115.1, 60.9, 60.5, 59.8, hexane/2-propanol 90/10, ow rate ¼ 1 mL minꢂ1, tr
¼
14.3.
11.86 min (major) and tr ¼ 14.50 min (minor). 1H NMR (600
(3S,4S)-1-(4-Carboethoxyphenyl)-3-(cyclohexyl)-4-phenyl-2-
MHz, CDCl3) d 7.96 (d, J ¼ 8.7 Hz, 2H), 7.43 (d, J ¼ 8.7 Hz, 2H),
azetidinone (3e). White solid, 51 mg, 68% yield (cis), 12% ee. 6.99 (t, J ¼ 7.9 Hz, 1H), 6.93–6.88 (m, 5H), 6.84 (d, J ¼ 7.2 Hz,
[a]2D0 ¼ ꢂ11.8 (c 0.57, CHCl3). The ee was determined by HPLC 2H), 5.42 (d, J ¼ 6.2 Hz, 1H), 4.99 (d, J ¼ 6.2 Hz, 1H), 4.35–4.31
analysis using a CHIRALPAK IA column, hexane/2-propanol 95/ (m, 2H), 2.17–2.15 (d, J ¼ 9.0 Hz, 6H), 1.35 (t, J ¼ 7.1 Hz, 3H). 13
C
5, ow rate ¼ 1.0 mL minꢂ1, tr ¼ 17.8 min (3S4S, major) and tr ¼ NMR (150 MHz, CDCl3) d 166.4, 166.0, 141.3, 137.9, 136.9, 133.8,
15.6 min (3R4R, minor) (ref. 12: CHIRALPAK IA column, hexane/ 130.8, 128.8, 128.6, 128.2, 127.8, 125.7, 124.2, 116.7, 60.8, 60.6,
2-propanol 90/10, ow rate ¼ 1.0 mL minꢂ1, cis: tr ¼ 14.4 min 60.4, 21.3, 21.0, 14.3. ESI-HRMS calcd for C26H26NO3+ [M + H]+:
(3R4R), tr ¼ 16.6 min (3S4S); trans: tr ¼ 19.6 min, tr ¼ 25.9 min). 400.1907, found 400.1899.
1H NMR (600 MHz, CDCl3) d 7.91 (d, J ¼ 8.1 Hz, 2H), 7.44–7.28
(3S,4S)-1-(4-Carboethoxyphenyl)-3,4-(3-methylphenyl)-2-
(m, 7H), 5.18 (d, J ¼ 5.9 Hz, 1H), 4.31 (d, J ¼ 7.0 Hz, 2H), 3.37– azetidinone (3j). Light yellow liquid, 71.9 mg, 90% yield (cis),
3.34 (m, 1H), 2.21 (s, 1H), 1.66 (s, 2H), 1.51 (s, 2H), 1.34 (t, J ¼ 89% ee. [a]2D0 ¼ ꢂ16.9 (c 1.32, CHCl3). The ee was determined by
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HPLC analysis using a Chiralcel OD-H column, hexane/2- 1H), 2.29 (s, 3H). 13C NMR (150 MHz, CDCl3) d 165.4, 135.3,
propanol 90/10, ow rate ¼ 1 mL minꢂ1, tr ¼ 12.24 min 134.5, 133.7, 132.2, 129.6, 128.9, 128.2, 128.1, 127.8, 127.13,
(major) and tr ¼ 15.45 min (minor). 1H NMR (600 MHz, CDCl3) 127.11, 117.2, 60.3, 60.2, 20.9.
d 7.97 (d, J ¼ 8.8 Hz, 2H), 7.44 (d, J ¼ 8.8 Hz, 2H), 7.00–6.95 (m,
(3S,4S)-1-(4-Chlorophenyl)-3,4-diphenyl-2-azetidinone (3o).
2H), 6.90–6.80 (m, 6H), 5.43 (d, J ¼ 6.2 Hz, 1H), 4.99 (d, J ¼ White solid, 53.4 mg, 80% yield (cis), 87% ee. [a]2D0 ¼ ꢂ8.13 (c
6.2 Hz, 1H), 4.35–4.31 (m, 2H), 2.15 (d, J ¼ 5.0 Hz, 6H), 1.35 (t, J 0.57, CHCl3). The ee was determined by HPLC analysis using
¼ 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) d 166.2, 166.0, 147.3, a CHIRALPAK IA column, hexane/2-propanol 90/10, ow rate ¼
137.9, 137.6, 133.8, 131.6, 130.8, 129.5, 128.8, 128.1, 128.0, 1.0 mL minꢂ1, tr ¼ 10.66 min (major) and tr ¼ 14.34 min
1
127.9, 127.7, 125.9, 125.7, 124.2, 116.7, 60.8, 60.6, 21.2, 21.2, (minor). H NMR (600 MHz, CDCl3) d 7.35 (d, J ¼ 8.8 Hz, 2H),
14.3. ESI-HRMS calcd for C26H26NO3+ [M + H]+: 400.1907, found 7.23 (d, J ¼ 8.8 Hz, 2H), 7.11–7.03 (m, 10H), 5.44 (d, J ¼ 6.1 Hz,
400.1898.
