Copper-catalyzed thioarylation or thioalkylation of halogenated 2-azetidinones using a thiol precursor

Article abstract of DOI:10.1007/s00706-018-2177-z

Abstract: The paper describes the synthesis and characterization data of new 2-azetidinones containing sulfide groups. Halogenated 2-azetidinones were synthesized by the reaction of ketenes, generated in situ from various carboxylic acid in the presence o

Full text of DOI:10.1007/s00706-018-2177-z

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-018-2177-z(0123456789(). -, vo Vl
)
0
1
2
3
4
5
6
7
8
9
-
)
.
o
l
V
)
ORIGINAL PAPER
Copper-catalyzed thioarylation or thioalkylation of halogenated
2-azetidinones using a thiol precursor
Maryam Ravandeh Ghotbabadi1 Maaroof Zarei1
•
Received: 9 December 2017 / Accepted: 18 February 2018
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2018
Abstract
The paper describes the synthesis and characterization data of new 2-azetidinones containing sulfide groups. Halogenated
2-azetidinones were synthesized by the reaction of ketenes, generated in situ from various carboxylic acid in the presence
of Vilsmeier reagent, with different Schiff bases. These compounds on further reaction with several aryl or alkyl halide
using copper(I) iodide and sodium thiosulfate produced novel 2-azetidinones including sulfide substituents in N-1 or C-3 or
1
C-4 position. The compounds have been characterized by elemental analysis and spectral (IR, H and 13C NMR) data.
Graphical abstract
Keywords b-Lactam Á 2-Azetidinone Á Thioarylation Á Thioalkylation Á Copper-catalyzed
Introduction
activities [6–8] and are also used as synthon for the syn-
thesis of several organic compounds [9–11]. Several syn-
thetic methods have been reported for the preparation of
the 2-azetidinone ring [12–20].
b-Lactam antibiotics comprises penicillins, cephalosporins,
cephamycins, monobactams, carbacephems, and car-
bapenems and are so named since they all contain the b-
lactam (2-azetidinone) moiety [1]. These miracle antibac-
terial drugs have served an important and highly successful
role in medicine and in pharmaceutical industry [2–4].
Ezetimibe has 2-azetidinone ring in its structure and is used
clinically as a cholesterol absorption inhibitor [5]. In
addition, 2-azetidinones possess various other biological
Sulfur-containing organic molecules are a very impor-
tant motif; particularly, aryl sulfides and their derivatives
are imperative molecules having biological, pharmaceuti-
cal, and material interest [21, 22]. Many synthetic methods
have been developed for the synthesis of aryl sulfides
[21–24]. The development of transition-metal-catalyzed
synthesis of aryl sulfides using a thiol precursor is also
reported [21, 25–30].
In the past few decades, synthesis of heterocyclic
compounds containing nitrogen and sulfur has been of
great interest for researchers, due to their potential use in
the pharmaceutical and medicinal applications [31].
& Maaroof Zarei
mzarei@hormozgan.ac.ir; maaroof1357@yahoo.com
1
Department of Chemistry, Faculty of Sciences, University of
Hormozgan, Bandar Abbas 71961, Iran
123

M. R. Ghotbabadi, M. Zarei
Some of b-lactam antibiotics such as penicillins, cepha-
losporins, and monobactams containing thioether group in
their structure [1]. N-Thiolated b-lactams (b-lactam com-
pounds have a sulfur substituent on the nitrogen center) have
been synthesized which have been represented a broad
family of bioactive molecules and the thiol-substituent was
effective at biological activities [32, 33]. Also, series of N-
sulfonyl monocyclic [34] and 3-thiolated b-lactams [35]
have been prepared and evaluated for their in vitro antibac-
terial and antifungal activities against pathogenic strains.
Hence, according to the above facts, the novel 2-aze-
tidinones having thioether moieties were synthesized using
copper-catalyzed thioetherification of 2-azetidinones with
thiol precursor.
thioether 5a, which was characterized by spectral data and
elemental analysis. To improve the yield and find the
optimum condition for the synthesis of 2-azetidinone 5a,
next, condition of reaction was investigated. All reactions
were monitored by TLC (Table 2).
According to Table 2, reaction of 2-azetidinone 3a and
iodobenzene in the presence of CuI as a catalyst, Na2S2
O3Á5H2O as a sulfur source and K2CO3 as a base in
dimethylformamide at 110–120 °C is the best condition
with the highest yield. The reaction was not performed at
room temperature.
With the optimized conditions in hand, the reactions of
different 2-azetidinones 3 with various aryl or alkyl halides
4 were examined to explore the scopes of the reaction
(Scheme 1). The results were shown in Table 3.
