Stereoselective synthesis and characterization of monocyclic cis-β-lactams containing 5-methyl-1,3,4-thiadiazole-2-thiol moiety

Article abstract of DOI:10.1002/jhet.4344

This article describes the stereoselective synthesis of monocyclic cis-β-lactams. The 2-(4-chlorophenoxy)-acetic acid or 2-phenoxy-acetic acid with a carboxylic acid activator 2-ethoxy carbonyl DCPN generate ketene in situ, which reacts with imines derived from substituted tetralone carbaldehyde yielded monocyclic cis-β-lactams having 5-methyl-1,3,4-thiadiazole-2-thiol moiety through [2+2] cyclo-addition reaction (Staudinger reaction). All structures of cis-β-lactams were elucidated by a spectral technique like FT-IR, ¹H and ¹³C NMR spectra, HRMS, and single X-ray crystallography. The cis configuration of the β-lactams was determined based on coupling constant (J) value using ¹H NMR for hydrogens H-3 and H-4 of the β-lactams ring. This work presents the synthesis of β-lactams more simply with high yields. The products were simply purified by crystallization technique.

Full text of DOI:10.1002/jhet.4344

Received: 28 May 2021
DOI: 10.1002/jhet.4344
Revised: 30 June 2021
Accepted: 7 July 2021
A R T I C L E
Stereoselective synthesis and characterization of
monocyclic cis-β-lactams containing 5-methyl-
1,3,4-thiadiazole-2-thiol moiety
Vedeshwar N. Singh
| Sitaram Sharma
Department of Chemistry, National
Institute of Technology Patna, Patna,
India
Abstract
This article describes the stereoselective synthesis of monocyclic cis-β-lactams.
The 2-(4-chlorophenoxy)-acetic acid or 2-phenoxy-acetic acid with a carboxylic
acid activator 2-ethoxy carbonyl DCPN generate ketene in situ, which reacts
with imines derived from substituted tetralone carbaldehyde yielded monocy-
clic cis-β-lactams having 5-methyl-1,3,4-thiadiazole-2-thiol moiety through
[2+2] cyclo-addition reaction (Staudinger reaction). All structures of cis-
β-lactams were elucidated by a spectral technique like FT-IR, 1H and 13C NMR
spectra, HRMS, and single X-ray crystallography. The cis configuration of the
β-lactams was determined based on coupling constant (J) value using 1H NMR
for hydrogens H-3 and H-4 of the β-lactams ring. This work presents the syn-
thesis of β-lactams more simply with high yields. The products were simply
purified by crystallization technique.
Correspondence
Sitaram Sharma, Department of
Chemistry, National Institute of
Technology Patna, Ashok Rajpath, Patna,
Bihar 800005, India.
Email: srsharma@nitp.ac.in
1 | INTRODUCTION
enzyme inhibitors [18], and insecticidal inhibitors [19]
(Figure 1). The research in this field is motivating to
Heterocycle derivatives play an important role in the
biochemical processes of the living organism [1]. The
four-membered cyclic amides are known as, β-lactams
or 2-azitidinone is an important heterocyclic strained
system because of its divergent class in the field of
chemistry, vital role in pharmaceutical products as well
in biology [2]. β-lactams ring is a key structural unit in
most widely used antibiotics such as penicillins, car-
bapenems, cephalosporins, and monobactams [3]. From
that time, it attracted researchers to develop the lower
cyclic amides.
β-lactams shows various other biologically important
functions such as antifungal [4], ezetimibe (cholesterol
absorption inhibitors) [5], cytotoxic [6], antifilarial [7],
thrombin inhibitors [8], human cytomegalovirus protease
inhibitors [9], antitumor [10], antihyperglycemic [11],
anti-HIV-1 protease [12], antimalarial activities [13],
analgesic activities [14], antitubercular [15], antip-
roliferative [16], antioxidant [17], serine-dependent
improve the antibiotics containing β-lactam rings as core
structure against bacterial resistance.
Due to the wide use of β-lactams in pharmaceuticals,
numerous synthetic methodologies have been described for
2-azetidinone [20]. The most widely used procedure for the
synthesis is [2+2] cycloaddition ketene-imine reaction
(Staudinger reaction) [21]. The generation of ketene
through reaction with acyl halides and tertiary amines
remains the most beneficial preparatory method [22]. But
the preparation through this route is highly difficult due to
the involvement of unstable acid chloride, which is difficult
to isolate. Consequently, various reagents have been used
as activators of carboxylic acid such as Phosphonitrilic
chlorides [23], propyl phosphonic anhydride (T3P) [24],
ethoxyquinoline-1-(2H)-carboxylate (EEDQ) [25], cyanuric
fluoride [21], 1,1-carbonyldiimidazole [26], 2-fluoro-
1-methyl pyridinium p-toluene sulfonate [20], thiocarbonyl
diimidazole [27], and ethyl chloroformate [28] have been
reported to generate ketenes. These reagents are expensive
J Heterocyclic Chem. 2021;1–11.
wileyonlinelibrary.com/journal/jhet
© 2021 Wiley Periodicals LLC.
1

2
SINGH AND SHARMA
FI GURE 1 Representative
examples of β-lactam rings
and poisonous. The method used for their product
ptseparation is column chromatography and the product for-
mation is necessarily temperature-dependent. An extremely
specific reagent ethyl-4,5-dichloro-6-oxopyridazine-1-(6H)-
carboxylate is convenient for conversion of mixed esters,
thioesters, amides, and carbonic anhydride from a carboxylic
acid [29]. It has been reported that 2-ethoxy carbonyl DCPN
are good leaving group [30], stable, atom-economic acyl
sources, and non-hygroscopic [31] in the reaction by carbox-
ylic acids [32].
