Synthesis of structurally diverse 2-azetidinones via staudinger reaction on a solid support

Article abstract of DOI:10.1246/bcsj.20100212

Trimellitic anhydride was attached to Merrifield resin and a ketene was generated from polymer-bound phthaloylglycine. Then this polymer reacted with imines in the presence of Vilsmeier reagent and triethylamine to afford the solid-phase-tethered β-lactam products. Selective cleavage of supported β-lactams by trifluoroacetic acid and methylhydrazine gave 4-carboxyphthalimido- and 3-amino-β-lactams, respectively. The trans-stereochemistry was found in all products.

Full text of DOI:10.1246/bcsj.20100212

320
Bull. Chem. Soc. Jpn. Vol. 84, No. 3, 320–327 (2011)
© 2011 The Chemical Society of Japan
Synthesis of Structurally Diverse 2-Azetidinones
via Staudinger Reaction on a Solid Support
Aliasghar Jarrahpour,*1 Abdolhamid Fadavi,2 and Maaroof Zarei1
1Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
2Islamic Azad University, Marvdasht Branch, Marvdasht, Iran
Received July 29, 2010; E-mail: jarrah@susc.ac.ir
Trimellitic anhydride was attached to Merrifield resin and a ketene was generated from polymer-bound
phthaloylglycine. Then this polymer reacted with imines in the presence of Vilsmeier reagent and triethylamine to afford
the solid-phase-tethered ¢-lactam products. Selective cleavage of supported ¢-lactams by trifluoroacetic acid and
methylhydrazine gave 4-carboxyphthalimido- and 3-amino-¢-lactams, respectively. The trans-stereochemistry was found
in all products.
The ¢-lactam unit is the key structural element of the
The application of combinatorial and related methodologies
to the chemistry of the ¢-lactam ring is a very attractive
challenge to modern medicinal chemistry, a fact that has been
recognized by different research groups around the world.15 In
the polymer-supported synthesis of ¢-lactams, the methods
reported in Ref. 5 have been used whereas one of the reactants
or reagent has been supported on soluble or insoluble
polymer.16
Herein, we summarize our efforts directed toward the
development of a new method for the synthesis of ¢-lactams
via ketene-imine cycloaddition using polymer-supported
ketene. This paper further deals with the methods for
deprotection of products from polymer.
Trimellitic anhydride was easily linked to Merrifield resin
via a classical synthetic method using triethylamine as a base
to give the polymer-supported trimellitic anhydride 1. The
chemical reaction was monitored by IR spectroscopy which
showed definitely the ester and anhydride functional groups.
Then the Merrifield resin-bound anhydride 1 reacted with
glycine in refluxing toluene for 24 h to afford polymer-
supported phthaloylglycine 2 (Scheme 1). The appearance of
carbonyl and hydroxy groups of COOH in the IR spectrum
confirmed the structure of 2.
The Staudinger reaction was used for the generation of the
¢-lactam ring. The [2 + 2] cycloaddition was performed by
adding imines 3a-3i, (chloromethylene)dimethylammonium
chloride (Vilsmeier reagent) (4), and triethylamine in excess to
a suspention of 2 in dry CH2Cl2 at room temperature to afford
polymer-supported ¢-lactams 5a-5i. In all cases the IR spectra
most widely employed family of ¢-lactam antibiotics and is
responsible for the observed biological activity. These miracle
drugs have improved the health and life expectancy of
humans.1 In addition to their well-recognized properties as
antibiotics, ¢-lactams have been recently shown to possess
other relevant biological activities.2 On the other hand, the
use of 2-azetidinones as building blocks in organic synthesis
and semi-synthesis of Taxol derivatives is now well estab-
lished.3
Building of the ¢-lactam (2-azetidinone) ring is a crucial
step in the synthesis of new ¢-lactam antibiotics, and develop-
ment of new preparative approaches toward ¢-lactam cycles
is highly important.4 Among several methods for the
synthesis of ¢-lactams,5 the [2 + 2] cycloaddition reaction of
Schiff bases with ketenes (Staudinger reaction)6 is mostly
applied.7
The use of polymeric supports in organic synthesis has
become a common practice, especially following the rapid
development of combinatorial chemistry.8 Primarily, the uses
of polymers in synthesis have fallen into one of two areas: (A)
the use of the polymer as a support for reactants or (B) the use
of the polymer as support for reagents and catalysts during a
reaction.9 IR spectroscopy is a fast and simple method for the
qualitative detection of certain functional groups on insoluble
supports.10
Interest in solid-phase heterocyclic chemistry originated
mainly in the pharmaceutical industry. Several review articles
have appeared covering the synthesis of heterocycles on
insoluble supports for the production of compound libraries
for drug discovery.11 One of the support types most frequently
used for solid-phase organic synthesis are styrene-divinylben-
zene copolymers (crosslinked polystyrene).12 Chloromethyl
polystyrene (Merrifield resin)13 has been used widely in the
polymer-supported synthesis of organic compounds.12 It is
commercially available and also has been prepared by several
methods.14
of polymer-supported ¢-lactams 5a-5i definitely showed the
¹1
carbonyl group of the 2-azetidinone ring at 1775-1781 cm
.
In the next step, the polymer-supported ¢-lactams 5a-5i
were cleaved by two methods, ester-bond cleavage and
dephthalation. The libraries of ¢-lactam compounds have
been developed using this solid-phase strategy (Table 1 and
Table 2). Overall yields ranged from good to very good for the
four-step synthetic sequence and exclusive formation of the
Published on the web February 26, 2011; doi:10.1246/bcsj.20100212

A. Jarrahpour et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 3 (2011)
321
O
O
O
Et3N
dioxane
O
M
+
M
Cl
O
HO
reflux
48h
O
O
O
O
1
Merrifield
resin
trimellitic
anhydride
NH2-CH2-CO2H
toluene, reflux
24h
O
O
O
N
O
M
R1N=CHR2
3a−3i
Et3N, CH2Cl2
O
N
CO2H
M
O
R2
R1
N
Me
Me
H
O
Cl
O
N
Cl
O
4
5a−5i
2
Scheme 1.
