Selectivities in the reaction of vicinal diimines and acyl chlorides

Article abstract of DOI:10.1016/j.tet.2011.10.044

The reaction of vicinal diimines and acyl chlorides in the presence of triethylamine produces 3-imino-β-lactams and/or bis-β-lactams chemo-, regio-, and stereoselectively, which are important intermediates in pharmaceutical and organic synthesis. The selectivities in the reaction have been investigated. The results indicate that all diimines react with various ketenes generated from acyl chlorides in the presence of triethylamine to give rise to cis-4-imino-β-lactams (mono-cis-β-lactams) diastereoselectively due to the electron-withdrawing property of the imino group in the vicinal diimines. Bis-β-lactams were obtained from diimines via the mono-cis-β-lactams as intermediates. Only ketenes with strong electron-donating substituents can react with the mono-cis-β-lactams to yield bis-β-lactams, affording a pair of C2-symmetric cis-bis-β- lactams with symmetric diimines, two or four pairs of diastereomeric bis-β-lactams with ketoaldehyde-derived unsymmetric diimines depending on the steric hindrance of their N-substituents. The current investigation provides very important information for the selective preparation of mono- and bis-β-lactams from vicinal diimines.

Full text of DOI:10.1016/j.tet.2011.10.044

Tetrahedron 67 (2011) 9690e9699
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selectivities in the reaction of vicinal diimines and acyl chlorides
,b,
Zhixin Wang a, Ning Chen a, Jiaxi Xu a
*
a State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing 100029, China
b Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, Nanchang 330013, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2011
Received in revised form 28 September 2011
Accepted 11 October 2011
Available online 19 October 2011
The reaction of vicinal diimines and acyl chlorides in the presence of triethylamine produces 3-imino-b-
lactams and/or bis-b-lactams chemo-, regio-, and stereoselectively, which are important intermediates in
pharmaceutical and organic synthesis. The selectivities in the reaction have been investigated. The re-
sults indicate that all diimines react with various ketenes generated from acyl chlorides in the presence
of triethylamine to give rise to cis-4-imino-
the electron-withdrawing property of the imino group in the vicinal diimines. Bis-
tained from diimines via the mono-cis- -lactams as intermediates. Only ketenes with strong electron-
donating substituents can react with the mono-cis- -lactams to yield bis- -lactams, affording a pair of
C2-symmetric cis-bis- -lactams with symmetric diimines, two or four pairs of diastereomeric bis-b-
b-lactams (mono-cis-
b-lactams) diastereoselectively due to
b
-lactams were ob-
Keywords:
b
Chemoselectivity
Diastereoselectivity
Diimine
Regioselectivity
Staudinger reaction
b
b
b
lactams with ketoaldehyde-derived unsymmetric diimines depending on the steric hindrance of their N-
substituents. The current investigation provides very important information for the selective preparation
of mono- and bis-b-lactams from vicinal diimines.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
from vicinal ketoaldehydes are still unclear to date. In our ongoing
project devoted to investigate the stereoselectivity in the reaction of
ketenes and imines (the Staudinger reaction), we hope to conduct
the reaction of various diimines and ketenes and to study the se-
lectivities in the reaction. Herein, we present our results on the se-
lectivities in the reactions of vicinal diimines and acyl chlorides in
the presence of triethylamine, including the diastereoselectivity in
Both 4-imino-
termediates in organic and pharmaceutical chemistry.1,2 4-Imino-
-lactams can be converted to 4-acyl- -lactams, which have been
widely used in the synthesis of
-amino acid derivatives3,4 and
b-lactams and bis-b-lactams are important in-
b
b
a
b-
amino acid derivatives5,6 via the ring-opening. They have also been
applied in the preparation of heterocyclic compounds,7e25 alka-
loids,23,26 antibiotics,27e31 even more complex natural products via
the formation of mono-
of mono- -lactams for unsymmetric diimines, the selectivity in the
formation of mono- and bis- -lactams, and the stereoselectivity in
the formation of bis- -lactams.
b-lactams, regioselectivity in the formation
b
the ring enlargement.23,32 Bis-
b
-lactams have been utilized in the
synthesis of fused bispyrrolidinones via one step conversion.33,34
Both 4-imino- -lactams and bis- -lactams have been prepared
b
b
b
b
from the reaction of acyl chlorides and vicinal diimines in the
presence of tertiary amines.34 A few examples on the reactions of
vicinal diimines and acyl chlorides have been reported pre-
viously.34e37 Reactions of dimethylketene generated from iso-
butanoyl chloride and diimines formed from 2,3-butanedione
2. Results and discussion
2.1. Diastereoselectivity in the formation of mono-b-lactams
in reactions of vicinal diketone-derived diimines and acyl
chlorides
and 1,2-diphenylethanedione gave rise to mono-
Reactions of glyoxal-derived diimines and various acyl chlorides
produced cis-mono- and bis-
-lactams.34 However, the diaster-
eoselectivity in the formation of mono- -lactams and the selectivity
in the formation of mono/bis- -lactams for the vicinal diketone-
derived diimines, and the regio- and diastereoselectivities in the
formation of mono- -lactams for unsymmetric diimines generated
b
-lactams.35e37
Alcaide and co-workers reported that glyoxal-derived diimines
reacted with various acyl chlorides produced cis-mono- and bis-b-
b
b
lactams stereospecifically.34 We first hoped to investigate the dia-
stereoselectivity in the reaction of vicinal diketone-derived diimines
and representative ketenes, generated from substituted acetyl
chlorides in the presence of triethylamine. A series of 2,3-
butanedione-derived diimines 1aed was prepared via the reaction
of 2,3-butanedione and 4-methoxyaniline (4-anisidine),38 aniline,38
benzylamine,39 and dibenzylmethylamine (benzhydrylamine),
b
b
* Corresponding author. Tel./fax: þ86 10 64435565; e-mail address: jxxu@
mail.buct.edu.cn (J. Xu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.044

Z. Wang et al. / Tetrahedron 67 (2011) 9690e9699
9691
respectively, according to reported methods. Diimine 1a reacted
with various acyl chlorides 2, including ethoxyacetyl chloride (2a),
phthalimidoacetyl chloride (PhthNCH2COCl) (2b), chloroacetyl
chloride (2c), and propionyl chloride (2d), respectively, in benzene
in the presence of triethylamine (TEA) in a molar ratio of 1:1.2:1.5 for
diimine/acyl chloride/TEA (Table 1, entries 1e4). For each of cases, 4-
O
R1
O
PMP
O
PMP
N
N
N
N
N
N
Me
R2
R1
PMP
O
PMP
H
H
Ph
H
CH3
CH3
Ph
cis-( )-3ed
3ab 3dd
cis-( )-
-
cis-( )-3aa
R
1 = PMP, Ph, Bn, DPM
imino-
yields. Diimines 1b,c reacted with propionyl chloride (2d), re-
spectively, to afford 4-imino- -lactams 3bdecd in satisfactory
b-lactams 3aaead were generated in satisfactory to good
R2 = PhthN, Cl, Me
NOE correlation
b
yields (Table 1, entries 5 and 6). However, diimine 1d with bulky N-
Fig. 1. NOE correlations in mono-cis-b-lactams 3aae3ed.
substituent diphenylmethyl group reacted with propionyl chloride
(2d) to give rise to 4-imino-b-lactam 3dd in a low yield (42%) due to
the steric hindrance of the bulky diphenylmethyl group, decreasing
the reaction rate (Table 1, entry 7).
lactams. It is some difficult to distinguish these two singlet methyl
groups. To obtain an unambiguous result on the identification of
the stereostructure, one of the representative products (3bd) was
selected to subject the X-ray single crystal diffraction (XRD) anal-
Table 1
ysis. The XRD results indicate that 3bd is indeed a cis-mono-
b-
Reaction of symmetric diimines 1 and acyl chlorides 2
lactam (Fig. 2),40 further revealing that mono-
b
-lactams 3aaedd
R1
O
R1
N
are in cis-configuration because 3bd was prepared from a ketene
with weak electron-donating substituent (Me) and an imine with
less bulky N-substituent (Ph). For mono-b-lactam 3ed, the corre-
lation between its 3-hydrogen and 4-phenyl group was observed in
its NOESY spectrum. On the other hand, benzoxime is more
electron-withdrawing than acetoxime. Thus, 3ed should be in cis-
configuration.