1,3,4-Thiadiazole having β-lactams (heterocyclic
compounds) shows several types of biological properties
such as anticancer [33], antimicrobial [34], antidepres-
sant [35], antiparasitic [1,36], and so forth. In modern
times, a various 1,3,4-thiadiazole moiety containing
monocyclic β-lactams reported and shows antifungal
and antibacterial [37], antiinflammatory, analgesic,
and ulcerogenic properties [38]. Based upon the stated
facts, we investigated that a series of monocyclic
β-lactams were synthesized via an acid activator
2-ethoxy carbonyl DCPN or ethyl-4,5-dichloro-6-
and (6ba–6bf) in the presence of respective Schiff's bases
(5a–5f) of aromatic imines (Scheme 2).
We have pondered over the reaction conditions,
amount of reagent, and different solvents used to maxi-
mize the yield of the product via optimization. The inves-
tigation of the scope and optimization conditions for this
model reaction leads to the selection of carboxylic acid
activator 2-ethoxy carbonyl DCPN (2) for the synthesis
of β-lactams (Table 1). First, 2-(4-chlorophenoxy)-acetic
acid (1b, 1.0 mmol) and 2-ethoxy carbonyl DCPN
(2, 1.0 mmol) in toluene were refluxed for 3 h 30 min to
give mixed anhydride as a product and was monitored by
thin layer chromatography (TLC). In the same pot,
Schiff's base (5d, 1.0 mmol) and triethylamine (1.6 mmol)
were refluxed for 9 h yielded no product (entry
1, Table 1). Next, the same reaction condition was
repeated with the addition of Schiff's base (5d, 1.0 mmol),
Et3N in the same pot and was stirred overnight at room
temperature. The only trace amount of product was pro-
vided by the reaction (entry 2, Table 1). Then we
proceeded with the same reaction at 0ꢀC by stirring the
reaction mixture overnight, the desired product formed
52% yield (Table 1, entry 3). Now, we optimized the same
reaction conditions by replacing toluene/chloroform with
toluene/CH2Cl2. We observed that on refluxing the mix-
ture to afford no desired product. But at 0ꢀC and a stir-
ring trace amount of product formation took place. But
in the same solvent at room temperature, 72% yield was
obtained (entry 4–6, Table 1). Furthermore, we per-
formed the reaction in acetonitrile/CH2Cl2 solvent at
room temperature and at constant stirring 30% product
was yielded (entry 7, Table 1). In addition, in dioxane/
CH2Cl2 the same reaction condition gave a 45% yield
(entry 8, Table 1).
oxopyridazine-1-(6H)-carboxylate
and
substituted
tetralone carbaldehyde.
2 | RESULTS AND DISCUSSION
In our research article, 12 monocyclic cis-β-lactams (6aa–
6af) and (6ba–6bf) have been synthesized (Figure 2) by a
stereoselective ketene-imine [2+2] cyclo-addition reac-
tion (Staudinger reaction) in presence of carboxylic
acid activator ethyl-4,5-dichloro-6-oxopyridazine-1-(6H)-
carboxylate (2).
In the first scheme, 2-(4-chlorophenoxy)-acetic acid
or 2-phenoxy-acetic acid (1a–b) in toluene solvent was
added in carboxylic acid activator 2-ethoxy carbonyl
DCPN (2) to get mixed anhydride (3a–3b) and 2-ethoxy
carbonyl DCPN (4) as co-product (Scheme 1). The
obtained mixed anhydrides (3a–3b) reacted with
triethylamine in dry CH2Cl2 to give ketene, which is
converted into monocyclic cis-β-lactam hybrids (6aa–6af)
Afterward, we performed the reaction by varying
amounts, that is, the number of millimoles of acid activa-
tor (2) and acid (1b) in toluene/CH2Cl2 at room tempera-
ture and constant stirring as the reaction condition.
When the amount of acid (1b) was increased, the yield of
product formation was 88%, which is considerably good
(entry 9, Table 1). After that, the amount of acid

SINGH AND SHARMA
3
FIGURE 2 Library of
synthesized monocyclic cis-
β-lactam conjugates
activator (2) was increased, rest reactants remaining one
equivalent, we found that the yield decreases from the
previous case and comes to be 75% (entry 10, Table 1).
Then decreasing acid activator (2), increasing acid (1b),
and keeping Schiff's base (5d) as one equivalent gave 60%
yield (entry 11, Table 1). Consequently, yield decreases
to 42% when acid activator (2, 0.50 mmol) was taken
(entry 12, Table 1). As an observation, we can say that
increasing acid (1b, 1.3 mmol), but keeping acid activator
(2) and Schiff's base (5d) one equivalent at room temper-
ature gave maximum yield. Now, we investigated various
acid and base catalysts for this model reaction. Among
the tested acids and bases likes ϸ-toluene sulfonic acid,
acetic acid, K2CO3, Et3N, DABCO (1,4-diazabicyclo
[2.2.2] octane), and DBU in CH2Cl2 as solvents, the yield
was very poor with DABCO, DBU (1,8-Diazabicyclo
[5.4.0] undec-7-ene), and K2CO3 bases and could not iso-
late the product. When ϸ-toluene sulfonic acid and acetic

4
SINGH AND SHARMA
SCHEME 1 The mixed
anhydride (3a–3b) synthesized
from an acid activator
SCHEME 2 The new
synthesis of monocyclic cis-
β-lactams hybrids (6aa–6af) and
(6ba–6bf)
TABLE 1 The optimization conditions of a model reaction for the synthesis 6ad using 2-ethoxy carbonyl DCPNa
Weight of acid
activator
2 (mmol)
Weight
of acid 1b
(mmol)
Schiff
base
5d (mmol)
Isolated
yieldb
(%)
Sequence of
solvent
Reaction
conditiona
Entry
1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.3
1.0
1.2
1.2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
Toluene/Chloroform
Toluene/Chloroform
Toluene/Chloroform
Toluene/CH2Cl2
Toluene/CH2Cl2
Toluene/CH2Cl2
Acetonitrile/CH2Cl2
Dioxane/CH2Cl2
Toluene/CH2Cl2
Toluene/CH2Cl2
Toluene/CH2Cl2
Toluene/CH2Cl2
Refluxing
0ꢀC, stirring
rt, stirring
Refluxing
0ꢀC, stirring
rt, stirring
rt, stirring
rt, stirring
rt, stirring
rt, stirring
rt, stirring
rt, stirring
Nil
Trace
52
2
1.0
3
1.0
4
1.0
Nil
Trace
72
5
1.0
6
1.0
7
1.0
30
8
1.0
45
9
1.0
88
10
11
12
1.25
0.75
0.50
75
60
42
aReaction condition: 2-(4-chlorophenoxy)-acetic acid (1b, 1.3 mmol), 2-ethoxy carbonyl DCPN (2, 1.0 mmol), Schiff's base (5d, 1.0 mmol), solvent: toluene/
CH2Cl2 (15 mL), triethylamine (1.6 mmol).