The purity of the compounds was checked by TLC and
1
Results and discussion
elemental analysis. Spectral data (IR, H NMR, and 13C
NMR) of all the compounds were in full agreement with
the proposed structures. IR spectra of b-lactams 5a–5p
showed sharp peaks at 1731–1765 cm-1 due to b-lactam
carbonyl group. Also signal for aldehyde carbonyl group of
products 5a, 5e, 5h, 5k, and 5o were observed at
1723–1732 cm-1. Their 1H NMR spectra showed well-
separated doublet of doublet for H-4 and H-3 protons of cis
b-lactams 5a–5p. The signals appeared at 9.85–10.08 ppm
for the carbonyl of CHO group in compounds 5a, 5e, 5h,
5k, and 5o. Peaks at 161.8–164.4 ppm were attributed to
the 2-azetidinone carbonyl and 190.2–192.4 ppm was
referred to the aldehyde carbonyl confirmed by 13C NMR.
According to a reported mechanism for the thioarylation
or thioalkylation using sodium thiosulfate as a thiol pre-
cursor [10, 30], it is suggested that the reaction performed
via formation of aryl or alkyl thiosulfate and organo-copper
intermediates (Scheme 2).
We started our studies by synthesis of cis 2-azetidinones
containing aryl chloride substituents in N-1 or C-3 or C-4
position (Table 1). Previously application of Vilsmeier
reagent in the preparation of 2-azetidinones via ketene-
imine cycloaddition has been reported [36, 37].
Schiff base 1 on reaction with substituted acetic acid 2
in the presence of Vilsmeier reagent and triethylamine at
room temperature afforded cis 2-azetidinones 3a–3f.
1H NMR spectra of compound 3a–3f displayed two
signals about 5.2 and 5.5 ppm for H-4 and H-3, respec-
tively, with the coupling constant about 4.7 Hz, this clearly
indicated the cis stereochemistry for 2-azetidinones 3a–3f
(the coupling constant H-3 and H-4 (J3,4 [ 4.0 Hz) for the
cis stereoisomer and (J3,4 B 3.0 Hz) for the trans
stereoisomer) [38, 39].
Compound 3a, treated with iodobenzene in the presence
of CuI and S8 at 110 °C, afforded 2-azetidinone containing
Table 1 Synthesis of 2-azetidinones containing aryl chloride substituents
Comp.
R1
R2
R3
Yield/%
3a
3b
3c
3d
3e
3f
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
C6H5
PhO
95
74
82
40
82
88
2-NaphthO
PhO
4-ClC6H4
C6H5
2-NaphthO
4-ClC6H4O
PhO
4-MeOC6H4
2-Cl-3-pyridyl
C6H5
4-NO2C6H4
123

Copper-catalyzed thioarylation or thioalkylation of halogenated 2-azetidinones using a thiol…
Table 2 Reaction condition in the synthesis of 2-azetidinone 5a
Entry
Cu source
S source
Base
Solvent
Yield/%
1
CuI
S8/KF
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
DMF
DMSO
PEG400
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
70
–
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
S8/KF
3
S8/KF
–
4
S8/KF
78
70
60
81
65
–
5
S8/KF
6
Cu(OAc)2
CuI
S8/KF
7
Na2S2O3Á5H2O
Na2S2O3Á5H2O
Na2S2O3Á5H2O
Na2S2O3Á5H2O
Thiourea
Thiourea
Thiourea
Thiourea
8
Cu(OAc)2
CuI
9
10
11
12
13
14
Cu(OAc)2
CuI
36
34
72
–
Cu(OAc)2
CuI
Cu(OAc)2
–
Scheme 1
thioalkylation of halogenated-2-azetidinones using CuI as a
catalyst, Na2S2O3Á5H2O as a sulfur sources and K2CO3 as a
base gave desired products in moderate to excellent yields.
Purification of products was simple and proceeded without
the use of column chromatography.
Conclusion
We have developed a protocol for the synthesis of new
2-azetidinones containing sulfide groups in N-1 or C-3 or
C-4 position. Copper-catalyzed thioarylation or
123

M. R. Ghotbabadi, M. Zarei
Table 3 Scope of the
thioarylation or thioalkylation
of halogenated-2-azetidinones
123

Copper-catalyzed thioarylation or thioalkylation of halogenated 2-azetidinones using a thiol…
Scheme 2
129.8, 130.9, 131.3, 132.5, 133.8, 135.7, 155.9, 156.6
Experimental
(aromatic carbons), 162.4 (CO, b-lactam) ppm.
