Utilization of DMFPhCOCl adduct as an acid activator in a new and convenient method for preparation of β-lactams

Article abstract of DOI:10.1246/bcsj.20110323

An efficient one-pot synthesis of β-lactams by the reaction of imines with acetic acid derivatives in the presence of DMF and benzoyl chloride adduct, a cheap reagent, has been described. Optimization of solvents, temperature, and molar ratio of reagent w

Full text of DOI:10.1246/bcsj.20110323

360
Bull. Chem. Soc. Jpn. Vol. 85, No. 3, 360-368 (2012)
© 2012 The Chemical Society of Japan
Utilization of DMF-PhCOCl Adduct as an Acid Activator
in a New and Convenient Method for Preparation of ¢-Lactams
Maaroof Zarei
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
Received October 24, 2011; E-mail: mzarei@hormozgan.ac.ir
An efficient one-pot synthesis of ¢-lactams by the reaction of imines with acetic acid derivatives in the presence of
DMF and benzoyl chloride adduct, a cheap reagent, has been described. Optimization of solvents, temperature, and molar
ratio of reagent was also performed. Several types of ¢-lactams including monocyclic, spirocyclic, N-alkyl, 3-butadienyl,
and 3-electron-withdrawing group have been synthesized by this method in good to excellent yields. All steps of the
reaction proceed at room temperature.
For about 80 years, the ¢-lactam antibiotics such as
DMF and benzoyl chloride adduct 1 has been used pre-
viously for the formylation of alcohols at room temperature.13
According to above facts, in this paper the simple and efficient
procedure for the preparation of ¢-lactams by the Staudinger
reaction from imines and substituted carboxylic acids using
DMF and benzoyl chloride adduct is described.
penicillins, cephalosporins, carbapenems, and monobactams
have served as a powerful line of defense against bacterial
infections.1 Of course, the appearance of new types of bacteria
resistant to the more commonly used ¢-lactam antibiotics is a
problem of worldwide importance and it gives further impe-
tus to the synthesis of new ¢-lactams.2 The new cholesterol
absorption inhibitor, Ezetimibe, has a ¢-lactam skeleton.3
Besides being antibacterial and cholesterol absorption inhibitor
drugs, various other biological activities have been discovered
to be associated with ¢-lactams.4 Azetidin-2-ones (¢-lactams)
can be employed as useful intermediates in organic synthesis
as a term coined by Ojima,5 a ¢-lactam synthon method.6 ¢-
Lactams have also proven highly popular as side-chain equiv-
alents for the synthesis of Taxol and Taxotere, as well as
numerous analogues.7
DMF and benzoyl chloride adduct 1 was generated in situ
by reaction of N,N-dimethylformamide (DMF) and benzoyl
chloride in dry CH2Cl2 at room temperature (Scheme 1).
Then the adduct 1 in dry CH2Cl2 was added to a solution of
Schiff base 2a, carboxylic acid 3a, and triethylamine in dry
CH2Cl2 at room temperature. After usual workup and crystal-
lization from ethyl acetate, azetidin-2-one 4a was obtained
in 91%. This reaction is simple and clean because DMF and
triethylammonium salt by-products were removed by simple
aqueous work-up. Next the effect of solvents, temperature, and
molar ratio of reagent were examined. According to Table 1,
DMF or benzoyl chloride alone was inactive in the synthesis
of azetidin-2-one 4a. Among the solvents considered, dichloro-
methane showed the best result and cold media decreased
the yield. As it is shown in the table, the highest yield of
4a was obtained when 1.3 mmol of the adduct 1 and 1.3 mmol
carboxylic acid 3a react with 1.0 mmol of Schiff base 2a in dry
dichloromethane at room temperature (Entry 8).
Building of a ¢-lactam ring is a crucial step in the synthesis
of new ¢-lactams and due to the importance of this structural
framework, the development of new synthetic methods for the
formation of the ¢-lactam ring continues to be a challenging
area in organic chemistry.8
The Staudinger reaction (ketene-imine cycloaddition) is
the most widely used and simple reaction for the synthesis
of azetidin-2-ones which Professor Hermann Staudinger first
reported in 1907.9 After over 100 years, this general reaction
yielding ¢-lactams remains one of the key methods for the
synthesis of these strained heterocycles.10 Most often, the ketene
components used in the Staudinger reaction are usually
produced in situ by the elimination of an acyl chloride in the
presence of a base.11 Other methods for ketene generation that
are occasionally used are conceptually similar to the elimination
of acyl chlorides but use different carboxy activating reagents.
Activation of a carboxylic acid followed by treatment with
triethylamine has been used to generate a ketene.12 These
methods are conventionally useful when the acid halides are
not commercially available, difficult to prepare or when they are
unstable. The high cost, unavailability, pollution, and low yields
are disadvantages of some these acid activators. Furthermore
in some cases, heating or cooling of the reaction is necessary.
On the basis of these successful results, the azetidin-2-ones
4a-4p were synthesized by treatment of 1.0 mmol of imines 2,
1.3 mmol of substituted acetic acids 3, and 1.3 mmol of adduct
1 in the presence of triethylamine in dry dichloromethane at
room temperature and they were purified by crystallization
from EtOAc (Table 2). All products were characterized by their
O
O
Me
Me
Me
H
O
Ph
+
N
N
Ph
Cl
O
H
Me
Cl
1
Scheme 1.
Published on the web February 23, 2012; doi:10.1246/bcsj.20110323

M. Zarei
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
361
spectral data and elemental analyses. The cis stereochemistry
was assigned by the comparison of the coupling constant H-3
and H-4 (J3,4 > 4.0 Hz).