N
Cl
TEA, PhH
80 o
R2
+
N
R1
C
R2
O
N
R1
1
2
cis-( )-3
PMP = 4-MeOC6H4, DPM = Ph2CH
Entry
Symmetric diimine 1 Acyl chloride 2
Product 3
1
R1
2
R2
3
Yielda (%)
1
2
3
4
5
6
7
1a
PMP
2a
2b
2c
2d
2d
2d
2d
EtO
PhthN
Cl
Me
Me
cis-3aa
cis-3ab
cis-3ac
cis-3ad
cis-3bd
cis-3cd
cis-3dd
76
87
70
71
73
69
42
1b
1c
1d
Ph
Bn
DPM
Me
Me
a
Isolated yield was obtained in the ratio of 1e/2d at 1:1.2 after column chro-
matography and recrystallization.
The reaction of aromatic vicinal diketone-derived diimines and
acyl chlorides was also investigated. To observe the diaster-
eoselectivity in the reaction, a ketene bearing weak electron-
donating substituent was chosen because it may produce either
cis-
Benzildiimine (1e) was prepared from benzil and 4-methoxyaniline
and reacted with propionyl chloride (2d) to afford mono- -lactam
b-lactams or trans-b-lactams depending on different imines.
b
3ed in 50% yield in the ratio of 1e/2d at 1:1.2. The yield was im-
proved to 92% when propionyl chloride was increased to 5 equiv
(Scheme 1).
Ph
PMP
Ph
Ph
N
Cl
PMP
TEA, PhH
80 oC
N
Ph
+
O
2d
N
Fig. 2. Stereostructure of mono-b-lactam cis-3bd.
O
PMP
3ed
N
1e
PMP
cis-( )-
The diastereoselectivity follows our previous proposal on the
stereoselectivity of the Staudinger reaction.41e44 That is, the dia-
stereoselectivity is a result of the competition between the direct
conrotatory ring closure and the isomerization of imine moiety in
the zwitterionic intermediates generated from ketenes and imines
(Scheme 2). Strong electron-donating ketene substituents, strong
electron-withdrawing imine C-substituents and bulky imine N-
Scheme 1. Reaction of benzildiimine (1e) with propionyl chloride (2d).
The stereostructure of products was identified on the basis of
the NOESY spectra of the representative products. There existed
a strong correlation between 3-hydrogen and the hydrogens in 4-
methyl on the
b
-lactam ring in each of the mono-
b
-lactam prod-
substituents prefer the formation of cis-b-lactams, while weak
ucts determined. Furthermore, a weak correlation between the
methylene in the ethoxy group and the methyl in the acetoxime
electron-donating and electron-withdrawing ketene substituents,
and electron-donating imine C-substituents dominate the forma-
moiety in
correlations indicate that the stereostructure of the mono-
tams 3aaedd is cis-configuration. However, the peaks of the 4-
methyl on the -lactam ring and the methyl in the acetoxime
moiety in the 1H NMR spectra are too close for most mono-
b
-lactam 3aa was also observed (Fig. 1). Both of the
tion of trans-b-lactams. The results reveal that the diketone-
derived diimines show similar diastereoselectivity as the glyoxal-
derived diimines in the Staudinger reactions, affording mono-cis-
b-lac-
b
b-lactams, because the imino groups derived from both formyl and
b
-
acyl groups are relative strong electron-withdrawing substituents

9692
Z. Wang et al. / Tetrahedron 67 (2011) 9690e9699
R1
N
Direct
H
conrotatory
ring-closure
R2
O
R1
N
N
R1
R2
R2
H
R1
cis-(+)-3
N
H
R1
+
C
O
N
R1
N
O
R1
N
H
R2
R2
N
conrotatory
ring-closure
R1
A
1
H
isomerization
N
R1 = PMP, Ph, Bn, Ph2CH
R2 = EtO, PhthN, Cl, Me
R1
N
O
O
R1
3
trans-(+)-
B
Scheme 2. Mechanism in the formation of mono-cis-
b-lactams from ketenes and diimines.
in diimines, increasing the rate of ring closure. No isomerization
occurs during reactions.
ketimine in pyruvic aldehyde-derived diimines reacts with ketenes
generated from acyl chlorides. For the two imine groups in the
unsymmetric diimines 1feg, the ketimine is more electron-rich
than the aldimine, favorably attacking ketenes in the nucleophilic
addition step. On the other hand, the stable conformation of dii-
mines 1 is s-trans-configuration and the ketimine attacks ketenes
more predominantly than the aldimine in steric hindrance as well
(C vs D, Fig. 3). These rationalize the reason why the ketimine in the
2.2. Regio- and diastereoselectivities in the formation of
mono-b-lactams in the reaction of vicinal ketoaldehyde-
derived unsymmetric diimines and acyl chlorides
Although diketone and glyoxal-derived diimines show similar
diastereoselectivities in the reactions with acyl chlorides,34 we are
interested in the selectivity in the reaction of vicinal ketoaldehyde-
derived unsymmetric diimines and acyl chlorides. Representative
unsymmetric diimines 1feg with less and more bulky N-sub-
stituents were prepared from pyruvic aldehyde and 4-
methoxyaniline and diphenylmethylamine, respectively. Unsym-
metric diimine 1f reacted with the representative acyl chlorides
2a,d, respectively, in the presence of triethylamine in the molar
ratio of 1/2/TEA at 1:1.2:1.3 to afford the corresponding mono-cis-
unsymmetric diimines 1feg reacts with acyl chlorides
specifically.
2
R1
R1
R1
O
N
R2
O
N
N
Cl TEA, PhH
80 oC
R2
or
Me
H
N
+
R1
Me
R2
N
O
2
N
1f-g
R1
H
R1
b-lactams 3fa,fd in good yields (Table 2, entries 1 and 2). Unsym-
cis-( )-3
3'
metric diimine 1g reacted with acyl chlorides 2aed, respectively, in
the presence of triethylamine in the molar ratio of 1/2/TEA at
Scheme 3. Reaction of unsymmetric diimines 1feg with acyl chlorides 2.
1:2.5:3 to afford the corresponding mono-cis-b-lactams 3gaegd in
satisfactory to good yields (Table 2, entries 3e6), in which more
acyl chlorides were added to improve the yields because the dii-
mine 1g with bulky N-substituent.
R1
N
R1
N
R2
R2
H
H
Me
N
H
Table 2
Reaction of unsymmetric diimines 1 and acyl chlorides 2
C
O
C
O
O
R1
N
Me
R1
R1
R1
N
N
TEA, PhH
80 oC
Cl
R2
D
C
H
+
N
R1
favorably
disfavorably
R2
O
2
N
H
R1
Fig. 3. Regioselective attacks in the reaction of unsymmetric diimines 1feg and
cis-( )-3
1f-g
ketenes.
Entry
Unsymmetric diimine 1
Acyl chloride 2
Product 3
1
R1
2
R2
3
Yielda (%)
The configuration of product 3fd was determined on the basis of
its NOESY spectrum (See SD for details). The correlation between 3-
hydrogen and 4-methyl was observed, demonstrating that they are
1
2
3
4
5
6
1f
PMP
2a
2d
2a
2b
2c
2d
EtO
Me
EtO
PhthN
Cl
cis-3fa
cis-3fd
cis-3ga
cis-3gb
cis-3gc
cis-3gd
80
77
1g
DPM
82b
84c
50c
95c
in the same side of the
configuration. The diimine 1f reacted with methylketene with
weak electron-donating substituent to afford cis- -lactam 3fd, in-
b-lactam ring. That is, the b-lactam is in cis-
Me
b
a
dicating that the other products from diimine 1f and acyl chlorides
2bed should be in cis-configuration and all products from imine 1g
should be in cis-configuration as well due to bulky imine N-
substituent.