All required chemicals were purchased from Merck, Fluka,
or Acros chemical companies. The melting points were
determined on an Electrothermal 9200 apparatus. IR
spectra were measured on a Galaxy series FT-IR 5000
spectrometer. NMR spectra were recorded in DMSO-d6
1-(4-Chlorophenyl)-3-(naphthalen-2-yloxy)-4-phenylaze-
tidin-2-one (3d, C25H18ClNO2) Cream color solid; m.p.:
233–237 °C; IR (KBr): m = 1753 (CO, b-lactam) cm-1; 1H
ꢀ
NMR (300 MHz): d = 5.09 (H-4, d, 1H, J = 4.6 Hz), 5.44
(H-3, d, 1H, J = 4.6 Hz), 6.97–7.24 (ArH, d, 2H), 7.26–7.30
(ArH, m, 11H), 7.32–7.34 (ArH, m, 1H), 7.52–7.73 (ArH, m,
2H) ppm; 13C NMR (75 MHz): d = 62.1 (C-4), 82.9 (C-3),
111.7, 121.2, 124.2, 126.9, 127.9, 128.3, 128.5, 128.7,
128.9, 129.0, 129.7, 130.6, 131.7, 133.9, 135.9, 138.1, 155.9
(aromatic carbons), 161.9 (CO, b-lactam) ppm.
using a Bruker spectrophotometer (1H NMR 300 MHz, 13
C
NMR 75 MHz) with tetramethylsilane as an internal stan-
dard and coupling constants were given in cycles per sec-
ond (Hz). Elemental analyses were run on a Vario EL III
elemental analyzer. Thin-layer chromatography was car-
ried out on silica gel 254 analytical sheets obtained from
Fluka. (Chloromethylene)dimethylammonium chloride
(Vilsmeier reagent) 2 was obtained as a white solid by a
reported procedure [40]. b-Lactams 3a–3f were prepared
according to reported methods and spectral data for 3a, 3c,
3e, and 3f have been previously reported [41–44].
General procedure for the synthesis of 2-azetidinones 5a–
5p A one-necked flask was charged with CuI (0.3 mmol),
potassium
carbonate
(5 mmol),
Na2S2O3Á5H2O
(1.5 mmol), alkyl/aryl halide (1.25 mmol), 2-azetidinones
3a–3f (1.25 mmol), and 5 cm3 DMF. The mixture was
stirred at 110–120 °C overnight. The reaction mixture was
cooled to room temperature. Water (10 cm3) was added to
the reaction mixture, and organics were extracted with
EtOAc (3 9 10 cm3). Evaporation of the solvent followed
by purification by crystallization from 95% ethanol pro-
vided the corresponding products.
4-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-(naphthalen-2-
yloxy)azetidin-2-one (3b, C26H20ClNO3) White solid;
ꢀ
m.p.: 181–184 °C; IR (KBr): m = 1749 (CO, b-lactam)
1
cm-1; H NMR (300 MHz): d = 3.79 (OMe, s, 3H), 5.34
(H-4, d, 1H, J = 5.1 Hz), 5.66 (H-3, d, 1H, J = 5.1 Hz),
6.89–6.95 (ArH, m, 3H), 7.10–7.23 (ArH, d, 2H),
7.30–7.33 (ArH, d, 2H), 7.58–7.61 (ArH, m, 4H),
7.67–7.70 (ArH, m, 4H) ppm; 13C NMR (75 MHz):
d = 56.3 (OMe), 62.1 (C-4), 81.9 (C-3), 110.9, 114.1,
117.9, 120.9, 124.2, 126.0, 126.9, 127.9, 128.4, 129.0,
1-(4-Methoxyphenyl)-3-phenoxy-4-[4-(phenylthio)phenyl]aze-
tidin-2-one (5a, C28H23NO3S) White solid; m.p.: 171–
174 °C; IR (KBr): mꢀ = 1755 (CO, b-lactam) cm-1
;
1H
NMR (300 MHz): d = 3.83 (s, 3H, OMe), 5.20 (d, 1H,
123

M. R. Ghotbabadi, M. Zarei
1
J = 4.6 Hz, H-4), 5.62 (d, 1H, J = 4.6 Hz, H-3),
6.89–7.03 (m, 5H, ArH), 7.06–7.09 (m, 7H, ArH),
7.10–7.34 (m, 6H, ArH) ppm; 13C NMR (75 MHz):
d = 56.3 (OMe), 61.9 (C-4), 81.7 (C-3), 116.0, 120.4,
122.8, 127.6, 128.5, 128.9, 129.5, 130.8, 132.1, 134.1,
135.0, 135.7, 136.1, 146.1, 156.4, 157.8 (aromatic car-
bons), 162.1 (CO, b-lactam) ppm.
