A facile and effective synthesis of 2-azetidinones via phosphonitrilic chloride

Article abstract of DOI:10.1016/j.tet.2013.05.121

The Staudinger reaction of imines to β-lactams was successfully achieved with substituted acetic acid and phosphonitrilic chloride in one-pot under mild conditions. Several types of β-lactams, especially 3-electron-withdrawing group β-lactams, can be synthesized by this versatile and efficient method in good to excellent yields. This method is simple, clean, and the by-products were removed by simple aqueous work-up. The effects of solvents, molar ratio of reagent, and the temperature were considered.

Full text of DOI:10.1016/j.tet.2013.05.121

Tetrahedron 69 (2013) 6620e6626
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Tetrahedron
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A facile and effective synthesis of 2-azetidinones via phosphonitrilic
chloride
*
Maaroof Zarei
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The Staudinger reaction of imines to
b
-lactams was successfully achieved with substituted acetic acid and
-lactams, especially 3-
-lactams, can be synthesized by this versatile and efficient method in
Received 27 March 2013
Received in revised form 17 May 2013
Accepted 28 May 2013
phosphonitrilic chloride in one-pot under mild conditions. Several types of
electron-withdrawing group
b
b
good to excellent yields. This method is simple, clean, and the by-products were removed by simple
aqueous work-up. The effects of solvents, molar ratio of reagent, and the temperature were considered.
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 2 June 2013
Keywords:
2-Azetidinone
Staudinger reaction
b-Lactam
Phosphonitrilic chloride
Schiff base
Ketene
1. Introduction
potential antimalarials,20 anti-influenzavirus,21 antihypergly-
cemic,22 central nervous system (CNS) active agents,23 combatant
Phosphonitrilic chloride
1
(1,3,5-triaza-2,4,6-triphosphorin-
of neurological diseases,24 antiproliferative activities,25 antituber-
2,2,4,4,6,6-hexachloride) is a precursor to poly(dichlorophospha-
zene) or inorganic rubber1 and is used for the synthesis of dande-
lion dendrimers.2 It has been widely used in organic reactions,3
such as the conversion of aldoximes to nitriles,4 the Beckmann
rearrangement of ketoximes to lactams,5 and the conversion of
sulfonic acids into the corresponding sulfonyl chlorides.6 Also,
phosphonitrilic chloride has been used as activator of carboxylic
acids to formation of amides and hydrazides.7 This compound can
be prepared by reaction of PCl5 and NH4Cl, although it is com-
mercially available.8
cular,26 anti-oxidant,27 and insecticidal activities.28
Furthermore, b-lactams have received wide use as key synthons
for many classes of compounds in organic synthesis,29 especially in
the semisynthesis of Taxol derivatives.30
b-Lactams (2-azetidinones) have served humanity for several
decades in its war against the infections caused by bacteria and are
responsible for saving millions of lives.9 Ezetimibe 2 is a new drug
as cholesterol absorption inhibitor for clinical use that it has 2-
azetidinone ring in its structure.10 Literature survey reveals that
2-azetidinones shown to possess other relevant biological activi-
ties,11 which include human cytomegalovirus (HCMV) inhibitor,12
human leukocyte elastase (HLE) inhibitor,13 thrombin inhibitor,14
porcine pancreatic elastase (PPE) inhibitor,15 HIV-1 protease in-
hibitor,16 cysteine protease inhibitor,17 anticancer,18 antifungal,19
Many synthetic methods have been developed for the formation
of the
and several review for this subject has been published.31 Mostly,
synthesis of
b-lactam ring because of tremendous important of b-lactams
b
-lactams through [2þ2] cycloaddition reaction of
ketenes with imines (Staudinger reaction)32 is applied.33 Reaction
of acyl halides with tertiary amines remains the most useful ap-
proach for generation of ketenes.34 But use of acyl chloride has
some drawbacks. The preparation, isolation, and handling of acid
chlorides are difficult, their stability is low and some of acid halides
are not commercially available. Scientists have reported carboxylic
acid activators to solve this problem.35 Some of these acid activators
* Tel.: þ98 761 766 0063; fax: þ98 761 667 0714; e-mail addresses: mzarei@
hormozgan.ac.ir. maaroof1357@yahoo.com.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.121

M. Zarei / Tetrahedron 69 (2013) 6620e6626
6621
require low or high temperatures, inconvenient reaction conditions
for their execution, and are often accompanied by painful chro-
matographic separations to remove by-products from desired
products.
To the best of our knowledge, there have been no reports
employing phosphonitrilic chloride as a reagent for the activation
of carboxylic acids in the synthesis of 2-azetidinones. Hence, based
on the aforementioned, phosphonitrilic chloride was utilized as
activating agent for carboxylic acids to afford 2-azetidinones.
chloride to 0.6 equiv did not improve the yield (entry 8). Cold media
poorly decreased the yield of -lactam 5a (entry 9). Then reaction of
1.0 mmol imine, 1.5 mmol acid, and 0.5 mmol phosphonitrilic
chloride in the presence of triethylamine in dry dichloromethane at
room temperature is the best condition.
b
With the best conditions in hands, the scope of the reaction was
extended to a diverse range of 2-azetidinones. As can be seen from
Table 2, a wide range of carboxylic acids and imines containing
aromatic and aliphatic substituents can all be converted into the
corresponding 2-azetidinones in excellent yields and with high
purity.