Isolated yield in the ratio of 1/2 at 1:1.2 after column chromatography and
recrystallization.
b
Yield in ratio of 1/2 at 1:2.5 in dicloromethane at 25 ꢀC.
Yield in ratio of 1/2 at 1:2.5.
c
The configuration of product 3gd was further confirmed by 1D-
The products obtained from the reaction of diimines 1feg were
identified as the structure 3 rather than 30 (Scheme 3) because the
products show a CHCCH3 system with a singlet at downfield for an
aldimine hydrogen, not two vicinal hydrogens (AM system) in the
NOE (Fig. 4). When 3-hydrogen on the
3% NOE was observed for the hydrogens of 4-methyl on the
tam ring, which demonstrates that 3-hydrogen and 4-methyl group
are in the same side of the -lactam ring, indicating that the
lactam is in cis-configuration.
b
-lactam ring was irradiated,
b
-lac-
b
b-
b
-lactam ring in their 1H NMR spectra. The results indicate that the

Z. Wang et al. / Tetrahedron 67 (2011) 9690e9699
9693
with ethoxyacetyl chloride (2a), only the corresponding mono-
b-
lactams 3 were obtained, no bis- -lactam was found in the reaction
b
mixtures (also see Table 2, entries 3e6), even acyl chlorides 2bed
were increased to 5 equiv, revealing that only ethoxyacetyl chloride
(2a) can react with diimines 1 to give rise to bis-
results demonstrate that the electronic effect of the ketene
substituents R2 is very important for the formation of bis-
-lactams.
b-lactams. The
b
Thus, the further investigation focuses on the reactions of ethox-
yacetyl chloride (2a) and representative diimines 1a,f,g (Table 3)
and the stereostructure of the bis-b-lactam products.
We initially used symmetric diimine 1a and ethoxyacetyl chlo-
ride (2a) as the model substrates to study the formation selectivity
of the corresponding mono- and bis-b-lactams 3aa and 4aa. We
conducted the reaction in different molar ratios of starting mate-
rials in the presence of TEA in dichloromethane (DCM) at room
Fig. 4. 1H NMR and 1D-NOE spectra of cis-3gd.
Table 3
Selectivity in the reaction of diimines 1a,f,g and ethoxyacetyl chloride (2a)
H
O
EtO
Me
R1
N
R
H
R1
EtO
O
EtO
N
Cl TEA
N
R1
(+)
R
+
+ EtO
R
N
R1
N
O
O
(+)
R1
N
R1
4
rel-(2R,2'R,3S,3'S)-
RS-4
2a
cis-3
1
H
R1
Me
O
R1
Me
O
O
EtO
H
N
N
H
H
Me
EtO
N
EtO
EtO
+
+
OEt
OEt
R1
+
H
N
H
H
R
N
H
N
O
R1
(+)
(+)
O
R1
O
R1
(+)
4
rel-(2R,2'S,3S,3'R)-4
rel-(2R,2'S,3S,3'S)-
rel-(2R,2'R,3S,3'R)-4
RR-4
4
SR-4
SS-
Entry
Diimine 1
Ratio 1/2a/TEA
Solvent
Temp (ꢀC)
Product
3
Yielda (%)
4
Yielda (%)
4
Yielda (%)
4
Yield (%)
1
2
3
4
5
1a
1a
1a
1a
1f
1:2.5:3.0
1:5:6
1:2:2.5
1:2.5:3.0
1:2.5:3.0
DCM
DCM
PhH
PhH
PhH
20
20
80
80
80
cis-3aa
cis-3aa
cis-3aa
d
81
81
63
d
d
d
d
d
d
d
d
d
d
d
d
d
d
RS-4aa
RS-4aa
RS-4ea
12
83
53
d
d
d
d
d
d
NDb
d
d
NDb
d
SR-4fa
SS-4fa
RR-4fa
SS-4fa
RR-4fa
d
6
1f
1:5:6
PhH
80
d
d
RS-4ea
59
SR-4fa
11c
15c
9c
d
d
d
7
8
9
1g
1g
1g
1:2.5:3.0
1:2.5:3.0
1:5:6
DCM
PhH
PhH
20
80
cis-3ga
cis-3ga
d
82
30
d
d
d
42
65
d
d
9
14
RS-4ga
RS-4ga
SR-4ga
SR-4ga
d
d
a
Isolated yield after column chromatography and recrystallization.
Not determined.
NMR yield.
b
c
2.3. Selectivity in the formation of mono- and bis-
b
-lactams
temperature (20 ꢀC) and in benzene at 80 ꢀC (Table 3, entries 1e4,
also see Table 1). In dichloromethane, only mono- -lactam 3aa was
obtained in the yield of 81% whatever the molar ratio of diimine 1a
and acyl chloride 2a varied from 1:2.5 to 1:5 (Table 3, entries 1 and
in the reactions of diimines and acyl chlorides and the
stereostructure of bis- -lactams
b
b
Although Alcaide and co-workers explored the formation se-
2). However, a mixture of mono-
were obtained in refluxing benzene in the molar ratio of 1:2 (Table
1, entry 3) and bis- -lactam 4aa was obtained in a yield of 83% as
sole product in the molar ratio of 1:2.5 (Table 1, entry 4, Scheme 4).
The results demonstrate that diimine 1a first reacted with one
b-lactam 3aa and bis-b-lactam 4aa
lectivity of mono- and bis-b-lactams in the reactions of glyoxal-
derived diimines,34 the selectivity is still unclear in the reactions
of vicinal diketone-derived diimines and ketoaldehyde-derived
diimines. To extend the application of the reaction in the selec-
b
tive preparation of various mono- and bis-
diimines and ketenes, we investigated the formation selectivity of
mono- and bis- -lactams in the reactions of representative vicinal
diketone and ketoaldehyde-derived diimines 1 and acyl chlorides 2.
The representative diimines 1a,f,g were screened first with acyl
chlorides 2aed in the molar ratio of 1/2 at 1:2.5 in the presence of
triethylamine in refluxing benzene at 80 ꢀC. Except for the reactions
b
-lactams from different
molecule of 2a to form mono-cis-
Mono-cis- -lactam 3aa further reacted with another molecule of 2a
to afford bis- -lactam product 4aa. The results also demonstrate
that temperature and solvent are not key factors in the formation of
mono- -lactam. However, they are very important in the prepa-
ration of bis- -lactams. Alcaide and co-workers also reported that
high temperature is beneficial for the formation of bis-
-lactams.34
b-lactam 3aa in the reaction.
b
b
b
b
b
b

9694
Z. Wang et al. / Tetrahedron 67 (2011) 9690e9699
After generating the first
b
-lactam ring, the
b
-lactam ring, as bulky
Secondly, we conducted the reaction of bulky unsymmetric
diimine 1g with the N-diphenylmethyl (DPM) group and ethox-
yacetyl chloride (2a) (Scheme 5). As diimine 1a, only mono-cis-
groups in imines, remarkably inhibits the formation of the second
-lactam ring. Thus, in order to form the second ring, a strong
b
b-
electron-donating ketene, such as ethoxylketene and high tem-
perature are demanded.
