Facile Synthesis of Some Chlorinated and Heteroatom-Rich Monocyclic β-Lactams via the Staudinger Reaction of Acyclic S -Alkylisothioureas

Article abstract of DOI:10.1055/s-0035-1562474

The optimized preparation of a rare class of highly functionalized (chlorinated and heteroatom-rich) monocyclic β-lactams by the Staudinger reaction of reactive acyclic S-alkylisothioureas with dichloroketene is presented. The use of acyclic S-alkylisothi

Full text of DOI:10.1055/s-0035-1562474

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
N. Dawra, R. N. Ram
Paper
Synthesis
Facile Synthesis of Some Chlorinated and Heteroatom-Rich
Monocyclic β-Lactams via the Staudinger Reaction of Acyclic
S-Alkylisothioureas
Nisha Dawra*a,b
Ram Nath Ramb
R1
O
R2
R1
R4
N
S
N
Cl2CHCOCl (1 equiv)
N
S
Cl
R4
R3
Et3N (2 equiv)
R3
N
Cl
a School of Engineering and Technology, BML Munjal University,
Gurgaon, Haryana 122413, India
b Department of Chemistry, Indian Institute of Technology
Delhi, Hauz Khas, New Delhi 110016, India
nishadawra@gmail.com
CH2Cl2, 0 °C, 5 min
R2
Acyclic S-alkylisothiourea
10 examples
Yield: 52–69%
R
1 = aryl, benzyl;
R2 = Me; R2–R3 = -(CH2)2O(CH2)2-
R3 = Ph; R4 = allyl, Me, benzyl, phenylethyl
Monocyclic b-lactam
Single-step reaction
Reaction time: 5 minutes
Easy isolation by crystallization
Highly functionalized b-lactams
Received: 29.05.2016
Accepted after revision: 11.06.2016
Published online: 15.08.2016
A chlorine substituent at the α-position of the β-lactam
ring is well known to enhance the chemical reactivity and it
also offers a great diversity regarding the biological activi-
ty2a,7 (Figure 1). Monocyclic β-lactams bearing different he-
teroatoms or heteroatom substituents at the α- or β-posi-
tion of the β-lactam ring are endowed with a broad spec-
trum of biological activities.8 Monocyclic β-lactams bearing
a morpholinyl group at the β-position of the β-lactam ring
exhibit good antibiotic activity.9
DOI: 10.1055/s-0035-1562474; Art ID: ss-2016-t0391-op
Abstract The optimized preparation of a rare class of highly function-
alized (chlorinated and heteroatom-rich) monocyclic β-lactams by the
Staudinger reaction of reactive acyclic S-alkylisothioureas with di-
chloroketene is presented. The use of acyclic S-alkylisothioureas in the
Staudinger β-lactam synthesis has been demonstrated for the first
time. The present method is mild, economical and wide in scope.
Key words monocyclic β-lactams, dichloroketene, acyclic S-alkyliso-
thioureas, Staudinger reaction, chlorinated, heteroatom rich
Cl
O
α
Cl
X
N
β
Y
Heterocyclic compounds are of immense importance
both in chemistry and biology. The majority of the natural
products, drugs and biologically active compounds are rich
in heteroatoms. Heteroatom-rich organic compounds, par-
ticularly those containing heteroatoms such as N, O, S and
Cl, are well known to behave as reactive intermediates in
organic synthesis, while a few others exhibit interesting
biological activities.1 Monocyclic β-lactams are important
as antibiotics2 and inhibitors of β-lactamases2a,3 and other
mammalian enzymes that regulate important physiological
processes in human beings and other animals.4 The synthe-
sis of novel β-lactams is an emerging area of research in or-
ganic synthesis due to the problem of ever-increasing bac-
terial resistance to the existing β-lactam antibiotics.5 The
use of monocyclic β-lactams as versatile synthetic interme-
diates has been well documented in the literature.6 Ring
transformations of the β-lactam ring have been used as an
efficient and straightforward method for the synthesis of a
variety of azaheterocycles, such as 1,4-diazepanes,6a pyrro-
lidines,6e aziridines,6g piperazines6a,h and azetidines,6e,g
which are promising compounds in the field of drug design.
X, Y = N or S heteroatom substituent
Figure 1 General structure of a heteroatom-rich monocyclic β-lactam
A literature survey revealed that the synthesis of β,β-di-
amino-substituted monocyclic β-lactams and α-S,β-N-
disubstituted monocyclic β-lactams has been scarcely re-
ported. The very few reported methods for the synthesis of
such β-N-substituted β-lactams involve the [2+2] cycload-
dition of alkenes to isocyanates,10 the [2+2] cycloaddition of
β,β-disubstituted enamines to aryl isocyanates9 or the
Staudinger reaction of amidines with ketenes.8h,11 However,
all of the aforesaid methods have some limitations with re-
gard to the nature of substituents present on the β-lactam
ring, and the low product stability and low product yields
in some cases. These drawbacks prompted us to develop a
more efficient method to synthesize some novel, chlorinat-
ed and heteroatom-rich β-N-substituted monocyclic β-lact-
ams.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
N. Dawra, R. N. Ram
Paper
Synthesis
To the best of our knowledge, monocyclic β-lactams
having the two different heteroatom substituents N and S
at the same position (α or β) are not known. Furthermore, a
recent search has shown that monocyclic β-lactams bearing
all three of the heteroatom substituents N, S and Cl in a sin-
gle molecular framework are unreported. Only a few exam-
ples of non-chlorinated bicyclic β-lactams having both a ni-
trogen and a sulfur substituent at the β-position of the β-
lactam ring have been reported,12 which were prepared by
the [2+2] cycloaddition of ketenes across cyclic iso-
thioureas.
