Efficient synthesis of α-alkylidene-β-lactams via NaOH-promoted intramolecular aza-Michael addition of α-carbamoyl ketene-S,S-acetals in aqueous media

Article abstract of DOI:10.1016/j.tet.2008.03.093

A facile and efficient synthesis of substituted α-alkylidene-β-lactams have been developed via a NaOH-promoted intramolecular aza-Michael addition of α-carbamoyl, α-(1-chlorovinyl) ketene-S,S-acetals and subsequent nucleophilic vinylic substitution (S_NV) reaction in alcoholic aqueous media.

Full text of DOI:10.1016/j.tet.2008.03.093

Tetrahedron 64 (2008) 4959–4966
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of a-alkylidene-b-lactams via NaOH-promoted intramolecular
aza-Michael addition of a-carbamoyl ketene-S,S-acetals in aqueous media
,b,
Yang Yang a, Dexuan Xiang a, Xiaoliang Zhao a, Yongjiu Liang b, Jie Huang a, Dewen Dong a
*
a Department of Chemistry, Northeast Normal University, Changchun 130024, China
b Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and efficient synthesis of substituted a-alkylidene-b-lactams have been developed via a NaOH-
promoted intramolecular aza-Michael addition of a-carbamoyl, a-(1-chlorovinyl) ketene-S,S-acetals and
subsequent nucleophilic vinylic substitution (SNV) reaction in alcoholic aqueous media.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 11 November 2007
Received in revised form 22 March 2008
Accepted 28 March 2008
Available online 1 April 2008
Keywords:
Aqueous media
2-Azetidinone
b-Lactams
Michael addition
Vilsmeier reagent
1. Introduction
the construction of suitable substituted 2-azetidinone skeletons
are still desirable.
2-Azetidinone ring is a common structural feature of several
families of b-lactam antibiotics (e.g., penicillins, cephalosporins,
and carbapenems) that have been widely used as therapeutic
agents, anti-cancer agents, and enzyme inhibitors.1,2 Particularly,
the recent discoveries of some natural monocyclic b-lactams
(monobactams) displaying high anti-bacterial activity indicate
that the 2-azetidinone ring is the key unit and the minimum
requirement for biological activity.3,4 The pharmacological im-
portance of b-lactams and their utility as building blocks in
organic synthesis have directed considerable research activity to-
ward the synthesis of suitably substituted 2-azetidinone rings.5,6
Intensive research has generated numerous synthetic approaches,
involving ketene–imine cycloadditions (the Staudinger reaction),7
ester enolate–imine condensations (the Gilman–Speeter re-
action),8 cyclization reactions of b-amino acids or esters,9 coupling
reactions of alkynes with nitrones,8 photoinduced rearrange-
ments,10 carbene insertions,11 and radical cyclizations,12 among
others. Nevertheless, to match the increasing scientific and prac-
tical demand for b-lactams, new and efficient methodologies for
Over the past few decades, the utility of a-oxo ketene-S,S-ac-
etals as versatile intermediates in organic synthesis has been
recognized.13 During the course of our studies on the reaction of
a-acyl ketene-S,S-acetals under Vilsmeier conditions,14 we noted
that the readily synthesized a-(1-chlorovinyl) ketene-S,S-acetals
showed promising structural characteristics that could be exploi-
ted in further organic transformations. Inspired by these findings
and our continuing interest in the utilization of b-oxo amide
derivatives in the synthesis of carbo- and heterocycles,15 we
synthesized a-carbamoyl, a-(1-chlorovinyl) ketene-S,S-acetals 2
from a-acyl, a-carbamoyl ketene-S,S-acetals 1 and explored their
synthetic potential. As a result, an efficient one-pot synthesis of
highly substituted a-alkylidene-b-lactams 3 was developed from
readily available 2 in aqueous media (Scheme 1). Herein, we wish
to describe our results and present a proposed mechanistic
scenario.
O
O
O
O
R3O
Me
R1
SR2
1 POCl3/DMF
NHR
Cl
R2S
NHR1
SR2
NaOH (aq)
R3OH
N
R2S
SR2
R2S
3
2
1
* Corresponding author. Tel./fax: þ86 431 85098635.
E-mail address: dongdw663@nenu.edu.cn (D. Dong).
Scheme 1. Synthesis of a-alkylidene-b-lactams 3 from a-acyl, a-carbamoyl ketene-S,S-
acetals 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.093

4960
Y. Yang et al. / Tetrahedron 64 (2008) 4959–4966
Table 1
Synthesis of compounds 2 from substrates 1 under Vilsmeier conditions
O
O
O
Me
R2S
NHR1
NHR1
Cl
POCl3/DMF
SR2
R2S
SR2
1
2
Entry
1
R1
R2
2
Yielda [%]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
C6H5
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
2a
85
82
86
87
86
84
91
90
86
88
87
83
2b
2c
2d
2e
2f
2g
2h
2i
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
2,4-Me2C6H3
2,4-Me2C6H3
Me
Figure 1. ORTEP drawing of (E)-3a.
9
chemistsovertheyearsmainlybecauseof theirbiologicallyactivities
and their utilities as useful building blocks in organic synthesis.18–20
The above findings encouraged us to investigate the reactions of
2a for the construction of the 2-azetidinone skeletons under varied
conditions. Thus, a series experiments were carried out with the
aim at optimizing the reaction conditions, including the base, sol-
vents, and reaction temperature. It was found that in the presence
of K2CO3 (aq) in ethanol, the reaction proceeded sluggishly to afford
both isomers of 3a in much lower yields. Even no desired product
3a was obtained when 2a was treated with NaOH, NaH or NaOEt in
absolute ethanol. We assumed that in the above cases, water might
merely act as a better co-solvent for the employed base thus pro-
moting the target cyclization. The accelerating properties of water
when used as a convenient additive or co-solvent in other organic
reactions have been reported elsewhere and therefore other roles
should be considered.21 Using ethanol as a reactant, we performed
the reaction of 2a with aqueous NaOH in other solvents such as
CH2Cl2, DMF, THF, and water. By comparison, the optimal condi-
tions were obtained when 2a (2.0 mmol) was subjected to NaOH
(aq, 1.0 N, 3.0 equiv) in ethanol (25 mL) at 30 ꢀC for 12 h, whereby
the yields of (E)- and (Z)-3a could reach 69 and 23%, respectively
(Table 2, entry 1).
10
11
12
1j
1k
1l
2j
2k
2l
Me
a
Isolated yields.
2. Results and discussion
2.1. Synthesis of a-(1-chlorovinyl), a-carbamoyl ketene-S,S-
acetals 2
The substrates, a-acyl, a-carbamoyl ketene-S,S-acetals 1, were
prepared from commercially available b-oxo amides in water in
excellent yields following the procedure described in our previous
work.16 Upon treatment of compounds 1 with Vilsmeier reagent
(POCl3/DMF, 1.1 equiv) at 0 ꢀC for 10 h, a series of compounds 2a–l
were synthesized in good yields (Table 1). The structure of 2a was
confirmed by the X-ray single-crystal analyses.17
2.2. Synthesis of substituted a-alkylidene-b-lactams 3
Having established the optimal conditions for the cyclization,
we intended to determine its scope with respect to the amide and
sulfanyl functionalities, and the nucleophilic species involved. Thus,
substrates 2b–l bearing varied amide groups were treated with
aqueous NaOH in ethanol under the optimized reaction conditions
as for 3a. The effectiveness of the cyclization proved to be suitable
for N-arylamides 2b–j affording the corresponding compounds of
type 3 in moderate to good yields (Table 2, entries 2–10). It is worth
noting that in all the cases of 2b–j, only isomer (E)-3 was obtained.
For N-alkylamides 2k and 2l, the reactions proceeded smoothly
to furnish the corresponding 3k and 3l, in which both (E)- and (Z)-
isomers were obtained with the (E)-isomer as the predominant one
(Table 2, entries 11 and 12). All the results revealed that the cycli-
zation reaction exhibited high stereoselectivity.
With compounds 2a–l in hand, we selected 2-[bis (methyl-
thio)methylene]-3-chloro-N-phenylbut-3-enamide 2a as the model
compound to examine its behavior under different basic conditions.