Treatment of imine 5 derived from 4-methoxy-1-naphthyl-
amine with various acetic acid derivatives in the presence
of reagent 1 at room temperature gave cis-azetidin-2-ones
6a-6c which were purified by crystallization from EtOAc
(Scheme 2).
dure described in the literature.14 Reaction of (prop-2-enyloxy)-
acetic acid (7) and corresponding imines in the presence of
adduct 1 yielded the cis-azetidin-2-ones 8a-8c in excellent
yield (Scheme 3).
¢-Lactams 9a-9c were also easily obtained from sorbic acid
(hexa-2,4-dienoic acid) by this method and purified by short
column chromatography on silica gel (Scheme 4). The trans
stereochemistry was deduced from H-3 and H-4 coupling
constants (J3,4 ¯ 3.0). [2 + 2] Cycloaddition reactions be-
tween butadienyl ketene (generated in situ) and corresponding
imines gave the 3-butadienylazetidin-2-ones 9a-9c. Previously
Mahajan and co-workers were synthesized trans-dienyl-
azetidin-2-one derivatives from sorbyl chloride and imines
in the presence of triethylamine in CH2Cl2 and Diels-Alder
reaction of these compounds has been investigated.15
Then to check the generality of this method, we synthesized
azetidin-2-ones 10a-10f from imines derived from aliphatic
amines (Scheme 5). Azetidin-2-ones 10a-10f were purified
by crystallization from EtOAc. The good to excellent yields of
products showed the versatility of this method in the synthesis
of different ¢-lactams.
(Prop-2-enyloxy)acetic acid (7) was prepared from prop-2-
enyl alcohol (allyl alcohol) and chloroacetic acid by a proce-
Table 1. Reaction Condition in the Synthesis of Azetidin-2-
one 4a
PhO-CH2COOH
4-MeOC6H4-N=CH-C6H4-4-Cl
+
2a
3a
C6H4-4-Cl
PhO
1
N
Et3N
O
C6H4-4-OMe
The DMF and benzoyl chloride adduct 1 was also success-
fully employed for the synthesis of C-3 spiro-¢-lactams.
Treatment of xanthene-9-carboxylic acid with various imines
in the presence of the adduct 1 and triethylamine afforded
pure spiro-¢-lactams 11a-11c after crystallization from EtOAc
(Scheme 6).
Although the [2 + 2] cycloaddition reaction of ketene-imine
using ¡-electron-withdrawing substituted carboxylic acids
generally fails for the synthesis of azetidin-2-ones, this method
was successfully extended to the synthesis of 3-azido and 3-
acetyl-¢-lactams. cis-3-Azido-¢-lactams 12a-12c and trans-3-
acetyl-¢-lactams 13a-13c were synthesized from azidoacetic
acid,16 acetoacetic acid,17 and corresponding imines using
4a
Quantity of reagent Yield
Entry Reagent Solvent Temp
/mmol
/%
1
2
3
4
5
6
7
8
9
DMF
PhCOCl CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.3
1.0
®
®
91
63
76
48
72
93
79
1
1
1
1
1
1
1
CH2Cl2
DMF
THF
Toluene
CH2Cl2 0 °C
CH2Cl2
CH2Cl2
rt
rt
Table 2. Synthesis of Azetidin-2-ones 4a-4p by Adduct 1
R2
R3
O
1
R3CH2COOH
R1N=CHR2
+
N
Et3N
R1
2
3
4
Entry
R1
R2
R3
Product
Isolated yield/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-MeOC6H4
4-MeOC6H4
4-EtOC6H4
4-EtOC6H4
4-MeOC6H4
4-EtOC6H4
4-EtOC6H4
4-MeOC6H4
4-MeOC6H4
4-EtOC6H4
C6H5
4-MeOC6H4
4-EtOC6H4
C6H5
4-MeOC6H4
4-EtOC6H4
4-ClC6H4
PhO
PhO
PhO
PhO
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
93
89
90
89
91
87
85
89
83
91
90
88
86
92
94
91
4-MeOC6H4
4-NO2C6H4
CH=CHPh
4-MeC6H4
CH=CHPh
4-NO2C6H4
4-ClC6H4
PhO
PhthN
PhthN
PhthN
PhthN
2-NaphthO
2-NaphthO
2-NaphthO
MeO
4-MeC6H4
4-ClC6H4
4-NO2C6H4
4-MeOC6H4
4-MeC6H4
4-NO2C6H4
4-NO2C6H4
4-MeOC6H4
MeO
2,4-Cl2C6H3O
2,4-Cl2C6H3O

362
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Utilization of DMF-PhCOCl Adduct for Preparation of ¢-Lactams
Me
R
1, CH
2Cl2
+
RCH2COOH
N
MeO
N
Et3N , rt
O
Me
OMe
6a, R = PhO
6b, R = MeO
92%
84%
5
6c, R = PhthN 87%
Scheme 2.
R2
O
CH2Cl2
1,
R1N=CHR2
OH
+
N
O
Et3N , rt
O
R1
8a, R1 = C6H5 ; R2 = 4-NO2C6H4
O
88%
7
8b, R1 = 4-MeOC6H4 ; R2 = 4-ClC6H4 85%
8c, R1 = 4-EtOC6H4 ; R2 = 4-MeC6H4 89%
Scheme 3.
R2
CH2Cl2
1,
R1N=CHR2
OH
+
N
Et3N , rt
O
R1
O
9a, R1 = 4-MeOC6H4 ; R2 = 4-ClC6H4 67%
sorbic acid
9b, R1 = 4-EtOC6H4 ; R2 = 4-NO2C6H4 61%
9c, R1 = 4-MeOC6H4 ; R2 = 4-MeC6H4 62%
Scheme 4.