bIsolated yield.

SINGH AND SHARMA
5
FIGURE 3 The mechanism
of synthesis of monocyclic cis-
β-lactams
acid were used, no reaction took place. But in the case of
the Et3N base, the product of (6ad) gave the highest yield
and easily isolated in the presence of CH2Cl2 solvent.
Encouraged by these results and optimization conditions,
we have newly synthesized the β-lactam derivatives by a
simple reaction condition, easy aqueous workup, high
atom economy, and good yields. All the products were
simply purified by the crystallization technique.
β-lactams (6bd) and (6bf). This spectrum shows the
two CH2 groups, along with 12 CH and CH3 groups,
which confirms the structure of β-lactams. The HRMS
data displayed each structure of the β-lactams as well.
In addition, for reconfirmation of these structures, we
also visualized the synthesized structure (6aa) and
(6ad) using a single crystal XRD (Figures 4 and 5).
The Staudinger reaction mechanism is described in
the following manner as below. In the initial step,
nucleophilic nitrogen atom attacks on the electrophilic
center of ketene carbon that is generated in situ from
the reaction of mixed anhydride and triethylamine as a
base to obtain a zwitterionic intermediate and then in
the final step, they undergo ring closer reaction
followed by conrotatory manner to afford a four-
membered cyclic amide known as β-lactams (Figure 3)
[39–41].
All the structures of newly synthesized compounds
were identified by the spectral technique such as
FT-IR, 1H and 13C NMR spectra, HRMS, and X-ray
crystallography data. The infra-red spectra recorded for
β-lactams ring show stretching frequency band at
1739–1759 cmÀ1 for the carbonyl group, at 1605–
1591 cmÀ1 for imines (C=N group), and 744–763 cmÀ1
for the C-S-C group. The stereochemistry of the β-
lactam compounds was dictated by the coupling con-
stants using 1H NMR for hydrogens H-3 and H-4.
The 1H NMR depicted J = 5.0–5.1 Hz for cis-
stereoisomers because of coupling constant (J) value of
H-3 and H-4, for cis isomer JÀ3,4 > 4 Hz and trans iso-
mer JÀ3,4 ≤ 3 Hz. This confirmed the cis geometry of
β-lactams synthesized [42–45]. The 13C NMR spectra
were recorded at a characteristic peak at 161.89–
166.35 ppm for β-lactams carbonyl carbon. DEPT spec-
tra were used to evaluate the peak multiplicity of
3 | EXPERIMENTAL SECTION
In our synthesis work, we used all necessary chemicals
bought from Merck chemicals companies, Acros organic,
and Sigma-Aldrich and used without further purification.
The melting points were determined with open capil-
laries by the EI melting point apparatus and were incor-
rect. The IR spectra were recorded from the
spectrophotometer on Shimadzu FT-IR in ATR cmÀ1. H
1
and 13C NMR spectral data recorded on Bruker Advance
II 400 MHz spectrophotometer using 400 MHz for 1H
NMR spectra and 100 MHz for 13C NMR spectra, respec-
tively, in a CDCl3 solvent and an internal standard
(Tetramethyl silane or TMS). The chemical shifts were
determined using the δ scale measured in parts per mil-
lion (ppm), which are downfield from TMS as a standard
reference. CDCl3 solvent peaks were recorded as the stan-
1
dard reference for H NMR spectra (δ = 7.28 ppm) and
13C NMR spectra (δ = 77.0 ppm). The notation for split-
ting patterns of NMR follows as multiplicity (s: singlet, d:
doublet, t: triplet, q: quartet, m: multiplet, dd: doublet of
doublet, and dt: doublet of triplet), and which coupling
constant values were reported in Hz. High-resolution
mass spectroscopy was recorded with the help of an
electrospray ionization time-of-flight (ESI-TOF) mass
analyzer. Analytically, TLC was used to study the pro-
gress of reaction, which was carried out on silica gel 254.

6
SINGH AND SHARMA
FIGURE 4 ORTEP diagram of compound 6aa (2065126). A crystallizing solvent of the molecules CH2Cl2 was trapped in the structure
(right top quadrant)
FIGURE 5 ORTEP diagram
of compound 6ad (2065741)
3.1 | Synthesis of ethyl-4,5-dichloro-
6-oxopyradazine-1-(6H)-carboxylate (2)
dry CH2Cl2 in a dry round-bottom flask were stirred at 5ꢀC
for 10 min. Ethyl chloroformate (2.0 mmol) in 5 mL dry
CH2Cl2 was added dropwise to the reaction mixture and
monitored by TLC. On the completion of the reaction, the
obtained product was washed with water five times.