The 2-azteidinones 5aeu were synthesized by treatment of
1.0 mmol of imines 3, 1.5 mmol of substituted acetic acids 4, and
0.5 mmol of phosphonitrilic chloride 1 in the presence of triethyl-
amine in dry dichloromethane at room temperature (Scheme 1,
Table 2). The purification of 2-azteidinones 5aeu was performed by
crystallization from EtOAc after simple aqueous work-up. All
products were characterized by their spectral data and elemental
analyses. The stereochemistry of them were assigned by the com-
parison of the coupling constant H-3 and H-4 (J3,4>4.0 Hz) for the
cis stereoisomer and (J3,4ꢀ3.0 Hz) for the trans stereoisomer.31e
Phosphonitrilic chloride 1 was successfully employed for the
2. Results and discussion
As a model substrate to determine the best reaction conditions,
a set of experiments using N-benzylideneaniline 3a and phenoxy-
acetic acid 4a in the presence of Et3N were performed to examine
the effects of solvents, temperature, and different amount of
phosphonitrilic chloride in the synthesis of 2-azetidinone 5a. As it
is shown in Table 1, dry dichloromethane was the best solvent for
this reaction. For optimization of amount of phenoxyacetic acid,
3 equiv of phenoxyacetic acid relative to the equivalent phospho-
nitrilic chloride were used. According to Table 1, the highest yield
was obtained when 1.5 mmol phenoxyacetic acid and 0.5 mmol
phosphonitrilic chloride were reacted with 1.0 mmol of imine 3a
(Table 1, entry 7). An increase in the amount of phosphonitrilic
synthesis of 3-allyloxy b-lactams 7aec. The treatment of (prop-2-
enyloxy)acetic acid (allyloxyacetic acid) 6, prepared from allyl al-
cohol and chloroacetic acid by a reported procedure,36 with various
Schiff bases and phosphonitrilic chloride in the presence of trie-
thylamine afforded cis 2-azetidinones 7aec after crystallization
from EtOAc (Scheme 2).
Table 1
Reaction condition in the synthesis of 2-azetidinone 5a
L
-Menthoxyacetic acid (2-((1S,2S,5S)-2-isopropyl-5-methylcycl-
ohexyloxy)acetic acid) was prepared from -menthol and
chloroacetic acid by a procedure described in the literature.37 The
reaction of -menthoxyacetic acid 8 and the corresponding imines
8
L
L
in the presence of phosphonitrilic chloride yielded the cis 2-
azetidinones 9aec in good yields (Scheme 2).
Entry
Solvent
Temp
Phosphonitrilic chloride (mmol)
Yield (%)
Benzothiazoles and their derivatives have recently received in-
terest in the field of physiologically and pharmacologically activi-
ties.38 Previously Bahekar and co-workers synthesized 1-
benzothiazol-2-yl azetidin-2-ones and the anti-inflammatory ac-
1
2
3
4
5
6
7
8
9
Toluene
CH2Cl2
THF
rt
rt
rt
rt
rt
rt
rt
rt
0.3
0.3
0.3
0.3
0.3
0.4
0.5
0.6
0.5
57
73
51
48
29
82
95
92
90
DMF
tivity of these compounds has been investigated.39
b-Lactams
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
11aec were also easily obtained from various Schiff bases 10 de-
rived from 2-aminobenzothiazole by this method and purified by
crystallization from EtOAc (Scheme 2).
0
ꢁC
Table 2
Synthesis of 2-azetidinones 5aeu using phosphonitrilic chloride
Entry
R1
R2
R3
cis/trans
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
C6H5
4-ClC6H4
C6H5
4-EtOC6H4
4-MeOC6H4
4-EtOC6H4
4-EtOC6H4
4-MeOC6H4
4-MeOC6H4CH2
4-EtOC6H4
C6H5
4-MeOC6H4
C6H5CH2
PhO
PhO
PhO
PhO
cis
cis
cis
cis
5a
5b
5c
5d
5e
5f
5g
5h
5i
95
92
94
88
83
81
86
85
90
92
89
92
93
89
90
77
86
91
93
90
84
4-MeOC6H4
CH]CHPh
CH]CHPh
4-ClC6H4
4-NO2C6H4
4-MeOC6H4
4-NO2C6H4
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
4-NO2C6H4
4-MeC6H4
4-ClC6H4
4-MeOC6H4
C6H5CH2
PhthN
PhthN
PhthN
PhthN
2-NaphthO
2-NaphthO
2-NaphthO
2,4-Cl2C6H3O
2,4-Cl2C6H3O
MeO
MeO
MeS
MeS
PhS
PhO
MeO
MeS
cis
trans
trans
trans
cis
cis
cis
cis
cis
cis
cis
cis
cis
cis
cis
cis
cis
9
10
11
12
13
14
15
16
17
18
19
20
21
5j
5k
5l
4-EtOC6H4
4-MeOC6H4CH2
4-MeOC6H4
4-MeO-naphthyl
Me
5m
5n
5o
5p
5q
5r
5s
5t
4-ClC6H4
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
4-MeOC6H4
3,4-(MeO)2C6H3CH2
3,4-(MeO)2C6H3CH2
3,4-(MeO)2C6H3CH2
4-NO2C6H4
5u

6622
M. Zarei / Tetrahedron 69 (2013) 6620e6626
temperature gave trans 2-azetidinones 13aec, which were purified
by short column chromatography on silica gel (Scheme 3). Pre-
viously the synthesis and antimicrobial activity of cis 3-(methyl-
R1
R2
R3
O
1, Et3N
R3CH2COOH
R1CH=NR2
+
N
CH2Cl2, rt
sulfonyl) b-lactams using 3-methylthio b-lactams and m-CPBA have
been reported.41 Steric hindrance of sulfonyl group on ketene me-
diates to synthesis of trans 2-azetidinones 13aec from 2-tosylacetic
acid (Scheme 3). Phosphonitrilic chloride 1 was also successfully
3
4
5a-u
Scheme 1.
employed for the synthesis of 3-acetyl-b-lactams 15aec. The
R1
7a, R1 = 4-MeC6H4 ; R2 = 4-NO2C6H4
7b, R1 = C6H5 ; R2 = C6H5
86%
88%
O
Et3N
1,
R1CH=NR2
+
OCH2CO2H
N
CH2Cl2 , rt
O
R2
7c, R1 = 4-MeOC6H4 ; R2 = 4-MeOC6H4 88%
6
R1
R2
Et3N
9a, R1 = 4-NO2C6H4 ; R2 = 4-MeOC6H4 59%
O
O
1,
+ R1CH=NR2
OCH2COOH
CH2Cl2 , rt
9b, R1 = 4-ClC6H4 ; R2 = C6H5
9c, R1 = 4-MeOC6H4 ; R2 = 4-MeOC6H4 64%
62%
N
8
R1
S
R2
11a, R1 = 4-ClC6H4 ; R2 = PhO
11b, R1 = 4-ClC6H4 ; R2 = MeO
11c, R1 = C6H5 ; R2 = 2,4-Cl2C6H4O
86%
83%
84%
N
S
Et3N
1,
CH2Cl2 , rt
R2CH2CO2H
+
N=CHR1
N
N
O
10
Scheme 2.