lactam 3ga was obtained in DCM in the molar ratio of 1g/2a at 1:2.5
(Table 3, entry 7). However, at the same molar ratio, a mixture of
mono-cis-
obtained in refluxing benzene (Table 3, entry 8). When ethox-
yacetyl chloride was increased to 5 equiv, all mono-cis- -lactam
3ga was converted to the two bis- -lactams 4ga in yields of 65% and
14%, respectively. NMR spectra indicate that the two products are
a couple of diastereoisomeric bis-cis- -lactams. Their stereo-
structures were identified on the basis of the previous reported
results34 and the reaction mechanism. On comparison with the
product RS-4aa, the major product was assigned as RS-4ga with the
relative configuration of 2R,20R,3S,30S. It generated from cis-3ga and
ethoxyketene via the more stable conformation of cis-3ga and less
steric hindrance process (Top process in Scheme 5). The minor
product was assigned as SR-4ga with the relative configuration of
2R,20S,3S,30R. It generated from cis-3ga and ethoxyketene via the
less stable conformation of cis-3ga and more steric hindrance
process (Bottom process in Scheme 5).
b-lactam 3ga and two different bis-b-lactams 4ga were
H
O
b
PMP
EtO
Me
N
H
Cl
b
TEA, PhH
80 o
N
EtO
EtO
+
PMP
Me
C
O
N
N
O
b
PMP
PMP (+)
2a
1a
rel-(2R,2'R,3S,3'S)
4aa
RS-
O
C
less hindrance
PMP
N
PMP
+
PMP
N
N
H
Cl
TEA, PhH
80 oC
EtO
EtO
EtO
OEt
O
N
N
N
O
O
PMP
(+)
PMP
2a
PMP (+)
1a
more steric hindrance
rel-(3S,4R)
3aa
cis-
PMP
O-
EtO
O
N
C
conrotatory
ring closure
EtO
N
EtO
OEt
PMP
(+)
N
To further verify the structural identification of the products cis-
3ga, RS-4aa, RS-4ga, and SR-4ga, the key representative products
cis-3ga, RS-4ga, and SR-4ga were subjected single crystal X-ray
diffraction analysis.40 Their stereostructures are shown in Fig. 5.
The results indicate that the XRD structures are in complete
N
O
O
PMP
E
PMP
rel-(2R,2'R,3S,3'S)
4aa
RS-
Scheme 4. Reaction and mechanism in the formation of bis-
metric diimine 1a and 2a.
b-lactam 4aa from sym-
H
O
DPM
O
EtO
Me
DPM
N
N
H
H
Me
H
TEA, PhH
80 oC
Cl
EtO
N
EtO
+
OEt
EtO
+
DPM
(+)
H
DPM
rel-(2R,2'R,3S,3'S)
RS-4ga 65%
H
H
N
N
O
(+)
O
O
DPM
N
2a
DPM
rel-(2R,2'S,3S,3'R)
1g
SR-4ga 14%
less steric hindrance
DPM
O
C
DPM
DPM
O-
EtO
O
N
N
N
C
H
H
conrotatory
ring closure
EtO
H
EtO
EtO
TEA, PhH
N
EtO
+
OEt
H
DPM
OEt
O
80 oC
N
N
N
N
O
O
DPM
Cl
O
(+)
DPM
(+)
DPM
F
DPM
1g
2a
rel-(2R,2'R,3S,3'S)
RS-4ga 65%
major
-O
C
O
C
DPM
O
EtO
DPM
H
N
conrotatory
ring closure
N
EtO
EtO
more steric hindrance
DPM
EtO
N
H
OEt
(+)
EtO
H
N
H
O
N
DPM
N
DPM
O
O
DPM
rel-(2R,2'S,3S,3'R)
SR-4ga 14%
minor
rel-(3S,4R)
G
cis-3ga
Scheme 5. Reaction and mechanism in the formation of bis-
b-lactams 4ga from bulky unsymmetric diimine 1g and 2a.
1H and 13C NMR spectra of 4aa reveal that the molecule has
symmetry and its NOESY spectrum indicates that both of the two
lactam-rings are cis-configuration. Thus, the product 4aa should be
a C2-symmetric compound as the reported product generated from
the reaction of glyoxal-derived diimine and ethoxyacetyl chloride
according to the similar formation mechanism.34 Its formation
agreement with the structures we proposed, respectively, sup-
porting our identification.
Finally, the reaction of unsymmetric diimine 1f and ethox-
yacetyl chloride (2a) was conducted. A major diastereomers of bis-
b-lactams 4fa were obtained in the yield of 53% with other three
diastereomers in the molar ratio of 1f/2a at 1:2.5. Similarly, the
stereostructure of the major product was assigned as RS-4fa with
the relative configuration of 2R,20R,3S,30S on the basis of NMR
spectra and the formation mechanism. It generated from cis-3fa
and ethoxyketene via the more stable conformation of cis-3fa and
less steric hindrance process. When ethoxyacetyl chloride (2a) was
increased to 5 equiv to improve the yields, bis-b-lactam RS-4fa
increased slightly from 53% to 59%. Its other three diastereomers
were obtained in yields of 15%, 11%, and 9%, respectively (See SD for
process is shown in Scheme 4. As we know, the formation of bis-b-
lactam is stepwise. Hence, during the reaction, cis-3aa generated
first and its less bulky conformation reacted with another molecule
of ethoxyketene to produce intermediate E, which further un-
derwent a conrotatory ring closure to give rise to product RS-4aa
with relative configuration of 2R,20R,3S,30S (Only the configuration
of the new generated chiral atoms is put before the compound
number, similarly hereinafter.).

Z. Wang et al. / Tetrahedron 67 (2011) 9690e9699
9695
Fig. 5. Stereostructures of mono-b-lactam cis-3ga and bis-b-lactams RS-4ga and SR-4ga.
details). Although they are inseparable on silica gel column after
many attempts, their stereostructures can be assigned on the basis
of the 1H NMR spectrum of their mixture. In the mixture, the most
isomer (15% yield) and the least one (9% yield) show trans-
mono-
substituents can react with mono-
tams. Ethoxyacetyl chloride reacted with symmetric diimines to
afford a pair of C2-symmetric cis-bis- -lactams, with unsymmetric
b
-lactams. Only ketenes with strong electron-donating
b
-lactams to yield bis- -lac-
b
b
configuration of the
diimine 1f due to their vicinal hydrogen coupling constants of 1.6
and 1.7 Hz, respectively, while the middle one (11% yield) shows
cis-configuration of the b-lactam ring derived from the aldimine
b
-lactam ring derived from the aldimine in
diimines to produce two or four pairs of diastereomers depending
on the steric hindrance of the diimine N-substituents, and the
major products with pseudo C2 symmetry. The current results
provide very important information for the selective preparation of
due to its vicinal hydrogen coupling constant of 5.4 Hz. The results
indicate that the isomerization of imine moiety in the zwitterionic
intermediates generated from ethoxyketene and the aldimine in
mono- and bis-b-lactams from vicinal diimines.
4. Experimental section
4.1. General
diimine 1f occurred during the formation of the second
b-lactam
ring in the reaction. Thus, on the basis of the 1H NMR spectrum and
the reaction mechanism, the stereostructures of the three bis-b-
lactam products were assigned as SS-4fa with rel-(2R,20S,3S,30S)
configuration in 15% yield, SR-4fa with rel-(2R,20S,3S,30R) in 11%
yield, and RR-4fa with rel-(2R,20R,3S,30R) in 9% yield. Their forma-
tion processes are shown in Scheme 6.