To
a
solution of 4,5-dichloropyradazin-3-(2H)-one
(2.0 mmol) and triethylamine (2.3 mmol) as a base in 15 mL

SINGH AND SHARMA
7
The organic layer was separated and dried over anhydrous
sodium sulfate and then removed by the solvent by reduced
pressure. The residue was purified by the recrystallization,
which was performed by THF/n-hexane in good yield [46].
White solid; 81% yield (0.192 gm, 1.62 mmol); IR (ATR
cmÀ1): 3062, 1784, 1684, 1605, 1274, 950, 752 cmÀ1 [47].
(ÀCH2), 27.1 (ÀCH2), 56.4 (ÀOCH3), 61.0 (C-4 of
β-lactam), 81.0 (C-3 of β-lactam), 94.8, 115.3, 122.5, 125.6,
127.1, 127.7, 128.8, 129.5, 129.7, 132.5, 133.3, 135.4, 137.0,
145.7, 153.9, 157.0, 162.7, 164.6 (C=C & aromatic car-
bons), 166.2 (C=O of β-lactam); HRMS (ESI-TOF): m/z
calcd for C31H30N3O5S2 [M+H]+ 588.1621, found
588.1633.
3.2 | General procedure for the synthesis
of newly monocyclic 2-azetidinone (6aa–
6af) and (6ba–6bf)
3.2.2 | 1-(3,4-dimethoxyphenyl)-4-(1-((5-
methyl-1,3,4-thiadiazol-2-yl)-thio)-3,4-
dihydronaphthalen-2-yl)-3-phenoxyazetidin-
2-one (6ab)
To a solution of ethyl-4,5-dichloro-6-oxopyridazine-1-(6H)-
carboxylate (2, 1.0 mmol) and 2-(4-chlorophenoxy)-acetic
acid/2-phenoxy acetic acid (1a–b, 1.25 mmol) in toluene in
a dry round-bottom flask were refluxed for 3.5 h and moni-
tored by TLC. On the completion of the reaction, the solvent
was extracted by reduced pressure. After that obtained resi-
due dissolved in dry CH2Cl2, followed by proper Schiff's base
(5a–f, 1.0 mmol), that is, aromatic imine and triethylamine
(1.6 mmol) in 5 mL dry CH2Cl2 added dropwise and stirred
overnight at room temperature of the reaction mixture. On
the completion of the reaction, the reaction mixture was
washed with a cold aqueous solution (sodium bicarbonate
and water) three times and extracting the organic layer by
CH2Cl2 solvent. The organic layer dried over anhydrous
Na2SO4 and removed by vacuum distillation process to
afford the crude products. The purification process was per-
formed by initially washing through diethyl ether followed
by recrystallization from dry CH2Cl2 and petroleum ether to
give pure monocyclic cis-β-lactams (6aa–6af) and (6ba–6bf),
respectively. All compounds were confirmed by spectral
Milky white crystalline solid; 82% yield (0.457 gm,
0.82 mmol); mp 148–150ꢀC; IR (ATR cmÀ1): 1755 (C=O
group of β-lactam), 1591 (ÀC=N), 763 (C-S-C) cmÀ1; H
1
NMR (400 MHz, CDCl3): δ 2.34–2.42 (1H, m, ÀCH2), 2.50
(3H, s, ÀCH3), 2.66–2.74 (2H, m, ÀCH2), 2.77–2.84 (1H, m,
ÀCH2), 3.84 (3H, s, ÀOCH3), 3.89 (3H, s, ÀOCH3), 5.53
(1H, d, J = 5.1 Hz, H-4 of β-lactam), 6.17 (1H, d,
J = 5.1 Hz, H-3 of β-lactam), 6.72 (1H, d, J = 8.5 Hz, ArH),
6.78 (1H, d, J = 8.7 Hz, ArH), 6.96–6.98 (3H, m, ArH), 7.15
(1H, d, J = 8.5 Hz, ArH), 7.20–7.24 (4H, m, ArH), 7.39 (1H,
s, ArH), 7.71 (1H, d, J = 8.7 Hz, ArH); 13C NMR (100 MHz,
CDCl3): δ 15.6 (ÀCH3), 25.7 (ÀCH2), 27.0 (ÀCH2), 56.2
(ÀOCH3), 60.8 (C-4 of β-lactam), 81.1 (C-3 of β-lactam),
102.1, 108.0, 111.4, 115.3, 122.4, 125.7, 127.1, 127.6, 128.8,
129.6, 129.7, 131.1, 132.6, 137.1, 145.9, 146.4, 149.7, 157.1,
162.5, 165.1 (C=C & aromatic carbons), 166.3 (C=O of
β-lactam); HRMS (ESI-TOF): m/z calcd for C30H28N3O4S2
[M+H]+ 558.1516, found 558.1526.
1
analysis such as FT-IR, H and 13C NMR spectra, HRMS,
and X-ray crystallography technique (Electronic Supplemen-
tary Information).