cm-1; H NMR (300 MHz): d = 3.65 (s, 3H, OMe), 5.16
(d, 1H, J = 4.6 Hz, H-4), 5.48 (d, 1H, J = 4.6 Hz, H-3),
6.87–7.10 (d, 2H, ArH), 7.10–7.12 (m, 4H, ArH),
7.28–7.33 (m, 5H, ArH), 7.34–7.55 (m, 6H, ArH),
7.60–7.66 (m, 1H, ArH), 10.08 (s, 1H, CHO) ppm; 13C
NMR (75 MHz): d = 55.6 (OMe), 60.8 (C-4), 80.9 (C-3),
110.9, 113.9, 118.7, 120.7, 123.9, 126.9, 127.6, 128.2,
128.7, 129.4, 129.9, 130.0, 131.1, 131.6, 133.5, 134.0,
135.1, 135.3, 136.1, 143.0, 152.7, 156.8 (aromatic car-
bons), 164.0 (CO, b-lactam), 192.4 (CHO) ppm.
4-[[4-[1-(4-Methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl]-
phenyl]thio]benzaldehyde (5b, C29H23NO4S) White solid;
ꢀ
m.p.: 173–175 °C; IR (KBr): m = 1731 (CHO), 1754 (CO,
b-lactam), 2715, 2804 (CH, aldehyde) cm-1 1H NMR
;
1-(4-Methoxyphenyl)-3-(naphthalen-2-yloxy)-4-[4-(phenylthio)-
`
phenyl]azetidin-2-one (5f, C32H25NO3S) Creme-color solid;
(300 MHz): d = 3.70 (s, 3H, OMe), 5.22 (d, 1H,
J = 4.9 Hz, H-4), 5.71 (d, 1H, J = 4.9 Hz, H-3), 6.92–7.03
(m, 5H, ArH), 7.11–7.18 (m, 8H, ArH), 7.22–7.33 (d, 2H,
ꢀ
m.p.: 172–175 °C; IR (KBr): m = 1758 (CO, b-lactam)
cm-1; 1H NMR (300 MHz): d = 3.72 (s, 3H, OMe), 5.31 (d,
1H, J = 4.7 Hz, H-4), 5.63 (d, 1H, J = 4.7 Hz, H-3),
6.90–7.09 (m, 9H, ArH), 7.11–7.33 (m, 8H, ArH), 7.50–7.70
(m, 3H, ArH) ppm; 13C NMR (75 MHz): d = 55.7 (OMe),
61.6 (C-4), 81.8 (C-3), 111.7, 113.7, 118.1, 121.2, 123.5,
126.9, 127.0, 127.7, 127.9, 128.6, 129.3, 129.8, 131.2, 131.5,
133.8, 135.1, 135.3, 135.9, 136.2, 155.7, 156.2 (aromatic
carbons), 162.2 (CO, b-lactam) ppm.
ArH), 7.45–7.66 (d, 2H, ArH), 9.90 (s, 1H, CHO) ppm; 13
C
NMR (75 MHz): d = 56.6 (OMe), 62.0 (C-4), 83.8 (C-3),
114.3, 116.6, 120.5, 122.4, 128.0, 129.8, 130.1, 131.6,
131.6, 134.2, 142.7, 156.0, 157.8 (aromatic carbons), 163.3
(CO, b-lactam), 192.0 (CHO) ppm.
4-[4-(Hexylthio)phenyl]-1-(4-methoxyphenyl)-3-phenoxy-
azetidin-2-one (5c, C28H31NO3S) White solid; m.p.: 178–
-1
ꢀ
180 °C; IR (KBr): m = 1740 (CO, b-lactam) cm
;
1H
1-[4-(Hexylthio)phenyl]-3-phenoxy-4-phenylazetidin-2-one
NMR (300 MHz): d = 0.99 (t, 3H, J = 6.5 Hz, Me),
1.31–1.40 (m, 6H, 3CH2), 1.76–1.81 (m, 2H, SCH2CH2),
2.96 (t, 2H, J = 5.4 Hz, SCH2), 3.82 (s, 3H, OMe), 5.28 (d,
1H, J = 4.4 Hz, H-4), 5.60 (d, 1H, J = 4.4 Hz, H-3),
6.92–7.01 (m, 5H, ArH), 7.13–7.16 (d, 2H, ArH),
7.23–7.33 (m, 6H, ArH) ppm; 13C NMR (75 MHz):
d = 14.0 (Me), 22.9, 28.3, 29.0, 31.6 (CH2), 34.2 (SCH2),
55.9 (OMe), 61.8 (C-4), 84.2 (C-3), 113.9, 116.2, 121.1,
123.0, 129.2, 129.9, 130.9, 138.2, 146.1, 156.0, 158.1
(aromatic carbons), 162.5 (CO, b-lactam) ppm.