R2
R3
O
CH Cl
1,
2
2
R3CH2COOH
R1N=CHR2
+
N
Et3N , rt
R1
10a, R1 = 4-MeOC6H4CH2 ; R2 = 4-NO2C6H4 ; R3 = PhO
10b, R1 = 4-MeOC6H4CH2 ; R2 = 4-NO2C6H4 ; R3 = PhthN 85%
92%
10c, R1 = C6H5CH2 ; R2 = 4-NO2C6H4 ; R3 = PhO
88%
10d, R1 = C6H5CH2 ; R2 = 4-NO2C6H4 ; R3 = PhthN
10e, R1 = Me ; R2 = 4-NO2C6H4 ; R3 = PhO
86%
80%
10f, R1 = Me ; R2 = 4-MeC6H4 ; R3 = PhthN
77%
Scheme 5.

M. Zarei
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
363
O
O
R2
1,
Et3N , rt
CH2Cl2
R1N=CHR2
+
N
O
R1
O
OH
11a, R1 = C6H5 ; R2 = 4-NO2C6H4
82%
87%
xanthene-9-
carboxylic
acid
11b, R1 = 4-EtOC6H4 ; R2 = 4-NO2C6H4
11c, R1 = 4-MeOC6H4 ; R2 = 4-MeOC6H4 85%
Scheme 6.
R2
N3
O
CH Cl
1,
2
2
R1N=CHR2
+
N3
OH
Et3N , rt
N
O
R1
12a, R1 = 4-EtOC6H4 ; R2 = 4-MeC6H4
69%
azidoacetic
acid
12b, R1 = 4-MeOC6H4 ; R2 = 4-ClC6H4 68%
12c, R1 = C6H5 ; R2 = C6H5
60%
O
R2
O
O
CH Cl
1,
2
2
R1N=CHR2
+
OH
Et3N , rt
N
O
R1
acetoacetic
acid
13a, R1 = 4-MeOC6H4 ; R2 =4-MeOC6H4
13b, R1 = 4-EtOC6H4 ; R2 = 4-NO2C6H4
13c, R1 = C6H5 ; R2 = C6H5
59%
62%
52%
Scheme 7.
the adduct 1 in the presence of Et3N at room temperature,
respectively (Scheme 7).
ring closure and the isomerization of the imine moiety in
the zwitterionic intermediate.18 According to the above, it
is suggested that the reaction proceeds via formation of an
activated ester (Scheme 8) of which the same mechanism has
been already reported.12c,12t
Many different experimental factors, such as reaction
temperature, solvent, electronic effects, and the steric hindrance
of the ketene and imine substituents may affect the stereo-
chemistry of ¢-lactams in the Staudinger reaction. The imine,
the nucleophile, attacks the lowest unoccupied molecular
orbital (LUMO) of the ketene carbonyl group giving rise to a
zwitterionic intermediate and a subsequent ring closure of the
zwitterionic intermediate producing the ¢-lactam. This inter-
mediate was detected and characterized by IR spectroscopy.
When the direct ring closure of the zwitterionic intermediate
is fast enough, the final ¢-lactam product is cis, while when
the direct ring closure is not so fast, the isomerization of the
imine moiety in the zwitterionic intermediate occurs to form a
sterically more favorable intermediate, which produces the final
trans-¢-lactam product. The relative (cis/trans) stereoselectiv-
ity is generated as a result of the competition between the direct
Conclusion
In summary, DMF and benzoyl chloride adduct is a highly
reactive acid activator which provides a convenient route to
azetidin-2-ones from imines and a variety of carboxylic acids
with good to excellent yields and good purity. The present
methods offer several advantages in terms of simplicity,
applicability, mildness, high yields, and availability of the
reagents. Compared to other acid activators, it has been found
to be superior in terms of its cost and safety, making them
industrially viable. Also, this method, unlike some other
methods, needs no heating or cooling of the reaction in the
preparation of reagent and in the cycloaddition steps.

364
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Utilization of DMF-PhCOCl Adduct for Preparation of ¢-Lactams
O
Me
O
H
Ph
Cl
N
PhCOO
Me
H
O
Me
Et3N
CH2R3
1
R3CH2COOH
R3CH2COO
N
O
- H+
Me
activated ester
H
O
PhCOO
Me
- DMF, - Et3NH+ PhCOO-
NEt3
R3CH=C=O
N
O
CHR3
H
Me
H H
R2
R3
R3
R2
R3CH=C=O
R1N=CHR2
+
N
N
R1
O
R1
O
zwitterionic
intermediate
Cis
H H
N
R3
R2
R1
R3
R2
R1
N
O
O
Trans
Scheme 8.
perature and the mixture was stirred overnight. In the case
of DMF and THF, water was added and extraction by CH2Cl2
was performed. Then the organic solution was washed succes-
sively with saturated NaHCO3 (20 mL) and brine (20 mL). The
organic layer was dried (Na2SO4), filtered and the solvent was
removed under reduced pressure to give the crude products.
¢-Lactams 4a-4p, 6a-6c, 8a-8c, 10a-10f, and 11a-11c were
purified by crystallization from ethyl acetate and ¢-lactams
9a-9c, 12a-12c, and 13a-13c by short column chromatog-
raphy (hexane/EtOAc 9:1).