Ethoxyacetyl chloride reacted with symmetric diimines pre-
pared from glyoxal and 2,3-butanedione with 4-methoxyaniline
gave rise to only a pair of enantiomers with C2 symmetry in each
of cases. However, it reacted with unsymmetric ketoaldehyde-
derived diimines with bulky N-substituents to generate two pairs
of diastereomeric cis-bis-b-lactams, one with pseudo C2 symmetry,
one with pseudo i symmetry, and with unsymmetric ketoaldehyde-
derived diimines with less bulky N-substituents to produce four
pairs of diastereomeric bis-b-lactams, two pairs with cisecis-bis-b-
Melting points were determined on a melting point apparatus
and are uncorrected. 1H NMR spectra were recorded at 200, 300, or
400 MHz in CDCl3 with TMS as the internal standard. 13C NMR
spectra were recorded at 50.3, 75.5, or 100.6 MHz in CDCl3 with
CDCl3 as the internal standard at 77.0 ppm. NOESY and 1D-NOE
were determined from Bruker 400 plus NMR spectrometer. IR
spectra were determined directly. HRMS spectra were performed
on an LC/MSD TOF mass spectrometer.
Symmetric diimines 1aed were prepared from 2,3-butanedione
with aniline,38 4-methoxyaniline,38 benzylamine,39 and diphe-
nylmethylamine. Symmetric diimine 1e was synthesized from
benzil and 4-methoxyaniline. Unsymmetric diimines 1f,g were
derived from 30% pyruvic aldehyde aqueous solution with 4-
methoxyaniline and diphenylmethylamine. All acyl chlorides 2
were generated from the corresponding carboxylic acids with SOCl2
according to our reported literatures.45,46
lactams, two pairs with cisetrans-bis-b-lactams.
3. Conclusion
The selectivities in the Staudinger reaction of representative
vicinal diimines and acyl chlorides have been investigated. The
results indicate that all diimines react with various ketenes gen-
erated from acyl chlorides in the presence of a tertiary amine to give
rise to cis-4-imino-b-lactams (mono-cis-b-lactams) due to strong
electron-withdrawing imino groups as the imine C-substituents in
4.2. General procedure for the reaction of vicinal diimines 1
and acyl chlorides 2
A solution of acyl chloride (1.2e5 mmol) in anhydrous benzene
(5 mL) was added dropwise to a solution of diimine (1 mmol) and
triethylamine (0.152e0.606 g, 1.5e6 mmol) in toluene (10 mL). The
resulting mixture was stirred at 80 ꢀC under nitrogen for 4e16 h,
which was determined by TLC monitoring. The reaction mixture
was then diluted with CH2C12 (20 mL) and subsequently washed
with saturated aqueous NaHCO3 solution (20 mL) and brine
(2ꢁ10 mL). After dried over anhydrous Na2SO4 and removal of
solvent, the residue was purified via recrystallization with EtOAc or
a mixture of EtOAc and hexanes or via flash column chromatog-
raphy (silica gel, a mixture of hexanes and EtOAc as eluent) to afford
the product.
the reaction. For vicinal ketoaldehyde-derived diimines, they al-
ways produce cis-aldimino-b-lactams because electron-rich keti-
mines prefer to attack ketenes favorably in both electronic and
steric effects to generate zwitterionic intermediates, which favor
the direct ring closure due to their electron-withdrawing aldi-
mines. The results reveal that both the diketone-derived diimines
and the ketoaldehyde-derived diimines show similar diaster-
eoselectivity as the glyoxal-derived diimines in the formation of
mono-b-lactams. Bis-b-lactams were obtained from diimines via

9696
Z. Wang et al. / Tetrahedron 67 (2011) 9690e9699
PMP
N
Cl TEA, PhH
EtO
+
80 oC
H
O
N
2a
PMP
1f
H
H
H
H
PMP
O
O
PMP
O
O
EtO
EtO
Me
N
H
N
H
Me
H
Me
H
Me
H
EtO
EtO
N
EtO
EtO
N
OEt
OEt
+
+
+
PMP
PMP
(+)
H
H
H
N
N
N
N
(+)
O
PMP
O
PMP (+)
(+)
PMP
O
O
PMP
rel-(2R,2'R,3S,3'R)
rel-(2R,2'R,3S,3'S)
rel-(2R,2'S,3S,3'R)
SR-4fa 11%
rel-(2R,2'S,3S,3'S)
SS-4fa 15%
4fa
RR 4fa
RS-
59%
-
9%
PMP
O
OEt PMP
O- conrotatory
ring closure
N
H
O
N
C
EtO
O
Et
N
PMP
H
H
N
PMP
OEt
O
(+)
I
rel-(2R,2'S,3S,3'S)
SS-4fa 15%
isomerization
PMP
less steric hindrance
PMP
O
C
O-
PMP
H +
N
EtO
H
N
C
O
N
H
H
EtO
conrotatory
ring closure
EtO
EtO
TEA, PhH
OEt
N
EtO
OEt
O
PM
P
80 oC
N
N
N
O
N
O
Cl
PMP
O
(+)
PMP
PMP
H
1f
(+)
PMP
2a
rel-(2R,2'R,3S,3'S)
4fa
RS-
59%
-O
C
O
EtO
C
PMP
O
PMP
conrotatory
ring closure
N
H
N
H
PMP
(+)
EtO
EtO
more steric hindrance
N
H
EtO
EtO
OEt
(+)
H
N
PMP
rel-(2R,2'S,3S,3'R)
SR-4fa 11%
N
O
N
PMP
O
PMP
3fa
O
cis-( )-
J
isomerization
-O
C
EtO
H
PMP
O
conrotatory
N
O
EtO
ring closure
N
EtO
PMP
H
N
O
(+)
N
PMP
rel-(2R,2'R,3S,3'R)
RR 4fa
PMP
EtO
-
9%
K
Scheme 6. Reaction and mechanism in the formation of bis-b-lactams 4fa from unsymmetric diimine 1f and 2a.
4.2.1. rel-(3R,4S)-3-Ethoxy-1-(4-methoxyphenyl)-4-[(E)-1-(4-
methoxyphenylimino)ethyl]-4-methylazetidin-2-one (cis-
CH3). 13C NMR (75 MHz, CDCl3)
142.7, 134.5, 131.6, 130.5, 123.7, 120.4, 119.9, 114.3, 113.9, 71.1, 64.3,
d: 169.6, 166.7, 161.1, 156.7, 155.9,
3aa). Reaction was conducted in 1 mmol of diimine 1a, 1.2 mmol of
acid chloride 2a, and 1.5 mmol of Et3N.
55.4, 55.3, 24.0, 17.5. IR (KBr) n
(cmꢂ1): 1757, 1718 (C]O), 1648 (C]
N). HRMS (ESI) calcd for C28H26N3O5 [MþH]þ m/z: 484.1867, found
Yellowish oil, 0.288 g, yield: 75.6%. 1H NMR (300 MHz, CDCl3)
d:
484.1868.
7.38e6.87 (m, 8H, ArH), 4.55 (s,1H, OCH), 3.81 (s, 3H, OCH3), 3.79 (s,
3H, OCH3), 3.78e3.71 (m, 2H, OCH2), 1.93 (s, 3H, CH3), 1.88 (s, 3H,
4.2.3. rel-(3R,4S)-3-Chloro-1-(4-methoxyphenyl)-4-[(E)-1-(4-
methoxyphenylimino)ethyl]-4-methylazetidin-2-one (cis-3ac). Reac-
tion was conducted in 1 mmol of diimine 1a, 1.2 mmol of acid
chloride 2c, and 1.5 mmol of Et3N.
CH3), 1.26 (t, J¼7.0 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3)
d: 171.0,
163.1, 156.1, 155.8, 143.6, 129.80, 129.78, 119.9, 118.3, 114.3, 114.0,
90.5, 70.2, 67.4, 55.0, 19.5, 17.3, 14.9. IR (KBr) n
(cmꢂ1): 1754 (C]O),
1652 (C]N). HRMS (ESI) calcd for C22H27N2O4 [MþH]þ m/z:
Colorless crystals, 0.221 g, yield 69.7%, mp 72.5e74.0 ꢀC 1H NMR
383.1965, found 383.1968.