O
S
O
Na2SO3
ClCH2CO2H
NaOH
SO2Cl
SO2Na
OH
NaHCO3
O
Not isolated
12
O
S
1 13a, R1 = 4-NO2C6H4 ; R2 = 4-EtOC6H4 51%
13b, R1 = 4-MeOC6H4 ; R2 = 4-MeOC6H4 55%
R
O
O
S
Et N
1,
3
R1CH=NR2
+
OH
O
N
O
CH2Cl2
rt
O
R2
13c, R1 = 4-ClC6H4 ; R2 = C6H5
49%
12
Scheme 3.
The synthesis of 3-electron-withdrawing 2-azetidinones by the
[2þ2] cycloaddition reaction of keteneeimine using -electron-
treatment of acetoacetic acid 14 with the corresponding imines in
the presence of phosphonitrilic chloride and triethylamine afforded
pure 3-acetyl-b-lactams 15aec after purification by short column
chromatography on silica gel (Scheme 4).
a
withdrawing substituted carboxylic acids is one of the main prob-
lems in the synthesis of 2-azetidinones. To check the generality of
this method, the synthesis of 3-electron-withdrawing 2-
azetidinones also were investigated. Firstly, 2-tosylacetic acid 12
was synthesized from p-toluenesulfonyl chloride in two stage as
described in Scheme 5.40 Treatment of 2-tosylacetic acid 12 with
various imines in the presence of phosphonitrilic chloride at room
This method was successfully extended to the synthesis of C-3
spiro-
with various imines in the presence of phosphonitrilic chloride and
triethylamine afforded spiro- -lactams 17aed, which were purified
by crystallization from EtOAc (Scheme 4).
b-lactams. The reaction of xanthene-9-carboxylic acid 16
b

M. Zarei / Tetrahedron 69 (2013) 6620e6626
6623
O
15a, R1 = 4-ClC6H4 ; R2 =4-EtOC6H4
15b, R1 = C6H5 ; R2 = C6H5CH2
59%
62%
R1
O
O
Et N
1,
3
R1CH=NR2
+
OH
N
CH2Cl2 , rt
O
R2
15c, R1 = 4-MeOC6H4 ; R2 = 4-MeOC6H4 52%
14
17a, R1 = 4-MeOC6H4 ; R2 = Me
17b, R1 = 4-ClC6H4 ; R2 = C6H5
82%
87%
O
O
1,
Et3N
R1
R2
R1CH=NR2
+
CH2Cl2 , rt
17c, R1 = 4-ClC6H4 ; R2 = 4-MeOC6H4CH2 85%
17d, R1 = 4-MeOC6H4 ; R2 = 4-MeOC6H4
N
CO2H
O
85%
16
Scheme 4.
Temperature, solvent, electronic effects, and the steric hin-
drance of the ketene and imine substituents affect the stereo-
between the direct ring closure and the isomerization of the imine
moiety in the zwitterionic intermediate. Ketenes derived from
chemistry of
b
-lactams in the Staudinger reaction. According to
phthalimidoacetic acid (
acetoacetic acid 14 have more steric hindrance than other ketenes,
and then lead to trans isomer. Cis -lactam 5e have obtained from
phthalimidoketene because styryl group on C-4 of -lactam ring
prepare enough space to stability of zwitterionic intermediate and
b-lactams 5feh), tosylacetic acid 12, and
a reported mechanism for the Staudinger reaction42 and for OH
activation using phosphonitrilic chloride,3f it is suggested that the
reaction performed via formation of an activated ester (Scheme 5).
One mol phosphonitrilic chloride can activate three moles of acid to
generate in situ three moles of ketene. Then ketene reacts with
imines to form a zwitterionic intermediate, which undergoes
b
b
then direct ring closure to form cis b-lactam 5e.
a conrotatory ring closure to produce the b-lactam. The relative (cis/
trans) stereoselectivity is generated as a result of the competition
3. Conclusion
In summary, an evaluation of the cycloaddition reaction between
carboxylic acids and imines using phosphonitrilic chloride demon-
strated that this method has high efficiency and was thus used to
Cl
Cl
O
C
P
N
P
N
P
Cl
Et3N
- H+
1
prepare a series of
ologyallowing for awide functional grouptolerance and monocyclic,
spirocyclic, N-alkyl, and 3-electron-withdrawing group -lactams
b-lactams. This method provides a new method-
R3CH2COOH
Cl
R3CH2COO
Cl
R3H2C
O
N
Cl
b
Cl
activated ester
are obtained in good to excellent yields. This reaction is clean and the
by-products were removed by simple aqueous work-up.
P
Cl
Cl
N
P
N
O
O
Cl
P
- Et3NH Cl
NEt3
P
Cl
R3CH=C=O +
C
N
P
N
P
Cl
N
R3HC
Cl
Cl
4. Experimental section
4.1. Chemical reagents
O
H
N
18
ketene
O
P
All required chemicals were purchased from Merck, Fluka or
Acros chemical companies. The melting points were determined on
a Buchi 535 apparatus and are uncorrected. IR spectra were mea-
sured on a galaxy series FT-IR 5000 spectrometer. NMR spectra
were recorded in CDCl3 using a Bruker spectrophotometer (1H NMR
300 MHz, 13C NMR 75 MHz) using tetramethylsilane as an internal
standard and coupling constants were given in cycles per second
(Hertz). Elemental analyses were run on a Vario EL III elemental
analyzer. Thin-layer chromatography was carried out on silica gel
254 analytical sheets obtained from Fluka. Column chromatogra-
phy was performed on silica gel 60 (Merck, 70e230 mesh). Spectral
data for 5aee, 5hej, 5l, 5n, 5per, 7a, 15c, and 17d have been pre-
viously reported.35b,35d,35f,41,42b,43
N
P
N
P
R3CH2COO
R3CH=C=O
R3CH=C=O
+
18
+
O
O
N
ketene
R2
H H
R3
ring
R3
R2
closure
R1N=CHR2
+
N
N
R1
O
R1
O
zwitterionic
intermediate
cis
isomerization
R3
H H
ring
closure
R2
4.2. General procedure for the synthesis of 2-azetidinones
R3
R2
N
N
R1
A phosphonitrilic chloride (0.5 mmol) was added to a solution of
the substituted acetic acid (1.5 mmol), the Schiff base (1.0 mmol),
and Et3N (5.0 mmol) in dry CH2Cl2 (15 mL) at room temperature
and the mixture was stirred overnight. The mixture was washed
O
O
R1
trans
Scheme 5.