Therefore, in view of the above facts, herein we disclose
a simple, broader and efficient route of general applicabili-
ty for the synthesis of such interesting and intriguing
monocyclic β-lactams having the aforesaid unprecedented
grouping and positioning of chlorine, nitrogen and sulfur
heteroatom substituents. The well-documented Staudinger
method was chosen for the construction of the β-lactam
ring.13 We proposed that the properly substituted acyclic S-
alkylisothioureas containing the substituted N and S atoms
could serve as excellent precursors for the synthesis of the
desired α,α-dichloro-β-N,β-S-disubstituted monocyclic β-
lactams. However, until now, the use of acyclic S-alkyliso-
thioureas in the Staudinger reaction has not been reported.
The general synthetic strategy to construct the above-
mentioned persubstituted monocyclic β-lactams began
with the synthesis of trisubstituted thioureas 3 (Scheme 1)
which were prepared by nucleophilic addition of sec-
amines 2 to aryl/alkyl isothiocyanates 1 in ethanol at room
temperature (25–30 °C) according to a literature proce-
dure.14
R4 Br
4
R2
R2
R3
R1
R4
N
S
R1 NH
EtOH
25–30 °C, 1 h
R1NCS
N
+
R2R3NH
N
K2CO3, acetone
reflux, 1–8 h
R3
S
1
2
3
5
Scheme 1 General route for the synthesis of acyclic S-alkylisothioureas 5
Purification of the crude solid products by recrystalliza-
tion in ethanol afforded the trisubstituted thioureas 3 in
quantitative yields. The crucial acyclic S-alkylisothioureas 5
were accessed by reacting the trisubstituted thioureas 3
with the appropriate alkylating agents 4 in refluxing ace-
tone using anhydrous potassium carbonate as a base. Puri-
fication of the crude products by silica gel column chroma-
tography furnished the desired acyclic S-alkylisothioureas 5
in 88–98% yield. Thereafter, the Staudinger reaction of S-al-
kylisothioureas 5 with dichloroketene was investigated. To
explore the feasibility of this approach, we first attempted
the reaction of isothiourea 5a with dichloroketene generat-
ed in situ by the reaction of dichloroacetyl chloride with
triethylamine. Numerous attempts at this reaction were
made by varying the solvent, reaction temperature, stoi-
chiometric ratio of the reagents and reaction time, as
shown in Table 1. Disappointingly, complete decomposition
of the starting material was observed in benzene at 25–
30 °C (Table 1, entry 1).
Table 1 Optimization of the Staudinger Reaction of Isothiourea 5aa
N
S
O
Cl2CHCOCl
Et3N
N
N
S
Cl
Cl
N
O
O
5a
6a
Entry
Cl2CHCOCl (mol equiv) Et3N (mol equiv) Solvent
Temp (°C)
Time (min) Ratiob 5a/6a
Yieldc,d (%)
Recovered 5a
6a
1
2
3
4
5
6
7
2
2
2
2
1
1
1
2
2
2
2
2
2
1
benzene
Et2O
25–30
120
120
720
120
60
–
extensive decomposition
–
–
–
–
–
0
1:0
1:0
–
74
Et2O
25–30
76
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
0
0
0
extensive decomposition
partial decomposition
–
1:1
0:1
5:85
5
54
5
slight decomposition
–
a All reactions were performed with isothiourea 5a (1 mmol), under a nitrogen atmosphere.
b Calculated by 1H NMR analysis of the crude reaction mixture.
c Isolated yield of 5a after purification by column chromatography.
d Isolated yield of 6a after purification by precipitation from EtOH.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
N. Dawra, R. N. Ram
Paper
Synthesis
However, neither product formation nor decomposition
was observed, both at 0 °C and 25–30 °C, when diethyl
ether was used as a solvent (Table 1, entries 2 and 3). Curi-
ously, extensive decomposition of the starting material was
observed in dichloromethane (CH2Cl2), even at 0 °C, after 2
hours (Table 1, entry 4). From these experiments, it was
presumed that the reaction probably occurred in CH2Cl2 at
0 °C, but the β-lactam product 6a decomposed under these
reaction conditions. This may be due to a susceptibility of
β-lactam product 6a towards excess dichloroacetyl chloride
and longer reaction time. In order to suppress the decom-
position in CH2Cl2 at 0 °C, the amount of dichloroacetyl
chloride was reduced to 1 equivalent and the time was re-
duced to 1 hour. Interestingly, after 1 hour the 1H NMR
spectrum of the crude reaction mixture indicated the pres-
ence of the β-lactam 6a and the starting material 5a in a 1:1
ratio, and partial decomposition was also observed (Table 1,
entry 5). The reaction was indeed cleaner under these con-
ditions, providing greater latitude for further manipulation.
Thus, the influence of the reaction time and the stoichio-
metric ratio of dichloroacetyl chloride for the successful
synthesis of the monocyclic β-lactam 6a soon became very
apparent. Pleasingly, considerable success was realized
when the reaction of isothiourea 5a with dichloroketene
was performed for only 5 minutes under similar reaction
conditions as used for the previous experiment. These con-
ditions resulted in complete conversion of the starting ma-
terial into product without any decomposition (Table 1, en-
try 6).