Table 1. Cleavage of the Resin-Bound ¢-Lactams 5a-5i
with TFA or AlCl3
Table 2. Dephthalation of the Resin-Bound ¢-Lactams
5a-5i with MeNHNH2
Yield/%a)
Product
R1
R2
Yield/%a)
Product R1
R2
TFA AlCl3
8a
8b
8c
8d
8e
8f
8g
8h
8i
4-EtOC6H4
4-EtOC6H4
4-EtOC6H4
4-EtOC6H4
C6H5
C6H5
4-MeOC6H4
C6H5CH2
4-MeC6H4
4-NO2C6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
C6H5
4-MeOC6H4
4-NO2C6H4
4-ClC6H4
58
61
53
56
58
50
51
55
53
6a
6b
6c
6d
6e
6f
4-EtOC6H4
4-MeC6H4
4-NO2C6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
C6H5
68
71
66
78
73
64
75
72
70
49
46
45
46
53
50
55
51
48
4-EtOC6H4
4-EtOC6H4
4-EtOC6H4
C6H5
C6H5
6g
6h
6i
4-MeOC6H4
C6H5CH2
4-(C6H5N=N)C6H4 4-ClC6H4
4-MeOC6H4
4-NO2C6H4
4-(C6H5N=N)C6H4
a) Overall isolated yield (based on the initial loading level of
Merrifield resin).
a) Overall isolated yield (based on the initial loading level of
Merrifield resin).
that the preparation of the ¢-lactam ring via classical ketene-
imine cycloaddition reaction leads to ¢-lactams with cis-
selectivity17 although trans-¢-lactams have been obtained by
other methods,18 refluxing in toluene19 and catalytic asymmet-
ric Staudinger reaction.20 The stereochemistry is mainly
dominated by electronic effects and steric hindrance of ketene
and imine substituents.21 The cis-3-phthalimido-¢-lactams
have been previously synthesized via cycloaddition of imines
and activated acetic acid derivatives22 while the stereochem-
istry is all trans in this solid-supported method. The mechanism
is perhaps similar to our previously reported mechanism for
the Staudinger reaction from acetic acid derivatives and
imines using methoxymethylene-N,N-dimethyliminium salt
(Scheme 3).23
trans-isomer was detected in all cases. Different ¢-lactam
derivatives with various substitutents at positions 1 and 4 were
obtained including many potential intermediates for the syn-
thesis of active compounds. For instance p-ethoxyphenyl, p-
methoxyphenyl, p-chlorophenyl, p-nitrophenyl, and carboxyl
group undergo facile functional group transformations, and free
amino group at C-3 allows the introduction of amide side
chain, present in most of the ¢-lactam antibiotics.
Cleavage of resins 5a-5i using trifluoroacetic acid (TFA) or
aluminum chloride (AlCl3) resulted in the trans-4-carboxy-
phthalimido-¢-lactams 6a-6i (Scheme 2 and Table 1). While
treatment with AlCl3 gave 45-55% overall yield, use of 10%
TFA in CH2Cl2 was found to be the most effective method for
the cleavage, affording ¢-lactams 6a-6i in 64-78% overall
isolated yield (based on the loading of starting Merrifield
In another way, the polymer-supported ¢-lactams 5a-5i were
treated with methylhydrazine to give 3-amino-¢-lactams 8a-8i
(Scheme 4 and Table 2). The appearance of NH2 peaks in IR
1
resin). The presence of H-3, H-4, hydroxy group in H NMR
1
spectra and carboxyl group in IR spectra definitely confirmed
the structure of ¢-lactams 6a-6i.
and H NMR spectra confirmed the synthesis of 3-amino-¢-
lactams 8a-8i. The polymer-supported 2-methylphthalazine-
l,4(2H,3H)-dione 9 was cleaved by trifluoroacetic acid to
hydroxymethyl resin 7.
trans-Stereochemistry was deduced from H-3 and H-4
1
coupling constants in H NMR (J ¯ 2.5 Hz). It is noteworthy

322
Bull. Chem. Soc. Jpn. Vol. 84, No. 3 (2011)
Synthesis of 2-Azetidinones via Staudinger Reaction
O
O
HO
M
O
TFA or AlCl3
O
O
M
+
OH
R2
N
R2
R1
N
O
O
N
N
R1
O
O
5a−5i
6a−6i
7
Scheme 2.
Cl
Me
Cl
Me
Me Cl
N
O
H
N
Me
Et3N
- H+
R3CH2COOH
R3CH2COO
R3H2C
O
H
activated ester
- DMF, - Et3NH+ Cl-
NEt3
Cl
Me
R3CH=C=O
O
N
Me
R3HC
H
O
H
H H
R2
R3
R3
R2
R3CH=C=O
R1N=CHR2
+
N
N
R1
R1
O
O
zwitterionic
intermediate
H H
R3
R2
R1
R3
R2
N
N
O
R1
O
Scheme 3.
O
O
O
M
R2
H2N
O
NH
MeNHNH2
O
+
M
O
NMe
N
R2
R1
N
CH2Cl2
rt
R1
O
O
O
N
O
5a−5i
8a−8i
9
Scheme 4.

A. Jarrahpour et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 3 (2011)
323
O
O
O
DCC, DMAP
CH2Cl2, rt
O
M
+
OH
O
HO
M
O
O
O
O
trimellitic
anhydride
7
1
Scheme 5.
The resulting hydroxymethyl resin 7 was transformed to
polymer-supported trimellitic anhydride 1 by dicyclohexylcar-
bodiimide (DCC) and trimellitic anhydride (Scheme 5).
General Procedure and Synthesis of Schiff Bases 3a-3i.
A mixture of corresponding amine (10.0 mmol) and corre-
sponding aldehyde (10.0 mmol) was refluxed in ethanol
for 3 h. After cooling the solution, the precipitate was
filtered and washed with ethanol to give pure Schiff bases
3a-3i.