6624
M. Zarei / Tetrahedron 69 (2013) 6620e6626
successively with saturated NaHCO3 (15 mL) and brine (15 mL). The
carbons),162.5 (CO, b-lactam); Anal. Calcd for C19H20N2O5S: C, 58.75;
organic layer was dried (Na2SO4), filtered, and the solvent was re-
H, 5.19; N, 7.21. Found: C, 58.68; H, 5.31; N, 7.26.
moved under reduced pressure to give the crude products.
b-Lac-
tams 5aeu, 7aed, 11aec, 17aed were purified by crystallization
4.2.7. 3-(Allyloxy)-1,4-diphenylazetidin-2-one (7b). White solid.
from ethyl acetate,
from 96% ethanol,
raphy (hexane/EtOAc 7:3), and
b
b
-lactams 9aec were purified by crystallization
-lactams 13aec by short column chromatog-
-lactams 15aec by short column
Mp: 85e87 ꢁC. IR (KBr) cmꢂ1: 1756 (CO, -lactam); 1H NMR
b
d
4.40e4.49 (CH2O-allyl, m, 2H), 5.17e5.29 (vinilic H, m, 2H), 5.43
(H-4, d, 1H, J¼4.8), 5.58 (H-3, d, 1H, J¼4.8), 5.79e5.88 (vinilic H, m,
1H), 6.86e7.75 (ArH, m, 10H); 13C NMR
55.1 (CH2O-allyl), 63.7 (C-
4), 83.0 (C-3), 107.5, 111.4, 115.9, 123.4, 123.8, 126.0, 129.3, 130.1,
144.6, 155.8 (C]C, aromatic carbons), 162.7 (CO, -lactam); Anal.
b
chromatography (hexane/EtOAc 9:1).
d
4.2.1. 2-(2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-oxoazetidin-3-
b
yl)isoindoline-1,3-dione (5f). White solid. Mp: 228e230 ꢁC. IR (KBr)
Calcd for C18H17NO2: C, 77.42; H, 6.13; N, 5.01. Found: C, 77.48; H,
6.25; N, 5.07.
cmꢂ1: 1726, 1753 (CO, phth), 1780 (CO,
b
-lactam); 1H NMR
d
3.61
(OMe, s, 3H), 5.17 (H-4, d, 1H, J¼2.3), 5.39 (H-3, d, 1H, J¼2.3),
6.71e7.90 (ArH, m, 12H); 13C NMR
56.3 (OMe), 64.9 (C-4), 66.3 (C-
3), 113.7, 117.5, 120.3, 121.1, 124.6, 125.0, 129.2, 136.8, 139.4, 143.8,
157.3 (aromatic carbons), 162.7 (CO, phth), 165.9 (CO, -lactam);
d
4.2.8. 3-(Allyloxy)-1,4-bis(4-methoxyphenyl)azetidin-2-one
White solid. Mp: 91e93 ꢁC. IR (KBr) cmꢂ1: 1752 (CO, -lactam); 1H
NMR 3.57, 3.67 (2OMe, 2s, 6H), 4.47e4.55 (CH2O-allyl, m, 2H),
(7c).
b
b
d
Anal. Calcd for C24H17ClN2O4: C, 66.59; H, 3.96; N, 6.47. Found: C,
66.68; H, 4.11; N, 6.53.
5.09e5.17 (vinilic H, m, 2H), 5.50 (H-4, d, 1H, J¼4.8), 5.49 (H-3, d,
1H, J¼4.8), 5.84e5.92 (vinilic H, m, 1H), 6.75e7.91 (ArH, m, 8H); 13C
NMR
d 54.5 (CH2O-allyl), 55.7, 56.3 (2OMe), 61.6 (C-4), 81.4 (C-3),
4.2.2. 2-(1-(4-Methoxybenzyl)-2-(4-chlorophenyl)-4-oxoazetidin-3-
110.3, 112.8, 114.3, 125.2, 125.8, 127.1, 131.9, 133.5, 149.6, 157.0 (C]C,
aromatic carbons), 161.9 (CO, -lactam); Anal. Calcd for C20H21NO4:
C, 70.78; H, 6.24; N, 4.13. Found: C, 70.86; H, 6.34; N, 4.06.
yl)isoindoline-1,3-dione (5g). White solid. Mp: 110e112 ꢁC. IR (KBr)
b
cmꢂ1: 1739, 1777 (CO, phth), 1783 (CO,
b
-lactam); 1H NMR
d
3.68
(OMe, s, 3H), 3.83, 4.87 (CH2-benzyl, 2d, 2H, J¼14.4), 5.35 (H-4, d,1H,
J¼2.5), 5.60 (H-3, d, 1H, J¼2.5), 6.83e7.81 (ArH, m, 12H); 13C NMR
4.2.9. 3-Menthoxy-1-(4-methoxyphenyl)-4-(4-nitrophenyl)-azeti-
d
43.7 (CH2), 55.4 (OMe), 61.8 (C-4), 63.5 (C-3), 113.5, 116.2, 121.4,
din-2-one (9a). White solid. Mp: 181e183 ꢁC. IR (KBr) cmꢂ1: 1332,
126.9,128.6,129.2,134.7,142.2,144.5,147.3,151.8 (aromatic carbons),
160.3 (CO, phth),162.9 (CO, -lactam); Anal. Calcd for C25H19ClN2O4:
1554 (NO2),1744 (CO, b d 0.29e2.08 (H menthoxy,
-lactam); 1H NMR
b
m, 18H), 3.11 (CHeO menthoxy, m, 1H), 3.59 (OMe, s, 3H), 4.83 (H-4,
C, 67.19; H, 4.29; N, 6.27. Found: C, 67.26; H, 4.39; N, 6.21.
d, 1H, J¼4.6), 5.21 (H-3, d, 1H, J¼4.6), 6.82e8.12 (ArH, m, 8H); 13C
NMR
d 16.4, 21.2, 22.5, 23.9, 26.4, 31.3, 35.3, 41.1, 47.7 (menthoxy
4.2.3. 1-Benzyl-3-(naphthalen-2-yloxy)-4-(4-nitrophenyl)-azetidin-
carbons), 56.4 (OMe), 63.6 (C-4), 81.7 (CHeO, menthoxy), 83.1 (C-
3), 112.8, 122.5, 123.2, 126.8, 133.1, 138.4, 146.0, 155.7 (aromatic
carbons), 163.9 (CO, b-lactam); Anal. Calcd for C26H32N2O5: C,
69.01; H, 7.13; N, 6.19. Found: C, 68.93; H, 7.25; N, 6.13.