Thus, the reaction of 2a was performed in aqueous NaOH (2.0 equiv,
1.0 N)/ethanol at ambient temperature (20 ꢀC) for 15 h. Workup
and purification by column chromatography of the resulting
mixture furnished two main products, which were characterized
as (E)- and (Z)-3-(1-ethoxyethylidene)-4,4-bis(methylthio)-1-phe-
nylazetidin-2-ones, i.e., (E)-3a and (Z)-3a, on the basis of their
spectral and analytical data (Scheme 2). The structure and stereo-
chemistry of (E)-3a were established by the X-ray single-crystal
analysis (Fig. 1).17 The results suggest that ethanol plays dual roles
as a co-solvent and a nucleophilic species in the cyclization
reaction.
As an extension of the above cyclization, a series of reactions
was performed on substrates 2 in methanol under the otherwise
identical conditions. Thus, the corresponding substituted 2-azeti-
dinones of type (E)-3 were synthesized stereoselectively from
amides 2a–l in moderate to good yields (Table 2, entries 13–24). It
was observed that, only in the case of N-alkylamide 2k, both iso-
mers (E)-, and (Z)-3w were obtained with the ratio of 5:2 (Table 2,
entry 23). The validity of this 2-azetidinone synthesis was further
evaluated in isopropanol by using 2a as a representative example
(Table 2, entry 25). However, when 2a was subjected to aqueous
NaOH in tert-butanol, the cyclization to the corresponding 2-
azetidinone was unsuccessful, and only the intact substrate was
recovered (Table 2, entry 26). This may be due to the weak nucle-
ophilicity and the hindered stereo effect of the bulky tert-butyl
It is of interest to note that the obtained compounds (E)- and (Z)-
3a have remarkable structural and functional complexity since they
contain the key skeleton of b-lactams. Certainly, the substituted
a-alkylidene-b-lactams, as an important subset of azetidinones,
have attracted significant interest among synthetic and medicinal
O
O
O
EtO
Me
Me
NaOH (aq)
EtOH
NHPh
SMe
N
Ph
Cl
MeS
N
Ph
+
EtO
SMe
(E)-3a
MeS
MeS
(Z)-3a
SMe
2a
Scheme 2. The reaction of 2a in NaOH (aq)/EtOH.

Y. Yang et al. / Tetrahedron 64 (2008) 4959–4966
4961
Table 2
O
O
Synthesis of a-alkylidene-b-lactams 3 from 2 in aqueous media
OH-
R1
N
R1
N
H
_
O
Cl
SR2
O
Cl
R3O
R2S
O
NHR1
SR2
A
2
Cl
R2S
R1
NaOH (aq)
R3OH
R2S
SR2
H+
N
Me
SR2
R2S
R3
H
2
3
O
O
HOR3
Me
Me
Entry
2
R1
R2
R3
Time [h]
3
Yielda [%]
R1
N
R1
N
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5
C6H5
Me
Et
Et
Et
12
21
15
18
19
26
11
48
44
42
56
50
36
42
38
48
40
58
34
48
56
32
56
60
32
48
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
69 (23)
61
80
76
88
68
94
67
64
77
43 (18)
52 (21)
78
56
57
59
84
60
87
63
60
54
41 (16)
47
45
Cl
B
Cl
SR2
R2S
R2S SR2
C
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
2,4-Me2C6H3
2,4-Me2C6H3
Me
Me
Et
Et
Et
Me
Et
Et
Et
R3
H
O
Me
Et
Et
Et
O
O
OH-
OR3
Me
Cl
R1
N
R1
N
9
Me
Et
Et
Et
Me
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2j
2k
2l
R S SR2
2
R2S
SR2
D
Me
Et
Et
Et
Me
C6H5
C6H5
Scheme 3. Plausible mechanism for the cyclization of 2 in aqueous media.
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2a
2a
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
i-Pr
t-Bu
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
2,4-Me2C6H3
2,4-Me2C6H3
Me
alkoxide from the side of alkylthio groups. Thus, when methyl
group is attached to the nitrogen atom, alkoxide may attack from
the side of alkylthio groups. Actually, substituents on the sulfur of 2
and the nucleophilicity of alkoxide also affect the stereochemistry.
3s
3t
3u
3v
3w
3x
3y
3z
3. Conclusion
Me
C6H5
C6H5
In summary, we have described a facile and efficient synthesis
of substituted a-alkylidene-b-lactams of type 3 via NaOH-pro-
moted intramolecular cyclization reaction of a-carbamoyl, a-(1-
chlorovinyl) ketene-S,S-acetals 2 in alcoholic aqueous media. The
key cyclization involves intramolecular aza-Michael addition of 2
and subsequent SNV reaction with alcohol under basic conditions.
The simplicity of execution, ready availability of substrates, and
important synthetic potential of products make this synthetic
strategy attractive and practical. Further studies on the expansion
of the scope and synthetic utility of this protocol are in progress.
No reaction
a
Isolated yields for (E)-3 and the data in parentheses for (Z)-3.
group of the alkoxide nucleophile. Nevertheless, we provided
an alternative access to a-alkylidene-b-lactams 3 via aqueous base-
induced cyclization of a-carbamoyl ketene-S,S-acetals 2 in the
presence of alcoholic co-solvent. It should be noted that the rich-
ness of the functionality of substituted a-alkylidene-b-lactams 3
may render them versatile as synthons in further synthetic trans-
formations, for example, upon hydrogenation or Michael addition
reaction to produce the corresponding substituted b-lactams ana-
logues bearing two chiral carbon atoms.
4. Experimental
4.1. General
Pak and co-workers had ever reported the synthesis of 2-qui-
nolinones through thermal cyclization of a-carbamoyl ketene-S,S-
acetals 1 in NaH/DMF.22 Recently, they corrected the structure of
the product as substituted 4-quinolinone, and proposed an aza-
Michael addition mechanism and trapped the unstable 2-azetidi-
none intermediates by the use of alkylhalides.23 On the basis of
our results obtained together with the reported literatures,23,24
a plausible mechanism for the cyclization reaction of amides 2
is presented in Scheme 3. The transformation commences from
an intramolecular aza-Michael addition of the nitrogen atom to the
unsaturated b-carbon of 2 under basic conditions, generating
a carboanionic intermediate A. Clearly, anionic A is stabilized via
delocalization of negative charge to the adjacent vinyl and amide
groups, and can be regarded as a 1,3-nucleophilic 3-carbon species,
which subsequently undergoes protonation reaction in alcoholic
aqueous media to afford intermediate B. Finally, the displacement
of chloride of B by alkoxide via a nucleophilic vinylic substitution
(SNV)25 reaction gives rise to 2-azetidinone 3. During the SNV
reaction, the hydrogen bonding interaction between intermediate
B and alcohol leads to the formation of intermediates C and D, and
hence results in the high stereoselectivity of products 3. On the
other hand, alkylthio groups might be distorted by bulkier sub-
stituents on the nitrogen atom, and this protects the attack of
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
purified by column chromatography over silica gel. 1H NMR and 13
C
NMR spectra were recorded at 500 MHz and 125 MHz, respectively,
with TMS as internal standard. IR spectra (KBr) were recorded on
a FTIR spectrophotometer in the range of 400–4000 cmꢁ1
.
4.2. Typical for the synthesis of 2a–l (2a as an example)
The Vilsmeier reagent was prepared by adding POCl3 (10 mmol)
dropwise to ice cold dry DMF (5 mL) under stirring. The mixture was
thenstirredfor10–15 minat0 ꢀC.TotheaboveVilsmeierreagentwas
added 2-[bis(methylthio)methylene]-3-oxo-N-phenylbutanamide
1a (10 mmol) as a solution in DMF (20 mL). Then the mixture was
allowed towarm to roomtemperature andthenstirred for 12 h. After
the starting material was consumed (monitored by TLC), the reaction
mixture was poured into saturated aqueous NaCl (50 mL). The mix-
ture was extracted with dichloromethane (3ꢂ30 mL), the combined
organic phase was washed with water (2ꢂ30 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was purified
by flash chromatography (silica gel, petroleum ether/diethyl ether
12:1) to give 2a (2.55 g, 85%) as a white solid.