Conclusion
In summary, we applied the Merrifield resin-bound phtha-
loylglycine for solid-phase polymer-supported synthesis of ¢-
lactams. 4-Carboxyphthalimido- and 3-amino-¢-lactams were
obtained selectively by cleavage of supported ¢-lactam by
trifluoroacetic acid and methylhydrazine, respectively. In this
method, purification is facilated by simple filtration, avoiding
time-consuming separation techniques; subsequent reactants
and reagents can be added in excess to drive reactions to
completion. The resulting hydroxymethyl resin from the
cleavage stage was easily converted to starting Merrifield
resin-bound phthaloylglycine in two steps.
4-Ethoxyphenyl-N-(4-methylbenzylidene)amine
(3a):
Light-yellow solid (2.05 g, 91%). Mp 149-151 °C. IR
(KBr) cm¹1: 1353, 1534 (NO2), 1617 (C=N). GC-MS m/z =
225 [M+]. Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N,
6.22%. Found: C, 80.08; H, 6.84; N, 6.15%.
4-Ethoxyphenyl-N-(4-nitrobenzylidene)amine (3b): Yel-
¹1
low crystal (2.62 g, 97%). Mp 124-126 °C. IR (KBr) cm
:
1353, 1536 (NO2), 1620 (C=N). 1H NMR (CDCl3): ¤ 1.33
(Me, t, 3H, J = 7.0 Hz), 3.88 (OCH2, q, 2H, J = 7.0 Hz), 6.81-
8.18 (ArH, m, 8H), 8.44 (HC=N, s, 1H). 13C NMR (CDCl3):
¤ 14.8 (Me), 63.7 (OCH2), 115.1-154.5 (aromatic carbons),
158.7 (C=N). GC-MS m/z = 270 [M+]. Anal. Calcd for
C15H14N2O3: C, 66.66; H, 5.22; N, 10.36%. Found: C, 66.62;
H, 5.39; N, 10.32%.
Experimental
General.
All required chemicals were purchased from
1
Merck, Fluka, and Acros chemical companies. H NMR and
13C NMR spectra were recorded in DMSO-d6 and CDCl3
using a Bruker Avance DPX instrument (1H NMR 250 MHz,
13C NMR 62.9 MHz). Chemical shifts are reported in ppm (¤)
downfield from TMS. All of the coupling constants (J) are in
Hertz. The mass spectra were recorded on a Shimadzu GC-MS
QP 1000 EX instrument. Elemental analyses were run on a
Thermo Finnigan Flash EA-1112 series. Melting points were
determined in open capillaries with a Buchi 510 melting point
apparatus and are not corrected. Thin-layer chromatography
was carried out on silica gel 254 analytical sheets obtained
from Fluka.
N-(4-Chlorobenzylidene)-4-ethoxyphenylamine
(3c):
Milky-colored solid (2.43 g, 94%). Mp 92-94 °C. IR (KBr)
1
cm¹1: 1620 (C=N). H NMR (CDCl3): ¤ 1.43 (Me, t, 3H, J =
7.0 Hz), 4.00 (OCH2, q, 2H, J = 7.0 Hz), 6.87-7.80 (ArH, m,
8H), 8.39 (HC=N, s, 1H). 13C NMR (CDCl3): ¤ 14.8 (Me),
63.6 (OCH2), 114.9-156.4 (aromatic carbons), 157.9 (C=N).
GC-MS m/z = 261 [M+, 37Cl], 259 [M+, 35Cl]. Anal. Calcd
for C15H14ClNO: C, 69.36; H, 5.43; N, 5.39%. Found: C,
69.29; H, 5.49; N, 5.44%.
4-Ethoxyphenyl-N-(4-methoxybenzylidene)amine (3d):
Milky-colored solid (2.42 g, 95%). Mp 128-130 °C. IR
1
Preparation of Polymer-Supported Trimellitic Anhy-
dride 1. To the Merrifield resin (1.0 g, 1.2 mmol g¹1), swollen
in dioxane (20 mL) were added the trimellitic anhydride (1,2,4-
benzenetricarboxylic 1,2-anhydride) (0.9 g, 4.8 mmol) followed
by Et3N (1.7 mL, 12 mmol) and the reaction mixture was
refluxed for 48 h. The reaction was filtered and the resin was
washed with H2O (60 mL), dioxane (60 mL), EtOH (60 mL),
and CH2Cl2 (60 mL). The resin was dried by suction on a sinter
glass. IR (KBr) cm¹1: 1724 (CO, ester), 1741, 1776 (CO, phth).
Preparation of Polymer-Supported Phthaloylglycine 2.
Finely powdered glycine (0.27 g, 3.6 mmol) was added to a
pre-swollen polymer-supported trimellitic anhydride 1 (1.0 g,
1.0 mmol g¹1, theoretical load) in toluene (20 mL). The mixture
was refluxed for 24 h, filtered and the resin was washed with
H2O (60 mL), DMF (60 mL), EtOH (60 mL), and CH2Cl2
(60 mL). The resin was dried by suction on a sinter glass. IR
(KBr) cm¹1: 1728 (CO, ester), 1743 (COOH), 1737, 1778 (CO,
phth), 2840-3339 (OH).
(KBr) cm¹1: 1612 (C=N). H NMR (CDCl3): ¤ 1.41 (Me, t,
3H, J = 7.0 Hz), 3.86 (OMe, s, 3H), 4.03 (OCH2, q, 2H,
J = 7.0 Hz), 6.88-7.83 (ArH, m, 8H), 8.39 (HC=N, s, 1H).
13C NMR (CDCl3): ¤ 14.9 (Me), 55.4 (OMe), 63.6 (OCH2),
114.1-157.7 (aromatic carbons), 161.9 (C=N). GC-MS m/z =
255 [M+]. Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N,
5.49%. Found: C, 75.17; H, 6.80; N, 5.45%.
(4-Methoxybenzylidene)aniline (3e): Yellow solid (1.90 g,
90%). Mp 60-62 °C. IR (KBr) cm¹1: 1621 (C=N). GC-MS
m/z = 211 [M+]. Anal. Calcd for C14H13NO: C, 79.59; H,
6.20; N, 6.63%. Found: C, 79.48; H, 6.33; N, 6.56%.