(5g, C27H29NO2S) White solid; m.p.:193–196 °C; IR
(KBr): m = 1765 (CO, b-lactam) cm-1
;
1H NMR
ꢀ
(300 MHz): d = 0.99 (t, 3H, J = 6.1 Hz, Me), 1.27–1.40
(m, 6H, 3CH2), 1.66–1.77 (m, 2H, SCH2CH2), 2.88 (t, 2H,
J = 8.0 Hz, SCH2), 5.10 (d, 1H, J = 5.2 Hz, H-4), 5.54 (d,
1H, J = 5.2 Hz, H-3), 6.84–7.00 (m, 3H, ArH), 7.10–7.13
(d, 2H, ArH), 7.23–7.40 (m, 9H, ArH) ppm; 13C NMR
(75 MHz): d = 12.9 (Me), 22.8, 28.7, 29.1, 32.0 (CH2),
34.4 (SCH2), 64.0 (C-4), 83.8 (C-3), 116.4, 122.8, 124.6,
126.7, 127.9, 128.3, 129.4, 133.9, 134.7, 136.0, 147.2,
159.2 (aromatic carbons), 164.4 (CO, b-lactam) ppm.
4-[4-(Hexylthio)phenyl]-1-(4-methoxyphenyl)-3-(naphthalen-
2-yloxy)azetidin-2-one (5d, C32H33NO3S) White solid;
4-[[4-(2-Oxo-3-phenoxy-4-phenylazetidin-1-yl)phenyl]thio]-
ꢀ
m.p.: 184–186 °C; IR (KBr): m = 1747 (CO, b-lactam)
benzaldehyde (5h, C28H21NO3S) Cream solid; m.p.: 245–
1
cm-1; H NMR (300 MHz): d = 0.97 (t, 3H, J = 6.0 Hz,
249 °C; IR (KBr): m = 1724 (CHO), 1757 (CO, b-lactam),
ꢀ
1
Me), 1.29–1.43 (m, 6H, 3CH2), 1.74–1.83 (m, 2H, SCH2-
CH2), 2.92 (t, 2H, J = 6.1 Hz, SCH2), 3.80 (s, 3H, OMe),
5.36 (d, 1H, J = 4.8 Hz, H-4), 5.69 (d, 1H, J = 4.8 Hz,
H-3), 6.86–7.10 (d, 2H, ArH), 7.12–7.30 (d, 2H, ArH),
7.32–7.36 (m, 7H, ArH), 7.54–7.61 (m, 2H, ArH),
7.66–7.80 (d, 2H, ArH) ppm; 13C NMR (75 MHz):
d = 13.7 (Me), 23.1, 27.9, 29.1, 32.0 (CH2), 34.9 (SCH2),
55.8 (OMe), 61.5 (C-4), 83.2 (C-3), 111.7, 114.4, 119.0,
120.9, 123.6, 127.3, 127.5, 127.9, 128.6, 129.1, 129.5,
131.1, 131.4, 132.0, 135.8, 138.6, 156.6, 156.8 (aromatic
carbons), 161.8 (CO, b-lactam) ppm.
2709, 2811 (CH, aldehyde) cm-1; H NMR (300 MHz):
d = 5.24 (d, 1H, J = 5.0 Hz, H-4), 5.50 (d, 1H,
J = 5.0 Hz, H-3), 6.94–7.07 (m, 5H, ArH), 7.22–7.38 (m,
11H, ArH), 7.61–7.63 (d, 2H, ArH), 9.89 (s, 1H, CHO)
ppm; 13C NMR (75 MHz): d = 60.8 (C-4), 83.6 (C-3),
113.7, 122.5, 122.6, 127.0, 127.9, 128.6, 129.4, 130.1,
131.1, 132.0, 133.3, 133.7, 134.6, 138.8, 143.3, 158.9
(aromatic carbons), 164.1 (CO, b-lactam), 190.2 (CHO)
ppm.