2-one (5k). White solid. Mp: 141e143 ꢁC. IR (KBr) cmꢂ1: 1347, 1539
(NO2), 1748 (CO,
2H, J¼15.0), 4.75 (H-4, d, 1H, J¼4.8), 5.51 (H-3, d, 1H, J¼4.8),
6.63e8.08 (ArH, m, 16H); 13C NMR
43.7 (CH2), 61.9 (C-3), 81.6 (C-
b
-lactam); 1H NMR
d
3.93, 4.86 (CH2-benzyl, 2d,
d
4), 108.6, 109.7, 114.1, 118.5, 118.8, 120.3, 122.7, 124.8, 125.2, 128.6,
129.4, 129.8, 131.0, 135.3, 138.6, 144.9, 151.7, 155.9 (aromatic car-
4.2.10. 4-(4-Chlorophenyl)-3-menthoxy-1-phenylazetidin-2-one
(9b). White solid. Mp: 188e190 ꢁC. IR (KBr) cmꢂ1: 1741 (CO,
b
-lac-
0.24e2.13 (H menthoxy, m, 18H), 3.16 (CHeO men-
thoxy, m, 1H), 4.75 (H-4, d, 1H, J¼4.8), 5.32 (H-3, d, 1H, J¼4.8),
6.87e7.84(ArH, m, 9H);13CNMR
15.9, 20.6, 22.7, 23.4, 27.1, 30.7, 37.0,
bons), 163.6 (CO,
b
-lactam); Anal. Calcd for C26H20N2O4: C, 73.57; H,
tam); 1H NMR
d
4.75; N, 6.60. Found: C, 73.68; H, 4.88; N, 6.67.
d
4.2.4. 3-(2,4-Dichlorophenoxy)-1-(4-methoxybenzyl)-4-(4-nitrophe-
42.3, 46.8 (menthoxy carbons), 64.4 (C-4), 82.1 (CHeO, menthoxy),
84.9(C-3),114.0,120.9,122.4,125.6,133.8,136.3,145.7,153.9(aromatic
carbons),164.2 (CO, b-lactam); Anal. Calcd for C25H30ClNO2: C, 72.89;
nyl)azetidin-2-one (5l). Light-yellow solid. Mp: 84e86 ꢁC. IR (KBr)
cmꢂ1: 1344,1557 (NO2),1751 (CO,
b
-lactam); 1H NMR
d
3.60 (OMe, s,
3H), 3.81, 4.75 (CH2-benzyl, 2d, 2H, J¼14.7), 4.93 (H-4, d, 1H, J¼5.0),
H, 7.34; N, 3.40. Found: C, 72.99; H, 7.47; N, 3.48.
5.45 (H-3, d, 1H, J¼5.0), 6.77e8.08 (ArH, m, 11H); 13C NMR
d 45.9
(CH2), 55.6 (OMe), 63.1 (C-3), 82.7 (C-4), 113.5, 114.6, 116.0, 117.2,
119.5, 120.3, 125.8, 126.2, 128.0, 128.9, 133.6, 147.5, 152.1, 155.8 (aro-
4.2.11. 3-Menthoxy-1,4-bis(4-methoxyphenyl)azetidin-2-one
(9c). White solid. Mp: 181e183 ꢁC. IR (KBr) cmꢂ1: 1746 (CO,
b-
matic carbons), 163.6 (CO,
b-lactam); Anal. Calcd for C23H18Cl2N2O5:
lactam); 1H NMR
d 0.33e2.21 (H menthoxy, m, 18H), 3.20 (CHeO
C, 58.37; H, 3.83; N, 5.92. Found: C, 58.49; H, 3.97; N, 5.98.
menthoxy, m, 1H), 3.63, 3.69 (2OMe, 2s, 6H), 4.77 (H-4, d, 1H,
J¼5.0), 5.29 (H-3, d, 1H, J¼5.0), 6.76e8.06 (ArH, m, 8H); 13C NMR
4.2.5. 1-(3,4-Dimethoxybenzyl)-4-(4-chlorophenyl)-3-methoxyaze-
d 16.7, 21.4, 23.7, 24.5, 28.1, 32.6, 37.8, 40.3, 46.8 (menthoxy car-
bons), 55.4, 56.2 (2OMe), 62.9 (C-4), 81.4 (CHeO, menthoxy), 83.5
(C-3), 110.7, 121.5, 122.9, 124.7, 134.4, 137.1, 146.7, 156.3 (aromatic
tidin-2-one (5t). White solid. Mp: 77e79 ꢁC. IR (KBr) cmꢂ1: 1755
(CO,
b
-lactam); 1H NMR
d
3.22, 3.68, 3.72 (3OMe, 3s, 9H), 4.03, 4.79
(CH2-benzyl, 2d, 2H, J¼14.5), 4.65 (H-4, d, 1H, J¼4.5), 5.47 (H-3, d,
carbons), 163.4 (CO, b-lactam); Anal. Calcd C27H35NO4: C, 74.11; H,
8.06; N, 3.20. Found: C, 74.03; H, 8.15; N, 3.15.
1H, J¼4.5), 6.86e7.84 (ArH, m, 7H); 13C NMR
d
40.9 (CH2), 55.1, 56.0,
56.7 (3OMe), 63.2 (C-3), 84.4 (C-4), 114.7, 118.3, 121.9, 123.5, 129.1,
129.8, 132.7, 137.4, 142.8, 151.4 (aromatic carbons), 163.2 (CO,
lactam); Anal. Calcd for C19H20ClNO4: C, 63.07; H, 5.57; N, 3.87.