4962
Y. Yang et al. / Tetrahedron 64 (2008) 4959–4966
4.3. Selected data for 2a–l
1H), 6.87 (d, J¼9.0 Hz, 2H), 7.49 (d, J¼9.0 Hz, 2H), 7.56 (s, 1H); 13C
NMR (125 MHz, CDCl3): d¼15.0, 15.2, 29.3, 29.5, 55.8, 114.4, 120.5,
121.9, 130.9, 134.7, 138.3, 145.3, 156.9, 162.9; IR (KBr, neat): n¼3239,
2932, 1602, 1541, 1513, 1454, 1252, 831, 684 cmꢁ1. Anal. Calcd for
4.3.1. 2-(Bis(methylthio)methylene)-3-chloro-N-phenylbut-3-
enamide (2a)
White solid; mp 129–131 ꢀC; 1H NMR (500 MHz, CDCl3): d¼2.44
(d, J¼3.0 Hz, 6H), 5.58 (s, 1H), 5.76 (s, 1H), 7.14 (t, J¼7.5 Hz, 1H), 7.34
(t, J¼8.0 Hz, 2H), 7.58 (d, J¼8.0 Hz, 2H), 7.62 (s, 1H); 13C NMR
(125 MHz, CDCl3): d¼18.7, 120.1, 120.8, 124.9, 129.3, 134.9, 135.2,
137.8, 150.2, 162.9; IR (KBr, neat): n¼3291, 1699, 1650, 1620, 1597,
1539, 1436, 1396, 905, 757 cmꢁ1. Anal. Calcd for C13H14ClNOS2: C,
52.07; H, 4.71; N, 4.67. Found: C, 52.20; H, 4.87; N, 4.82.
Crystal data for 2a: C13H14ClNOS2, Mr¼299.82, approximate di-
mensions of crystal fragment 0.34ꢂ0.31ꢂ0.27 mm3, orthorhombic,
space group Pna2 (1), a¼9.868(2), b¼17.237(4), c¼8.728(2) Å, V¼
C16H20ClNO2S2: C, 53.69; H, 5.63; N, 3.91. Found: C, 53.81; H, 5.72;
N, 3.85.
4.3.7. 2-(Bis(methylthio)methylene)-3-chloro-N-(4-chloro-
phenyl)but-3-enamide (2g)
White solid; mp 133–135 ꢀC; 1H NMR (500 MHz, CDCl3): d¼2.44
(s, 6H), 5.57 (s, 1H), 5.76 (s, 1H), 7.29 (d, J¼8.0 Hz, 2H), 7.53 (d,
J¼8.0 Hz, 2H), 7.63 (s, 1H); 13C NMR (125 MHz, CDCl3): d¼18.7,
121.0, 121.4, 129.3, 129.9, 134.7, 134.8, 136.4, 151.2, 162.8; IR (KBr,
neat): n¼3294, 1649, 1599, 1539, 1491, 1396, 1320, 1261, 831,
737 cmꢁ1. Anal. Calcd for C13H13Cl2NOS2: C, 46.71; H, 3.92; N, 4.19.
Found: C, 46.57; H, 3.80; N, 4.31.
1881.2(5) Å3, T¼293(2) K, Z¼4,
r
calcd
¼1.342 Mg mꢁ3
,
2q
max
¼
56.80ꢀ, Mo Ka radiation (l¼0.71073 Å), R1¼0.0584 (for 10,386
reflections with I>2s(I)), wR2¼0.1227, and S¼1.025 for 163 pa-
rameters and 3285 unique reflections. Minimum/maximum re-
4.3.8. 2-(Bis(ethylthio)methylene)-3-chloro-N-(4-chloro-
phenyl)but-3-enamide (2h)
sidual electron density ꢁ0.370/0.345 e Åꢁ3
.
White solid; mp 110–111 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.27–
1.32 (m, 6H), 2.88–2.94 (m, 4H), 5.55 (s, 1H), 5.74 (s, 1H), 7.30 (d,
J¼8.5 Hz, 2H), 7.54 (d, J¼8.5 Hz, 2H), 7.65 (s, 1H); 13C NMR
(125 MHz, CDCl3): d¼14.7, 14.9, 29.2, 29.3, 120.6, 121.0, 129.0, 129.5,
134.3, 136.1, 137.3, 146.5, 162.7; IR (KBr, neat): n¼3290, 1699, 1651,
1598, 1532, 1437, 1396, 1255, 830, 734 cmꢁ1. Anal. Calcd for
4.3.2. 2-(Bis(ethylthio)methylene)-3-chloro-N-phenylbut-3-
enamide (2b)
White solid; mp 93–94 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.28–
1.32 (m, 6H), 2.88–2.94 (m, 4H), 5.56 (s, 1H), 5.73 (s, 1H), 7.13 (t,
J¼7.0 Hz, 1H), 7.34 (t, J¼8.0 Hz, 2H), 7.58 (d, J¼8.0 Hz, 2H), 7.62 (s,
1H); 13C NMR (125 MHz, CDCl3): d¼15.0, 15.1, 29.3, 29.6, 120.1,
120.6, 124.9, 129.3, 134.7, 137.9, 138.2, 145.8, 163.0; IR (KBr, neat):
C15H17Cl2NOS2: C, 49.72; H, 4.73; N, 3.87. Found: C, 49.65; H, 4.57;
N, 3.96.
n¼3272, 2968, 1649, 1600, 1540, 1440, 1323, 1260, 971, 757 cmꢁ1
.
Anal. Calcd for C15H18ClNOS2: C, 54.94; H, 5.53; N, 4.27. Found: C,
54.81; H, 5.63; N, 4.39.
4.3.9. 2-(Bis(methylthio)methylene)-3-chloro-N-(2,4-dimethyl-
phenyl)but-3-enamide (2i)
White solid; mp 93–94 ꢀC; 1H NMR (500 MHz, CDCl3): d¼2.25 (s,
3H), 2.29 (s, 3H), 2.45 (d, J¼7.0 Hz, 6H), 5.58 (s, 1H), 5.76 (s, 1H), 7.00
4.3.3. 2-(Bis(methylthio)methylene)-3-chloro-N-p-tolylbut-3-
enamide (2c)
(s, 1H), 7.02 (d, J¼8.0 Hz, 1H), 7.45 (s, 1H), 7.80 (d, J¼8.0 Hz, 1H); 13
C
White solid; mp 103–105 ꢀC; 1H NMR (500 MHz, CDCl3): d¼2.32
(s, 3H), 2.43 (d, J¼3.0 Hz, 6H), 5.57 (s, 1H), 5.74 (s, 1H), 7.13 (d,
J¼8.0 Hz, 2H), 7.46 (d, J¼8.0 Hz, 2H), 7.61 (s, 1H); 13C NMR
(125 MHz, CDCl3): d¼18.6, 21.2, 120.2, 120.7, 129.8, 134.6, 134.9,
135.3, 135.4, 149.8, 162.8; IR (KBr, neat): n¼3281, 2923, 2854, 1649,
1539, 1512, 1456, 672 cmꢁ1. Anal. Calcd for C14H16ClNOS2: C, 53.57;
H, 5.14; N, 4.46. Found: C, 53.71; H, 5.02; N, 4.39.
NMR (125 MHz, CDCl3): d¼16.6, 17.3, 17.4, 19.9, 119.2, 121.7, 126.3,
128.0, 130.1, 131.8, 134.0, 148.7, 161.5; IR (KBr, neat): n¼3197, 2996,
1699, 1639, 1556, 1512, 1456, 1372, 899, 741 cmꢁ1. Anal. Calcd for
C15H18ClNOS2: C, 54.94; H, 5.53; N, 4.27. Found: C, 54.86; H, 5.69; N,
4.15.
4.3.10. 2-(Bis(ethylthio)methylene)-3-chloro-N-(2,4-dimethyl-
phenyl)but-3-enamide (2j)
4.3.4. 2-(Bis(ethylthio)methylene)-3-chloro-N-p-tolylbut-3-
enamide (2d)
White solid; mp 119–120 ꢀC; 1H NMR (500 MHz, CDCl3):
d¼1.28–1.33 (m, 6H), 2.26 (s, 3H), 2.29 (s, 3H), 2.90–2.94 (m, 4H),
5.57 (s, 1H), 5.74 (s, 1H), 7.00 (s, 1H), 7.03 (d, J¼8.0 Hz, 1H), 7.43 (s,
1H), 7.80 (d, J¼8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d¼14.6, 14.9,
17.7, 20.9, 29.1, 29.2, 120.1, 122.7, 127.3, 129.1, 131.1, 132.8, 134.7,
134.9, 138.1, 145.4, 162.6; IR (KBr, neat): n¼3197, 2966, 2925, 1638,
White solid; mp 75–77 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.28–
1.33 (m, 6H), 2.33 (s, 3H), 2.88–2.94 (m, 4H), 5.56 (s, 1H), 5.73 (s,
1H), 7.15 (d, J¼8.0 Hz, 2H), 7.47 (d, J¼8.0 Hz, 2H), 7.58 (s, 1H); 13C
NMR (125 MHz, CDCl3): d¼15.0, 15.2, 21.2, 29.3, 29.5, 120.1, 120.5,
129.8, 134.5, 134.7, 135.3, 138.3, 145.5, 162.9; IR (KBr, neat): n¼3278,
2923, 1649, 1539, 1556, 1512, 1456, 1399, 684 cmꢁ1. Anal. Calcd for
1539, 1523, 1455, 1263, 899, 741 cmꢁ1
.