3-Phenoxy-4-phenyl-1-[4-(phenylthio)phenyl]azetidin-2-
one (5i, C27H21NO2S) White solid; m.p.: 240–244 °C; IR
(KBr): m = 1746 (CO, b-lactam) cm-1
;
1H NMR
ꢀ
4-[[4-[1-(4-Methoxyphenyl)-3-(naphthalen-2-yloxy)-4-oxo-
azetidin-2-yl]phenyl]thio]benzaldehyde (5e, C33H25NO4
(300 MHz): d = 5.26 (d, 1H, J = 4.9 Hz, H-4), 5.57 (d,
1H, J = 4.9 Hz, H-3), 6.91–7.24 (m, 8H, ArH), 7.25–7.38
(m, 11H, ArH) ppm; 13C NMR (75 MHz): d = 62.3 (C-4),
ꢀ
S) White solid; m.p.: 131–135 °C; IR (KBr): m = 1723
(CHO), 1744 (CO, b-lactam), 2703, 2792 (CH, aldehyde)
123

Copper-catalyzed thioarylation or thioalkylation of halogenated 2-azetidinones using a thiol…
82.2 (C-3), 109.3, 117.0, 122.8, 126.7, 127.8, 127.9, 128.6,
129.6, 129.9, 130.9, 131.6, 133.7, 134.5, 135.3, 138.0,
157.7, (aromatic carbons), 161.9 (CO, b-lactam) ppm.
133.3, 134.5, 156.5, 157.9 (aromatic carbons), 162.6 (CO,
b-lactam) ppm.
1-(4-Methoxyphenyl)-4-phenyl-3-[4-(phenylthio)phenoxy]-
1-[4-(Hexylthio)phenyl]-3-(naphthalen-2-yloxy)-4-phen-
azetidin-2-one (5n, C28H23NO3S) Cream solid; m.p.: 164–
-1
ylazetidin-2-one (5j, C31H31NO2S) Cream solid; m.p.:
168 °C; IR (KBr): m = 1740 (CO, b-lactam) cm
;
1H
ꢀ
240–244 °C; IR (KBr): m = 1753 (CO, b-lactam) cm-1; 1H
NMR (300 MHz): d = 3.78 (s, 3H, OMe), 5.30 (d, 1H,
J = 4.3 Hz, H-4), 5.74 (d, 1H, J = 4.3 Hz, H-3),
6.66–6.68 (d, 2H, ArH), 7.03–7.09 (m, 3H, ArH),
7.17–7.36 (m, 13H, ArH) ppm; 13C NMR (75 MHz):
d = 55.3 (OMe), 63.5 (C-4), 84.2 (C-3), 114.7, 116.2,
121.3, 126.3, 127.9, 128.0, 128.7, 129.6, 130.9, 131.4,
131.9, 133.3, 134.7, 136.1, 155.2, 158.3 (aromatic car-
bons), 162.6 (CO, b-lactam) ppm.
ꢀ
NMR (300 MHz): d = 0.98 (t, 3H, J = 6.0 Hz, Me),
1.26–1.40 (m, 6H, 3CH2), 1.62–1.72 (m, 2H, SCH2CH2),
2.90 (t, 2H, J = 7.9 Hz, SCH2), 5.26 (d, 1H, J = 4.5 Hz,
H-4), 5.53 (d, 1H, J = 4.5 Hz, H-3), 7.04–7.20 (d, 2H,
ArH), 7.22–7.35 (m, 10H, ArH), 7.50–7.72 (m, 4H, ArH)
ppm; 13C NMR (75 MHz): d = 15.3 (Me), 21.9, 27.9,
28.8, 31.7 (CH2), 35.2 (SCH2), 62.4 (C-4), 81.7 (C-3),
111.7, 115.7, 123.9, 124.4, 126.8, 127.3, 127.5, 128.1,
128.4, 128.9, 131.5, 135.5, 136.1, 154.9, (aromatic car-
bons), 160.6 (CO, b-lactam) ppm.
4-[[4-[[1-(4-Methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl]-
oxy]phenyl]thio]benzaldehyde (5o, C29H23NO4S) White
ꢀ
solid; m.p.: 185–188 °C; IR (KBr): m = 1728 (CHO), 1754
4-[[4-[3-(Naphthalen-2-yloxy)-2-oxo-4-phenylazetidin-1-yl]-
(CO, b-lactam), 2717, 2808 (CH, aldehyde) cm-1 1H
;
phenyl]thio]benzaldehyde (5k, C32H23NO3S) Cream solid;
NMR (300 MHz): d = 3.83 (s, 3H, OMe), 5.15 (d, 1H,
J = 4.6 Hz, H-4), 5.51 (d, 1H, J = 4.6 Hz, H-3),
6.81–6.96 (d, 2H, ArH), 7.14–7.25 (d, 2H, ArH), 7.25–7.49
(m, 9H, ArH), 7.65–7.68 (d, 4H, ArH), 9.91 (s, 1H, CHO)
ppm; 13C NMR (75 MHz): d = 56.1 (OMe), 61.8 (C-4),
81.1 (C-3), 113.8, 115.9, 120.4, 126.8, 127.9, 128.2, 130.1,
130.8, 131.1, 132.0, 133.8, 134.2, 143.5, 150.9, 156.4,
158.4 (aromatic carbons), 162.3 (CO, b-lactam), 192.2
(CHO) ppm.