Found: C, 63.16; H, 5.70; N, 3.94.
b
-
4.2.12. 1-(Benzo[d]thiazol-2-yl)-4-(4-chlorophenyl)-3-phenoxyaze-
tidin-2-one (11a). Pale yellowish solid. Mp: 171e173 ꢁC. IR (KBr)
cmꢂ1: 1638 (C]N), 1755 (CO, -lactam); 1H NMR
b d 4.53 (H-4, d, 1H,
J¼5.1), 5.37 (H-3, d, 1H, J¼5.1), 6.81e8.26 (ArH, m, 13H); 13C NMR
4.2.6. 1-(3,4-Dimethoxybenzyl)-3-(methylthio)-4-(4-nitrophenyl)-
d 61.5 (C-3), 83.8 (C-4), 114.3, 119.5, 120.1, 120.3, 123.2, 123.5, 127.2,
azetidin-2-one (5u). White solid. Mp: 55e57 ꢁC. IR (KBr) cmꢂ1: 1338,
127.7, 128.9, 129.2, 129.6, 130.4, 131.0, 148.4 (aromatic carbons),
163.9 (C]N), 164.5 (CO, -lactam); Anal. Calcd for C22H15ClN2O2S:
1550 (NO2),1747 (CO,
b
-lactam); 1H NMR
d
2.18 (SMe, s, 3H), 3.53, 3.61
b
(2OMe, 2s, 6H), 4.00, 4.68 (CH2-benzyl, 2d, 2H, J¼14.7), 4.54 (H-4, d,
C, 64.94; H, 3.72; N, 6.88. Found: C, 65.03; H, 3.84; N, 6.95.
1H, J¼4.4), 5.52 (H-3, d, 1H, J¼4.4), 6.92e7.96 (ArH, m, 7H); 13C NMR
d
15.7 (SMe), 41.5 (CH2), 56.3, 57.0(2OMe), 62.4(C-3), 82.8(C-4),111.9,
4.2.13. 1-(Benzo[d]thiazol-2-yl)-4-(4-chlorophenyl)-3-methoxyazeti-
116.3, 122.7, 123.3, 125.2, 127.5, 135.8, 136.4, 146.2, 152.1 (aromatic
din-2-one (11b). White solid. Mp: 145e147 ꢁC. IR (KBr) cmꢂ1: 1641

M. Zarei / Tetrahedron 69 (2013) 6620e6626
6625
(C]N), 1749 (CO,
b
-lactam); 1H NMR
d
3.27 (OMe, s, 3H), 4.46 (H-4,
(CO,
b
-lactam); 1H NMR
d
2.85 (Me-N, s, 3H), 3.66 (OMe, s, 3H), 5.12
d, 1H, J¼4.8), 5.30 (H-3, d, 1H, J¼4.8), 6.73e8.20 (ArH, m, 8H); 13C
(H-4, s, 1H), 6.72e7.85 (ArH, m, 12H); 13C NMR
d
28.3 (Me-N), 55.9
(OMe), 61.4 (C-4), 73.0 (C-3), 113.7, 119.2, 121.8, 122.2, 122.8, 129.5,
134.7, 150.9, 153.1, 155.4 (aromatic carbons), 164.6 (CO, -lactam);
Anal. Calcd for C23H19NO3: C, 77.29; H, 5.36; N, 3.92. Found: C, 77.22;
H, 5.47; N, 3.86.
NMR
d 55.4 (OMe), 62.2 (C-3), 84.6 (C-4), 118.3, 119.0, 121.5,
121.8, 124.9, 125.4, 128.2, 128.7, 139.5, 146.1 (aromatic carbons),
163.3 (C]N), 164.0 (CO, -lactam); Anal. Calcd for C17H13ClN2O2S:
C, 59.21; H, 3.80; N, 8.12. Found: C, 59.31; H, 3.94; N, 8.07.
b
b
4.2.14. 1-(Benzo[d]thiazol-2-yl)-3-(naphthalen-2-yloxy)-4-phenyla-
4.2.21. 2-(4-Chlorophenyl)-1-phenylspiro[azetidine-3,90-xanthen]-4-
zetidin-2-one (11c). Pale yellowish solid. Mp: 190e192 ꢁC. IR (KBr)
one (17b). White solid. Mp: 207e209 ꢁC. IR (KBr) cmꢂ1: 1748 (CO,
cmꢂ1: 1644 (C]N), 1743 (CO,
b
-lactam); 1H NMR
d
4.71 (H-4, d, 1H,
b d C
-lactam); 1H NMR 5.12 (H-4, s, 1H), 6.84e7.82 (ArH, m, 17H); 13
J¼4.6), 5.45 (H-3, d, 1H, J¼4.6), 6.93e8.31 (ArH, m, 16H); 13C NMR
NMR
126.2, 129.1, 129.6, 131.6, 142.0, 146.8, 147.4, 152.7 (aromatic car-
bons), 163.6 (CO, -lactam); Anal. Calcd for C27H18ClNO2: C, 76.50;
d 61.9 (C-4), 75.0 (C-3), 111.9, 117.3, 119.9, 123.1, 123.7, 125.0,
d
60.9 (C-3), 83.4 (C-4), 108.3, 110.5, 113.9, 115.4, 119.0, 119.7, 122.8,
123.3, 126.5, 127.2, 127.9, 128.4, 129.7, 130.2, 132.8, 134.1, 135.0,
145.2, 148.7, 157.4 (aromatic carbons), 162.8 (C]N), 164.2 (CO,
b
b
-
H, 4.28; N, 3.30. Found: C, 76.59; H, 4.41; N, 3.36.
lactam); Anal. Calcd for C26H18N2O2S: C, 73.91; H, 4.29; N, 6.63.
Found: C, 73.88; H, 4.39; N, 6.55.