Further, the requirement of excess base (Et3N) in the
Staudinger reaction was also investigated by performing
another experiment in which the amount of triethylamine
was reduced to 1 equivalent, keeping the rest of the param-
eters the same. Interestingly, on monitoring the progress of
the reaction by TLC after 5 minutes, the presence of a small
amount of the starting material 5a along with the product
6a was observed (Table 1, entry 7). Decomposition was also
noticed. Thus, it appears that the basic medium is quite
necessary for the success of the Staudinger reaction of 5a
with dichloroketene.
Therefore, 1 equivalent of dichloroacetyl chloride, 2
equivalents of triethylamine, CH2Cl2 as solvent, 0 °C as reac-
tion temperature and 5 minutes as reaction time were con-
sidered as the optimized reaction conditions for the
Staudinger reaction of acyclic S-alkylisothioureas for the
synthesis of the desired persubstituted monocyclic β-lac-
tams. Thus, several α,α-dichloro-β-N,β-S-disubstituted
monocyclic β-lactams 6 were successfully synthesized by
the Staudinger reaction of acyclic S-alkylisothioureas 5
with dichloroketene in 52–69% yield (Table 2).
Table 2 Yields of S-Alkylisothioureas 5a and Monocyclic β-Lactams 6b
R1
O
R2
R3
R2
R3
R
4 Br
4
R1
R4
N
S
R1 NH
S
N
Cl2CHCOCl (1 mol equiv)
N
S
Cl
N
K2CO3, acetone
reflux, 1–8 h
Et3N (2 mol equiv)
CH2Cl2, 0 °C, 5 min
R4
R3
N
Cl
3
5
R2
6
Entry
R1
Ph
R2
R3
R4
Timec (h)
Yieldd (%) of 5
Yielde (%) of 6
1
2
-(CH2)2O(CH2)2-
allyl
allyl
Bn
2
2
5a
5b
5c
5d
5e
5f
96
94
96
93
95
95
89
98
98
88f
6a
6b
6c
6d
6e
6f
54
67
68
69
56
56
69
55
59
52
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
Ph
6
4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
o-MeC6H4
Ph
Bn
8
5
Bn
7
6
Bn
8
7
Bn
6
5g
5h
5i
6g
6h
6i
8
(CH2)2Ph
Me
4
9
Ph
1
10
Bn
Bn
10
5j
6j
a Reaction conditions: 3 (5 mmol), 4 (5 mmol), acetone (30 mL).
b Reaction conditions: 5 (2 mmol), Cl2CHCOCl (2 mmol), Et3N (4 mmol), CH2Cl2 (20 mL).
c Reaction time for the conversion of 3 into 5.
d Isolated yield of 5 after purification by column chromatography.
e Isolated yield of 6 after purification by precipitation from EtOH.
f Yield of the crude product.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
N. Dawra, R. N. Ram
Paper
Synthesis
The structures of all new compounds synthesized in the
as the stationary phase with n-hexane/EtOAc mixtures as the mobile
phase. Solvents were evaporated on a rotary evaporator under re-
duced pressure using an aspirator. The trisubstituted thioureas were
prepared by the reaction of alkyl/aryl isothiocyanates with sec-
amines according to a reported procedure.14 Dichloroacetyl chloride is
commercially available and was used as received. Et3N was dried over
KOH pellets overnight and distilled over CaH2. Acetone was dried by
distillation over anhydrous K2CO3. CH2Cl2 was dried by distillation
over P2O5.
1
present work were supported by IR, H NMR and 13C NMR
spectroscopy, and HRMS data. The structure of the mono-
cyclic β-lactams was further confirmed by single-crystal X-
ray diffraction data of the monocyclic β-lactam 6i (Figure
2).
Acyclic S-Alkylisothioureas 5; General Procedure
To a solution of the trisubstituted thiourea 3 (5 mmol) in dried ace-
tone (30 mL) were added anhydrous K2CO3 (0.829 g, 6 mmol) and an
allyl/alkyl bromide 4 (5 mmol), and the reaction mixture was heated
at reflux. After completion of the reaction, the reaction mixture was
cooled and filtered to remove the insoluble K2CO3. The crude product
was purified by silica gel column chromatography (n-hexane/EtOAc,
95:5 v/v), except for the isothiourea 5j which was highly unstable and
decomposed on column chromatography. Thus, 5j was used as such
without further purification in the Staudinger reaction. The pure acy-
clic S-alkylisothioureas 5a–i were thus obtained in 89–98% yield as
yellowish or colorless liquids or white solids.
Allyl N-Phenylmorpholine-4-carbimidothioate (5a)15
Yellowish liquid; yield: 1.259 g (96%).
IR (KBr): 3083, 2970, 1608, 1589, 1484, 1444, 1370, 1269, 1242, 1195,
1156, 1112, 1025, 767, 698, 574 cm–1
.