3.2.3 | 1-(4-methoxyphenyl)-4-(1-((5-methyl-
1,3,4-thiadiazol-2-yl)-thio)-3,4-dihydronaphthal-
2-yl)-3-phenoxyazetidin-2-one (6ac)
3.2.1 | 4-(1-((5-methyl-1,3,4-thiadiazol-2-yl)-
thio)-3,4-dihydronaphthalen-2-yl)-3-phenoxy-
1-(3,4,5-trimethoxyphenyl)-azetidin-2-one (6aa)
Yellowish white crystalline solid; 85% yield (0.448 gm,
0.85 mmol); mp 234–236ꢀC; IR (ATR cmÀ1): 1751 (C=O
1
group of β-lactam), 1593 (ÀC=N), 754 (C-S-C) cmÀ1; H
Yellowish white crystalline solid; 81% yield (0.476 gm,
NMR (400 MHz, CDCl3): δ 2.32–2.38 (1H, m, ÀCH2), 2.48
(3H, s, ÀCH3), 2.65–2.76 (2H, s, ÀCH2), 2.79–2.84 (1H, m,
ÀCH2), 3.77 (3H, s, ÀOCH3), 5.52 (1H, d, J = 5.1 Hz, H-4
of β-lactam), 6.17 (1H, d, J = 5.1 Hz, H-3 of β-lactam), 6.85
(2H, d, J = 9.0 Hz, ArH), 6.93–6.98 (3H, m, ArH), 7.12–
7.16 (1H, m, ArH), 7.21 (4H, dd, J = 8.3, 6.7 Hz, ArH), 7.39
(2H, d, J = 9.0 Hz, ArH), 7.72–7.74 (1H, m, ArH); 13C
NMR (100 MHz, CDCl3): δ 15.6 (ÀCH3), 25.7 (ÀCH2), 27.0
(ÀCH2), 55.5 (ÀOCH3), 60.6 (C-4 of β-lactam), 81.1 (C-3 of
β-lactam), 114.6, 115.2, 118.4, 122.4, 125.8, 127.1, 127.6,
128.8, 129.7, 129.7, 130.7, 132.6, 137.1, 146.0, 156.8, 157.1,
162.3, 165.4 (C=C & aromatic carbons), 166.3 (C=O of
0.81 mmol); mp 165–167ꢀC; IR (ATR cmÀ1): 1751 (C=O
1
group of β-lactam), 1591 (ÀC=N), 759 (C-S-C) cmÀ1; H
NMR (400 MHz, CDCl3): δ 2.38–2.46 (1H, m, ÀCH2),
2.51 (3H, s, ÀCH3), 2.65–2.75 (2H, m, ÀCH2), 2.78–2.86
(1H, m, ÀCH2), 3.80 (3H, s, ÀOCH3), 3.83 (6H, s,
ÀOCH3), 5.55 (1H, d, J = 5.1 Hz, H-4 of β-lactam), 6.18
(1H, d, J = 5.1 Hz, H-3 of β-lactam), 6.75 (2H, s, ArH),
6.96 (1H, s, ArH), 6.98 (2H, t, J = 3.3 Hz, ArH), 7.17 (1H,
dd, J = 7.1, 4.7 Hz, ArH), 7.20 (2H, d, J = 6.4 Hz, ArH),
7.23 (2H, d, J = 8.0 Hz, ArH), 7.68 (1H, d, J = 8.9 Hz,
ArH); 13C NMR (100 MHz, CDCl3): δ 15.6 (ÀCH3), 25.8

8
SINGH AND SHARMA
β-lactam); HRMS (ESI-TOF): m/z calcd for C29H26N3O3S2
[M+H]+ 528.1410, found 528.1414 [48].
HRMS (ESI-TOF): m/z calcd for C31H30N3O5S2 [M+H]+
588.1621, found 588.1621.
3.2.4 | 4-(6-methoxy-1-((5-methyl-1,3,4-
thiadiazol-2-yl)-thio)-3,4-dihydro-naphthalen-2-
yl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)-
azetidin-2-one (6ad)
3.2.6 | 4-(6-methoxy-1-((5-methyl-
1,3,4-thiadiazol-2-yl)-thio)-3,4-dihydro-
naphthalen-2-yl)-1-(4-methoxyphenyl)-
3-phenoxyazetidin-2-one (6af)
Yellowish crystalline solid; 88% yield (0.543 gm,
Yellowish white crystalline solid; 85% yield (0.474 gm,
0.88 mmol); mp 173–175ꢀC; IR (ATR cmÀ1): 1751 (C=O
0.85 mmol); mp 194–196ꢀC; IR (ATR cmÀ1): 1750 (C=O
1
1
group of β-lactam), 1593 (ÀC=N), 754 (C-S-C) cmÀ1; H
group of β-lactam), 1605 (ÀC=N), 754 (C-S-C) cmÀ1; H
NMR (400 MHz, CDCl3): δ 2.34–2.43 (1H, m, ÀCH2),
2.51 (3H, s, ÀCH3), 2.62–2.71 (2H, m, ÀCH2), 2.74–2.82
(1H, m, ÀCH2), 3.79 (3H, s, ÀOCH3), 3.80 (3H, s,
ÀOCH3), 3.82 (6H, s, ÀOCH3), 5.53 (1H, d, J = 5.1 Hz,
H-4 of β-lactam), 6.16 (1H, d, J = 5.1 Hz, H-3 of
β-lactam), 6.68–6.71 (2H, m, ArH), 6.74 (2H, s, ArH), 6.95
(1H, s, ArH), 6.97 (2H, d, J = 5.7 Hz, ArH), 7.20–7.26
(2H, m, ArH), 7.60 (1H, d, J = 9.0 Hz, ArH); 13C NMR
(100 MHz, CDCl3): δ 15.6 (ÀCH3), 25.7 (ÀCH2), 27.7
(ÀCH2), 55.3 (ÀOCH3), 56.4 (ÀOCH3), 61.0 (C-4 of
β-lactam), 81.0 (C-3 of β-lactam), 94.8, 111.7, 113.8, 115.3,
122.4, 125.4, 127.3, 129.3, 129.7, 133.4, 135.3, 138.9, 142.3,
153.9, 157.0, 160.0, 162.8, 165.0 (C=C & aromatic car-
bons), 166.1 (C=O of β-lactam); HRMS (ESI-TOF): m/z
calcd for C32H32N3O6S2 [M+H]+ 618.1727, found
618.1727.