Benzylideneaniline (3f): Light yellow solid (1.56 g, 86%).
Mp 40-42 °C. IR (KBr) cm¹1: 1624 (C=N). GC-MS m/z =
181 [M+]. Anal. Calcd for C13H11N: C, 86.15; H, 6.12; N,
7.73%. Found: C, 86.24; H, 6.29; N, 7.63%.
N-(4-Methoxybenzylidene)-4-methoxyphenylamine (3g):
¹1
Gray solid (2.14 g, 89%). Mp 137-139 °C. IR (KBr) cm
:
1620 (C=N). GC-MS m/z = 241 [M+]. Anal. Calcd for

324
Bull. Chem. Soc. Jpn. Vol. 84, No. 3 (2011)
Synthesis of 2-Azetidinones via Staudinger Reaction
C15H15NO2: C, 74.67; H, 6.27; N, 5.81%. Found: C, 74.75; H,
6.40; N, 5.92%.
(CO, phth), 165.3 (CO, ¢-lactam), 174.7 (CO, COOH). GC-
MS m/z = 470 [M+]. Anal. Calcd for C27H22N2O6: C, 68.93;
H, 4.71; N, 5.95%. Found: C, 69.06; H, 4.84; N, 5.88%.
2-[1-(4-Ethoxyphenyl)-2-(4-nitrophenyl)-4-oxoazetidin-3-
N-(4-Nitrobenzylidene)phenylmethanamine (3h):
Or-
ange solid (2.06 g, 86%). Mp 55-57 °C. IR (KBr) cm¹1: 1337,
1511 (NO2), 1623 (C=N). GC-MS m/z = 240 [M+]. Anal.
Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66%. Found:
C, 70.09; H, 5.18; N, 11.78%.
yl]-1,3-dioxoisoindoline-5-carboxylic Acid (6b):
yellow solid (0.18 g, 71%). Mp >230 °C. IR (KBr) cm
Pale
¹1
:
1346, 1523 (NO2), 1718 (CO, COOH), 1736, 1771 (CO, phth),
1
N-(4-Chlorobenzylidene)-4-(phenyldiazenyl)aniline (3i):
1780 (CO, ¢-lactam), 2903-3530 (OH). H NMR (DMSO-d6):
¹1
Orange solid (2.69 g, 84%). Mp 156-158 °C. IR (KBr) cm
:
¤ 1.30 (Me, t, 3H, J = 6.9 Hz), 3.99 (OCH2, q, 2H, J = 6.9 Hz),
5.23 (H-4, d, 1H, J = 2.5 Hz), 5.59 (H-3, d, 1H, J = 2.5 Hz),
6.80-7.85 (ArH, m, 11H), 13.41 (COOH, brs, 1H). 13C NMR
(DMSO-d6): ¤ 15.4 (Me), 59.1 (OCH2), 61.0 (C-4), 64.6 (C-3),
114.3-156.7 (aromatic carbons), 161.1 (CO, phth), 165.8 (CO,
¢-lactam), 173.1 (CO, COOH). GC-MS m/z = 501 [M+].
Anal. Calcd for C26H19N3O8: C, 62.28; H, 3.82; N, 8.38%.
Found: C, 62.16; H, 3.88; N, 8.43%.
1609 (C=N). GC-MS m/z = 321 [M+, 37Cl], 319 [M+, 35Cl].
Anal. Calcd for C19H14ClN3: C, 71.36; H, 4.41; N, 13.14%.
Found: C, 71.45; H, 4.60; N, 13.03%.
General Procedure for the Solid-Phase Polymer-Sup-
ported Synthesis of ¢-Lactams 5a-5i. Polymer-supported
phthaloylglycine 2 (1.0 g, 0.9 mmol g¹1, theoretical load) was
swollen in dry CH2Cl2 (15 mL) and the corresponding imine
(3.6 mmol), chloromethylenedimethylammonium chloride (4)
(5.4 mmol), and triethylamine (9.0 mmol) were added at room
temperature. The mixture was stirred overnight at room
temperature and the filtered resin was washed with H2O
(2 © 10 mL), DMF (2 © 10 mL), EtOH (2 © 10 mL), and
CH2Cl2 (2 © 10 mL) and dried in vacuo to provide Merrifield
resin-bound ¢-lactams 5a-5i.
General Procedure for the Cleavage of ¢-Lactams 5 from
Merrifield Resin. With trifluoroacetic acid (TFA): Merri-
field resin-bound ¢-lactams 5a-5i (0.5 mmol) were treated at
room temperature with 10% TFA in CH2Cl2 (5 mL) for 1 h. The
mixture was filtered, washed with CH2Cl2 (2 © 8 mL) and then
with H2O (10 mL). The organic phase was dried and evaporated
under reduced pressure to give 4-carboxyphthalimido-¢-lac-
tams 6a-6i.
With aluminum chloride (AlCl3): Merrifield resin-bound
¢-lactams 5a-5i (0.5 mmol) were swollen in CH2Cl2 (4 mL) for
30 min at room temperature. After cooling to 0 °C, aluminum
chloride (0.27 g, 2.0 mmol) was added and the mixture was
stirred for 30 min at the same temperature. The resin was
filtered and washed with EtOAc (2 © 3 mL). The filtrate was
transferred to a separatory funnel, washed with 0.5 M HCl
(5 mL) and aqueous layers were extracted with EtOAc (l © 3
mL). The combined extracts were dried and evaporated to give
4-carboxyphthalimido-¢-lactams 6a-6i.
With methylhydrazine (MeNHNH2): To the pre-swollen
polymer-supported ¢-lactams 5a-5i (0.5 mmol) in dry CH2Cl2
(5 mL) methylhydrazine (0.04 mL, 0.7 mmol) was added and
the reaction mixture was stirred at room temperature for 32 h.
The resin was filtered and washed with CH2Cl2 (2 © 5 mL).
The filtrate was washed with H2O (10 mL), saturated NaHCO3
(10 mL), dried over anhydrous Na2SO4, and evaporated to give
3-amino-¢-lactams 8a-8i.