3-(Naphthalen-2-yloxy)-4-(4-nitrophenyl)-1-phenyl-
azetidin-2-one (4k): Light-yellow solid. Mp: 189-191 °C; IR
(KBr) cm¹1: 1356, 1529 (NO2), 1749 (CO, ¢-lactam); 1H NMR
(300 MHz, CDCl3): ¤ 5.43 (H-4, d, 1H, J = 5.1 Hz), 5.63 (H-3,
d, 1H, J = 5.1 Hz), 6.90-8.18 (ArH, m, 16H); 13C NMR (75
MHz, CDCl3): ¤ 62.4 (C-4), 82.7 (C-3), 110.4, 115.7, 116.9,
118.2, 119.0, 123.5, 124.2, 126.6, 127.3, 128.9, 129.1, 129.9,
133.6, 134.4, 143.8, 146.5, 152.9, 157.1 (aromatic carbons),
162.4 (CO, ¢-lactam); Anal. Calcd for C25H18N2O4: C, 73.16;
H, 4.42; N, 6.83%. Found: C, 73.24; H, 4.55; N, 6.77%.
1,4-Bis(4-methoxyphenyl)-3-(naphthalen-2-yloxy)-
Experimental
General.
All required chemicals were purchased from
Merck, Fluka, and Acros chemical companies. The melting
points were determined on a Buchi 535 apparatus and are
uncorrected. IR spectra were measured on a galaxy series FT-IR
5000 spectrometer. NMR spectra were recorded on a Bruker
spectrophotometer (1H NMR 300 MHz, 13C NMR 75 MHz)
using tetramethylsilane as an internal standard and coupling
constants are given in cycles per second (Hz). 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 chromatography
was performed on silica gel 60 (Merck, 70-230 mesh). Spectral
data for 4a-4j, 4m, 4o, 10c, 10f, 11b, 11c, 12b, and 12c have
been previously reported.12c-12e,12j
General Procedure for the Synthesis of Azetidin-2-ones
Using DMF and Benzoyl Chloride Adduct. To a stirred
solution of benzoyl chloride (0.15 mL, 0.18 g, 1.3 mmol) in dry
dichloromethane (5 mL) was added dry dimethylformamide
(0.1 mL, 0.1 g, 1.3 mmol) at room temperature and stirred for
5 min. Then this suspension mixture was added to a solution
of the substituted acetic acid (1.3 mmol), corresponding Schiff
base (1.0 mmol), and dry triethylamine (4.0 mmol) in 15 mL
dry solvents (CH2Cl2, DMF, THF, and toluene) at room tem-
azetidin-2-one (4l):
Light-yellow solid. Mp: 173-175 °C;
IR (KBr) cm¹1: 1745 (CO, ¢-lactam); 1H NMR (300 MHz,
CDCl3): ¤ 3.68, 3.74 (2OMe, s, 6H), 5.48 (H-4, d, 1H, J =
4.9 Hz), 5.60 (H-3, d, 1H, J = 4.9 Hz), 6.82-7.89 (ArH, m,

M. Zarei
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
365
15H); 13C NMR (75 MHz, CDCl3): ¤ 55.1, 55.8 (OMe), 63.5
(C-4), 81.5 (C-3), 108.6, 111.3, 115.9, 117.4, 117.7, 121.9,
123.5, 124.2, 125.0, 129.1, 129.7, 130.4, 131.8, 136.2, 145.7,
150.8, 154.0, 156.2 (aromatic carbons), 161.6 (CO, ¢-lactam);
Anal. Calcd for C27H23NO4: C, 76.22; H, 5.45; N, 3.29%.
Found: C, 76.16; H, 5.57; N, 3.32%.
3-Methoxy-4-(4-nitrophenyl)-1-phenylazetidin-2-one
(4n): White solid. Mp: 124-126 °C; IR (KBr) cm¹1: 1347,
1539 (NO2), 1746 (CO, ¢-lactam); 1H NMR (300 MHz,
CDCl3): ¤ 3.31 (OMe, s, 3H), 4.81 (H-4, d, 1H, J = 4.5 Hz),
5.10 (H-3, d, 1H, J = 4.5 Hz), 6.71-7.93 (ArH, m, 9H);
13C NMR (75 MHz, CDCl3): ¤ 56.6 (OMe), 64.0 (C-4), 84.7
(C-3), 118.3, 119.1, 123.5, 127.9, 128.6, 133.1, 136.9, 156.8
(aromatic carbons), 164.1 (CO, ¢-lactam); Anal. Calcd for
C16H14N2O4: C, 64.42; H, 4.73; N, 9.39%. Found: C, 64.49;
H, 4.84; N, 9.45%.
(aromatic carbons), 160.9 (CO, phth), 163.5 (CO, ¢-lactam);
Anal. Calcd for C29H22N2O4: C, 75.31; H, 4.79; N, 6.06%.
Found: C, 75.40; H, 4.93; N, 6.13%.
3-(Allyloxy)-4-(4-nitrophenyl)-1-phenylazetidin-2-one
(8a): White solid. Mp: 62-64 °C; IR (KBr) cm¹1: 1347, 1533
(NO2), 1752 (CO, ¢-lactam); 1H NMR (300 MHz, CDCl3):
¤ 4.53-4.58 (CH2O, m, 2H), 5.11-5.24 (vinylic H, m, 2H),
5.36 (H-4, d, 1H, J = 4.4 Hz), 5.57 (H-3, d, 1H, J = 4.4 Hz),
5.88-5.96 (vinylic H, m, 1H), 6.85-8.09 (ArH, m, 9H);
13C NMR (75 MHz, CDCl3): ¤ 56.9 (OCH2), 62.7 (C-4), 83.2
(C-3), 110.2, 112.8, 119.5, 123.2, 123.8, 128.8, 129.4, 135.9,
146.0, 151.7 (C=C, aromatic carbons), 164.2 (CO, ¢-lactam);
Anal. Calcd for C18H16N2O4: C, 66.66; H, 4.97; N, 8.64%.