4.2.22. 2-(4-Chlorophenyl)-1-(methoxybenzyl)spiro-[azetidine-3,ꢂ910-
xanthen]-4-one (17c). White solid. Mp: 157e159 ꢁC. IR (KBr) cm
:
4.2.15. 1-(4-Ethoxyphenyl)-4-(4-nitrophenyl)-3-tosylazetidin-2-one
1743 (CO,
benzyl, 2d, 2H, J¼14.5), 5.25 (H-4, s, 1H), 6.74e7.92 (ArH, m, 16H);
13C NMR
42.6 (CH2), 56.3 (OMe), 62.7 (C-4), 74.0 (C-3), 108.1, 114.7,
117.3, 117.9, 118.3, 121.5, 123.7, 126.0, 126.6, 128.1, 128.7, 132.0, 146.2,
154.5 (aromatic carbons), 163.1 (CO, -lactam); Anal. Calcd for
b d 3.71 (OMe, s, 3H), 3.90, 4.73 (CH2-
-lactam); 1H NMR
(13a). White solid. Mp: 166e168 ꢁC. IR (KBr) cmꢂ1: 1149,1322 (SO2),
1337, 1551 (NO2), 1747 (CO,
b
-lactam); 1H NMR
d
1.34 (Me, t, 3H,
d
J¼7.0), 2.21 (Me, s, 3H), 3.96 (OCH2, q, 2H, J¼7.0), 4.48 (H-4, d, 1H,
J¼2.4), 5.46 (H-3, d, 1H, J¼2.4), 6.86e8.10 (ArH, m, 12H); 13C NMR
b
d
14.1, 23.7 (2Me), 61.4 (OCH2), 62.1 (C-4), 81.9 (C-3), 113.1, 118.4,
C29H22ClNO3: C, 74.43; H, 4.74; N, 2.99. Found: C, 74.51; H, 4.87;
N, 3.05.
122.5, 122.8, 123.0, 128.6, 129.2, 134.8, 137.2, 141.0, 146.4, 157.1 (ar-
omatic carbons), 162.8 (CO, -lactam); Anal. Calcd for C24H22N2O6S:
b
61.79; H, 4.75, N, 6.00. Found: C, 61.86; H, 4.85; N, 6.06.
Acknowledgements
4.2.16. 1,4-Bis(4-methoxyphenyl)-3-tosylazetidin-2-one (13b). White
Thanks are due to Hormozgan University Research Council for
the financial support of this study.
solid. Mp: 173e175 ꢁC. IR (KBr) cmꢂ1: 1155, 1319 (SO2), 1744 (CO,
b-
lactam); 1H NMR
d 2.16 (Me, s, 3H), 3.59, 3.63 (2OMe, 2s, 6H), 4.43 (H-
4, d, 1H, J¼2.5), 5.55 (H-3, d, 1H, J¼2.5), 6.79e7.85 (ArH, m, 12H); 13C
References and notes
NMR
d 22.4 (Me), 55.4, 56.0 (2OMe), 62.7 (C-4), 83.3 (C-3), 112.4,
115.7, 120.0, 121.5, 121.7, 125.4, 126.1, 131.9, 132.5, 138.3, 148.7, 153.4
(aromatic carbons), 161.6 (CO, -lactam); Anal. Calcd for C24H23NO5S:
C, 65.89; H, 5.30; N, 3.20. Found: C, 65.83; H, 5.39; N, 3.15.
1. Mark, J. E.; Allcock, H. R.; West, R. Inorganic Polymers; Prentice Hall: Englewood,
NJ, 1992.
b
2. Labarre, J.-F.; Crasnier, F.; Labarre, M.-C.; Sournies, F. Synlett 1996, 799e805.
3. (a) Allcock, H. R. J. Am. Chem. Soc. 1964, 86, 2591e2595; (b) Hashimoto, M.;
Obora, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2008, 73, 2894e2897; (c) Voz-
nicova, R. K.; Taraba, J.; Prihoda, J.; Alberti, M. Polyhedron 2008, 27, 2077e2082;
(d) Rolland, O.; Griffe, L.; Poupot, M.; Maraval, A.; Ouali, A.; Coppel, Y.; Fournie,
J. J.; Bacquet, G.; Turrin, C. O.; Caminade, A. M.; Majoral, J. P.; Poupot, R.
Chem.dEur. J. 2008, 14, 4836e4850; (e) Pandey, S. K.; Bisai, A.; Singh, V. K.
Synth. Commun. 2007, 37, 4099e4103; (f) Zarei, M. Tetrahedron Lett. 2013, 53,
1100e1102.
4.2.17. 4-(4-Chlorophenyl)-1-phenyl-3-tosylazetidin-2-one (13c).
White solid. Mp: 191e193 ꢁC. IR (KBr) cmꢂ1: 1151, 1327 (SO2), 1743
(CO,
b
-lactam); 1H NMR
d
2.25 (Me, s, 3H), 4.39 (H-4, d, 1H, J¼2.5),
5.52 (H-3, d, 1H, J¼2.5), 6.90e7.74 (ArH, m, 13H); 13C NMR
d 23.4
(Me), 61.5 (C-4), 82.6 (C-3), 114.5, 116.9, 123.1, 123.7, 124.2, 127.9,
128.3, 131.7, 134.2, 142.6, 144.5, 150.7 (aromatic carbons), 162.1 (CO,
4. Rosini, G.; Baccolini, G.; Cacchi, S. J. Org. Chem. 1973, 38, 1060e1061.
5. Hashimoto, M.; Obora, Y.; Ishii, Y. Org. Process Res. Dev. 2009, 13, 411e414.
6. Bahrami, K. Synlett 2011, 2671e2674.
b
-lactam); Anal. Calcd for C22H18ClNO3S: C, 64.15; H, 4.40; N, 3.40.
7. Caglioti, L.; Poloni, M.; Rosini, G. J. Org. Chem. 1968, 33, 2979e2981.
8. (a) Holleman, A. F.; Wiberg, E. Inorganic Chemistry; Academic: San Diego, CA,
2001; (b) Audrieth, L. F.; Steinman, R.; Toy, A. D. F. Chem. Rev. 1943, 43, 109e133.
9. (a) Ceric, H.; Sindler-Kulyk, M.; Kovacevic, M.; Peric, M.; Zivkovic, A. Bioorg.