NMR (400 MHz, CDCl3): δ 2.30–2.36 (1H, m, ÀCH2),
2.49 (3H, s, ÀCH3), 2.61–2.70 (2H, m, ÀCH2), 2.74–2.80
(1H, m, ÀCH2), 3.77 (3H, s, ÀOCH3), 3.79 (3H, s,
ÀOCH3), 5.51 (1H, d, J = 5.1 Hz, H-4 of β-lactam), 6.15
(1H, d, J = 5.0 Hz, H-3 of β-lactam), 6.70 (2H, d,
J = 7.8 Hz, ArH), 6.85 (2H, d, J = 9.0 Hz, ArH), 6.93–
6.96 (3H, m, ArH), 7.20 (2H, t, J = 7.8 Hz, ArH), 7.36–
7.40 (2H, m, ArH), 7.65 (1H, d, J = 8.4 Hz, ArH); 13C
NMR (100 MHz, CDCl3): δ 15.6 (ÀCH3), 25.5 (ÀCH2),
27.5 (ÀCH2), 55.3 (ÀOCH3), 55.5 (ÀOCH3), 60.6 (C-4 of
β-lactam), 81.1 (C-3 of β-lactam), 111.7, 113.8, 114.6,
115.2, 118.4, 122.3, 125.5, 127.4, 129.4, 129.6, 130.7, 139.0,
142.6, 156.8, 157.1, 160.0, 162.4, 165.7 (C=C & aromatic
carbons), 166.2 (C=O of β-lactam); HRMS (ESI-TOF):
m/z calcd for C30H28N3O4S2 [M+H]+ 558.1516, found
558.1520 [48].
3.2.5 | 1-(3,4-dimethoxyphenyl)-
4-(6-methoxy-1-((5-methyl-1,3,4-thia-diazol-
2-yl)-thio)-3,4-dihydronaphthalen-2-yl)-
3-phenoxyazetidin-2-one (6ae)
3.2.7 | 3-(4-chlorophenoxy)-4-(1-((5-methyl-
1,3,4-thiadiazol-2-yl)-thio)-
3,4-dihydronaphthalen-2-yl)-
1-(3,4,5-trimethoxyphenyl)-azetidin-2-one (6ba)
White crystalline solid; 81% yield (0.476 gm, 0.81 mmol);
Pale yellow crystalline solid; 86% yield (0.535 gm,
mp 186–188ꢀC; IR (ATR cmÀ1): 1753 (C=O group of
0.86 mmol); mp 129–131ꢀC; IR (ATR cmÀ1): 1755 (C=O
β-lactam), 1595 (ÀC=N), 752 (C-S-C) cmÀ1
;
1H NMR
group of β-lactam), 1593 (ÀC=N), 758 (C-S-C) cmÀ1; H
1
(400 MHz, CDCl3): δ 2.32–2.40 (1H, m, ÀCH2), 2.50 (3H,
s, ÀCH3), 2.62–2.72 (2H, m, ÀCH2), 2.75–2.80 (1H, m,
ÀCH2), 3.79 (3H, s, ÀOCH3), 3.84 (3H, s, ÀOCH3), 3.88
(3H, s, ÀOCH3), 5.52 (1H, d, J = 5.1 Hz, H-4 of β-lactam),
6.15 (1H, d, J = 5.1 Hz, H-3 of β-lactam), 6.68–6.72 (3H,
s, ArH), 6.77 (1H, d, J = 8.6 Hz, ArH), 6.94–6.96 (2H, m,
ArH), 6.97 (1H, s, ArH), 7.19–7.26 (2H, m, ArH), 7.38
(1H, d, J = 2.3 Hz, ArH), 7.63 (1H, d, J = 9.0 Hz, ArH);
13C NMR (100 MHz, CDCl3): δ 15.6 (ÀCH3), 25.6
(ÀCH2), 27.5 (ÀCH2), 55.3 (ÀOCH3), 56.1 (ÀOCH3), 60.8
(C-4 of β-lactam), 81.0 (C-3 of β-lactam), 102.1, 108.0,
111.4, 111.7, 113.8, 115.2, 122.3, 125.5, 127.4, 129.3, 129.6,
131.1, 139.0, 142.5, 146.4, 149.6, 157.1, 160.0, 162.5, 165.5
(C=C & aromatic carbons), 166.2 (C=O of β-lactam);
NMR (400 MHz, CDCl3): δ 2.36–2.43 (1H, m, ÀCH2), 2.56
(3H, s, ÀCH3), 2.62–2.75 (2H, m, ÀCH2), 2.77–2.83 (1H,
m, ÀCH2), 3.80 (3H, s, ÀOCH3), 3.83 (6H, s, ÀOCH3),
5.51 (1H, d, J = 5.1 Hz, H-4 of β-lactam), 6.18 (1H, d,
J = 5.1 Hz, H-3 of β-lactam), 6.74 (2H, s, ArH), 6.91 (2H,
d, J = 9.0 Hz, ArH), 7.15–7.18 (3H, m, ArH), 7.22–7.26
(2H, m, ArH), 7.68 (1H, d, J = 8.2 Hz, ArH); 13C NMR
(100 MHz, CDCl3): δ 15.6 (ÀCH3), 25.8 (ÀCH2), 27.1
(ÀCH2), 56.4 (ÀOCH3), 61.0 (C-4, β-lactam), 81.1 (C-3,
β-lactam), 94.7, 116.6, 125.7, 127.1, 127.6, 127.7, 128.9,
129.6, 129.6, 132.4, 133.2, 135.4, 136.9, 145.3, 153.9, 155.5,
162.3, 164.1 (C=C & aromatic carbons), 166.3 (C=O of
β-lactam);
HRMS
(ESI-TOF):
m/z
calcd
for
C31H29ClN3O5S2 [M+H]+ 622.1232, found 622.1241.