Figure 2 ORTEP diagram of the monocyclic β-lactam 6i
1H NMR (300 MHz, CDCl3): δ = 7.27 (t, J = 7.8 Hz, 2 H, Ar-H), 7.01 (t, J =
7.5 Hz, 1 H, Ar-H), 6.88 (d, J = 7.8 Hz, 2 H, Ar-H), 5.74–5.61 (m, 1 H,
CH2=CH-CH2), 5.09–5.02 (m, 2 H, CH2=CH-CH2), 3.74 (t, J = 4.2 Hz, 4 H,
CH2OCH2), 3.63 (t, J = 4.2 Hz, 4 H, CH2NCH2), 3.05 (d, J = 7.2 Hz, 2 H,
CH2=CH-CH2).
13C NMR (75.5 MHz, CDCl3): δ = 154.3, 149.5, 133.5, 128.6, 122.4,
121.6, 117.7, 66.7, 48.6, 35.3.
In conclusion, the so-far unprecedented Staudinger re-
action of acyclic S-alkylisothioureas with dichloroketene
has been successfully accomplished for the first time for the
synthesis of a variety of chlorinated and heteroatom-rich
monocyclic β-lactams. The method is quite general and the
starting materials used are inexpensive and readily accessi-
ble. The purification procedures are convenient and do not
involve chromatographic methods. The β-lactams thus syn-
thesized belong to a rarely reported class of highly func-
tionalized β-lactams having high heteroatom density. These
attributes make them important building blocks in organic
synthesis and interesting targets for biological studies.
Allyl N-Methyl-N,N′-diphenylcarbamimidothioate (5b)
Yellowish liquid; yield: 1.327 g (94%); Rf = 0.59 (5% n-hexane/EtOAc).
IR (KBr): 3059, 2968, 1606, 1578, 1492, 1344, 1252, 1206, 1116, 1029,
920, 762, 697 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.18 (m, 7 H, Ar-H), 7.05–6.94
(m, 3 H, Ar-H), 5.61–5.48 (m, 1 H, CH2=CH-CH2), 5.00–4.95 (m, 2 H,
CH2=CH-CH2), 3.38 (s, 3 H, NMe), 2.91 (d, J = 7.2 Hz, 2 H, CH2=CH-CH2).
13C NMR (75.5 MHz, CDCl3): δ = 154.1, 149.5, 146.2, 133.5, 128.9,
128.7, 126.1, 125.6, 122.6, 121.6, 117.4, 41.6, 35.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H19N2S: 283.1263; found:
283.1268.
The entire data analysis of all the compounds synthesized in the pres-
ent work was done in the Chemistry Instrumentation Lab, IIT Delhi,
New Delhi. IR spectra were recorded on Nicolet Protégé 460 ES-P and
Cary 600 Series FT-IR spectrometers by taking solid samples as KBr
pellets and liquids as thin films on KBr discs. NMR spectra were re-
corded on a Bruker 300-MHz FT-NMR spectrometer as solutions in
CDCl3 with TMS as internal standard. Multiplicities are indicated by
the following abbreviations: s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), dd (doublet doublet). DEPT spectra were rou-
tinely recorded to identify different types of carbons. Mass spectra
were recorded on a micrOTOF-Q II, ESI-TOF/MS mass spectrometer
(ESI-TOF) in the positive ion mode. Melting points were determined
on a Fischer Scientific electrically heated apparatus by taking the
samples in a glass capillary sealed at one end, and are uncorrected.
The progress of reactions was monitored by TLC using glass plates
coated with TLC-grade silica gel. Iodine was used for visualizing the
spots. For column chromatography, silica gel (60–120 mesh) was used
Benzyl N-Methyl-N,N′-diphenylcarbamimidothioate (5c)
White solid; yield: 1.596 g (96%); mp 42–44 °C; Rf = 0.58 (5% n-hex-
ane/EtOAc).
IR (KBr): 3054, 2973, 1603, 1565, 1486, 1454, 1429, 1345, 1291, 1255,
1203, 1111, 1072, 1027, 993, 902, 886, 764, 698 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.32–7.17 (m, 8 H, Ar-H), 7.14–7.09
(dd, J = 8.7, 1.2 Hz, 2 H, Ar-H), 7.03–6.99 (m, 3 H, Ar-H), 6.89 (dd, J =
8.7, 1.2 Hz, 2 H, Ar-H), 3.47 (s, 2 H, SCH2), 3.30 (s, 3 H, NMe).
13C NMR (75.5 MHz, CDCl3): δ = 153.9, 149.4, 146.0, 137.2, 128.8,
128.7, 128.6, 128.2, 127.0, 125.8, 125.4, 122.5, 121.5, 41.4, 36.4.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
N. Dawra, R. N. Ram
Paper
Synthesis
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H21N2S: 333.1420; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H23N2S: 347.1576; found:
333.1416.
347.1577.
Benzyl N′-(4-Methoxyphenyl)-N-methyl-N-phenylcarbamimido-
thioate (5d)
2-Phenethyl N-Methyl-N,N′-diphenylcarbamimidothioate (5h)
Colorless liquid; yield: 1.698 g (98%); Rf = 0.59 (5% n-hexane/EtOAc).
IR (KBr): 2965, 1606, 1576, 1494, 1453, 1343, 1249, 1207, 1168, 1116,
White solid; yield: 1.686 g (93%); mp 48–50 °C; Rf = 0.58 (5% n-hex-
ane/EtOAc).
996, 762, 696 cm–1
.