Found: C, 66.73; H, 5.11; N, 8.57%.
3-(Allyloxy)-4-(4-chlorophenyl)-1-(4-methoxyphenyl)-
azetidin-2-one (8b):
White solid. Mp: 71-73 °C;
3-(2,4-Dichlorophenoxy)-1-(4-ethoxyphenyl)-4-(4-me-
thoxyphenyl)azetidin-2-one (4p): White crystalline solid.
Mp: 155-157 °C; IR (KBr) cm¹1: 1748 (CO, ¢-lactam);
1H NMR (300 MHz, CDCl3): ¤ 1.31 (Me, t, 3H, J = 6.9 Hz),
3.59 (OMe, s, 3H), 3.99 (OCH2, q, 2H, J = 6.9 Hz), 5.40 (H-4,
d, 1H, J = 4.4 Hz), 5.52 (H-3, d, 1H, J = 4.4 Hz), 6.71-7.54
(ArH, m, 11H); 13C NMR (75 MHz, CDCl3): ¤ 14.6 (Me), 55.5
(OMe), 61.1 (OCH2), 63.4 (C-4), 83.2 (C-3), 113.6, 117.3,
118.0, 126.8, 127.1, 127.5, 129.3, 129.7, 130.1, 130.7, 132.4,
138.1, 150.8, 155.9 (aromatic carbons), 161.2 (CO, ¢-lactam);
Anal. Calcd for C24H21Cl2NO4: C, 62.89; H, 4.62; N, 3.06%.
Found: C, 62.81; H, 4.76; N, 3.11%.
IR (KBr) cm¹1: 1754 (CO, ¢-lactam); 1H NMR (300 MHz,
CDCl3): ¤ 3.67 (OMe, s, 3H), 4.47-4.54 (CH2O, m, 2H), 5.17-
5.27 (vinylic H, m, 2H), 5.33 (H-4, d, 1H, J = 4.7 Hz), 5.52 (H-
3, d, 1H, J = 4.7 Hz), 5.82-5.94 (vinylic H, m, 1H), 6.79-7.72
(ArH, m, 8H); 13C NMR (75 MHz, CDCl3): ¤ 55.7 (OMe), 56.4
(OCH2), 63.5 (C-4), 82.3 (C-3), 108.8, 111.5, 116.1, 122.8,
123.2, 126.5, 127.0, 138.4, 142.9, 157.4 (C=C, aromatic car-
bons), 163.7 (CO, ¢-lactam); Anal. Calcd for C19H18ClNO3: C,
66.38; H, 5.28; N, 4.07%. Found: C, 66.44; H, 5.39; N, 4.13%.
3-(Allyloxy)-1-(4-ethoxyphenyl)-4-p-tolylazetidin-2-one
(8c): White solid. Mp: 68-70 °C; IR (KBr) cm¹1: 1751 (CO,
¢-lactam); 1H NMR (300 MHz, CDCl3): ¤ 1.38 (Me, t, 3H,
J = 7.0 Hz), 2.30 (Me, s, 3H), 3.91 (OCH2, q, 2H, J = 7.0 Hz),
4.49-4.55 (CH2O-allyl, m, 2H), 5.14-5.25 (vinylic H, m, 2H),
5.38 (H-4, d, 1H, J = 4.5 Hz), 5.59 (H-3, d, 1H, J = 4.5 Hz),
5.85-5.96 (vinylic H, m, 1H), 6.84-7.65 (ArH, m, 8H);
13C NMR (75 MHz, CDCl3): ¤ 14.2, 22.1 (Me), 56.9 (CH2O-
allyl), 60.6 (OCH2), 62.7 (C-4), 83.5 (C-3), 109.3, 110.1, 118.7,
121.9, 122.4, 124.8, 128.5, 133.0, 147.1, 154.3 (C=C, aromatic
carbons), 163.9 (CO, ¢-lactam); Anal. Calcd for C21H23NO3: C,
74.75; H, 6.87; N, 4.15%. Found: C, 74.67; H, 6.99; N, 4.08%.
3-(Buta-1,3-dienyl)-4-(4-chlorophenyl)-1-(4-methoxy-
1-(4-Methoxynaphthalen-1-yl)-3-phenoxy-4-p-tolyl-
azetidin-2-one (6a):
White solid. Mp: 182-184 °C; IR
¹1
(KBr) cm
:
1751 (CO, ¢-lactam); 1H NMR (300 MHz,
CDCl3): ¤ 2.44 (Me, s, 3H), 3.62 (OMe, s, 3H), 5.27 (H-4, d,
1H, J = 4.8 Hz), 5.57 (H-3, d, 1H, J = 4.8 Hz), 6.75-8.03
(ArH, m, 15H); 13C NMR (75 MHz, CDCl3): ¤ 22.5 (Me), 55.6
(OMe), 61.4 (C-4), 83.3 (C-3), 107.4, 109.7, 111.0, 112.8,
113.3, 115.9, 117.4, 118.5, 119.1, 122.4, 130.8, 131.5, 132.2,
137.9, 147.4, 150.8, 152.7, 157.5 (aromatic carbons), 163.4
(CO, ¢-lactam); Anal. Calcd for C27H23NO3: C, 79.20; H, 5.66;
N, 3.42%. Found: C, 79.31; H, 5.80; N, 3.49%.