2-[2-(4-Chlorophenyl)-1-(4-ethoxyphenyl)-4-oxoazetidin-
3-yl]-1,3-dioxoisoindoline-5-carboxylic Acid (6c):
White
solid (0.16 g, 66%). Mp >230 °C. IR (KBr) cm¹1: 1711 (CO,
COOH), 1730, 1767 (CO, phth), 1776 (CO, ¢-lactam), 2820-
3508 (OH). 1H NMR (DMSO-d6): ¤ 1.37 (Me, t, 3H, J =
6.9 Hz), 3.91 (OCH2, q, 2H, J = 6.9 Hz), 5.16 (H-4, d, 1H,
J = 2.5 Hz), 5.30 (H-3, d, 1H, J = 2.5 Hz), 6.67-8.01 (ArH, m,
11H), 13.29 (COOH, brs, 1H). 13C NMR (DMSO-d6): ¤ 14.5
(Me), 61.7 (OCH2), 62.6 (C-4), 64.3 (C-3), 117.8-157.3
(aromatic carbons), 160.9 (CO, phth), 166.4 (CO, ¢-lactam),
175.0 (CO, COOH). GC-MS m/z = 492 [M+, 37Cl], 490 [M+,
35Cl]. Anal. Calcd for C26H19ClN2O6: C, 63.61; H, 3.90; N,
5.71%. Found: C, 63.70; H, 4.02; N, 5.78%.
2-[1-(4-Ethoxyphenyl)-2-(4-methoxyphenyl)-4-oxoazeti-
din-3-yl]-1,3-dioxoisoindoline-5-carboxylic
White solid (0.19 g, 78%). Mp >230 °C. IR (KBr) cm
Acid
(6d):
¹1
:
1724 (CO, COOH), 1736, 1770 (CO, phth), 1782 (CO, ¢-
lactam), 2875-3618 (OH). 1H NMR (DMSO-d6): ¤ 1.27 (Me, t,
3H, J = 7.0 Hz), 3.63 (OMe, s, 3H), 3.75 (OCH2, q, 2H,
J = 7.0 Hz), 4.91 (H-4, d, 1H, J = 2.4 Hz), 5.25 (H-3, d, 1H,
J = 2.4 Hz), 6.74-7.96 (ArH, m, 11H), 13.11 (COOH, brs,
1H). 13C NMR (DMSO-d6): ¤ 15.1 (Me), 56.3 (OMe), 60.0
(OCH2), 62.4 (C-4), 63.8 (C-3), 114.8-159.5 (aromatic
carbons), 162.2 (CO, phth), 167.1 (CO, ¢-lactam), 173.7
(CO, COOH). GC-MS m/z = 486 [M+]. Anal. Calcd for
C27H22N2O7: C, 66.66; H, 4.56; N, 5.76%. Found: C, 66.58; H,
4.67; N, 5.64%.
2-[2-(4-Methoxyphenyl)-4-oxo-1-phenylazetidin-3-yl]-
1,3-dioxoisoindoline-5-carboxylic Acid (6e): White solid
(0.16 g, 73%). Mp >230 °C. IR (KBr) cm¹1: 1719 (CO,
COOH), 1729, 1761 (CO, phth), 1774 (CO, ¢-lactam), 2850-
1
3410 (OH). H NMR (DMSO-d6): ¤ 3.76 (OMe, s, 3H), 5.26
(H-4, d, 1H, J = 2.6 Hz), 5.36 (H-3, d, 1H, J = 2.6 Hz), 6.86-
7.82 (ArH, m, 12H), 13.19 (COOH, brs, 1H). 13C NMR
(DMSO-d6): ¤ 55.3 (OMe), 60.8 (C-4), 62.8 (C-3), 114.8-160.1
(aromatic carbons), 162.2 (CO, phth), 166.8 (CO, ¢-lactam),
172.5 (CO, COOH). GC-MS m/z = 442 [M+]. Anal. Calcd for
C25H18N2O6: C, 67.87; H, 4.10; N, 6.33%. Found: C, 67.95; H,
4.23; N, 6.40%.
2-[1-(4-Ethoxyphenyl)-2-oxo-4-p-tolylazetidin-3-yl]-1,3-
dioxoisoindoline-5-carboxylic Acid (6a):
White solid
(0.16 g, 68%). Mp >230 °C. IR (KBr) cm¹1: 1346, 1523
(NO2), 1712 (CO, COOH), 1732, 1769 (CO, phth), 1779 (CO,
¢-lactam), 2850-3460 (OH). 1H NMR (DMSO-d6): ¤ 1.26 (Me,
t, 3H, J = 7.0 Hz), 2.44 (Me, s, 3H), 4.08 (OCH2, q, 2H,
J = 7.0 Hz), 5.18 (H-4, d, 1H, J = 2.3 Hz), 5.56 (H-3, d, 1H,
J = 2.3 Hz), 6.68-7.84 (ArH, m, 11H), 13.34 (COOH, brs, 1H).
13C NMR (DMSO-d6): ¤ 15.3 (Me), 21.7 (Me), 60.2 (OCH2),
61.8 (C-4), 63.3 (C-3), 113.0-157.1 (aromatic carbons), 162.5
1,3-Dioxo-2-(2-oxo-1,4-diphenylazetidin-3-yl)isoindoline-
5-carboxylic Acid (6f):
White solid (0.13 g, 64%). Mp
>230 °C. IR (KBr) cm¹1: 1722 (CO, COOH), 1731, 1767 (CO,
phth), 1776 (CO, ¢-lactam), 2980-3636 (OH). 1H NMR

A. Jarrahpour et al.
Bull. Chem. Soc. Jpn. Vol. 84, No. 3 (2011)
325
(DMSO-d6): ¤ 5.29 (H-4, d, 1H, J = 2.6 Hz), 5.38 (H-3, d, 1H,
J = 2.6 Hz), 6.90-7.86 (ArH, m, 13H), 13.26 (COOH, brs, 1H).