Anal. Calcd for
17H22ClNOS2: C, 57.36; H, 6.23; N, 3.94. Found: C, 57.43; H, 6.35; N,
4.07.
C
C
16H20ClNOS2: C, 56.20; H, 5.90; N, 4.10. Found: C, 56.31; H, 6.03; N,
4.25.
4.3.11. 2-(Bis(methylthio)methylene)-3-chloro-N-methylbut-3-
enamide (2k)
4.3.5. 2-(Bis(methylthio)methylene)-3-chloro-N-(4-methoxy-
phenyl)but-3-enamide (2e)
White solid; mp 94–96 ꢀC; 1H NMR (500 MHz, CDCl3): d¼2.40
(d, J¼7.0 Hz, 6H), 2.91 (d, J¼5.0 Hz, 3H), 5.48 (s, 1H), 5.67 (s, 1H),
5.89 (s, 1H); 13C NMR (125 MHz, CDCl3): d¼15.7, 15.8, 24.4, 117.5,
132.3, 133.4, 145.3, 163.2; IR (KBr, neat): n¼3230, 2921, 1632, 1557,
1524, 1402, 1306, 1198, 801, 734 cmꢁ1. Anal. Calcd for C8H12ClNOS2:
C, 40.41; H, 5.09; N, 5.89. Found: C, 40.54; H, 4.97; N, 5.97.
White solid; mp 114–115 ꢀC; 1H NMR (500 MHz, CDCl3): d¼2.44
(s, 6H), 3.80 (s, 3H), 5.57 (s, 1H), 5.75 (s, 1H), 6.87 (d, J¼8.0 Hz, 2H),
7.49 (d, J¼8.0 Hz, 2H), 7.55 (s, 1H); 13C NMR (125 MHz, CDCl3):
d¼18.6, 18.7, 55.8, 114.4, 120.7, 122.0, 130.9, 134.9, 135.3, 149.7, 156.9,
162.8; IR (KBr, neat): n¼3267,1699,1648,1540,1507,1457,1414,1316,
1277,1172,1109,1023, 827, 762 cmꢁ1. Anal. Calcd for C14H16ClNO2S2:
C, 50.98; H, 4.89; N, 4.25. Found: C, 50.85; H, 4.80; N, 4.37.
4.3.12. 2-(Bis(ethylthio)methylene)-3-chloro-N-methylbut-3-
enamide (2l)
4.3.6. 2-(Bis(ethylthio)methylene)-3-chloro-N-(4-methoxy-
phenyl)but-3-enamide (2f)
White solid; mp 69–70 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.26–
1.29 (m, 6H), 2.84–2.92 (m, 4H), 2.97 (d, J¼5.0 Hz, 3H), 5.47 (s, 1H),
5.65 (s, 1H), 5.88 (s, 1H); 13C NMR (125 MHz, CDCl3): d¼14.6, 14.8,
26.6, 28.6, 28.7, 119.7, 134.2, 138.6, 143.3, 165.5; IR (KBr, neat):
White solid; mp 89–91 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.27–
1.32 (m, 6H), 2.87–2.94 (m, 4H), 3.80 (s, 3H), 5.55 (s, 1H), 5.72 (s,

Y. Yang et al. / Tetrahedron 64 (2008) 4959–4966
4963
n¼3236, 2927, 1632, 1541, 1452, 1403, 1179, 1084, 903, 788 cmꢁ1
.
129.7, 133.9, 134.4, 157.3, 157.7; IR (KBr, neat): n¼2924, 2854, 1738,
Anal. Calcd for C10H16ClNOS2: C, 45.18; H, 6.07; N, 5.27. Found: C,
45.26; H, 6.21; N, 5.15.
1659, 1513, 1461, 1349, 1287, 1049, 844 cmꢁ1. Anal. Calcd for
C18H25NO2S2: C, 61.50; H, 7.17; N, 3.98. Found: C, 61.38; H, 7.27; N,
4.12.
4.4. Typical for the synthesis of 3a–y (3a as an example)
4.5.5. (E)-3-(1-Ethoxyethylidene)-4,4-bis(ethylthio)-1-p-
tolylazetidin-2-one ((E)-3d)
To a 50 mL round-flask was added 2a (2.00 mmol, 0.60 g), EtOH
(25 mL), and a solution of NaOH (10.0 mmol, 0.40 g) in water
(10 mL). The mixture was stirred at room temperature for 12 h.
After the starting material was consumed (monitored by TLC), the
reaction mixture was poured into saturated aqueous NaCl (50 mL).
The mixture was extracted with dichloromethane (3ꢂ20 mL), the
combined organic phase was washed with water (2ꢂ30 mL), dried
over MgSO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography (silica gel, petroleum ether/
diethyl ether 15:1) to give (E)-3a (0.41 g, 69%) and (Z)-3a (0.14 g,
23%), respectively.
White solid; mp 77–79 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.13 (t,
J¼7.0 Hz, 6H), 1.38 (t, J¼7.0 Hz, 3H), 2.15 (s, 3H), 2.33 (s, 3H), 2.43–
2.54 (m, 4H), 4.47–4.52 (m, 2H), 7.16 (d, J¼8.0 Hz, 2H), 7.84 (d,
J¼8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): d¼13.7, 14.9, 17.6, 20.9,
23.7, 69.3, 79.8, 111.4, 117.5, 129.3, 129.7, 133.4, 134.1, 156.7, 157.4; IR
(KBr, neat): n¼2966, 2861, 2361, 1739, 1659, 1513, 1441, 1355, 1280,
1115, 844 cmꢁ1. Anal. Calcd for C18H25NO2S2: C, 61.50; H, 7.17; N,
3.98. Found: C, 61.39; H, 7.31; N, 4.11.
4.5.6. (E)-3-(1-Ethoxyethylidene)-1-(4-methoxyphenyl)-4,4-
bis(methylthio)azetidin-2-one ((E)-3e)
4.5. Selected data for 3a–y
White solid; mp 75–77 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.38 (t,
J¼7.0 Hz, 3H), 1.97 (s, 6H), 2.13 (s, 3H), 3.80 (s, 3H), 4.48–4.52 (m,
2H), 6.90 (d, J¼8.0 Hz, 2H), 7.88 (d, J¼8.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d¼12.5, 15.2, 17.6, 55.7, 69.7, 80.0, 109.7, 114.4,
119.2, 130.3, 156.4, 157.0, 157.6; IR (KBr, neat): n¼2923, 2853, 2361,
1735, 1665, 1509, 1463, 1361, 1284, 1179, 1052, 835 cmꢁ1. Anal. Calcd
for C16H21NO3S2: C, 56.61; H, 6.24; N, 4.13. Found: C, 56.48; H, 6.11;
N, 4.24.
4.5.1. (E)-3-(1-Ethoxyethylidene)-4,4-bis(methylthio)-1-phenyl-
azetidin-2-one ((E)-3a)
White solid; mp 92–93 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.39 (t,
J¼7.0 Hz, 3H), 1.97 (s, 6H), 2.14 (s, 3H), 4.49–4.54 (m, 2H), 7.12 (t,
J¼7.5 Hz, 1H), 7.36 (t, J¼8.0 Hz, 2H), 7.94 (d, J¼8.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d¼12.5, 15.2, 17.7, 69.8, 79.9, 109.7, 117.6, 124.2,
129.1, 136.9, 157.7, 157.8; IR (KBr, neat): n¼2921, 1732, 1652, 1591,
1504, 1456, 1396, 1354, 1310, 883, 786 cmꢁ1; MS: calcd m/z 309.1,
found 310.0 [(Mþ1)]þ. Anal. Calcd for C15H19NO2S2: C, 58.22; H,
6.19; N, 4.53. Found: C, 58.31; H, 6.07; N, 4.65.