(300 MHz, CDCl3)
(s, 6H, 2OCH3), 1.96 (s, 3H, CH3), 1.93 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3) : 169.2, 160.0, 157.2, 156.7, 144.0, 130.2, 120.6, 119.6, 115.0,
d: 7.41e6.69 (m, 8H, ArH), 4.85 (s, 1H, CHCl), 3.80
4. 2. 2. rel-(3R, 4R)-1-(4-Methoxyphenyl)-4-[(E)-1-(4-
methoxyphenylimino)ethyl]-4-methyl-3-phthalimidoazetidin-2-one
(cis-3ab). Reaction was conducted in 1 mmol of diimine 1a,
1.2 mmol of acid chloride 2b, and 1.5 mmol of Et3N.
d
114.8, 70.3, 65.5, 55.8, 21.0, 18.2. IR (KBr)
n
(cmꢂ1): 1760 (C]O),
1652 (C]N). HRMS (ESI) calcd for C20H22ClN2O3 [MþH]þ m/z:
373.1313, found 373.1320.
Colorless crystals, 0.430 g, yield: 86.9%, mp 178.0e179.5 ꢀC 1H
NMR (300 MHz, CDCl3)
d: 7.78e6.18 (m, 12H, ArH), 5.37 (s, 1H, CH),
4. 2. 4. re l-(3R, 4R) -1-(4-Methoxyphenyl)-4-[(E)-1-(4-
3.82 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 2.09 (s, 3H, CH3), 1.88 (s, 3H,
methoxyphenylimino)ethyl]-3,4-dimethylazetidin-2-one (cis-3ad).

Z. Wang et al. / Tetrahedron 67 (2011) 9690e9699
9697
Reaction was conducted in 1 mmol of diimine 1a, 1.2 mmol of acid
chloride 2d, and 1.5 mmol of Et3N.
3H, OCH3), 3.76 (s, 3H, OCH3), 3.74e3.60 (m, 2H, OCH2), 1.86 (s, 3H,
CH3), 1.20 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3)
d: 163.2,
Colorless crystals, 0.249 g, yield, 70.7%, mp 188.0e190.0 ꢀC 1H
162.1, 158.7, 156.6, 143.8, 130.1, 122.2, 119.1, 114.5, 114.4, 91.0, 67.4,
NMR (300 MHz, CDCl3)
d: 7.41e6.63 (m, 8H, ArH), 3.79 (s, 3H,
67.2, 55.5, 55.5, 18.2, 15.1. IR (KBr) n
(cmꢂ1): 1745 (C]O), 1629 (C]
OCH3), 3.78 (s, 3H, OCH3), 3.33 (q, J¼7.5 Hz, 1H, CH), 1.88 (s, 3H,
N). HRMS (ESI) calcd for C21H25N2O4 [MþH]þ m/z: 369.1809, found
CH3), 1.85 (s, 3H, CH3), 1.32 (d, J¼7.6 Hz, 3H, CH3). 13C NMR (75 MHz,
369.1810.
CDCl3) d: 170.7, 166.8, 156.1, 155.9, 143.8, 131.0, 120.0, 118.7, 114.3,
114.2, 67.5, 56.5, 55.4, 21.7, 17.9, 9.3. IR (KBr)
n
(cmꢂ1): 1742 (C]O),
4 . 2 .10 . r e l - ( 3 R , 4 R ) - 1 - ( 4 - M e t h o x y p h e n yl ) - 4 - [ ( E ) - ( 4 -
methoxyphenylimino)methyl]-3,4-dimethylazetidin-2-one (cis-3fd).
Reaction was conducted in 1 mmol of diimine 1f, 1.2 mmol of acid
chloride 2d, and 1.5 mmol of Et3N.
1652 (C]N). HRMS (ESI) calcd for C21H25N2O3 [MþH]þ m/z:
353.1860, found: 353.1864.
4.2.5. rel-(3R,4R)-3,4-Dimethyl-1-phenyl-4-[(E)-1-(phenylimino)-
ethyl]azetidin-2-one (cis-3bd). Reaction was conducted in 1 mmol
of diimine 1b, 1.2 mmol of acid chloride 2d, and 1.5 mmol of Et3N.
Colorless crystals, 0.214 g, yield 73.2%, mp 115.0e117.0 ꢀC 1H
Yellow oil, 0.260 g, yield 76.9%. 1H NMR (200 MHz, CDCl3)
d: 7.99
(s, 1H, CH]N), 7.30e6.72 (m, 8H, ArH), 3.70 (s, 3H, OCH3), 3.66 (s,
3H, OCH3), 3.21 (q, J¼7.6 Hz, 1H, CH), 1.76 (s, 3H, CH3), 1.21 (d,
J¼7.6 Hz, 3H, CH3). 13C NMR (50 MHz, CDCl3)
d: 167.0, 162.4, 158.5,
155.9, 143.5, 130.6, 121.9, 118.3, 114.3, 114.2, 63.7, 56.6, 55.3, 55.2,
NMR (300 MHz, CDCl3)
d
: 7.45e6.67 (m, 10H, ArH), 3.34 (q,
J¼7.6 Hz, 1H, CH), 1.92 (s, 3H, CH3), 1.84 (s, 3H, CH3), 1.34 (d,
19.9, 9.9. IR (KBr) n
(cmꢂ1): 1742 (C]O), 1644 (C]N). HRMS (ESI)
J¼7.6 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3)
d
: 170.4, 167.3, 150.7,
calcd for C20H23N2O3 [MþH]þ m/z: 339.1703, found 339.1709.
137.5, 129.1, 123.8, 123.7, 123.5, 118.7, 117.1, 67.3, 56.6, 21.7, 18.0, 9.2.
IR (KBr)
n
(cmꢂ1): 1744 (C]O), 1653 (C]N). HRMS (ESI) calcd for
4.2.11. rel-(3S,4R)-1-Diphenylmethyl-4-[(E)-(diphenylmethyl-imino)
methyl]-3-ethoxy-4-methylazetidin-2-one (cis-3ga). Reaction was
conducted in 1 mmol of diimine 1g, 2.5 mmol of acid chloride 2a,
and 3 mmol of Et3N in dichloromethane at room temperature.
Colorless crystals, 0.400 g, yield, 82.0%, mp 122.0e123.5 ꢀC 1H
C19H21N2O [MþH]þ m/z: 293.1648, found 293.1655.
4.2.6. rel-(3R,4R)-1-Benzyl-4-[(E)-1-(benzylimino)ethyl]-3,4-
dimethylazetidin-2-one (cis-3cd). Reaction was conducted in
1 mmol of diimine 1c, 1.2 mmol of acid chloride 2d, and 1.5 mmol of
Et3N.
NMR (300MHz, CDCl3) d: 7.65 (s, 1H, CH]N), 7.29e7.12 (m, 20H,
ArH), 5.52 (s, 1H, ArCH), 5.22 (s, 1H, ArCH), 4.36 (s, 1H, CHO), 3.48
(dq, J¼9.0, 7.0 Hz, 1H in OCH2), 3.26 (dq, J¼9.0, 7.0 Hz, 1H in OCH2),
1.58 (s, 3H, CH3), 0.88 (t, J¼7.0 Hz, 3H, CH3). 13C NMR (75 MHz,
Colorless crystals, 0.221 g, yield, 69.2%, mp 112e113.8 ꢀC 1H NMR
(200MHz, CDCl3)
d
: 7.38e7.35 (m, 10H, ArH), 4.77 (d, J¼15.0 Hz, 1H
in CH2N), 4.52 (s, 2H, CH2N), 4.40 (d, J¼15.0 Hz, 1H in CH2N), 3.06 (q,
CDCl3) d: 165.7, 163.5, 143.0, 142.9, 139.0, 138.5, 128.4, 128.3, 127.4,
J¼7.5 Hz,1H, CH), 1.77 (s, 3H, CH3), 1.29 (s, 3H, CH3), 1.13 (d, J¼7.5 Hz,
127.0, 89.9, 77.5, 67.0, 61.2, 61.2, 19.5, 14.6. IR (KBr)
n
(cmꢂ1): 1757
3H, CH3). 13C NMR (50 MHz, CDCl3)
d: 169.2, 168.8, 140.1, 137.1, 128.8,
(C]O), 1653 (C]N). HRMS (ESI) calcd for C33H33N2O2 [MþH]þ m/z:
128.34, 128.32, 127.4, 127.3, 126.5, 67.9, 55.6, 54.9, 45.0, 22.5, 16.3,
489.2537, found 489.2535.