SINGH AND SHARMA
9
3.2.8 | 3-(4-chlorophenoxy)-
1-(3,4-dimethoxyphenyl)-4-(1-((5-methyl-
1,3,4-thiadiazol-2-yl)-thio)-
3,4-dihydronaphthalen-2-yl)-azetidin-
2-one (6bb)
3.2.10 | 3-(4-chlorophenoxy)-4-(6-methoxy-
1-((5-methyl-1,3,4-thiadiazol-2-yl)-thio)-
3,4-dihydronaphthalen-2-yl)-
1-(3,4,5-trimethoxyphenyl)-azetidin-2-one (6bd)
Yellowish white crystalline solid; 88% yield (0.574 gm,
Yellow crystalline solid; 86% yield (0.535 gm, 0.86 mmol);
0.88 mmol); mp 154–156ꢀC; IR (ATR cmÀ1): 1739 (C=O
mp 190–192ꢀC; IR (ATR cmÀ1): 1751 (C=O group of
group of β-lactam), 1595 (ÀC=N), 744 (C-S-C) cmÀ1; H
1
β-lactam), 1591 (ÀC=N), 763 (C-S-C) cmÀ1
;
1H NMR
NMR (400 MHz, CDCl3): δ 2.32–2.41 (1H, m, ÀCH2),
2.56 (3H, s, ÀCH3), 2.59–2.66 (1H, m, ÀCH2), 2.69–2.77
(2H, m, ÀCH2), 3.79 (3H, s, ÀOCH3), 3.80 (3H, s,
ÀOCH3), 3.82 (6H, s, ÀOCH3), 5.49 (1H, d, J = 5.1 Hz,
H-4 of β-lactam), 6.16 (1H, d, J = 5.1 Hz, H-3 of
β-lactam), 6.71 (4H, d, J = 8.9 Hz, ArH), 6.90 (2H, d,
J = 9.0 Hz, ArH), 7.16 (2H, d, J = 9.0 Hz, ArH), 7.61 (1H,
d, J = 9.1 Hz, ArH); 13C NMR (100 MHz, CDCl3): δ 15.6
(ÀCH3), 25.7 (ÀCH2), 27.6 (ÀCH2), 55.3 (ÀOCH3), 56.4
(ÀOCH3), 61.0 (C-4 of β-lactam), 81.1 (C-3 of β-lactam),
94.8, 111.8, 113.8, 116.5, 125.3, 127.4, 127.5, 129.4, 129.6,
133.2, 135.4, 138.9, 141.9, 153.9, 155.6, 160.1, 162.3, 164.5
(C=C & aromatic carbons), 166.2 (C=O of β-lactam);
HRMS (ESI-TOF): m/z calcd for C32H31ClN3O6S2 [M
+H]+ 652.1337, found 652.1335.
(400 MHz, CDCl3): δ 2.31–2.40 (1H, m, ÀCH2), 2.55 (3H,
s, ÀCH3), 2.62–2.73 (2H, m, ÀCH2), 2.75–2.82 (1H, m,
ÀCH2), 3.84 (3H, s, ÀOCH3), 3.88 (3H, s, ÀOCH3), 5.49
(1H, d, J = 5.1 Hz, H-4 of β-lactam), 6.18 (1H, d,
J = 5.1 Hz, H-3 of β-lactam), 6.70 (1H, d, J = 9.0 Hz,
ArH), 6.77 (1H, d, J = 8.6 Hz, ArH), 6.91 (2H, d,
J = 9.0 Hz, ArH), 7.15 (2H, d, J = 3.3 Hz, ArH), 7.17 (1H,
d, J = 2.3 Hz, ArH), 7.22–7.26 (2H, m, ArH), 7.37 (1H, d,
J = 2.3 Hz, ArH), 7.72 (1H, d, J = 9.0 Hz, ArH); 13C
NMR (100 MHz, CDCl3): δ 15.6 (ÀCH3), 25.7 (ÀCH2),
27.0 (ÀCH2), 56.2 (ÀOCH3), 60.7 (C-4 of β-lactam), 81.2
(C-3 of β-lactam), 102.0, 108.0, 111.4, 116.6, 125.7, 127.1,
127.5, 127.7, 128.9, 129.6, 129.7, 130.9, 132.5, 137.0, 145.5,
146.5, 149.7, 155.6, 162.0, 164.7 (C=C & aromatic car-
bons), 166.3 (C=O of β-lactam); HRMS (ESI-TOF): m/z
calcd for C30H27ClN3O4S2 [M+H]+ 592.1126, found
592.1136.
3.2.11 | 3-(4-chlorophenoxy)-
1-(3,4-dimethoxyphenyl)-4-(6-methoxy-
1-((5-methyl-1,3,4-thiadiazol-2-yl)-thio)-
3,4-dihydronaphthalen-2-yl)-azetidin-
2-one (6be)
3.2.9 | 3-(4-chlorophenoxy)-
1-(4-methoxyphenyl)-4-(1-((5-methyl-
1,3,4-thiadiazol-2-yl)-thio)-
3,4-dihydronaphthalen-2-yl)-azetidin-
2-one (6bc)
White crystalline solid; 85% yield (0.499 gm,
0.85 mmol); mp 172–174ꢀC; IR (ATR cmÀ1): 1747 (C=O
group of β-lactam), 1597 (ÀC=N), 750 (C-S-C) cmÀ1; 1H
NMR (400 MHz, CDCl3): δ 2.28–2.36 (1H, m, ÀCH2),
2.56 (3H, s, ÀCH3), 2.59–2.65 (1H, m, ÀCH2), 2.67–2.77
(2H, m, ÀCH2), 3.79 (3H, s, ÀOCH3), 3.84 (3H, s,
ÀOCH3), 3.88 (3H, s, ÀOCH3), 5.48 (1H, d, J = 5.0 Hz,
H-4 of β-lactam), 6.15 (1H, d, J = 5.0 Hz, H-3 of
β-lactam), 6.68–6.72 (3H, m, ArH), 6.77 (1H, d,
J = 8.6 Hz, ArH), 6.90 (2H, d, J = 9.0 Hz, ArH), 7.15
(2H, d, J = 9.0 Hz, ArH), 7.36 (1H, d, J = 2.3 Hz, ArH),
7.64 (1H, d, J = 8.3 Hz, ArH); 13C NMR (100 MHz,
CDCl3): δ 15.6 (ÀCH3), 25.5 (ÀCH2), 27.5 (ÀCH2), 55.3
(ÀOCH3), 56.1 (ÀOCH3), 60.6 (C-4 of β-lactam), 81.1
(C-3 of β-lactam), 102.1, 108.0, 111.4, 111.7, 113.8,
116.5, 125.4, 127.4, 127.4, 129.4, 129.5, 131.0, 138.9,
142.1, 146.5, 149.6, 155.6, 160.1, 162.0, 165.1 (C=C &
aromatic carbons), 166.3 (C=O of β-lactam); HRMS
(ESI-TOF): m/z calcd for C31H29ClN3O5S2 [M+H]+
622.1232, found 622.1226.