ꢀ
m.p.: 300–303 °C; IR (KBr): m = 1732 (CHO), 1759 (CO,
b-lactam), 2706, 2801 (CH, aldehyde) cm-1 1H NMR
;
(300 MHz): d = 5.35 (d, 1H, J = 4.7 Hz, H-4), 5.62 (d,
1H, J = 4.7 Hz, H-3), 6.98–7.21 (d, 2H, ArH), 7.22–7.34
(m, 12H, ArH), 7.36–7.68 (m, 5H, ArH), 9.85 (s, 1H, CHO)
ppm; 13C NMR (75 MHz): d = 61.5 (C-4), 84.2 (C-3),
107.5, 110.9, 122.2, 124.2, 126.4, 127.5, 127.6, 128.8,
129.1, 129.9, 130.8, 131.1, 131.5, 133.8, 134.2, 135.3,
138.0, 156.3 (aromatic carbons), 162.2 (CO, b-lactam),
191.3 (CHO) ppm.
4-(4-Nitrophenyl)-3-phenoxy-1-[2-(phenylthio)pyridin-3-yl]-
azetidin-2-one (5p, C26H19N3O4S) White solid; m.p.: 193–
195 °C; IR (KBr): mꢀ = 1324, 1528 (NO2), 1616 (C=N,
3-(Naphthalen-2-yloxy)-4-phenyl-1-[4-(phenylthio)phenyl]-
azetidin-2-one (5l, C31H23NO2S) Pale-yellow solid; m.p.:
pyridine ring), 1748 (CO) cm-1 1H NMR (300 MHz):
;
233–235 °C; IR (KBr): m = 1752 (CO, b-lactam) cm-1; 1H
d = 5.21 (d, 1H, J = 5.0 Hz, H-4), 5.47 (d, 1H,
J = 5.0 Hz, H-3), 6.88–6.91 (m, 4H, ArH), 7.10 (d, 2H,
ArH), 7.22–7.28 (m, 4H, ArH), 7.74–7.79 (m, 4H, ArH),
8.02–8.04 (m, 3H, ArH) ppm; 13C NMR (75 MHz):
d = 64.6 (C-4), 83.9 (C-3), 115.9, 118.1, 118.9, 122.0,
124.8, 125.1, 125.6, 127.3, 129.7, 131.0, 135.7, 136.4,
138.5, 142.1, 148.6, 152.4, 157.8 (aromatic carbons), 164.3
(CO, b-lactam) ppm.
ꢀ
NMR (300 MHz): d = 5.19 (d, 1H, J = 4.5 Hz, H-4), 5.47
(d, 1H, J = 4.5 Hz, H-3), 6.95–7.15 (m, 5H, ArH),
7.16–7.20 (m, 13H, ArH), 7.22–7.33 (m, 1H, ArH),
7.39–51 (m, 1H, ArH), 7.52–7.70 (m, 1H, ArH) ppm; 13C
NMR (75 MHz): d = 60.3 (C-4), 81.4 (C-3), 105.9, 107.7,
111.3, 121.9, 124.1, 126.7, 127.4, 127.6, 127.9, 128.3,
128.9, 129.4, 129.7, 131.6, 132.2, 133.6, 135.7, 138.9,
153.4, 157.1 (aromatic carbons), 164.3 (CO, b-lactam)
ppm.
Acknowledgements Financial support from University of Hormozgan
Research Council is gratefully acknowledged.