IR (KBr): 3027, 2992, 2959, 2932, 1604, 1568, 1491, 1454, 1344, 1288,
1H NMR (300 MHz, CDCl3): δ = 7.36–7.12 (m, 10 H, Ar-H), 7.03–6.93
(m, 5 H, Ar-H), 3.37 (s, 3 H, NMe), 2.64–2.58 (m, 2 H, PhCH2CH2), 2.54–
2.48 (m, 2 H, PhCH2CH2).
13C NMR (75.5 MHz, CDCl3): δ = 154.6, 149.6, 146.3, 139.8, 129.0,
128.7, 128.34, 128.28, 126.3, 126.0, 125.6, 122.6, 121.5, 41.6, 36.1,
33.2.
1237, 1206, 1111, 1041, 891, 840, 769 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.29 (t, J = 7.5 Hz, 2 H, Ar-H), 7.22–7.09
(m, 6 H, Ar-H), 7.02 (d, J = 7.2 Hz, 2 H, Ar-H), 6.83 (s, 4 H, Ar-H), 3.76
(s, 3 H, OMe), 3.50 (s, 2 H, SCH2), 3.29 (s, 3 H, NMe).
13C NMR (75.5 MHz, CDCl3): δ = 155.5, 154.1, 146.2, 142.7, 137.3,
128.8, 128.7, 128.2, 127.0, 125.5, 125.2, 122.4, 113.9, 55.3, 41.4, 36.5.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H23N2OS: 363.1526; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H23N2S: 347.1576; found:
347.1576.
363.1525.
Methyl N-Methyl-N,N′-diphenylcarbamimidothioate (5i)
Benzyl N′-(4-Chlorophenyl)-N-methyl-N-phenylcarbamimido-
thioate (5e)
Yellowish liquid; yield: 1.256 g (98%); Rf = 0.59 (5% n-hexane/EtOAc).
IR (KBr): 3057, 1606, 1576, 1492, 1342, 1246, 1206, 1116, 1029, 762,
White solid; yield: 1.743 g (95%); mp 85–87 °C; Rf = 0.58 (5% n-hex-
ane/EtOAc).
696 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.36–7.24 (m, 6 H, Ar-H), 7.17 (t, J = 7.2
Hz, 1 H, Ar-H), 7.02–6.94 (m, 3 H, Ar-H), 3.37 (s, 3 H, NMe), 1.88 (s, 3
H, SMe).
13C NMR (75.5 MHz, CDCl3): δ = 156.4, 149.5, 146.3, 128.9, 128.6,
125.6, 125.4, 122.4, 121.4, 41.7, 15.7.
IR (KBr): 2966, 1603, 1574, 1491, 1453, 1328, 1208, 1115, 1086, 1030,
892, 833, 764 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.36–7.33 (m, 2 H, Ar-H), 7.30–7.19
(m, 6 H, Ar-H), 7.14–7.11 (m, 2 H, Ar-H), 7.04–7.01 (m, 2 H, Ar-H),
6.78 (d, J = 8.7 Hz, 2 H, Ar-H), 3.49 (s, 2 H, SCH2), 3.32 (s, 3 H, NMe).
13C NMR (75.5 MHz, CDCl3): δ = 154.2, 148.1, 145.8, 137.1, 128.9,
128.62, 128.56, 128.3, 127.6, 127.1, 126.0, 125.7, 122.8, 41.5, 36.6.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H17N2S: 257.1107; found:
257.1104.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H20ClN2S: 367.1030;
found: 367.1033.
Monocyclic β-Lactams 6; General Procedure
To a solution of the S-alkylisothiourea 5 (2 mmol) in dried CH2Cl2 (20
mL) was injected dried Et3N (0.404 g, 0.557 mL, 4 mmol) at room tem-
perature (25–30 °C) under a nitrogen atmosphere using Schlenk tech-
niques. Then, a solution of dichloroacetyl chloride (0.295 g, 0.192 mL,
2 mmol) in dried CH2Cl2 (5 mL) was added dropwise via a dropping
funnel with stirring over a period of 5 min at 0 °C. The reaction was
quenched immediately by diluting with CH2Cl2 (50 mL) and washing
successively with saturated NaHCO3 solution (2 × 20 mL) and brine
(2 × 20 mL). The CH2Cl2 layer was dried over anhydrous sodium sul-
fate, filtered and concentrated in vacuo to give the crude monocyclic
β-lactam as a dark pasty mass. The crude product was prone to de-
composition on column chromatography using either silica gel or
neutral alumina as the stationary phase. Therefore, it was purified by
dissolving in EtOH and allowing the solution to stand at 0 °C for 1–3 h.
The pure monocyclic β-lactams precipitated out as white solids in
52–69% yield. Further purification by recrystallization from EtOH or
benzene (in the case of 6i) afforded the pure monocyclic β-lactams
6a–j as colorless crystals.
Benzyl N′-(4-Bromophenyl)-N-methyl-N-phenylcarbamimido-
thioate (5f)
White solid; yield: 1.954 g (95%); mp 76–78 °C; Rf = 0.58 (5% n-hex-
ane/EtOAc).
IR (KBr): 3059, 2924, 1604, 1574, 1493, 1455, 1350, 1255, 1202, 1166,
1118, 1066, 1028, 1002, 893, 766 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.37–7.30 (m, 4 H, Ar-H), 7.26–7.19
(m, 4 H, Ar-H), 7.12 (d, J = 7.5 Hz, 2 H, Ar-H), 7.02 (d, J = 7.5 Hz, 2 H,
Ar-H), 6.73 (d, J = 8.1 Hz, 2 H, Ar-H), 3.49 (s, 2 H, SCH2), 3.32 (s, 3 H,
NMe).