phenyl)azetidin-2-one (9a):
White solid. Mp: 96-98 °C;
3-Methoxy-1-(4-methoxynaphthalen-1-yl)-4-p-tolyl-
IR (KBr) cm¹1: 1743 (CO, ¢-lactam); 1H NMR (300 MHz,
CDCl3): ¤ 3.65 (OMe, s, 3H), 3.73 (H-3, dd, 1H, J = 2.5,
8.3 Hz), 4.69 (H-4, d, 1H, J = 2.5 Hz), 5.17-5.24 (vinylic H, m,
2H), 5.84 (vinylic H, dd, 1H, J = 8.3, 15.9 Hz), 5.97 (vinylic
H, dd, 1H, J = 10.6, 15.9 Hz), 6.12 (vinylic H, m, 1H),
6.81-7.43 (ArH, m, 8H); 13C NMR (75 MHz, CDCl3): ¤ 55.7
(OMe), 61.0 (C-3), 63.5 (C-4), 112.6, 113.3, 117.5, 123.1,
123.6, 124.0, 127.4, 128.4, 135.3, 138.1, 140.9, 153.4 (C=C,
aromatic carbons), 164.2 (CO, ¢-lactam); Anal. Calcd for
C20H18ClNO2: C, 70.69; H, 5.34; N, 4.12%. Found: C, 70.75;
H, 5.49; N, 4.17%.
azetidin-2-one (6b):
White solid. Mp: 135-137 °C;
IR (KBr) cm¹1: 1745 (CO, ¢-lactam); 1H NMR (300 MHz,
CDCl3): ¤ 2.48 (Me, s, 3H), 3.29, 3.62 (2OMe, s, 6H), 4.84 (H-
4, d, 1H, J = 4.5 Hz), 5.26 (H-3, d, 1H, J = 4.6 Hz), 6.72-7.85
(ArH, m, 10H); 13C NMR (75 MHz, CDCl3): ¤ 23.7 (Me), 56.3,
57.1 (OMe), 63.7 (C-4), 82.8 (C-3), 108.8, 110.6, 112.3, 112.8,
118.0, 119.1, 123.9, 124.5, 131.9, 133.4, 136.2, 143.9, 151.6,
154.6 (aromatic carbons), 162.1 (CO, ¢-lactam); Anal. Calcd
for C22H21NO3: C, 76.06; H, 6.09; N, 4.03%. Found: C, 76.14;
H, 6.17; N, 3.95%.
2-[1-(4-Methoxynaphthalen-1-yl)-2-oxo-4-p-tolylazetidin-
3-(Buta-1,3-dienyl)-1-(4-ethoxyphenyl)-4-(4-nitrophenyl)-
3-yl]isoindoline-1,3-dione (6c):
White solid. Mp: 201-
azetidin-2-one (9b):
(KBr) cm : 1341, 1535 (NO2), 1745 (CO, ¢-lactam);
White solid. Mp: 93-95 °C; IR
¹1
203 °C; IR (KBr) cm¹1: 1738, 1776 (CO, phth), 1781 (CO, ¢-
1
lactam); H NMR (300 MHz, CDCl3): ¤ 2.44 (Me, s, 3H), 3.58
1H NMR (300 MHz, CDCl3): ¤ 1.26 (Me, t, 3H, J = 7.0 Hz),
3.77 (H-3, dd, 1H, J = 2.4, 8.1 Hz), 3.95 (OCH2, q, 2H, J =
7.0 Hz), 4.72 (H-4, d, 1H, J = 2.4 Hz), 5.22-5.30 (vinylic H, m,
2H), 5.80 (vinylic H, dd, 1H, J = 8.1, 16.0 Hz), 6.04 (vinylic
H, dd, 1H, J = 10.2, 16.0 Hz), 6.18 (vinylic H, m, 1H), 6.75-
8.11 (ArH, m, 8H); 13C NMR (75 MHz, CDCl3): ¤ 15.1 (Me),
(OMe, s, 3H), 5.26 (H-4, d, 1H, J = 4.7 Hz), 5.39 (H-3, d, 1H,
J = 4.7 Hz), 6.77-7.94 (ArH, m, 14H); 13C NMR (75 MHz,
CDCl3): ¤ 24.2 (Me), 56.7 (OMe), 61.2 (C-4), 64.2 (C-3),
106.4, 109.2, 111.4, 113.1, 113.6, 113.9, 120.3, 122.4, 122.9,
123.5, 124.1, 127.9, 132.3, 134.6, 139.7, 140.3, 149.4, 153.7

366
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
Utilization of DMF-PhCOCl Adduct for Preparation of ¢-Lactams
60.9 (OCH2), 61.5 (C-3), 63.2 (C-4), 110.7, 115.9, 116.3,
124.8, 125.5, 126.2, 128.1, 128.3, 132.9, 135.7, 150.3, 156.8
(C=C, aromatic carbons), 163.6 (CO, ¢-lactam); Anal. Calcd
for C21H20N2O4: C, 69.22; H, 5.53; N, 7.69%. Found: C, 69.15;
H, 5.67; N, 7.62%.
(75 MHz, CDCl3): ¤ 29.0 (Me-N), 62.4 (C-4), 82.7 (C-3),
112.7, 122.4, 129.1, 130.8, 134.6, 137.7, 151.8, 155.3 (aro-
matic carbons), 163.4 (CO, ¢-lactam). Anal. Calcd for
C16H14N2O4: C, 64.42; H, 4.73; N, 9.39%. Found: C, 64.51;
H, 4.88; N, 9.46%.