13C NMR (DMSO-d6): ¤ 61.2 (C-4), 62.7 (C-3), 117.6-137.1
(aromatic carbons), 162.0 (CO, phth), 166.8 (CO, ¢-lactam),
173.8 (CO, COOH). GC-MS m/z = 412 [M+]. Anal. Calcd for
C24H16N2O5: C, 69.90; H, 3.91; N, 6.79%. Found: C, 69.79; H,
4.03; N, 6.71%.
2-[1,2-Bis(4-methoxyphenyl)-4-oxoazetidin-3-yl]-1,3-di-
oxoisoindoline-5-carboxylic Acid (6g): White solid (0.18 g,
75%). Mp >230 °C. IR (KBr) cm¹1: 1727 (CO, COOH), 1733,
1765 (CO, phth), 1779 (CO, ¢-lactam), 2764-3390 (OH).
1H NMR (DMSO-d6): ¤ 3.74, 3.80 (2 © OMe, s, 6H), 5.26
(H-4, d, 1H, J = 2.4 Hz), 5.30 (H-3, d, 1H, J = 2.4 Hz), 6.49-
7.85 (ArH, m, 11H), 13.36 (COOH, brs, 1H). 13C NMR
(DMSO-d6): ¤ 55.3, 55.3 (2 © OMe), 61.1 (C-4), 62.8 (C-3),
114.3-160.2 (aromatic carbons), 161.7 (CO, phth), 166.9 (CO,
¢-lactam), 173.4 (CO, COOH). GC-MS m/z = 472 [M+].
Anal. Calcd for C26H20N2O7: C, 66.10; H, 4.27; N, 5.93%.
Found: C, 66.19; H, 4.40; N, 5.85%.
2-[1-Benzyl-2-(4-nitrophenyl)-4-oxoazetidin-3-yl]-1,3-di-
oxoisoindoline-5-carboxylic Acid (6h): White solid (0.17 g,
72%). Mp >230 °C. IR (KBr) cm¹1: 1350, 1536 (NO2), 1717
(CO, COOH), 1722, 1761 (CO, phth), 1775 (CO, ¢-lactam),
2845-3565 (OH). 1H NMR (DMSO-d6): ¤ 4.33, 5.02 (CH2-
benzyl, d, 2H, J = 14.9 Hz), 5.04 (H-4, d, 1H, J = 2.4 Hz), 5.63
(H-3, d, 1H, J = 2.4 Hz), 7.27-8.34 (ArH, m, 12H), 13.24
(COOH, brs, 1H). 13C NMR (DMSO-d6): ¤ 46.0 (CH2), 59.8
(C-4), 60.3 (C-3), 123.0-147.7 (aromatic carbons), 163.5 (CO,
phth), 166.6 (CO, ¢-lactam), 174.8 (CO, COOH). GC-MS
m/z = 471 [M+]. Anal. Calcd for C25H17N3O7: C, 63.69; H,
3.63; N, 8.91%. Found: C, 63.62; H, 3.75; N, 8.94%.
4, d, 1H, J = 2.1 Hz), 4.70 (H-3, d, 1H, J = 2.1 Hz), 6.46-8.18
(ArH, m, 8H). 13C NMR (CDCl3): ¤ 14.9 (Me), 63.9 (OCH2),
69.4 (C-4), 70.3 (C-3), 114.7-155.8 (aromatic carbons), 166.9
(CO, ¢-lactam). GC-MS m/z = 327 [M+]. Anal. Calcd for
C17H17N3O4: C, 62.38; H, 5.23; N, 12.84%. Found: C, 62.31;
H, 5.34; N, 12.76%.
3-Amino-4-(4-chlorophenyl)-1-(4-ethoxyphenyl)azetidin-
2-one (8c): White solid (0.08 g, 53%). Mp 122-124 °C. IR
(KBr) cm¹1: 1760 (CO, ¢-lactam), 3349, 3391 (NH2). 1H NMR
(CDCl3): ¤ 1.35 (Me, t, 3H, J = 7.0 Hz), 2.09 (NH2, brs, 2H),
3.90 (OCH2, q, 2H, J = 7.0 Hz), 3.95 (H-4, d, 1H, J = 1.9 Hz),
4.59 (H-3, d, 1H, J = 1.9 Hz), 6.73-7.37 (ArH, m, 8H).
13C NMR (CDCl3): ¤ 15.0 (Me), 63.9 (OCH2), 65.9 (C-4), 70.0
(C-3), 114.5-155.6 (aromatic carbons), 167.3 (CO, ¢-lactam).
GC-MS m/z = 318 [M+, 37Cl], 316 [M+, 35Cl]. Anal. Calcd
for C17H17ClN2O2: C, 64.46; H, 5.41; N, 8.84%. Found: C,
64.55; H, 5.58; N, 8.91%.
3-Amino-1-(4-ethoxyphenyl)-4-(4-methoxyphenyl)azeti-
din-2-one (8d): White solid (0.09 g, 56%). Mp 116-118 °C.
IR (KBr) cm¹1: 1762 (CO, ¢-lactam), 3351, 3397 (NH2).
1H NMR (CDCl3): ¤ 1.37 (Me, t, 3H, J = 6.9 Hz), 2.52 (NH2,
brs, 2H), 3.79 (OMe, s, 3H), 3.94 (OCH2, q, 2H, J = 6.9 Hz),
3.97 (H-4, d, 1H, J = 2.0 Hz), 4.56 (H-3, d, 1H, J = 2.0 Hz),
6.72-7.25 (ArH, m, 8H). 13C NMR (CDCl3): ¤ 14.8 (Me), 55.3
(OMe), 63.8 (OCH2), 66.2 (C-4), 69.8 (C-3), 113.4-159.7
(aromatic carbons), 167.6 (CO, ¢-lactam). GC-MS m/z = 312
[M+]. Anal. Calcd for C18H20N2O3: C, 69.21; H, 6.45; N,
8.97%. Found: C, 69.29; H, 6.57; N, 8.89%.