1H), 5.02 (d, J ¼ 6.1 Hz, 1H). 13C NMR (150 MHz, CDCl3) d 165.5,
(3S,4S)-1-(4-Carboethoxyphenyl)-3,4-(4-methylphenyl)-2-
136.2, 133.9, 131.8, 129.2, 129.1, 128.8, 128.3, 128.1, 128.0,
azetidinone (3k). Light yellow liquid, 63.9 mg, 80% yield (cis), 127.3, 127.1, 118.4, 60.6, 60.4.
79% ee. [a]2D0 ¼ ꢂ27.2 (c 0.94, CHCl3). The ee was determined by
(3S,4S)-1-(4-Bromophenyl)-3,4-diphenyl-2-azetidinone (3p).
HPLC analysis using a Chiralcel OD-H column, hexane/2- White solid, 62.0 mg, 82% yield (cis), 87% ee. [a]2D0 ¼ ꢂ10.23 (c
propanol 90/10, ow rate ¼ 1 mL minꢂ1, tr ¼ 8.84 min 0.72, CHCl3). The ee was determined by HPLC analysis using
(major) and tr ¼ 11.77 min (minor). 1H NMR (600 MHz, CDCl3) a CHIRALPAK IA column, hexane/2-propanol 90/10, ow rate ¼
d 7.95 (d, J ¼ 8.8 Hz, 2H), 7.42 (d, J ¼ 8.7 Hz, 2H), 6.94–6.89 (m, 1.0 mL minꢂ1, tr ¼ 11.44 min (major) and tr ¼ 15.40 min
1
8H), 5.44 (d, J ¼ 6.2 Hz, 1H), 4.98 (d, J ¼ 6.2 Hz, 1H), 4.35–4.31 (minor). H NMR (600 MHz, CDCl3) d 7.38 (d, J ¼ 8.8 Hz, 2H),
(m, 2H), 2.18 (d, J ¼ 7.2 Hz, 6H), 1.35 (t, J ¼ 7.1 Hz, 3H). 13C NMR 7.29 (d, J ¼ 8.8 Hz, 2H), 7.11–7.02 (m, 10H), 5.43 (d, J ¼ 6.1 Hz,
(150 MHz, CDCl3) d 166.4, 166.0, 141.3, 137.8, 136.8, 130.8, 1H), 5.02 (d, J ¼ 6.1 Hz, 1H). 13C NMR (150 MHz, CDCl3) d 165.6,
129.1, 128.9, 128.7, 128.7, 127.1, 125.7, 116.7, 60.8, 60.5, 60.3, 136.6, 133.9, 132.1, 131.8, 128.8, 128.3, 128.12, 128.06, 127.3,
+
21.1, 21.1, 14.3. ESI-HRMS calcd for C26H26NO3 [M + H]+: 127.1, 118.8, 116.7, 60.6, 60.4.
400.1907, found 400.1898.
(3S,4S)-1-(4-Fluorophenyl)-3,4-diphenyl-2-azetidinone (3q).
White solid, 44.4 mg, 70% yield (cis), 86% ee. [a]2D0 ¼ ꢂ7.0 (c
(3S,4S)-1-(4-Carboethoxyphenyl)-3-(3-methylphenyl)-4-(4-
methylphenyl)-2-azetidinone (3l). Light yellow liquid, 65.5 mg, 0.34, CHCl3). The ee was determined by HPLC analysis using
82% yield (cis), 79% ee. [a]2D0 ¼ ꢂ28.1 (c 0.89, CHCl3). The ee was a CHIRALPAK IA column, hexane/2-propanol 90/10, ow rate ¼
determined by HPLC analysis using a Chiralcel OD-H column, 1.0 mL minꢂ1, tr ¼ 10.43 min (major) and tr ¼ 13.67 min
hexane/2-propanol 90/10, ow rate ¼ 1 mL minꢂ1, tr
¼
(minor). H NMR (600 MHz, CDCl3) d 7.40–7.37 (m, 2H), 7.11–
1
10.94 min (major) and tr ¼ 14.99 min (minor). 1H NMR (600 6.96 (m, 12H), 5.44 (d, J ¼ 6.1 Hz, 1H), 5.02 (d, J ¼ 6.1 Hz, 1H).