13C NMR (75.5 MHz, CDCl3): δ = 154.3, 148.6, 145.9, 137.2, 131.6,
129.0, 128.7, 128.4, 127.2, 126.2, 125.8, 123.4, 115.4, 41.6, 36.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H20BrN2S: 411.0525;
found: 411.0525.
Benzyl N-Methyl-N-phenyl-N′-o-tolylcarbamimidothioate (5g)
Yellowish liquid; yield: 1.542 g (89%); Rf = 0.58 (5% n-hexane/EtOAc).
IR (KBr): 3028, 1608, 1582, 1493, 1454, 1337, 1253, 1215, 1114, 1030,
4-(Allylthio)-3,3-dichloro-4-morpholino-1-phenylazetidin-2-one
(6a)
Colorless needles; yield: 0.403 g (54%); mp 77–79 °C (EtOH); Rf = 0.48
(5% n-hexane/EtOAc).
893, 763, 698 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.39–7.35 (m, 2 H, Ar-H), 7.28–7.08
(m, 8 H, Ar-H), 7.02–6.93 (m, 3 H, Ar-H), 6.72 (d, J = 7.5 Hz, 1 H, Ar-H),
3.51 (s, 2 H, SCH2), 3.33 (s, 3 H, NMe), 2.13 (s, 3 H, Me).
13C NMR (75.5 MHz, CDCl3): δ = 154.1, 148.2, 146.4, 137.3, 130.0,
129.0, 128.9, 128.7, 128.3, 127.1, 126.0, 125.4, 125.2, 123.0, 120.8,
41.7, 36.6, 18.1.
IR (KBr): 2969, 1782, 1637, 1596, 1494, 1371, 1265, 1173, 1116, 890,
834, 798, 754 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 7.8 Hz, 2 H, Ar-H), 7.43 (t,
J = 7.8 Hz, 2 H, Ar-H), 7.27 (t, J = 7.8 Hz, 1 H, Ar-H), 5.64–5.50 (m, 1 H,
CH2=CH-CH2), 5.10–5.01 (m, 2 H, CH2=CH-CH2), 3.71 (t, J = 4.5 Hz, 4 H,
CH2OCH2), 3.39–3.31 (m, 3 H, CH2NCH2 and one allylic H of CH2=CH-
CH2), 3.19–3.05 (m, 3 H, CH2NCH2 and one allylic H of CH2=CH-CH2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
N. Dawra, R. N. Ram
Paper
Synthesis
13C NMR (75.5 MHz, CDCl3): δ = 158.2, 135.7, 131.4, 129.4, 126.5,
119.2, 119.1, 99.2, 91.3, 67.1, 47.3, 35.2.
4-(Benzylthio)-3,3-dichloro-1-(4-chlorophenyl)-4-[(methyl)(phe-
nyl)amino]azetidin-2-one (6e)
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H18Cl2N2O2SNa: 395.0358;
found: 395.0361.
Colorless plates; yield: 0.535 g (56%); mp 85–87 °C (EtOH); Rf = 0.47
(5% n-hexane/EtOAc).
IR (KBr): 3029, 2943, 1792, 1596, 1493, 1364, 1309, 1225, 1168, 1123,
4-(Allylthio)-3,3-dichloro-4-[(methyl)(phenyl)amino]-1-phe-
nylazetidin-2-one (6b)
1103, 1047, 838, 755 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.95 (d, J = 7.8 Hz, 2 H, Ar-H), 7.43 (d,
J = 7.8 Hz, 2 H, Ar-H), 7.29–7.24 (m, 4 H, Ar-H), 7.13–7.05 (m, 4 H, Ar-
H), 6.87 (br s, 2 H, Ar-H), 3.92 (d, J = 10.5 Hz, 1 H, SCHH), 3.35 (d, J =
10.5 Hz, 1 H, SCHH), 3.19 (s, 3 H, NMe).
Colorless needles; yield: 0.527 g (67%); mp 68–70 °C (EtOH); Rf = 0.48
(5% n-hexane/EtOAc).
IR (KBr): 3063, 2943, 1787, 1668, 1597, 1494, 1372, 1312, 1232, 1132,
1130, 1102, 987, 790, 753, 693 cm–1
.
13C NMR (75.5 MHz, CDCl3): δ = 158.2, 145.2, 134.4, 132.0, 129.7,
1H NMR (300 MHz, CDCl3): δ = 7.94 (d, J = 8.1 Hz, 2 H, Ar-H), 7.45 (t,
J = 7.8 Hz, 2 H, Ar-H), 7.35–7.23 (m, 5 H, Ar-H), 7.07 (t, J = 6.9 Hz, 1 H,
Ar-H), 5.44–5.36 (m, 1 H, CH2=CH-CH2), 4.94–4.88 (m, 2 H, CH2=CH-
CH2), 3.30 (dd, J = 11.7, 7.5 Hz, 1 H, CH2=CH-CHH), 3.20 (s, 3 H, NMe),
2.88 (dd, J = 11.7, 7.2 Hz, 1 H, CH2=CH-CHH).
129.0, 129.0, 128.5, 127.6, 123.3, 122.7, 120.1, 97.6, 92.5, 39.5, 37.5.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C23H19Cl3N2OSNa: 499.0176;
found: 499.0176.