Med. Chem. 2010, 18, 3053e3058; (b) Morin, R. B.; Gorman, M. Chemistry and
Found: C, 64.22; H, 4.51; N, 3.44.
4.2.18. 3-Acetyl-4-(4-chlorophenyl)-1-(4-ethoxyphenyl)azetidin-2-
one (15a). White solid. Mp: 57e59 ꢁC. IR (KBr) cmꢂ1: 1712 (CO,
ketone), 1747 (CO,
b
-lactam); 1H NMR
d
1.28 (Me, t, 3H, J¼6.9), 2.35
Biology of b-Lactam Antibiotics; Academic: New York, NY, 1982; (c) Long, T. E.;
Turos, E. Curr. Med. Chem.: Anti-Infect. Agents 2002, 1, 251e268; (d) Hwu, J. R.;
Ethiraj, S. K.; Hakimelahi, G. H. Mini-Rev. Med. Chem. 2003, 3, 305e313.
10. (a) Xu, X.; Fu, R.; Chen, J.; Chen, S.; Bai, S. Bioorg. Med. Chem. Lett. 2007, 17,
101e104; (b) Li, S.; Liu, G.; Jia, J.; Li, X.; Yu, C. J. Pharm. Biomed. Anal. 2006, 40,
987e992; (c) Burnett, D. A. Curr. Med. Chem. 2004, 11, 1873e1887.
11. (a) Gerona-Navarro, G.; de Vega, J. P.; Garcia-Lopez, M. T.; Andrei, G.; Snoeck, R.;
Balzarini, J.; De Clercq, E.; Gonzalez-Muniz, R. Bioorg. Med. Chem. Lett. 2004, 14,
2253e2256; (b) Yoakim, C.; Ogilvie, W.; Cameron, D. R.; Chabot, C.; Grande-
Matre, C.; Guse, I.; Hache, B.; Naud, J.; Kawai, S.; O’Meara, J. A.; Plante, R.; Deziel,
R. Antiviral Chem. Chemother. 1998, 9, 379e387.
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2010, 45, 5541e5560; (b) Veinberg, G.; Vorona, M.; Shestakova, I.; Kanepe, I.;
Lukevics, E. Curr. Med. Chem. 2003, 10, 1741e1757.
13. (a) Marchand-Brynaert, J.; Dive, G.; Galleni, M.; Gerard, S. Bioorg. Med. Chem.
2004, 12, 129e138; (b) Firestone, R. A.; Barker, P. L.; Pisano, J. M.; Ashe, B. M.;
Dahlgren, M. E. Tetrahedron 1990, 46, 2255e2262.
(MeCO, s, 3H), 3.86 (H-3, d, 1H, J¼2.4), 3.91 (OCH2, q, 2H, J¼6.9),
4.63 (H-4, d, 1H, J¼2.4), 6.74e7.69 (ArH, m, 8H); 13C NMR
d 14.5,
25.3 (2Me), 60.9 (OCH2), 62.2 (C-3), 67.5 (C-4), 113.0, 116.3, 121.7,
125.5, 130.4, 142.9, 144.5, 152.1 (aromatic carbons), 161.8 (CO, b-
lactam), 197.4 (CO, ketone); Anal. Calcd for C19H18ClNO3: C, 66.38;
H, 5.28; N, 4.07. Found: C, 66.45; H, 5.40; N, 4.12.
4.2.19. 3-Acetyl-1-benzyl-4-phenylazetidin-2-one
solid. Mp: 41e43 ꢁC. IR (KBr) cmꢂ1: 1709 (CO, ketone), 1751 (CO,
lactam); 1H NMR
2.33 (MeCO, s, 3H), 3.80 (H-3, d, 1H, J¼2.5), 3.91,
4.77 (CH2-benzyl, 2d, 2H, J¼14.7), 4.56 (H-4, d, 1H, J¼2.5), 6.84e7.48
(ArH, m, 8H); 13C NMR
24.1 (Me), 43.9 (CH2), 62.5 (C-3), 66.7 (C-4),
115.6,121.9,126.3,129.4,130.8,144.1,147.3,148.5 (aromatic carbons),
164.7 (CO, -lactam),199.1 (CO, ketone); Anal. Calcd for C18H17NO2: C,
(15b). White
b-
d
d
14. (a) Sutton, J. C.; Bolton, S. A.; Harti, K. S.; Huang, M. H.; Jacobs, G.; Meng, W.;
Zhao, G.; Bisacchi, G. S. Bioorg. Med. Chem. Lett. 2004, 14, 2233e2239.
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700e704.
b
77.40; H, 6.13; N, 5.01. Found: C, 77.49; H, 6.27; N, 4.94.
4.2.20. 2-(4-Methoxyphenyl)-1-methylspiro[azetidine-3,90-xanthen]-
17. (a) Setti, E. L.; Davis, D.; Janc, J. M.; Jeffery, D. A.; Cheung, H.; Yu, W. Bioorg. Med.
Chem. Lett. 2005, 15, 1529e1534.
4-one (17a). Milky-color solid. Mp: 135e137 ꢁC. IR (KBr) cmꢂ1: 1750

6626
M. Zarei / Tetrahedron 69 (2013) 6620e6626
18. (a) Chen, D.; Falsetti, S. C.; Frezza, M.; Milacic, V.; Kazi, A.; Cui, Q. C.; Long, T. E.;
Turos, E.; Ping Dou, Q. Cancer Lett. 2008, 268, 63e69; (b) Kazi, A.; Hill, R.; Long,
T. E.; Kuhn, D. J.; Turos, E.; Ping Dou, Q. Biochem. Pharmacol. 2004, 67, 365e374;
(c) Banik, B. K.; Banik, I.; Becker, F. F. Bioorg. Med. Chem. 2005, 13, 3611e3622;
(d) Banik, B. K.; Becker, F. F.; Banik, I. Bioorg. Med. Chem. 2004, 12, 2523e2528.
19. (a) O’Driscoll, M.; Greenhalgh, K.; Young, A.; Turos, E.; Dickey, S.; Lim, D. V.
Bioorg. Med. Chem. 2008, 16, 7832e7837; (b) Arnoldi, A.; Cabrini, R. M.; Farina,
G.; Merlinit, L. J. Agric. Food Chem. 1990, 38, 2197e2199.
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