4.5.7. (E)-3-(1-Ethoxyethylidene)-4,4-bis(ethylthio)-1-(4-
methoxyphenyl)azetidin-2-one ((E)-3f)
White solid; mp 61–63 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.12 (t,
J¼7.5 Hz, 6H), 1.38 (t, J¼7.0 Hz, 3H), 2.15 (s, 3H), 2.43–2.53 (m, 4H),
3.81 (s, 3H), 4.47–4.51 (m, 2H), 6.90 (d, J¼9.0 Hz, 2H), 7.88 (d,
J¼9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): d¼14.0, 15.2, 17.9, 24.4,
55.6, 69.6, 80.3, 111.7, 114.3, 119.4, 130.4, 156.2, 156.7, 157.5; IR (KBr,
neat): n¼2926, 2852, 2362, 1729, 1662, 1509, 1450, 1356, 1287, 1181,
1050, 839 cmꢁ1. Anal. Calcd for C18H25NO3S2: C, 58.82; H, 6.86; N,
3.81. Found: C, 58.95; H, 6.75; N, 3.93.
Crystal data for (E)-3a: C15H19NO2S2, Mr¼309.43, approximate
dimensions of crystal fragment 0.43ꢂ0.28ꢂ0.15 mm3, monoclinic,
space group P2(1)/c, a¼16.476(3), b¼14.837(3), c¼14.834(3) Å, b¼
116.56(3)ꢀ, V¼3243.5(11) Å3, T¼293(2) K, Z¼8, r
¼1.267 Mg mꢁ3
,
calcd
2qmax¼50.00ꢀ, Mo Ka radiation (l¼0.71073 Å), R1¼0.0505 (for
24,449 reflections with I>2s(I)), wR2¼0.1362, and S¼1.102 for 369
parameters and 5771 unique reflections. Minimum/maximum re-
sidual electron density ꢁ0.180/0.264 e Åꢁ3
.
4.5.8. (E)-1-(4-Chlorophenyl)-3-(1-ethoxyethylidene)-4,4-
bis(methylthio)azetidin-2-one ((E)-3g)
4.5.2. (Z)-3-(1-Ethoxyethylidene)-4,4-bis(methylthio)-1-phenyl-
azetidin-2-one ((Z)-3a)
White solid; mp 67–69 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.38 (t,
J¼7.0 Hz, 3H), 1.94 (s, 6H), 2.13 (s, 3H), 4.47–4.52 (m, 2H), 7.31 (d,
J¼8.0 Hz, 2H), 7.89 (d, J¼8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3):
d¼12.5, 15.2, 17.7, 69.9, 80.0, 109.4, 118.8, 129.2, 129.3, 135.3, 157.6,
158.2; IR (KBr, neat): n¼2919, 1732, 1654, 1492, 1354, 1292, 1180,
1050, 839, 791 cmꢁ1. Anal. Calcd for C15H18ClNO2S2: C, 52.39; H,
5.28; N, 4.07. Found: C, 52.54; H, 5.39; N, 4.14.
White solid; mp 85–87 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.35 (t,
J¼7.0 Hz, 3H), 2.04 (s, 6H), 2.36 (s, 3H), 4.43 (q, J¼7.0 Hz, 2H), 7.09 (t,
J¼7.0 Hz, 1H), 7.32 (t, J¼8.0 Hz, 2H), 7.88 (d, J¼8.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d¼13.3, 15.7, 17.0, 66.4, 80.9, 112.1, 117.4, 123.9,
129.1, 137.1, 157.2, 161.7; IR (KBr, neat): 2920, 1739, 1654, 1540, 1493,
1352,1281, 753 cmꢁ1. Anal. Calcd for C15H19NO2S2: C, 58.22; H, 6.19;
N, 4.53. Found: C, 58.33; H, 6.10; N, 4.64.
4.5.9. (E)-1-(4-Chlorophenyl)-3-(1-ethoxyethylidene)-4,4-
bis(ethylthio)azetidin-2-one ((E)-3h)
4.5.3. (E)-3-(1-Ethoxyethylidene)-4,4-bis(ethylthio)-1-phenyl-
azetidin-2-one ((E)-3b)
White solid; mp 76–78 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.12 (t,
J¼7.5 Hz, 6H), 1.38 (t, J¼7.0 Hz, 3H), 2.16 (s, 3H), 2.39–2.53 (m, 4H),
White solid; mp 79–81 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.12 (t,
J¼7.5 Hz, 6H), 1.38 (t, J¼7.0 Hz, 3H), 2.16 (s, 3H), 2.43–2.53 (m, 4H),
4.49–4.53 (m, 2H), 7.11 (t, J¼7.5 Hz, 1H), 7.35 (t, J¼7.5 Hz, 2H), 7.95
(d, J¼7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): d¼13.0,14.2,17.0, 23.1,
68.7, 79.2, 110.6, 116.8, 123.0, 128.0, 136.0, 156.4, 156.8; IR (KBr,
neat): n¼2921, 2850, 1738, 1652, 1593, 1456, 1352, 1285, 843,
752 cmꢁ1. Anal. Calcd for C17H23NO2S2: C, 60.50; H, 6.87; N, 4.15.
Found: C, 60.63; H, 6.72; N, 4.26.
4.47–4.51 (m, 2H), 7.31 (d, J¼8.5 Hz, 2H), 7.90 (d, J¼8.5 Hz, 2H); 13
C
NMR (125 MHz, CDCl3): d¼13.7, 14.9, 17.7, 23.8, 69.5, 80.0, 111.1,
118.7, 128.9, 135.1, 157.4, 157.7; IR (KBr, neat): n¼1740, 1659, 1494,
1353, 1290, 1120, 847, 826 cmꢁ1. Anal. Calcd for C17H22ClNO2S2: C,
54.90; H, 5.96; N, 3.77. Found: C, 54.79; H, 5.83; N, 3.65.
4.5.10. (E)-1-(2,4-Dimethylphenyl)-3-(1-ethoxyethylidene)-4,4-
bis(methylthio)azetidin-2-one ((E)-3i)
4.5.4. (E)-3-(1-Ethoxyethylidene)-4,4-bis(methylthio)-1-p-
tolylazetidin-2-one ((E)-3c)
White solid; mp 88–90 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.36 (t,
J¼7.0 Hz, 3H), 2.07 (s, 6H), 2.12 (s, 3H), 2.32 (s, 3H), 2.38 (s, 3H),
4.47–4.51 (m, 2H), 7.00 (d, J¼7.5 Hz, 1H), 7.07 (s, 1H), 7.45 (d,
J¼8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d¼11.9, 13.9, 16.9, 18.6,
20.0, 68.4, 79.8, 109.6, 123.7, 126.0, 130.3, 131.0, 134.6, 136.6, 155.2,
157.1; IR (KBr, neat): n¼2924, 2853, 1749, 1490, 1455, 1361, 1148,
White solid; mp 66–68 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.38 (t,
J¼7.0 Hz, 3H), 1.96 (s, 3H), 2.13 (s, 3H), 2.33 (s, 3H), 4.49–4.53 (m,
2H), 7.16 (d, J¼8.0 Hz, 2H), 7.83 (d, J¼8.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d¼12.5, 15.2, 17.7, 21.3, 69.8, 79.9, 109.7, 117.6,

4964
Y. Yang et al. / Tetrahedron 64 (2008) 4959–4966
1060, 765 cmꢁ1. Anal. Calcd for C17H23NO2S2: C, 60.50; H, 6.87; N,
4.15. Found: C, 60.64; H, 6.98; N, 4.31.
(125 MHz, CDCl3): d¼12.7, 16.4, 22.8, 60.2, 78.8, 110.7, 116.6, 122.8,
127.8, 135.6, 156.4, 157.1; IR (KBr, neat): n¼2920, 2852, 2359, 1739,
1683, 1593, 1471, 1375, 1283, 842, 753 cmꢁ1. Anal. Calcd for
4.5.11. (E)-1-(2,4-Dimethylphenyl)-3-(1-ethoxyethylidene)-4,4-
bis(ethylthio)azetidin-2-one ((E)-3j)
C16H21NO2S2: C, 59.41; H, 6.54; N, 4.33. Found: C, 59.53; H, 6.61; N,
4.41.