4-(Benzylthio)-1-(4-bromophenyl)-3,3-dichloro-4-[(methyl)(phe-
nyl)amino]azetidin-2-one (6f)
13C NMR (75.5 MHz, CDCl3): δ = 158.2, 145.3, 135.8, 131.0, 129.5,
128.4, 126.4, 123.0, 122.5, 119.1, 118.8, 97.7, 92.3, 39.5, 36.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C19H18Cl2N2OSNa: 415.0409;
Colorless plates; yield: 0.585 g (56%); mp 82–84 °C (EtOH); Rf = 0.47
(5% n-hexane/EtOAc).
found: 415.0430.
IR (KBr): 3070, 1787, 1597, 1494, 1455, 1366, 1301, 1262, 1218, 1169,
1094, 1032, 834, 754, 693 cm–1
.
4-(Benzylthio)-3,3-dichloro-4-[(methyl)(phenyl)amino]-1-phe-
nylazetidin-2-one (6c)
1H NMR (300 MHz, CDCl3): δ = 7.89 (d, J = 8.7 Hz, 2 H, Ar-H), 7.59 (d,
J = 8.7 Hz, 2 H, Ar-H), 7.33–7.28 (m, 2 H, Ar-H), 7.26–7.21 (m, 2 H, Ar-
H), 7.15–7.10 (m, 3 H, Ar-H), 7.05 (t, J = 7.2 Hz, 1 H, Ar-H), 6.89–6.86
(m, 2 H, Ar-H), 3.93 (d, J = 10.5 Hz, 1 H, SCHH), 3.35 (d, J = 10.5 Hz, 1 H,
SCHH), 3.19 (s, 3 H, NMe).
Colorless cubes; yield: 0.603 g (68%); mp 98–100 °C (EtOH); Rf = 0.47
(5% n-hexane/EtOAc).
IR (KBr): 3063, 2904, 1792, 1596, 1492, 1363, 1308, 1225, 1123, 1103,
754, 693 cm–1
.
13C NMR (75.5 MHz, CDCl3): δ = 158.2, 145.1, 134.9, 134.4, 132.6,
1H NMR (300 MHz, CDCl3): δ = 8.02 (d, J = 8.1 Hz, 2 H, Ar-H), 7.48 (t, J =
7.8 Hz, 2 H, Ar-H), 7.35–7.23 (m, 5 H, Ar-H), 7.12–7.10 (m, 3 H, Ar-H),
7.04 (t, J = 7.5 Hz, 1 H, Ar-H), 6.84 (d, J = 4.5 Hz, 2 H, Ar-H), 3.91 (d, J =
10.5 Hz, 1 H, SCHH), 3.37 (d, J = 10.5 Hz, 1 H, SCHH), 3.22 (s, 3 H,
NMe).
129.0, 128.5, 127.6, 123.2, 122.6, 120.3, 119.8, 97.5, 92.5, 39.5, 37.5.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C23H20BrCl2N2OS: 520.9851;
found: 520.9820.
4-(Benzylthio)-3,3-dichloro-4-[(methyl)(phenyl)amino]-1-o-
tolylazetidin-2-one (6g)
13C NMR (75.5 MHz, CDCl3): δ = 158.3, 145.3, 136.0, 134.6, 129.6,
129.1, 128.4, 127.5, 126.5, 123.0, 122.5, 118.9, 97.5, 92.5, 39.5, 37.5.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C23H20Cl2N2OSNa: 465.0566;
Colorless cubes; yield: 0.631 g (69%); mp 83–85 °C (EtOH); Rf = 0.48
(5% n-hexane/EtOAc).
found: 465.0551.
IR (KBr): 3062, 1797, 1595, 1493, 1455, 1359, 1298, 1069, 835, 779,
759 cm–1
.
4-(Benzylthio)-3,3-dichloro-1-(4-methoxyphenyl)-4-[(meth-
yl)(phenyl)amino]azetidin-2-one (6d)
1H NMR (300 MHz, CDCl3): δ = 7.62 (d, J = 7.8 Hz, 1 H, Ar-H), 7.38–
7.25 (m, 7 H, Ar-H), 7.10–7.08 (m, 4 H, Ar-H), 6.58–6.56 (m, 2 H, Ar-
H), 3.45 (s, 3 H, NMe), 3.29 (2 overlapping d, J = 16.5, 10.8 Hz, 2 H,
SCH2), 2.46 (s, 3 H, Me).
Colorless needles; yield: 0.653 g (69%); mp 108–110 °C (EtOH); Rf =
0.47 (5% n-hexane/EtOAc).
13C NMR (75.5 MHz, CDCl3): δ = 158.2, 145.4, 139.4, 135.8, 129.5,
128.4, 128.2, 126.43, 126.39, 122.9, 122.4, 118.9, 97.8, 92.4, 39.5, 34.8,
33.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C24H23Cl2N2OS: 457.0903;
found: 457.0895.
IR (KBr): 3062, 2931, 1779, 1597, 1510, 1454, 1371, 1302, 1251, 1170,
1129, 834, 698 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.94 (d, J = 9.0 Hz, 2 H, Ar-H), 7.32–
7.22 (m, 4 H, Ar-H), 7.13–7.11 (m, 3 H, Ar-H), 7.06–6.98 (m, 3 H, Ar-
H), 6.87–6.85 (m, 2 H, Ar-H), 3.90–3.86 (d, 1 H, overlapped by singlet
at 3.86, SCHH), 3.86 (s, 3 H, OMe), 3.37 (d, J = 10.5 Hz, 1 H, SCHH), 3.22
(s, 3 H, NMe).