3-(Buta-1,3-dienyl)-1-(4-methoxyphenyl)-4-p-tolyl-
2-(4-Nitrophenyl)-1-phenylspiro[azetidine-3,9¤-xanthen]-
azetidin-2-one (9c):
White solid. Mp: 93-95 °C;
4-one (11a):
Light-yellow solid. Mp: 195-197 °C; IR
IR (KBr) cm¹1: 1748 (CO, ¢-lactam); 1H NMR (300 MHz,
CDCl3): ¤ 2.37 (Me, s, 3H), 3.59 (OMe, s, 3H), 3.82 (H-3, dd,
1H, J = 2.4, 8.3 Hz), 4.74 (H-4, d, 1H, J = 2.4 Hz), 5.20-5.27
(vinylic H, m, 2H), 5.86 (vinylic H, dd, 1H, J = 8.3, 15.9 Hz),
6.00 (vinylic H, dd, 1H, J = 10.1, 15.9 Hz), 6.23 (vinylic H, m,
1H), 6.86-7.55 (ArH, m, 8H); 13C NMR (75 MHz, CDCl3): ¤
21.9 (Me), 56.0 (OMe), 62.4 (C-3), 63.7 (C-4), 109.5, 113.3,
118.2, 122.2, 123.0, 125.7, 127.5, 128.8, 134.1, 135.0, 142.6,
155.1 (C=C, aromatic carbons), 164.5 (CO, ¢-lactam); Anal.
Calcd for C21H21NO2: C, 78.97; H, 6.63; N, 4.39%. Found: C,
80.10; H, 6.77; N, 4.42%.
(KBr) cm : 1339, 1536 (NO2), 1753 (CO, ¢-lactam);
¹1
1H NMR (300 MHz, CDCl3): ¤ 5.24 (H-4, s, 1H), 6.74-8.05
(ArH, m, 17H); 13C NMR (75 MHz, CDCl3): ¤ 62.8 (C-4), 74.1
(C-3), 113.6, 115.1, 119.5, 122.7, 123.1, 125.4, 129.0, 129.7,
133.9, 143.8, 148.2, 150.3, 154.0, 157.5 (aromatic carbons),
164.2 (CO, ¢-lactam); Anal. Calcd for C27H18N2O4: C, 74.64;
H, 4.18; N, 6.45%. Found: C, 74.72; H, 4.28; N, 6.39%.
3-Azido-1-(4-ethoxyphenyl)-4-p-tolylazetidin-2-one (12a):
Pale-yellow solid. Mp: 93-95 °C; IR (CHCl3) cm¹1: 2121 (N3),
1745 (CO, ¢-lactam). 1H NMR (300 MHz, CDCl3): ¤ 1.33
(Me, t, 3H, J = 6.9 Hz), 2.36 (Me, s, 3H), 3.98 (OCH2, q,
2H, J = 6.9 Hz), 5.09 (H-4, d, 1H, J = 5.1 Hz), 5.47 (H-3, d,
1H, J = 5.1 Hz), 6.84-7.57 (ArH, m, 8H). 13C NMR (75 MHz,
CDCl3): ¤ 14.1, 22.5 (Me), 60.7 (OCH2), 62.2 (C-3), 65.4
(C-4), 110.3, 115.9, 121.4, 126.7, 127.3, 142.1, 144.9, 154.6
(aromatic carbons), 163.4 (CO, ¢-lactam). Anal. Calcd for
C18H18N4O2: C, 67.07; H, 5.63; N, 17.38%. Found: C, 67.15;
H, 5.75; N, 17.43%.
1-(4-Methoxybenzyl)-4-(4-nitrophenyl)-3-phenoxy-
azetidin-2-one (10a):
Light-yellow crystalline solid. Mp:
94-96 °C; IR (KBr) cm¹1: 1335, 1538 (NO2), 1748 (CO, ¢-
1
lactam); H NMR (300 MHz, CDCl3): ¤ 3.78 (OMe, s, 3H),
3.96, 4.80 (CH2-benzyl, 2d, 2H, J = 14.7 Hz), 4.86 (H-4, d,
1H, J = 4.5 Hz), 5.46 (H-3, d, 1H, J = 4.5 Hz), 6.68-8.11
(ArH, m, 13H). 13C NMR (75 MHz, CDCl3): ¤ 44.3 (CH2),
55.3 (OMe), 60.5 (C-3), 82.0 (C-4), 114.1, 115.2, 122.1,
123.3, 126.1, 128.9, 129.1, 129.4, 140.8, 147.9, 156.4, 159.5
(aromatic carbons), 164.9 (CO, ¢-lactam); Anal. Calcd for
C23H20N2O5: C, 68.31; H, 4.98; N, 6.93%. Found: C, 68.24;
H, 5.08; N, 6.98%.
3-Acetyl-1,4-bis(4-methoxyphenyl)azetidin-2-one (13a):
White solid. Mp: 71-73 °C; IR (KBr) cm¹1: 1711 (CO, ketone),
1756 (CO, ¢-lactam); 1H NMR (300 MHz, CDCl3): ¤ 2.37 (Me,
s, 3H), 3.71, 3.75 (2OMe, s, 6H), 3.92 (H-3, d, 1H, J = 2.4 Hz),
4.89 (H-4, d, 1H, J = 2.4 Hz), 6.78-7.50 (ArH, m, 8H);
13C NMR (75 MHz, CDCl3): ¤ 29.7 (Me), 55.3, 55.6 (OMe),
60.9 (C-3), 67.3 (C-4), 113.5, 118.1, 125.1, 125.8, 127.0,
144.5, 153.7, 156.3 (aromatic carbons), 161.8 (CO, ¢-lactam),
196.3 (CO, ketone); Anal. Calcd for C19H19NO4: C, 70.14; H,
5.89; N, 4.31%. Found: C, 70.07; H, 5.96; N, 4.34%.