10.2. IR (KBr)
n
(cmꢂ1): 1746 (C]O), 1652 (C]N). HRMS (ESI) calcd
for C21H25N2O [MþH]þ m/z: 321.1961, found 321.1967.
4.2.12. rel-(3S,4S)-1-Diphenylmethyl-4-[(E)-(diphenylmethyl-imino)
methyl]-2-methyl-3-phthalimidoazetidin-2-one (cis-3gb). Reaction
was conducted in 1 mmol of diimine 1g, 2.5 mmol of acid chloride
2b, and 3 mmol of Et3N.
4.2.7. rel-(3R,4R)-1-Diphenylmethyl-4-[(E)-1-(diphenylmethyl-im-
ino)ethyl]-3,4-dimethylazetidin-2-one (cis-3dd). Reaction was con-
ducted in 1 mmol of diimine 1d, 1.2 mmol of acid chloride 2d, and
1.5 mmol of Et3N.
Colorless crystals, 0.492 g, yield 83.5%, mp 202.0e203.0 ꢀC 1H
NMR (300 MHz, CDCl3)
ArH), 5.79 (s, 1H, NCH), 5.18 (s, 1H, CHAr), 5.01 (s, 1H, CHAr), 1.71 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3)
: 166.6, 162.8, 143.0, 142.7,
d: 7.84 (s, 1H, CH]N), 7.59e7.07 (m, 24H,
Colorless crystals, 0.200 g, yield 42.3%, mp 164.0e166.0 ꢀC 1H
NMR (200 MHz, CDCl3)
d: 7.46e7.18 (m, 20H, ArH), 5.70 (s, 1H, CH),
d
5.67 (s,1H, CH), 2.95 (q, J¼7.5 Hz,1H, CH),1.84 (s, 3H, CH3),1.40 (s, 3H,
139.0, 138.6, 134.0, 131.2, 128.7, 128.6, 128.5, 128.2, 128.1, 127.9,
127.8, 127.6, 126.9, 126.8, 126.5, 123.4, 77.5, 68.3, 63.0, 61.9, 21.7. IR
CH3), 1.05 (d, J¼7.5 Hz, 3H, CH3).13C NMR (50 MHz, CDCl3)
d: 168.9,
167.5, 144.0, 143.9, 141.9, 140.0, 128.8, 128.5, 128.4, 128.33, 128.27,
127.8,127.4,127.34,127.28,126.85,126.79,126.7, 68.4, 68.0, 62.9, 54.8,
(KBr) n
(cmꢂ1): 1766, 1722 (C]O), 1661 (C]N). HRMS (ESI) calcd for
C39H32N3O3 [MþH]þ m/z: 590.2434, found 590.2439.
22.8, 16.7, 10.6. IR (KBr)
n
(cmꢂ1): 1743 (C]O), 1653 (C]N). HRMS
(ESI) calcd for C33H33N2O [MþH]þ m/z: 473.2587, found 473.2591.
4.2.13. rel-(3S,4R)-1-Diphenylmethyl-4-[(E)-(diphenylmethyl-imino)
methyl]-3-chloro-4-methylazetidin-2-one (cis-3gc). Reaction was
conducted in 1 mmol of diimine 1g, 2.5 mmol of acid chloride 2c,
and 3 mmol of Et3N.
4 . 2 . 8 . r e l - ( 3 R , 4 S ) - 1 - ( 4 - M e t h o x y p h e n y l ) - 4 - [ ( E ) - ( 4 -
methoxyphenylimino)(phenyl)methyl]-3-methyl-4-phenylazetidin-2-
one(cis-3ed). Reaction was conducted in 1 mmol of diimine 1e,
1.2 mmol of acid chloride 2d, and 1.5 mmol of Et3N.
Colorless crystals, 0.240 g, yield 50.1%, mp 115.0e116.5 ꢀC 1H
NMR (300 MHz, CDCl3)
ArH), 5.48 (s, 1H, CHAr), 5.37 (s, 1H, CHAr), 4.67 (s, 1H, CHCl), 1.59 (s,
3H, CH3). 13C NMR (75 MHz, CDCl3)
: 162.3, 162.0, 142.8, 142.8,
138.8, 138.6, 128.7, 128.55, 128.52, 128.37, 128.30, 128.0, 127.8, 127.7,
d: 7.71 (s, 1H, CH]N), 7.27e7.20 (m, 20H,
Yellow oil 0.239 g, yield 50.3%. 1H NMR (300 MHz, CDCl3)
d:
7.50e6.59 (m, 18H, ArH), 3.88 (q, J¼7.5 Hz, 1H, CH), 3.71 (s, 3H,
d
OCH3), 3.69 (s, 3H, OCH3), 1.59 (d, J¼7.4 Hz, 3H, CH3). 13C NMR
(75 MHz, CDCl3)
d: 168.5, 166.5, 156.3, 156.0, 142.5, 139.6, 135.5,
127.6, 127.3, 127.2, 77.4, 65.7, 64.4, 62.4, 20.2. IR (KBr) n
(cmꢂ1): 1768
130.7, 128.5, 128.4, 127.9, 127.8, 127.4, 122.1, 121.5, 113.8, 113.5, 73.5,
(C]O), 1653 (C]N). HRMS (ESI) calcd for C31H28ClN2O [MþH]þ m/
z: 479.1885, found 479.1883.
60.4, 55.2, 12.3. IR (KBr)
n
(cmꢂ1): 1747 (C]O), 1626 (C]N). HRMS
(ESI) calcd for C31H29N2O3 [MþH]þ m/z: 477.2173, found 477.2173.
4.2.14. rel-(3S,4S)-1-Diphenylmethyl-4-[(E)-(diphenylmethyl-imino)
methyl]-3,4-dimethylazetidin-2-one (cis-3gd). Reaction was con-
ducted in 1 mmol of diimine 1g, 2.5 mmol of acid chloride 2d, and
3.0 mmol of Et3N.
4.2.9. rel-(3S,4R)-3-Ethoxy-1-(4-methoxyphenyl)-4-[(E)-(4-
methoxyphenylimino)methyl]-4-methylazetidin-2-one
(cis-3fa). -
Reaction was conducted in 1 mmol of diimine 1f, 1.2 mmol of acid
chloride 2a, and 1.5 mmol of Et3N.
Colorless crystals, 0.436 g, yield, 94.9%. Mp 113.0e115.0 ꢀC 1H
Yellow oil, 0.294 g, yield 80%. 1H NMR (400 MHz, CDCl3)
d
: 8.14
NMR (200MHz, CDCl3)
d: 7.62 (s,1H, CHN), 7.26e7.20 (m, 20H, ArH),
(s, 1H, CH]N), 7.38e6.82 (m, 8H, ArH), 4.52 (s, 1H, OCH), 3.81 (s,
5.55 (s, 1H, ArCH), 5.28 (s, 1H, ArCH), 3.10 (q, J¼7.6 Hz, 1H, CH), 1.50

9698
Z. Wang et al. / Tetrahedron 67 (2011) 9690e9699
(s, 3H, CH3), 1.04 (d, J¼7.6 Hz, 3H, CH3). 13C NMR (50 MHz, CDCl3)
d
:
4.2.19. rel-(2R,20S,3S,30R)-1,10-Di(diphenylmethyl)-3,30-diethoxy-2-
methyl-2,20-biazetidine-4,40-dione (SR-4ga). Reaction was conduct-
ed in 1 mmol of diimine 1g, 5 mmol of acid chloride 2a, and 6 mmol
of Et3N.