3-[4-(Hexylthio)phenoxy]-1-(4-methoxyphenyl)-4-phen-
ylazetidin-2-one (5m, C28H31NO3S) Cream solid; m.p.:
187–189 °C; IR (KBr): m = 1741 (CO, b-lactam) cm-1; 1H
References
ꢀ
NMR (300 MHz): d = 1.00 (t, 3H, J = 6.9 Hz, Me),
1.28–1.40 (m, 6H, 3CH2), 1.66–1.77 (m, 2H, SCH2CH2),
2.88 (t, 2H, J = 8.0 Hz, SCH2), 3.81 (s, 3H, OMe), 5.31 (d,
1H, J = 4.4 Hz, H-4), 5.76 (d, 1H, J = 4.4 Hz, H-3),
1. Cojocel C (2008) Beta-lactam antibiotics. In: De Broe ME, Porter
GA, Bennett WM, Deray G (eds) Clinical nephrotoxins. Springer,
Boston, p 293
2. Page EI (1992) The chemistry of b-lactams. Blackie Academic
and Professional, New York
6.90–6.95 (m, 4H, ArH), 7.14–7.33 (m, 9H, ArH) ppm; 13
C
3. Hwu JR, Ethiraj SK, Hakimelahi GH (2003) Mini Rev Med
Chem 3:305
NMR (75 MHz): d = 14.6 (Me), 22.7, 28.5, 29.3, 31.4
(CH2), 34.5 (SCH2), 55.2 (OMe), 63.7 (C-4), 83.9 (C-3),
114.2, 119.1, 120.6, 126.7, 127.9, 128.6, 130.3, 131.4,
123

M. R. Ghotbabadi, M. Zarei
4. Long TE, Turos E (2002) Curr Med Chem Antiinfect Agents
1:251
5. Burnett DA (2004) Curr Med Chem 11:1873
6. Carr M, Greene LM, Knox AJS, Lloyd DG, Zisterer DM, Meegan
MJ (2010) Eur J Med Chem 45:5752
25. Rostami A, Rostami A, Ghaderi A (2015) J Org Chem 80:8694
26. Park N, Park K, Jang M, Lee S (2011) J Org Chem 76:4371
27. Firouzabadi H, Iranpoor N, Samadi A (2014) Tetrahedron Lett
55:1212
28. Qiao Z, Wei J, Jiang X (2014) Org Lett 16:1212
29. Qiao Z, Liu H, Xiao X, Fu Y, Wei J, Li Y, Jiang X (2013) Org
Lett 15:2594
7. Mehta PD, Sengar NPS, Pathak AK (2010) Eur J Med Chem
45:5541
8. Basu S, Banik BK (2017) In: Banik BK (ed) Beta-lactams: novel
synthetic pathways and applications. Springer, Cham, p 285
9. Alcaide B, Almendros P, Aragoncillo C (2007) Chem Rev
107:4437
10. Ojima I, Delaloge F (1997) Chem Soc Rev 26:377
11. Palomo C, Oiarbide M (2010) In: Banik BK (ed) Topics in
heterocyclic chemistry, vol 22. Springer, Berlin, p 211
12. Fu N, Tidwell TT (2008) Tetrahedron 64:10465
13. Zarei M (2013) J Chem Res 37:25
14. Zarei M (2013) Monatsh Chem 144:1021
15. Brandi A, Cicchi S, Cordero FM (2008) Chem Rev 108:3988
16. Zarei M (2012) J Chem Res 36:118
17. Zarei M (2014) Tetrahedron Lett 55:5354
18. Nahmany M, Melman A (2006) J Org Chem 71:5804
19. Zarei M (2017) J Heterocycl Chem 54:1161
20. Keri RS, Hosamani KM, Shingalapur RV, Reddy HRS (2009)
Eur J Med Chem 44:5123
30. Li Y, Pu J, Jiang X (2014) Org Lett 16:2692
31. Xu P, Yu B, Li FL, Cai XF, Ma CQ (2006) Trends Microbiol
144:398
32. Chen D, Falsetti SC, Frezza M, Milacic V, Kazi A, Cui QC, Long
TE, Turos E, Dou PQ (2008) Cancer Lett 268:63
33. O’Driscoll M, Greenhalgh K, Young A, Turos E, Dickey S, Lim
DV (2008) Bioorg Med Chem 16:7832
34. Jarrahpour A, Zarei M (2006) Molecules 11:49
35. Zarei M, Mohamadzadeh M (2011) Tetrahedron 67:5832
36. Jarrahpour A, Fadavi A, Zarei M (2011) Bull Chem Soc Jpn
84:320
37. Jarrahpour A, Zarei M (2007) Tetrahedron Lett 48:8712
38. Georg GI (1993) The organic chemistry of b-lactams. Verlag
Chemie, New York
39. Zarei M (2014) Monatsh Chem 145:1495
40. Jarrahpour A, Zarei M (2009) Tetrahedron 65:2927
41. Zarei M (2017) J Chem Res 41:246
21. Prasad DJC, Sekar G (2011) Org Lett 13:1008
22. Feng M, Tang B, Liang SH, Jiang X (2016) Curr Top Med Chem
16:1200
23. Bierbeek AV, Gingras M (1998) Tetrahedron Lett 39:6283
24. Correa A, Carril M, Bolm C (2008) Angew Chem Int Ed 47:2880
42. Akkurt M, Karaca S, Jarrahpour A, Zarei M, Buyukgungor O
(2005) Acta Crystallogr Sect E 61:776
43. Zarei M, Jarrahpour A, Ebrahimi E, Aye M, Torabi Badrabady
SA (2012) Tetrahedron 68:5505
44. Jarrahpour A, Zarei M (2010) Tetrahedron 66:5017
123