3-Acetyl-1-(4-ethoxyphenyl)-4-(4-nitrophenyl)azetidin-2-
one (13b): White solid. Mp: 66-68 °C; IR (KBr) cm¹1: 1341,
1530 (NO2), 1709 (CO, ketone), 1753 (CO, ¢-lactam);
1H NMR (300 MHz, CDCl3): ¤ 1.38 (Me, t, 3H, J = 7.0 Hz),
2.31 (MeCO, s, 3H), 3.94 (H-3, d, 1H, J = 2.5 Hz), 4.04
(OCH2, q, 2H, J = 7.0 Hz), 4.74 (H-4, d, 1H, J = 2.5 Hz),
6.86-8.09 (ArH, m, 8H); 13C NMR (75 MHz, CDCl3): ¤ 15.1,
29.0 (Me), 60.5 (OCH2), 61.8 (C-3), 66.9 (C-4), 115.4, 117.9,
122.3, 124.6, 129.2, 143.8, 148.3, 154.5 (aromatic carbons),
162.4 (CO, ¢-lactam), 198.1 (CO, ketone); Anal. Calcd for
C19H18N2O5: C, 64.40; H, 5.12; N, 7.91%. Found: C, 64.48;
H, 5.23; N, 7.97%.
2-[1-(4-Methoxybenzyl)-2-(4-nitrophenyl)-4-oxoazetidin-
3-yl]isoindoline-1,3-dione (10b):
126 °C; IR (KBr) cm¹1: 1337, 1530 (NO2), 1735, 1772 (CO,
White solid. Mp: 124-
1
phth), 1788 (CO, ¢-lactam); H NMR (300 MHz, CDCl3): ¤
3.70 (OMe, s, 3H), 3.89, 4.84 (CH2-benzyl, 2d, 2H, J =
14.5 Hz), 5.22 (H-4, d, 1H, J = 4.6 Hz), 5.64 (H-3, d, 1H,
J = 4.6 Hz), 6.81-8.25 (ArH, m, 12H). 13C NMR (75 MHz,
CDCl3): ¤ 45.1 (CH2), 55.7 (OMe), 60.2 (C-4), 62.7 (C-3),
110.7, 114.5, 115.4, 127.7, 128.2, 128.5, 129.9, 144.6, 146.2,
148.5, 158.8 (aromatic carbons), 161.1 (CO, phth), 163.6
(CO, ¢-lactam); Anal. Calcd for C25H19N3O6: C, 65.64; H,
4.19; N, 9.19%. Found: C, 65.72; H, 4.31; N, 9.27%.
2-[1-Benzyl-2-(4-nitrophenyl)-4-oxoazetidin-3-yl]iso-
indoline-1,3-dione (10d): White crystalline solid. Mp: 137-
139 °C; IR (KBr) cm¹1: 1341, 1537 (NO2), 1732, 1774 (CO,
1
phth), 1784 (CO, ¢-lactam); H NMR (300 MHz, CDCl3): ¤
3.93, 4.81 (CH2-benzyl, 2d, 2H, J = 14.7 Hz), 5.25 (H-4, d,
1H, J = 5.0 Hz), 5.56 (H-3, d, 1H, J = 5.0 Hz), 6.84-8.17
(ArH, m, 13H). 13C NMR (75 MHz, CDCl3): ¤ 44.6 (CH2),
61.7 (C-4), 64.3 (C-3), 113.6, 119.1, 121.5, 127.1, 128.0,
128.2, 128.9, 141.5, 143.8, 146.3, 154.9 (aromatic carbons),
160.6 (CO, phth), 162.8 (CO, ¢-lactam); Anal. Calcd for
C24H17N3O5: C, 67.44; H, 4.01; N, 9.83%. Found: C, 67.54; H,
4.14; N, 9.75%.
1-Methyl-4-(4-nitrophenyl)-3-phenoxyazetidin-2-one
(10e): White solid. Mp: 91-93 °C; IR (KBr) cm¹1: 1333, 1531
(NO2), 1750 (CO, ¢-lactam). 1H NMR (300 MHz, CDCl3):
¤ 2.91 (Me-N, s, 3H), 5.14 (H-4, d, 1H, J = 4.5 Hz), 5.49
(H-3, d, 1H, J = 4.5 Hz), 6.73-8.06 (ArH, m, 9H). 13C NMR
3-Acetyl-1,4-diphenylazetidin-2-one (13c): White solid.
Mp: 77-79 °C; IR (KBr) cm¹1: 1712 (CO, ketone), 1752 (CO,
1
¢-lactam); H NMR (300 MHz, CDCl3): ¤ 2.35 (Me, s, 3H),
3.97 (H-3, d, 1H, J = 2.5 Hz), 4.82 (H-4, d, 1H, J = 2.5 Hz),
6.94-7.43 (ArH, m, 10H); 13C NMR (75 MHz, CDCl3): ¤ 28.8
(Me), 61.3 (C-3), 67.2 (C-4), 117.2, 119.5, 122.0, 122.7, 123.6,
124.1, 133.9, 140.4 (aromatic carbons), 163.1 (CO, ¢-lactam),
198.6 (CO, ketone); Anal. Calcd for C17H15NO2: C, 76.96; H,
5.70; N, 5.28%. Found: C, 80.05; H, 5.81; N, 5.24%.
Thanks are due to Hormozgan University Research Council
for the financial support of this study.

M. Zarei
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
367
Heterocyclic Scaffolds I: ß-Lactams in Topics in Heterocyclic
Chemistry, ed. by B. K. Banik, Springer-Verlag, Berlin, 2010,
Vol. 22, pp. 211-259. doi:10.1007/7081_2009_11.
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