169.4, 163.9, 143.2, 143.1, 140.0, 128.43, 128.39, 128.30, 128.27, 127.5,
127.4, 127.3, 127.3, 127.0, 77.6, 63.9, 61.7, 55.7, 21.4, 9.9. IR (KBr)
n
(cmꢂ1): 1748 (C]O), 1653(C]N). HRMS calcd for C32H31N2O
[MþH]þ m/z: 459.2431, found 459.2440.
Colorless crystals, yield 14%, mp 125.0e126.0 ꢀC 1H NMR
(300 MHz, CDCl3) d: 7.49e7.23 (m, 20H, ArH), 5.88 (s, 1H, ArCH),
4.2.15. rel-(2R,20R,3S,30S)-3,30-Diethoxy-1,10-bis(4-methoxyphen-yl)-
2,20-dimethyl-2,20-biazetidine-4,40-dione (RS-4aa). Reaction was
conducted in 1 mmol of diimine 1a, 2.5 mmol of acid chloride 2a,
and 3 mmol of Et3N.
5.84 (s, 1H, ArCH), 4.43 (d, J¼5.4 Hz, 1H, CH), 4.20 (d, J¼5.4 Hz, 1H,
CHO), 4.12 (dq, J¼8.9, 7.1 Hz, 1H in OCH2), 4.10 (s, 1H, CHO),
3.87e3.76 (m, 2H, OCH2), 3.31 (dq, J¼8.9, 7.1 Hz, 1H in OCH2), 1.55
(s, 3H, CH3),1.34 (t, J¼7.0 Hz, 3H, CH3), 1.25 (t, J¼7.0 Hz, 3H, CH3). 13
C
Colorless crystals, 0.390 g, yield 83.3%, mp 223.0e225.0 ꢀC 1H
NMR (75 MHz, CDCl3) d: 167.7, 166.6, 140.2, 140.0, 139.8, 139.6,
NMR (200 MHz, CDCl3)
d
: 6.90e6.49 (m, 8H, ArH), 4.44 (s, 2H, OCH),
128.9, 128.64, 128.60, 128.5, 128.4, 128.2, 127.9, 127.5, 127.3, 127.1,
4.08e3.87 (m, 2H, OCH2), 3.82e3.63 (m, 2H, 2OCH2), 3.72 (s, 6H,
89.0, 82.0, 67.1, 66.8, 65.8, 63.5, 61.9, 61.7, 18.9, 15.4, 15.3. IR (KBr) n
2OCH3), 1.93 (s, 6H, 2CH3), 1.29 (t, J¼6.9 Hz, 6H, 2CH3). 13C NMR
(cmꢂ1): 1752 (C]O). HRMS (ESI) calcd for C37H39N2O4 [MþH]þ m/z:
(50 MHz, CDCl3)
d
: 166.7, 157.3, 128.7, 123.8, 113.9, 90.3, 73.0, 68.1,
575.2904, found 575.2895.
55.2, 23.1, 15.4. IR (KBr)
n
(cmꢂ1): 1743 (C]O), 1635 (C]N). HRMS
(ESI) calcd for C26H33N2O6 [MþH]þ m/z: 469.2333, found 469.2333.
Acknowledgements
4.2.16. rel-(2R,20R,3S,30S)-3,30-Diethoxy-1,10-bis(4-methoxyphenyl)-
2-methyl-2,20-biazetidine-4,40-dione(RS-4fa). Reaction was con-
ducted in 1 mmol of diimine 1f, 5 mmol of acid chloride 2a, and
6 mmol of Et3N.
This work was supported by the National Natural Science
Foundation of China (Nos. 20972013 and 20772005), the Beijing
Natural Science Foundation (2092022), and specialized Research
Fund for the Doctoral Program of Higher Education, Ministry of
Education of China (No. 200800100010).
Colorless crystals, yield 59%, mp 215.0e216.5 ꢀC 1H NMR
(300 MHz, CDCl3)
d
: 6.97 (d, J¼8.6 Hz, 2H, ArH), 6.82 (d, J¼8.5 Hz,
2H, ArH), 6.46e6.44 (m, 4H, ArH), 4.83 (d, J¼5.5 Hz,1H, CH), 4.74 (d,
J¼5.5 Hz, 1H, CHO), 4.44 (s, 1H, CHO), 4.02e3.90 (m, 2H, OCH2),
3.79e3.71 (m, 2H, OCH2), 3.68 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 1.87
(s, 3H, CH3), 1.30 (t, J¼6.9 Hz, 3H, CH3), 1.29 (t, J¼6.9 Hz, 3H, CH3).
Supplementary data
Procedure for the preparation of diimines 1, copies of 1H and 13
NMR and NOESY spectra of diimines 1, mono- -lactams 3 and bis-
-lactams 4. Supplementary data associated with this article can be
C
13C NMR (75 MHz, CDCl3)
d: 167.1, 166.0, 157.3, 157.1, 130.0, 129.6,
b
b
122.2, 121.8, 114.2, 114.1, 90.1, 83.5, 69.6, 68.6, 68.2, 63.9, 55.6, 20.9,
n
(cmꢂ1): 1746 (C]O). HRMS (ESI) calcd for
found in the online version, at doi:10.1016/j.tet.2011.10.044. These
data include MOL files and InChIKeys of the most important com-
pounds described in this article.
15.7. IR (KBr)
C25H31N2O6 [MþH]þ m/z: 455.2177, found 455.2182.
4.2.17. Mixture of rel-(2R,20S,3S,30S/2R,20S,3S,30R/2R,20R,3S,30R)-3,30-
diethoxy-1,10-bis(4-methoxyphenyl)-2-methyl-2,20-biazetidine-4,40-
dione(SS-4fa/SR-4fa/RR-4fa). Reaction was conducted in 1 mmol of
diimine 1e, 5 mmol of acid chloride 2a, and 6 mmol of Et3N.
Colorless crystals, yield 35% (mixture: SS-4fa, 15%; SR-4fa: 11%;
RR-4fa: 9%), mp 195e213 ꢀC. SS-4fa: 7.26e6.55 (m, 8H, ArH), 4.57
(d, J¼1.6 Hz, 1H, CHO), 4.52 (d, J¼1.6 Hz, 1H, CH), 4.35 (s, 1H, CH),
4.02e3.50 (m, 4H, 2OCH2), 3.79 (s, 3H, OMe), 3.77 (s, 3H, OMe), 1.66
(s, 3H, Me), 1.34 (t, J¼7.1 Hz, 1H, CH3), 1.22 (t, J¼7.1 Hz, 3H, CH3). SR-
4fa: 7.26e6.55 (m, 8H, ArH), 4.83 (d, J¼5.4 Hz, 1H, CHO), 4.78 (d,
J¼5.4 Hz, 1H, CH), 4.32 (s, 1H, CH), 4.02e3.50 (m, 4H, 2OCH2), 3.74
(s, 3H, OMe), 3.76 (s, 3H, OMe), 1.75 (s, 3H, Me), 1.32 (t, J¼7.0 Hz, 3H,
CH3), 1.30 (t, J¼7.0 Hz, 3H, CH3). RR-4fa: 7.26e6.55 (m, 8H, ArH),
4.85 (d, J¼1.7 Hz, 1H, CHO), 4.55 (d, J¼1.7 Hz, 1H, CH), 4.38 (s, 1H,
CH), 4.02e3.50 (m, 4H, 2OCH2), 3.80 (s, 3H, OMe), 3.78 (s, 3H, OMe),
1.65 (s, 3H, Me),1.26 (t, J¼7.0 Hz, 3H, CH3),1.17 (t, J¼7.0 Hz, 3H, CH3).
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