White solid; mp 75–77 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.16 (t,
J¼7.5 Hz, 6H), 1.36 (t, J¼7.0 Hz, 3H), 2.15 (s, 3H), 2.33 (s, 3H), 2.37 (s,
3H), 2.53–2.65 (m, 4H), 4.46–4.50 (q, J¼7.5 Hz, 2H), 7.01 (d,
J¼8.0 Hz, 1H), 7.07 (s, 1H), 7.42 (d, J¼8.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3): d¼13.8,14.9,18.2,19.5, 21.1, 24.2, 69.3, 81.2,112.4,
125.2, 126.9, 131.3, 131.9, 135.8, 137.6, 156.0, 158.2; IR (KBr, neat):
4.5.18. (E)-3-(1-Methoxyethylidene)-4,4-bis(methylthio)-1-p-
tolylazetidin-2-one ((E)-3o)
White solid; mp 104–106 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.97
(s, 6H), 2.13 (s, 3H), 2.33 (s, 3H), 4.16 (s, 3H), 7.17 (d, J¼8.0 Hz, 2H),
7.84 (d, J¼8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): d¼12.5,17.3, 21.3,
61.6, 79.7, 110.1, 117.7, 129.7, 134.4, 140.0, 157.6, 158.3; IR (KBr, neat):
n¼2924, 2853, 2362, 1733, 1671, 1512, 1454, 1352, 1284, 1047,
837 cmꢁ1. Anal. Calcd for C15H19NO2S2: C, 58.22; H, 6.19; N, 4.53.
Found: C, 58.34; H, 6.11; N, 4.45.
n¼2924, 2855, 2361, 1739, 1664, 1498, 1348, 1280, 881, 772 cmꢁ1
.
Anal. Calcd for C19H27NO2S2: C, 62.43; H, 7.44; N, 3.83. Found: C,
62.54; H, 7.31; N, 3.95.
4.5.12. (E)-3-(1-Ethoxyethylidene)-1-methyl-4,4-bis(methyl-
thio)azetidin-2-one ((E)-3k)
4.5.19. (E)-4,4-Bis(ethylthio)-3-(1-methoxyethylidene)-1-p-tolyl-
azetidin-2-one ((E)-3p)
White solid; mp 39–41 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.33 (t,
J¼7.0 Hz, 3H), 1.97 (s, 6H), 2.03 (s, 3H), 2.81 (s, 3H), 4.37–4.41 (m,
2H); 13C NMR (125 MHz, CDCl3); d¼12.0, 14.8, 17.0, 23.1, 69.0, 79.5,
110.0, 154.5, 159.9; IR (KBr, neat): n¼2924, 2854, 2337, 1741, 1667,
1459, 1279 cmꢁ1. Anal. Calcd for C10H17NO2S2: C, 48.55; H, 6.93; N,
5.66. Found: C, 48.67; H, 7.01; N, 5.49.
White solid; mp 67–69 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.12 (t,
J¼7.0 Hz, 6H), 2.15 (s, 3H), 2.33 (s, 3H), 2.43–2.53 (m, 4H), 4.16 (s,
3H), 7.16 (d, J¼7.5 Hz, 2H), 7.84 (d, J¼7.5 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d¼14.0, 17.6, 21.3, 24.1, 61.5, 80.0, 112.1, 117.8,
129.6, 133.8, 134.4, 157.6, 158.0; IR (KBr, neat): n¼2924, 2853, 1733,
1664, 1509, 1454, 1349 cmꢁ1. Anal. Calcd for C17H23NO2S2: C, 60.50;
H, 6.87; N, 4.15. Found: C, 60.42; H, 7.01; N, 4.33.
4.5.13. (Z)-3-(1-Ethoxyethylidene)-1-methyl-4,4-bis(methyl-
thio)azetidin-2-one ((Z)-3k)
Colorless liquid; 1H NMR (500 MHz, CDCl3): d¼1.30 (t, J¼7.0 Hz,
3H), 2.05 (s, 6H), 2.24 (s, 3H), 2.76 (s, 3H), 4.39–4.44 (m, 2H); 13C
NMR (125 MHz, CDCl3): d¼12.7, 15.3, 16.9, 23.2, 66.2, 80.8, 111.7,
154.5, 163.6; IR (KBr, neat): n¼2922, 2337, 1744, 1671, 1411, 1363,
1277, 955 cmꢁ1. Anal. Calcd for C10H17NO2S2: C, 48.55; H, 6.93; N,
5.66. Found: C, 48.62; H, 7.05; N, 5.54.
4.5.20. (E)-3-(1-Methoxyethylidene)-1-(4-methoxyphenyl)-4,4-
bis(methylthio)azetidin-2-one ((E)-3q)
White solid; mp 60–62 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.97 (s,
3H), 2.13 (s, 3H), 3.81 (s, 3H), 4.16 (s, 3H), 6.91 (d, J¼8.5 Hz, 2H), 7.88
(d, J¼8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): d¼12.5, 17.3, 55.7,
61.5, 79.9, 110.1, 114.4, 119.2, 130.2, 156.4, 157.4, 158.0; IR (KBr, neat):
n¼2923, 2853, 1736, 1669, 1509, 1457, 1360, 1286, 1115, 673 cmꢁ1
.
4.5.14. (E)-3-(1-Ethoxyethylidene)-4,4-bis(ethylthio)-1-methyl-
azetidin-2-one ((E)-3l)
Anal. Calcd for C15H19NO3S2: C, 55.36; H, 5.88; N, 4.30. Found: C,
55.25; H, 5.71; N, 4.42.
Colorless liquid; 1H NMR (500 MHz, CDCl3): d¼1.21 (t, J¼7.0 Hz,
6H), 1.34 (t, J¼7.0 Hz, 3H), 2.05 (s, 3H), 2.43–2.50 (m, 4H), 2.82 (s,
3H), 4.36–4.40 (m, 2H); 13C NMR (125 MHz, CDCl3): d¼14.1, 14.7,
17.2, 23.0, 23.5, 68.9, 79.8, 117.7, 154.3, 159.9; IR (KBr, neat): n¼2927,
1746, 1675, 1361, 1282, 968, 841 cmꢁ1. Anal. Calcd for C12H21NO2S2:
C, 52.33; H, 7.68; N, 5.09. Found: C, 52.45; H, 7.82; N, 4.95.
4.5.21. (E)-4,4-Bis(ethylthio)-3-(1-methoxyethylidene)-1-(4-
methoxyphenyl)azetidin-2-one ((E)-3r)
White solid; mp 42–44 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.12 (t,
J¼7.5 Hz, 6H), 2.14 (s, 3H), 2.43–2.55 (m, 4H), 3.81 (s, 3H), 4.15 (s,
3H), 6.90 (d, J¼9.0 Hz, 2H), 7.88 (d, J¼9.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d¼14.0, 17.6, 23.0, 24.0, 55.6, 61.5, 80.2, 111.4,
114.3, 119.4, 130.3, 156.3, 157.4, 157.7; IR (KBr, neat): n¼2925, 2854,
1730,1662, 1509,1452,1355, 1243,1152,1050, 839 cmꢁ1. Anal. Calcd
for C17H23NO3S2: C, 57.76; H, 6.56; N, 3.96. Found: C, 57.92; H, 6.77;
N, 4.14.
4.5.15. (Z)-3-(1-Ethoxyethylidene)-4,4-bis(ethylthio)-1-methyl-
azetidin-2-one ((Z)-3l)
Colorless liquid; 1H NMR (500 MHz, CDCl3): d¼1.23 (t, J¼7.5 Hz,
6H), 1.32 (t, J¼7.0 Hz, 3H), 2.23 (s, 3H), 2.51–2.61 (m, 4H), 2.77 (s,
3H), 4.45–4.49 (m, 2H); 13C NMR (125 MHz, CDCl3): d¼14.3, 15.7,
17.2, 23.0, 23.5, 66.4, 81.2, 113.5, 154.3, 164.0; IR (KBr, neat): n¼2927,
1746, 1675, 1361, 1282, 968, 841 cmꢁ1. Anal. Calcd for C12H21NO2S2:
C, 52.33; H, 7.68; N, 5.09. Found: C, 52.44; H, 7.76; N, 5.01.