3-Amino-4-(4-methoxyphenyl)-1-phenylazetidin-2-one (8e):
¹1
White solid (0.08 g, 58%). Mp 129-131 °C. IR (KBr) cm
:
1
1758 (CO, ¢-lactam), 3338, 3391 (NH2). H NMR (CDCl3): ¤
2.17 (NH2, brs, 2H), 3.71 (OMe, s, 3H), 3.92 (H-4, d, 1H,
J = 1.9 Hz), 4.54 (H-3, d, 1H, J = 1.9 Hz), 6.54-7.27 (ArH, m,
9H). 13C NMR (CDCl3): ¤ 55.1 (OMe), 66.1 (C-4), 69.9 (C-3),
113.3-159.6 (aromatic carbons), 168.4 (CO, ¢-lactam). GC-
MS m/z = 268 [M+]. Anal. Calcd for C16H16N2O2: C, 71.62;
H, 6.01; N, 10.44%. Found: C, 71.53; H, 6.17; N, 10.36%.
2-{2-(4-Chlorophenyl)-4-oxo-1-[4-(phenyldiazenyl)phen-
yl]azetidin-3-yl}-1,3-dioxoisoindoline-5-carboxylic Acid (6i):
¹1
Orange-red solid (0.19 g, 70%). Mp >230 °C. IR (KBr) cm
:
1729 (CO, COOH), 1737, 1768 (CO, phth), 1781 (CO, ¢-
1
lactam), 2820-3538 (OH). H NMR (DMSO-d6): ¤ 5.31 (H-4,
d, 1H, J = 1.6 Hz), 5.44 (H-3, d, 1H, J = 1.6 Hz), 7.20-7.89
(ArH, m, 16H), 13.37 (COOH, brs, 1H). 13C NMR (DMSO-d6):
¤ 60.9 (C-4), 62.9 (C-3), 117.9-152.6 (aromatic carbons), 162.0
(CO, phth), 166.7 (CO, ¢-lactam), 173.9 (CO, COOH). GC-
MS m/z = 552 [M+, 37Cl], 550 [M+, 35Cl]. Anal. Calcd for
C30H19ClN4O5: C, 65.40; H, 3.48; N, 10.17%. Found: C, 65.32;
H, 3.61; N, 10.05%.
3-Amino-1,4-diphenylazetidin-2-one (8f):
White solid
(0.06 g, 50%). Mp 154-156 °C. IR (KBr) cm¹1: 1767 (CO, ¢-
1
lactam), 3348, 3401 (NH2). H NMR (CDCl3): ¤ 2.40 (NH2,
brs, 2H), 3.97 (H-4, d, 1H, J = 2.0 Hz), 4.61 (H-3, d, 1H,
J = 2.0 Hz), 6.55-7.33 (ArH, m, 10H). 13C NMR (CDCl3): ¤
66.5 (C-4), 69.9 (C-3), 113.4-146.8 (aromatic carbons), 168.3
(CO, ¢-lactam). GC-MS m/z = 238 [M+]. Anal. Calcd for
C15H14N2O: C, 75.61; H, 5.92; N, 11.76%. Found: C, 75.50; H,
6.08; N, 11.63%.
3-Amino-1-(4-ethoxyphenyl)-4-p-tolylazetidin-2-one (8a):
¹1
White solid (0.09 g, 58%). Mp 123-125 °C. IR (KBr) cm
:
1
1765 (CO, ¢-lactam), 3350, 3395 (NH2). H NMR (CDCl3): ¤
1.25 (Me, t, 3H, J = 6.8 Hz), 2.02 (NH2, brs, 2H), 2.23 (Me, s,
3H), 3.81 (OCH2, q, 2H, J = 6.8 Hz), 3.87 (H-4, d, 1H, J =
1.9 Hz), 4.47 (H-3, d, 1H, J = 1.9 Hz), 6.62-7.17 (ArH, m,
8H). 13C NMR (CDCl3): ¤ 14.0 (Me), 20.1 (Me), 62.8 (OCH2),
65.4 (C-4), 68.9 (C-3), 113.2-154.4 (aromatic carbons), 166.5
(CO, ¢-lactam). GC-MS m/z = 296 [M+]. Anal. Calcd for
C18H20N2O2: C, 72.95; H, 6.80; N, 9.45%. Found: C, 73.08; H,
6.93; N, 9.36%.
3-Amino-1,4-bis(4-methoxyphenyl)azetidin-2-one (8g):
¹1
White solid (0.08 g, 51%). Mp 131-133 °C. IR (KBr) cm
:
1
1761 (CO, ¢-lactam), 3353, 3409 (NH2). H NMR (CDCl3): ¤
2.03 (NH2, brs, 2H), 3.60, 3.65 (2 © OMe, s, 6H), 3.86 (H-4, d,
1H, J = 2.2 Hz), 4.46 (H-3, d, 1H, J = 2.2 Hz), 6.61-7.13
(ArH, m, 8H). 13C NMR (CDCl3): ¤ 54.3, 54.6 (2 © OMe),
65.2 (C-4), 68.9 (C-3), 112.3-158.7 (aromatic carbons), 166.7
(CO, ¢-lactam). GC-MS m/z = 298 [M+]. Anal. Calcd for
C17H18N2O3: C, 68.44; H, 6.08; N, 9.39%. Found: C, 68.52; H,
6.21; N, 9.46%.
3-Amino-1-(4-ethoxyphenyl)-4-(4-nitrophenyl)azetidin-2-
one (8b): White solid (0.10 g, 61%). Mp 141-143 °C. IR
(KBr) cm¹1: 1343, 1528 (NO2), 1763 (CO, ¢-lactam), 3362,
3409 (NH2). 1H NMR (CDCl3): ¤ 1.31 (Me, t, 3H, J = 7.2 Hz),
2.02 (NH2, brs, 2H), 3.95 (OCH2, q, 2H, J = 7.2 Hz), 4.03 (H-
3-Amino-1-benzyl-4-(4-nitrophenyl)azetidin-2-one (8h):
¹1
White solid (0.08 g, 55%). Mp 90-92 °C. IR (KBr) cm
:
1348, 1522 (NO2), 1766 (CO, ¢-lactam), 3340, 3388 (NH2).