MHz, CDCl3) d 7.96 (d, J ¼ 8.7 Hz, 2H), 7.43 (d, J ¼ 8.7 Hz, 2H), 13C NMR (150 MHz, CDCl3) d 165.3, 159.9, 158.3, 134.1, 133.9 (d,
6.98–6.81 (m, 8H), 5.45 (d, J ¼ 6.2 Hz, 1H), 4.98 (d, J ¼ 6.2 Hz, J ¼ 10.7), 132.0, 128.9, 128.3, 128.1, 128.0, 127.2, 127.1, 118.66,
1H), 4.35–4.31 (m, 2H), 2.17 (d, J ¼ 12.0 Hz, 6H), 1.35 (t, J ¼ 118.61, 116.0, 115.8, 60.53, 60.51. ESI-HRMS calcd for
7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) d 166.3, 166.0, 141.3,
C
21H17FNO+ [M + H]+: 318.1289, found 318.1284.
137.8, 137.7, 131.7, 130.8, 130.8, 129.5, 129.0, 127.99, 127.97,
(3S,4S)-3-(4-Fluorophenyl)-1,4-diphenyl-2-azetidinone (3r).
127.0, 125.9, 125.7, 116.7, 60.8, 60.50, 60.47, 21.2, 21.1, 14.3. White solid, 47.6 mg, 75% yield (cis), 84% ee. [a]2D0 ¼ ꢂ5.4 (c
ESI-HRMS calcd for C26H26NO3 [M + H]+: 400.1907, found 0.24, CHCl3). The ee was determined by HPLC analysis using
+
400.1898.
a CHIRALPAK IA column, hexane/2-propanol 85/15, ow rate ¼
(3S,4S)-1,3,4-Triphenyl-2-azetidinone (3m). White solid, 1.0 mL minꢂ1, tr ¼ 8.42 min (major) and tr ¼ 15.66 min (minor).
56.0 mg, 93% yield (cis), 91% ee. [a]2D0 ¼ ꢂ9.2 (c 0.54, CHCl3). 1H NMR (600 MHz, CDCl3) d 7.41–7.40 (m, 2H), 7.30–7.25 (m,
The ee was determined by HPLC analysis using a CHIRALPAK IA 2H), 7.14–7.01 (m, 8H), 6.79–6.76 (m, 2H), 5.45 (d, J ¼ 6.1 Hz,
column, hexane/2-propanol 90/10, ow rate ¼ 1.0 mL minꢂ1, tr 1H), 4.97 (d, J ¼ 6.1 Hz, 1H). 13C NMR (150 MHz, CDCl3) d 165.4,
¼ 10.35 min (3S4S, major) and tr ¼ 16.92 min (3R4R, minor). 162.7, 161.0, 137.6, 134.2, 130.5 (d, J ¼ 32.5), 129.1, 128.4, 128.1,
(ref. 12: CHIRALPAK IA column, hexane/2-propanol 90/10, ow 127.0, 124.2, 117.2, 115.1, 115.0, 60.2, 59.5. ESI-HRMS calcd for
rate ¼ 1.0 mL minꢂ1, cis: tr ¼ 11.4 min (3S4S), tr ¼ 19.2 min
C
21H17FNO+ [M + H]+: 318.1289, found 318.1290.
1
(3R4R); trans: tr ¼ 10.0 min, tr ¼ 13.2 min) H NMR (600 MHz,
CDCl3) d 7.42–7.41 (m, 2H), 7.30–7.25 (m, 2H), 7.11–7.04 (m,
11H), 5.47 (d, J ¼ 6.2 Hz, 1H), 5.01 (d, J ¼ 6.1 Hz, 1H). 13C NMR
Conflicts of interest
(150 MHz, CDCl3) d 165.7, 137.7, 134.4, 132.1, 129.1, 128.9, There are no conicts to declare.
128.2, 128.1, 127.9, 127.2, 127.1, 124.1, 117.2, 60.3, 60.3.
(3S,4S)-1-(4-Methylphenyl)-3,4-diphenyl-2-azetidinone (3n).
Acknowledgements
White solid, 44.5 mg, 71% yield (cis), 85% ee. [a]2D0 ¼ ꢂ12.19 (c
0.38, CHCl3). The ee was determined by HPLC analysis using We thank the National Natural Science Foundation of China
a CHIRALPAK IA column, hexane/2-propanol 90/10, ow rate ¼ (21672031), Chongqing Natural Science Foundation (cstc2019jcyj-
1.0 mL minꢂ1, tr ¼ 12.75 min (major) and tr ¼ 17.47 min msxmX0034 and cstc2017jcyjAX0352), and Scientic and Techno-
1
(minor). H NMR (600 MHz, CDCl3) d 7.3 (d, J ¼ 8.4 Hz, 2H), logical Research Program of Chongqing Municipal Education
7.10–7.03 (m, 12H), 5.43 (d, J ¼ 6.1 Hz, 1H), 4.99 (d, J ¼ 6.1 Hz, Commission (KJQN201900437) for nancial support.
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18114 | RSC Adv., 2020, 10, 18107–18114
This journal is © The Royal Society of Chemistry 2020