4.5.22. (E)-1-(4-Chlorophenyl)-3-(1-methoxyethylidene)-4,4-
bis(methylthio)azetidin-2-one ((E)-3s)
White solid; mp 71–73 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.95 (s,
6H), 2.12 (s, 3H), 4.16 (s, 3H), 7.31 (d, J¼8.0 Hz, 2H), 7.89 (d, J¼8.0 Hz,
2H); 13C NMR (125 MHz, CDCl3): d¼11.2, 16.1, 60.3, 78.6,108.5, 117.5,
128.0, 128.1, 134.0, 156.3, 158.0; IR (KBr, neat): n¼2919, 1734, 1664,
1593, 1491, 1452, 1359, 1291, 1150, 1057, 878 cmꢁ1. Anal. Calcd for
4.5.16. (E)-3-(1-Methoxyethylidene)-4,4-bis(methylthio)-1-phenyl-
azetidin-2-one ((E)-3m)
White solid; mp 62–64 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.98 (s,
6H), 2.15 (s, 3H), 4.18 (s, 3H), 7.13 (t, J¼7.5 Hz, 1H), 7.37 (t, J¼8.0 Hz,
2H), 7.95 (d, J¼8.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): d¼11.5, 16.4,
60.6, 78.8, 109.0, 116.6, 123.3, 128.1, 135.9, 156.7, 157.7; IR (KBr,
neat): 2982, 2358, 1731, 1664, 1592, 1492, 1354, 1284, 844,
755 cmꢁ1. Anal. Calcd for C14H17NO2S2: C, 56.92; H, 5.80; N, 4.74.
Found: C, 56.84; H, 5.68; N, 4.83.
C14H16ClNO2S2: C, 50.98; H, 4.89; N, 4.25. Found: C, 50.86; H, 4.98;
N, 4.34.
4.5.23. (E)-1-(4-Chlorophenyl)-4,4-bis(ethylthio)-3-(1-methoxy-
ethylidene)azetidin-2-one ((E)-3t)
White solid; mp 101–103 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.12
(t, J¼7.5 Hz, 6H), 2.16 (s, 3H), 2.41–2.52 (m, 4H), 4.15 (s, 3H), 7.32 (d,
J¼8.5 Hz, 2H), 7.90 (d, J¼8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3):
d¼9.3, 12.9, 19.3, 56.8, 75.4, 107.0, 114.3, 124.4, 130.6, 152.8, 154.2; IR
(KBr, neat): n¼2966, 2924, 1737, 1658, 1491, 1348, 1292, 1153, 1086,
884 cmꢁ1. Anal. Calcd for C16H20ClNO2S2: C, 53.69; H, 5.63; N, 3.91.
Found: C, 53.75; H, 5.54; N, 4.05.
4.5.17. (E)-4,4-Bis(ethylthio)-3-(1-methoxyethylidene)-1-phenyl-
azetidin-2-one ((E)-3n)
White solid; mp 60–63 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.12 (t,
J¼7.5 Hz, 6H), 2.16 (s, 3H), 2.44–2.54 (m, 4H), 4.16 (s, 3H), 7.11 (t,
J¼7.5 Hz, 1H), 7.35 (t, J¼8.0 Hz, 2H), 7.95 (d, J¼8.0 Hz, 2H); 13C NMR

Y. Yang et al. / Tetrahedron 64 (2008) 4959–4966
4965
4.5.24. (E)-1-(2,4-Dimethylphenyl)-3-(1-methoxyethylidene)-4,4-
bis(methylthio)azetidin-2-one ((E)-3u)
Science and Technology of Jilin Province (20050309-2) is greatly
acknowledged.
White solid; mp 91–92 ꢀC; 1H NMR (500 MHz, CDCl3): d¼2.08
(s, 6H), 2.11 (s, 3H), 2.32 (s, 3H), 2.39 (s, 3H), 4.14 (s, 3H), 7.00 (d,
J¼8.0 Hz, 1H), 7.08 (s, 1H), 7.44 (d, J¼8.0 Hz, 1H); 13C NMR
(125 MHz, CDCl3): d¼10.7, 15.3, 17.3, 18.8, 59.0, 78.4, 108.8, 122.5,
124.7, 129.0, 129.7, 133.3, 135.4, 155.0, 155.7; IR (KBr, neat): n¼2920,
References and notes
1. (a) Chemistry and Biology of b-Lactam Antibiotics; Morin, R. B., Gorman, M., Eds.;
Academic: New York, NY, 1982; Vols. 1–3; (b) The Chemistry of b-Lactams; Page,
M. I., Ed.; Blackie Academic & Professional: New York, NY, 1992; (c) Compre-
hensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V.,
Eds.; Pergamon: New York, NY, 1996; (d) Georg, G. I.; Ravikumar, V. The Organic
Chemistry of b-Lactams; Georg, G. I., Ed.; VCH: New York, NY, 1993; (e) South-
gate, R.; Branch, C.; Coulton, S.; Hunt, E. Recent Progress in the Chemical Synthesis
of Antibiotics and Related Microbial Products; Lukacs, G., Ed.; Springer: Berlin,
1993; Vol. 2, p 621; (f) Banik, B. K.; Srirajan, V. The Amide Linkage: Selected
Structural Aspects in Chemistry, Biochemistry and Material Science; Greenberg, A.,
Breneman, C. M., Liebman, J. F., Eds.; Wiley-Interscience: New York, NY, 2000;
Chapter 7, pp 157–214.
2. (a) For reviews on chemistry and biology of b-lactams, see: France, S.;
Weatherwax, A.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004, 37, 592–600; (b)
Singh, G. S. Tetrahedron 2003, 59, 7631–7649; (c) Recent aspects of the chem-
istry of b-lactams-II. Miller, M. J., Ed. Tetrahedron 2000, 56, 5553–5742; (d)
Singh, G. S. Mini Rev. Med. Chem. 2004, 4, 69–92; (e) Kidwai, M.; Sapra, P.;
Bhushan, K. R. Curr. Med. Chem. 1999, 6, 195–216; (f) Ojima, I. Acc. Chem. Res.
1995, 28, 383–389.
3. (a) Beauve, C.; Bouchet, M.; Touillaux, R.; Fastrez, J.; Marchand-Brynaert, J.
Tetrahedron 1999, 55, 13301–13320; (b) Ge´rard, S.; Dive, G.; Clamot, B.; Touil-
laux, R.; Marchand-Brynaert, J. Tetrahedron 2002, 58, 2423–2433; (c) Burnett,
D. A.; Caplen, M. A.; Davis, H. R., Jr.; Burrier, R. E.; Clader, J. W. J. Med. Chem.
1994, 37, 1733–1736.
4. (a) Mascaretti, O. A.; Boschetti, C. E.; Danelon, G. O.; Mata, E. G.; Roveri, O.
A. Curr. Med. Chem. 1995, 1, 441–470; (b) Edwards, P. D.; Bernstein, P. R.
Med. Res. Rev. 1994, 14, 127–194; (c) Page, M. I. Acc. Chem. Res. 1984, 17, 144–
151.
1667, 1375, 1341, 1277, 1054, 854 cmꢁ1
.
Anal. Calcd for
C
16H21NO2S2: C, 59.41; H, 6.54; N, 4.33. Found: C, 59.58; H, 6.39; N,
4.21.
4.5.25. (E)-1-(2,4-Dimethylphenyl)-4,4-bis(ethylthio)-3-(1-
methoxyethylidene)azetidin-2-one ((E)-3v)
White solid; mp 75–77 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.50 (t,
J¼7.5 Hz, 6H), 2.14 (s, 3H), 2.31 (s, 3H), 2.38 (s, 3H), 2.52–2.65 (m,
4H), 4.13 (s, 3H), 7.00 (d, J¼8.0 Hz, 1H), 7.07 (s, 1H), 7.41 (d, J¼8.0 Hz,
1H); 13C NMR (125 MHz, CDCl3): d¼13.8, 17.9, 19.5, 21.1, 24.2, 61.2,
81.1, 112.7, 125.3,126.9,131.3,131.9, 135.9,137.6, 157.0, 158.1; IR (KBr,
neat): n¼2921, 1734, 1661, 1488, 1348, 1297, 1131, 1054, 854,
751 cmꢁ1. Anal. Calcd for C18H25NO2S2: C, 61.50; H, 7.17; N, 3.98.
Found: C, 61.42; H, 7.31; N, 4.16.