326
Bull. Chem. Soc. Jpn. Vol. 84, No. 3 (2011)
Synthesis of 2-Azetidinones via Staudinger Reaction
1H NMR (CDCl3): ¤ 1.83 (NH2, brs, 2H), 4.02, 4.84 (CH2-
benzyl, d, 2H, J = 14.8 Hz), 4.58 (H-4, d, 1H, J = 2.4 Hz), 4.76
(H-3, d, 1H, J = 2.4 Hz), 7.13-8.24 (ArH, m, 9H). 13C NMR
(CDCl3): ¤ 44.8 (CH2), 61.6 (C-4), 65.3 (C-3), 123.7-147.8
(aromatic carbons), 170.0 (CO, ¢-lactam); GC-MS m/z = 297
[M+]. Anal. Calcd for C16H15N3O3: C, 64.64; H, 5.09; N,
14.13%. Found: C, 64.75; H, 5.18; N, 14.06%.
H.-Y. Zhang, Biochem. Biophys. Res. Commun. 2005, 333, 661.
3
a) B. Alcaide, P. Almendros, R. Carrascosa, T. M.
del Campo, Chem.®Eur. J. 2009, 15, 2496. b) B. Alcaide, P.
Almendros, C. Aragoncillo, Chem. Rev. 2007, 107, 4437. c) B.
Alcaide, P. Almendros, Synlett 2002, 381. d) I. Ojima, F. Delaloge,
Chem. Soc. Rev. 1997, 26, 377. e) H. Ge, J. T. Spletstoser, Y. Yang,
M. Kayser, G. I. Georg, J. Org. Chem. 2007, 72, 756. f) Y. Paik, C.
Yang, B. Metaferia, S. Tang, S. Bane, R. Ravindra, N. Shanker,
A. A. Alcaraz, S. A. Johnson, J. Schaefer, R. D. O’Connor, L.
Cegelski, J. P. Snyder, D. G. I. Kingston, J. Am. Chem. Soc. 2007,
129, 361. g) T. Ganesh, A. Norris, S. Sharma, S. Bane, A. A.
Alcaraz, J. P. Snyder, D. G. I. Kingston, Bioorg. Med. Chem. 2006,
14, 3447.
3-Amino-4-(4-chlorophenyl)-1-[4-(phenyldiazenyl)phenyl]-
azetidin-2-one (8i): Orange solid (0.10 g, 53%). Mp 164-
166 °C. IR (KBr) cm¹1: 1765 (CO, ¢-lactam), 3342, 3381
1
(NH2). H NMR (CDCl3): ¤ 2.18 (NH2, brs, 2H), 4.81 (H-4, d,
1H, J = 2.2 Hz), 4.89 (H-3, d, 1H, J = 2.2 Hz), 6.55-7.81
(ArH, m, 13H). 13C NMR (CDCl3): ¤ 60.1 (C-4), 60.4 (C-3),
112.5-153.0 (aromatic carbons), 174.7 (CO, ¢-lactam). GC-
MS m/z = 378 [M+, 37Cl], 376 [M+, 35Cl]. Anal. Calcd for
C21H17ClN4O: C, 66.93; H, 4.55; N, 14.87%. Found: C, 70.08;
H, 4.67; N, 14.93%.
General Method for Regeneration of Polymer-Supported
Trimellitic Anhydride 1. The resulting hydroxymethyl resin
7 (1.0 g, 1.2 mmol g¹1, theoretical load) was suspended in
CH2Cl2 (15 mL) and stirred with trimellitic anhydride (0.9 g,
4.8 mmol), dicyclohexylcarbodiimide (DCC) (1.5 g, 7.5 mmol),
and catalytic 4-dimethylaminopyridine (DMAP) for 8 h. The
reaction mixture was then filtered, washed with DMF (3 © 10),
EtOH (3 © 10), and CH2Cl2 (3 © 10), and dried.
4
See: Antimicrobial Agents: Antibacterials and Antifungals,
ed. by A. Bryskier, ASM Press, Washington, DC, 2005, Chap. 5-
14, pp. 113-446.
5
a) A. Brandi, S. Cicchi, F. M. Cordero, Chem. Rev. 2008,
108, 3988. b) G. S. Singh, Tetrahedron 2003, 59, 7631. c) F. H.
van der Steen, D. van Koten, Tetrahedron 1991, 47, 7503.
6
a) H. Staudinger, Justus Liebigs Ann. Chem. 1907, 356,
51. b) M. A. Sierra, M. Rodríguez-Fernández, L. Casarrubios,
M. Gómez-Gallego, M. J. Mancheño, Eur. J. Org. Chem. 2009,
2998.
7
a) C. Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide,
Curr. Med. Chem. 2004, 11, 1837. b) A. Jarrahpour, M. Zarei,
Tetrahedron Lett. 2009, 50, 1568. c) A. Jarrahpour, M. Zarei,
Molecules 2007, 12, 2364. d) A. Jarrahpour, D. Khalili, Tetra-
hedron Lett. 2007, 48, 7140.
The authors thank the Shiraz University Research Council
for financial support (Grant No. 88-GR-SC-23).
8
9
M. R. Buchmeiser, Chem. Rev. 2009, 109, 303.
a) T. J. Dickerson, N. N. Reed, K. D. Janda, Chem. Rev.
2002, 102, 3325. b) A. Solinas, M. Taddei, Synthesis 2007, 2409.
10 a) Y. Luo, X. Ouyang, R. W. Armstrong, M. M. Murphy,
J. Org. Chem. 1998, 63, 8719. b) B. Yan, Acc. Chem. Res. 1998,
31, 621.
11 a) V. Krchňák, M. W. Holladay, Chem. Rev. 2002, 102, 61.
b) R. G. Franzén, J. Comb. Chem. 2000, 2, 195. c) A. Nefzi, J. M.
Ostresh, R. A. Houghten, Chem. Rev. 1997, 97, 449. d) J. M. Nuss,
M. C. Desai, R. N. Zuckermann, R. Singh, P. A. Renhowe, D. A.
Goff, J. P. Chinn, L. Wang, H. Dorr, E. G. Brown, S. Subramanian,
Pure Appl. Chem. 1997, 69, 447.
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