13C NMR (75.5 MHz, CDCl3): δ = 157.9, 157.8, 145.4, 134.7, 129.1,
129.0, 128.4, 127.5, 122.9, 122.5, 120.6, 114.7, 97.5, 92.4, 55.5, 39.5,
37.4.
3,3-Dichloro-4-[(methyl)(phenyl)amino]-4-(2-phenethylthio)-1-
phenylazetidin-2-one (6h)
Colorless needles; yield: 0.503 g (55%); mp 86–88 °C (EtOH); Rf = 0.49
(5% n-hexane/EtOAc).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C24H22Cl2N2O2SNa: 495.0671;
found: 495.0659.
IR (KBr): 3071, 3028, 2928, 1787, 1597, 1494, 1453, 1366, 1306, 1227,
1172, 1121, 1102, 1049, 753, 730, 695 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
N. Dawra, R. N. Ram
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.91 (d, J = 7.8 Hz, 2 H, Ar-H), 7.43 (t,
J = 7.2 Hz, 2 H, Ar-H), 7.35–7.23 (m, 5 H, Ar-H), 7.15 (d, J = 5.7 Hz, 3 H,
Ar-H), 7.06 (t, J = 6.9 Hz, 1 H, Ar-H), 6.81 (d, J = 6.9 Hz, 2 H, Ar-H), 3.20
(s, 3 H, NMe), 2.96–2.80 (m, 1 H, CH2CH2Ph), 2.62–2.33 (m, 3 H,
CH2CH2Ph).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562474.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
13C NMR (75.5 MHz, CDCl3): δ = 158.2, 145.4, 139.4, 135.8, 129.5,
128.4, 128.2, 126.43, 126.39, 122.9, 122.4, 118.9, 97.8, 92.4, 39.5, 34.8,
33.8.
References
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HRMS (ESI-TOF): m/z [M + H]+ calcd for C24H23Cl2N2OS: 457.0903;
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3,3-Dichloro-4-[(methyl)(phenyl)amino]-4-(methylthio)-1-phe-
nylazetidin-2-one (6i)
Colorless cubes; yield: 0.433 g (59%); mp 100–102 °C (benzene); Rf =
0.49 (5% n-hexane/EtOAc).
IR (KBr): 3026, 1787, 1597, 1493, 1430, 1367, 1301, 1218, 1169, 1132,
1095, 753, 693 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.98–7.95 (m, 2 H, Ar-H), 7.44 (t, J = 7.5
Hz, 2 H, Ar-H), 7.35–7.22 (m, 5 H, Ar-H), 7.07 (t, J = 7.2 Hz, 1 H, Ar-H),
3.19 (s, 3 H, NMe), 1.97 (s, 3 H, SMe).
13C NMR (75.5 MHz, CDCl3): δ = 158.3, 145.4, 136.0, 129.5, 128.4,
126.3, 123.0, 122.4, 118.5, 97.2, 92.2, 39.6, 15.6.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H17Cl2N2OS: 367.0433;
found: 367.0416.
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1-Benzyl-4-(benzylthio)-3,3-dichloro-4-[(methyl)(phenyl)ami-
no]azetidin-2-one (6j)
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Colorless needles; yield: 0.476 g (52%); mp 102–104 °C (EtOH); Rf =
0.48 (5% n-hexane/EtOAc).
IR (KBr): 2829, 1792, 1596, 1495, 1454, 1429, 1382, 1306, 1226, 1101,
1067, 778, 700 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.26 (m, 9 H, Ar-H), 7.16–7.05
(m, 4 H, Ar-H), 6.72–6.70 (m, 2 H, Ar-H), 4.45 (d, J = 2.7 Hz, 2 H, NCH2),
3.56 (d, J = 11.4 Hz, 1 H, SCHH), 3.37 (d, J = 11.4 Hz, 1 H, SCHH), 3.09 (s,
3 H, NMe).
13C NMR (75.5 MHz, CDCl3): δ = 160.9, 145.6, 135.7, 134.3, 128.9,
128.8, 128.5, 128.3, 128.2, 127.5, 122.4, 122.1, 98.1, 90.9, 46.6, 39.3,
36.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C24H22Cl2N2OSNa: 479.0722;
found: 479.0702.
X-ray Crystal Structure Data of 6i
Formula sum: C17H16Cl2N2OS; formula weight: 367.29; crystal sys-
tem: monoclinic; space group: P2(1)/c; unit cell dimensions: a =
7.8189(18) Å, b = 16.387(4) Å, c = 13.218(3) Å, α = 90.00°, β =
93.190(4)°, γ = 90.00°; cell volume = 1691.0(7) Å3; Z = 4; Dcalcd = 1.443
g/cm3; RAll = 0.0346. Detailed X-ray crystallographic data are available
from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK, as supplementary publication no. CCDC
1009980.
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Acknowledgment
We are thankful to IIT Delhi for providing research facilities and the
Council of Scientific and Industrial Research, New Delhi for a research
fellowship to carry out this research work. The authors thank BML
Munjal University for providing support to publish this work.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
N. Dawra, R. N. Ram
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H