4.5.26. (E)-3-(1-Methoxyethylidene)-1-methyl-4,4-bis(methyl-
thio)azetidin-2-one ((E)-3w)
White solid; mp 43–45 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.97 (s,
6H), 2.03 (s, 3H), 2.83 (s, 3H), 4.06 (s, 3H); 13C NMR (125 MHz,
CDCl3): d¼12.0, 16.6, 23.0, 60.9, 79.3, 110.2, 155.5, 159.7; IR (KBr,
neat): n¼2922, 2362, 1744, 1675, 1455, 1416, 1363, 1280, 1047, 957,
833 cmꢁ1. Anal. Calcd for C9H15NO2S2: C, 46.32; H, 6.48; N, 6.00.
Found: C, 46.45; H, 6.34; N, 6.12.
5. Palomo, C.; Aizpurua, J. M.; Ganboa, I. Enantioselective Synthesis of b-Amino
Acids; Juaristi, E., Ed.; Wiley-VCH: New York, NY, 1997; pp 279–357.
6. (a) Kende, A. S.; Liu, K.; Kaldor, I.; Dorey, G.; Koch, K. J. Am. Chem. Soc. 1995, 117,
8258–8270; (b) Ojima, I.; Komata, T.; Qiu, X. J. Am. Chem. Soc. 1990, 112, 770–
774; (c) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org. Chem.
1999, 3223–3235; (d) Palomo, C.; Aizpurua, J. M.; Galarza, R.; Mielgo, A. Chem.
Commun. 1996, 633–634.
7. (a) Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51–123; (b) See Ref. 6c.
8. (a) Gilman, H.; Speeter, M. J. Am. Chem. Soc. 1943, 65, 2255–2256; (b) Hart, D. J.;
Ha, D. C. Chem. Rev. 1989, 89, 1447–1465; (c) Benaglia, M.; Cinquini, M.; Cozzi, F.
Eur. J. Org. Chem. 2000, 563–572.
4.5.27. (Z)-3-(1-Methoxyethylidene)-1-methyl-4,4-bis(methyl-
thio)azetidin-2-one ((Z)-3w)
Colorless liquid; yield: 16%; 1H NMR (500 MHz, CDCl3): d¼2.07
(s, 6H), 2.25 (s, 3H), 2.78 (s, 3H), 4.06 (s, 3H); 13C NMR (125 MHz,
CDCl3): d¼12.6, 16.4, 23.2, 57.8, 80.6, 111.5, 155.0, 163.4; IR (KBr,
9. Risi, C. D.; Pollini, G. P.; Veronese, A. C.; Bertolasi, V. Tetrahedron Lett. 1999, 40,
6995–6998.
10. Toda, F.; Miyamoto, H.; Inoue, M.; Yasaka, S.; Matijasic, I. J. Org. Chem. 2000, 65,
2728–2732.
neat): n¼2922, 2852, 2337, 1746, 1674, 1411, 1362, 1280, 845 cmꢁ1
.
Anal. Calcd for C9H15NO2S2: C, 46.32; H, 6.48; N, 6.00. Found: C,
46.22; H, 6.54; N, 6.10.
11. (a) Barrett, A. G. M.; Sturgess, M. A. Tetrahedron Lett. 1986, 27, 3811–3814; (b)
Basak, A.; Mandal, S. Tetrahedron Lett. 2002, 43, 4241–4243; (c) Brown, P.;
Southgate, R. Tetrahedron Lett. 1986, 27, 247–250; (d) Van der Steen, F. H.;
Van Koten, G. Tetrahedron 1991, 47, 7503–7524; (e) Taber, D. F.; Stiriba, S.-E.
Chem.dEur. J. 1998, 4, 990–992; (f) Padwa, A.; Krumpe, K. E. Tetrahedron
1992, 48, 5385–5453; (g) Doyle, M. P. Chem. Rev. 1986, 86, 919–939; (h)
Du¨rckheimer, W.; Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew. Chem.
, Int. Ed. Engl. 1985, 24, 180–202.
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Minakata, S.; Komatsu, M. J. Am. Chem. Soc. 2003, 125, 5632–5633; (b) Knight, J.;
Parsons, P. J.; Southgate, R. J. Chem. Soc., Chem. Commun. 1986, 78–80; (c) Anaya,
J.; Barton, D. H. R.; Gero, S. D.; Grande, M.; Martı´n, N.; Tachdijian, C. Angew.
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K.; Ikeda, M. Tetrahedron 1996, 52, 489–502.
4.5.28. (E)-4,4-Bis(ethylthio)-3-(1-methoxyethylidene)-1-methyl-
azetidin-2-one ((E)-3x)
Colorless liquid; 1H NMR (500 MHz, CDCl3): d¼1.21 (t, J¼7.0 Hz,
6H), 2.05 (s, 3H), 2.23 (s, 3H), 2.44–2.50 (m, 4H), 2.83 (s, 3H), 4.06 (s,
3H); 13C NMR (125 MHz, CDCl3): d¼14.5, 17.3, 22.9, 23.4, 61.2, 80.0,
112.4, 155.6, 160.1; IR (KBr, neat): 2924, 2361, 1739, 1671, 1363, 1277,
841 cmꢁ1. Anal. Calcd for C11H19NO2S2: C, 50.54; H, 7.33; N, 5.36.
Found: C, 50.67; H, 7.55; N, 5.24.
13. (a) For reviews on the chemistry of a-oxo ketene-(S,S)acetals, see: Dieter, R. K.
Tetrahedron 1986, 42, 3029–3096; (b) Junjappa, H.; Ila, H.; Asokan, C. V. Tetra-
hedron 1990, 46, 5423–5506; (c) Tominaga, Y. J. Heterocycl. Chem. 1989, 26,
1167–1204; (d) Kolb, M. Synthesis 1990, 171–190; (e) Ila, H.; Junjappa, H.;
Mohanta, P. K. Progress in Heterocyclic Chemistry; Gribble, G. H., Gilchrist, L. T.,
Eds.; Pergamon: Oxford, 2001; Vol. 13, Chapter 1, pp 1–24.
14. For our work on the Vilsmeier reactions, see: (a) Dong, D.; Liu, Y.; Zhao, Y.; Qi,
Y.; Wang, Z.; Liu, Q. Synthesis 2005, 85–91; (b) Sun, S.; Liu, Y.; Liu, Q.; Zhao, Y.;
Dong, D. Synlett 2004, 1731–1734; (c) Liu, Y.; Dong, D.; Liu, Q.; Qi, Y.; Wang, Z.
Org. Biomol. Chem. 2004, 2, 28–30; (d) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.;
Zhang, Q.; Dong, D. J. Org. Chem. 2003, 68, 9148–9150.
15. (a) Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.; Liu, Q. Org. Lett.
2007, 9, 2421–2423; (b) Xiang, D.; Yang, Y.; Zhang, R.; Liang, Y.; Pan, W.; Huang,
J.; Dong, D. J. Org. Chem. 2007, 72, 8593–8596; (c) Bi, X.; Dong, D.; Liu, Q.; Pan,
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4.5.29. (E)-3-(1-Isopropoxyethylidene)-4,4-bis(methylthio)-1-
phenylazetidin-2-one ((E)-3y)
White solid; mp 93–95 ꢀC; 1H NMR (500 MHz, CDCl3): d¼1.33
(d, J¼6.0 Hz, 6H), 1.96 (s, 6H), 2.17 (s, 3H), 5.36 (m, 1H), 7.11 (t,
J¼7.5 Hz, 1H), 7.35 (t, J¼7.5 Hz, 2H), 7.94 (d, J¼8.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d¼11.3, 21.2, 28.6, 74.3, 78.8, 107.7, 116.2, 122.8,
127.8, 127.9, 135.7, 155.4, 156.5; IR (KBr, neat): n¼2920, 2359, 1731,
1664, 1592, 1491, 1354, 1284, 1115, 879, 754 cmꢁ1. Anal. Calcd for
C
16H21NO2S2: C, 59.41; H, 6.54; N, 4.33. Found: C, 59.54; H, 6.42; N,
4.41.
Acknowledgements
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17. CCDC-641605 (2a) and CCDC-641607 (3a) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
Financial support of this research by the National Natural
Science Foundation of China (20572013 and 20711130229), the
Ministry of Education of China (105061), and the Department of

4966
Y. Yang et al. / Tetrahedron 64 (2008) 4959–4966
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