Yellowish white crystalline solid; 87% yield (0.489 gm,
0.87 mmol); mp 224–226ꢀC; IR (ATR cmÀ1): 1759 (C=O
group of β-lactam), 1593 (ÀC=N), 759 (C-S-C) cmÀ1; H
1
NMR (400 MHz, CDCl3): δ 2.27–2.36 (1H, m, ÀCH2),
2.53 (3H, s, ÀCH3), 2.61–2.69 (2H, m, ÀCH2), 2.71–2.80
(1H, m, ÀCH2), 3.76 (3H, s, ÀOCH3), 5.47 (1H, d,
J = 5.1 Hz, H-4 of β-lactam), 6.16 (1H, d, J = 5.1 Hz, H-3
of β-lactam), 6.83–6.88 (3H, m, ArH), 6.90 (1H, s, ArH),
7.14 (3H, d, J = 8.6 Hz, ArH), 7.18–7.23 (2H, m,
ArH), 7.36 (2H, d, J = 8.9 Hz, ArH), 7.71–7.74 (1H, m,
ArH); 13C NMR (100 MHz, CDCl3): δ 15.7 (ÀCH3), 25.7
(ÀCH2), 27.0 (ÀCH2), 55.6 (ÀOCH3), 60.6 (C-4 of
β-lactam), 81.2 (C-3 of β-lactam), 114.7, 116.6, 118.4,
125.9, 127.2, 127.5, 127.8, 129.0, 129.6, 129.9, 130.6, 132.5,
137.1, 145.6, 155.7, 157.0 (C=C & aromatic carbons),
161.9 (C=O of β-lactam); HRMS (ESI-TOF): m/z calcd
for C29H25ClN3O3S2 [M+H]+ 562.1020, found 562.1024.

10
SINGH AND SHARMA
3.2.12 | 3-(4-chlorophenoxy)-4-(6-methoxy-
1-((5-methyl-1,3,4-thiadiazol-2-yl)-thio)-
3,4-dihydronaphthalen-2-yl)-
for single crystal XRD. The authors confirm that the data
supporting the findings of this study are available and
provided the CCDC of the compound 6aa (2065126)
and compound 6ad (2065741) within the article in its
supplementary materials.
1-(4-methoxyphenyl)-azetidin-2-one (6bf)
Yellowish white crystalline solid; 88% yield (0.521 gm,
0.88 mmol); mp 180–182ꢀC; IR (ATR cmÀ1): 1749 (C=O
ORCID
1
group of β-lactam), 1597 (ÀC=N), 752 (C-S-C) cmÀ1; H
Vedeshwar N. Singh https://orcid.org/0000-0001-9162-
3016
Sitaram Sharma https://orcid.org/0000-0001-5074-2676
NMR (400 MHz, CDCl3): δ 2.24–2.32 (1H, m, ÀCH2),
2.53 (3H, s, ÀCH3), 2.57–2.65 (2H, m, ÀCH2), 2.67–2.75
(1H, m, ÀCH2), 3.76 (3H, s, ÀOCH3), 3.78 (3H, s,
ÀOCH3), 5.45 (1H, d, J = 5.1 Hz, H-4 of β-lactam), 6.14
(1H, d, J = 5.1 Hz, H-3 of β-lactam), 6.70 (2H, dd,
J = 9.0, 2.9 Hz, ArH), 6.82 (1H, s, ArH), 6.85 (1H, s,
ArH), 6.86 (1H, s, ArH), 6.89 (1H, s, ArH), 7.12 (2H, d,
J = 8.7 Hz, ArH), 7.35 (2H, d, J = 9.1 Hz, ArH), 7.64 (1H,
d, J = 8.5 Hz, ArH); 13C NMR (100 MHz, CDCl3): δ 15.7
(ÀCH3), 25.6 (ÀCH2), 27.5 (ÀCH2), 55.4 (ÀOCH3), 55.6
(ÀOCH3), 60.5 (C-4 of β-lactam), 81.2 (C-3 of β-lactam),
111.8, 113.9, 114.7, 116.5, 118.4, 125.4, 127.4, 127.5, 129.6,
129.6, 130.6, 139.0, 142.2, 155.7, 156.9, 160.1, 161.9, 165.4
(C=C & aromatic carbons), 166.4 (C=O of β-lactam);
HRMS (ESI-TOF): m/z calcd for C30H27ClN3O4S2 [M
+H]+ 592.1126, found 592.1140.
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How to cite this article: V. N. Singh, S. Sharma,
J. Heterocycl. Chem. 2021, 1. https://doi.org/10.
1002/jhet.4344