A convenient synthesis of 2-azetidinones via 2-fluoro-1-methylpyridinium p-toluenesulfonate

Article abstract of DOI:10.1007/s00706-012-0918-y

The application and versatility of 2-fluoro-1-methylpyridinium p-toluenesulfonate as acid activator in the synthesis of several β-lactams under mild reaction conditions by use of ketene-imine cycloaddition reactions has been investigated. The effects of s

Full text of DOI:10.1007/s00706-012-0918-y

Monatsh Chem (2013) 144:1021–1025
DOI 10.1007/s00706-012-0918-y
ORIGINAL PAPER
A convenient synthesis of 2-azetidinones via
2-fluoro-1-methylpyridinium p-toluenesulfonate
Maaroof Zarei
Received: 4 September 2012 / Accepted: 28 December 2012 / Published online: 14 February 2013
Ó Springer-Verlag Wien 2013
Abstract The application and versatility of 2-fluoro-1-
methylpyridinium p-toluenesulfonate as acid activator in
the synthesis of several b-lactams under mild reaction
conditions by use of ketene–imine cycloaddition reactions
has been investigated. The effects of solvents, molar ratio
of reagents, and temperature were considered. The method
was also used for preparation of b-lactams substituted in
position 3 by electron-withdrawing groups. The products
are obtained in good to excellent yields.
the rate of polymerization [9], and for separation and
identification of phenols [10].
The b-lactam (2-azetidinone) nucleus is the core of the
biological activity of a large class of antibiotics character-
ized by the presence of this four-membered ring and
differentiated by side chains, unsaturation, heteroatoms,
and, in many cases, by the presence of five or six-membered
rings. After the discovery of penicillins and cephalosporins
as classical b-lactam antibiotics and clinically useful active
agents, b-lactam chemistry has grown substantially in the
past few decades [11]. These compounds also have cho-
lesterol absorption inhibitor activity; ezetimibe is a new
drug for this purpose [12]. Furthermore b-lactams have a
variety of other biological activity [13–15]. b-Lactams are
not only useful in pharmaceutical applications, but are also
used as intermediates and synthons for synthesis of several
organic compounds [16, 17] and in the semi-synthesis of
taxol derivatives [18]. Because of their importance, the
development of efficient routes for synthesis of b-lactams is
of significant research interest.
Keywords 2-Azetidinones Á b-Lactam Á
Staudinger reaction Á 2-Fluoro-1-methylpyridinium
p-toluenesulfonate Á Ketene
Introduction
2-Halopyridinium salts have been found to be effective
coupling reagents for preparation of carboxylic acid
derivatives. One of these reagents is 2-fluoro-1-methylpy-
ridinium p-toluenesulfonate (FMPTS, 1). The activated
carboxylic acid 2 can be obtained by reaction of carboxylic
acids and reagent 1 (Fig. 1). These activated carboxylic
acids have been used for preparation of esters, amides, acyl
fluorides, cyclic imidates, and thiol esters [1–5]. Reagent 1
has also been used for formation of the N-methylpyridini-
um ether derivative of propofol [6], formation of the N-
methylpyridinium derivative to improve detection of bu-
prenorphine by liquid chromatography–mass spectrometry
[7], analysis of steroid estrogens in water [8], to promote
The Staudinger reaction ([2 ? 2] ketene–imine cycload-
dition reaction) [19, 20] is regarded as one of the most
fundamental and versatile methods for synthesis of structur-
ally diverse 2-azetidinone derivatives, even though many
other synthetic methods have been developed [21, 22]. Ket-
enes are usually generated in situ by reaction of acyl halides
with tertiary amines [23–28]. Low availability, instability,
and difficulty of preparation are some drawbacks of appli-
cation of acyl halides. Acid activators have been used for the
one-pot synthesis of 2-azetidinones from imines and car-
boxylic acids without the need for acyl halides [29–39].
An easy and versatile procedure for preparation of
2-azetidinones by the Staudinger reaction from imines and
substituted carboxylic acids using 2-fluoro-1-methylpyrid-
inium p-toluenesulfonate (1) is described herein.
M. Zarei (&)
Department of Chemistry, College of Sciences, Hormozgan
University, 71961 Bandar Abbas, Iran
e-mail: maaroof1357@yahoo.com; mzarei@hormozgan.ac.ir
123

1022
M. Zarei
Table 1 Optimization of reaction conditions for synthesis of 5a
O
C
Entry
Solvent
Temp.
Reagent 1/mmol
Yield/%
N
OTs
F
R
N
OTs
O
Me
Me
2
1
2
3
4
5
6
7
8
CHCl3
THF
rt
1.0
1.0
1.0
1.0
1.0
1.5
2.0
1.5
73
38
54
72
61
92
91
82
1
rt
DMF
rt
Fig. 1 Structures of 2-fluoro-1-methylpyridinium p-toluenesulfonate
(1) and activated carboxylic acid 2
CH2Cl2
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
Results and discussion
rt
0 °C
Aldimines were prepared in quantitative yield by conden-
sation of amines and aldehydes. Treatment of a solution of
1.0 mmol Schiff base 3a in dry CHCl3 with 1.0 mmol
phenoxyacetic acid (4a) and 1.0 mmol 2-fluoro-1-meth-
ylpyridinium p-toluenesulfonate in the presence of
triethylamine afforded 2-azetidinone 5a in 73 % yield after
purification (Scheme 1). The presence of the new com-
pound was confirmed by TLC monitoring, and spectral data
confirmed the structure of 2-azetidinone 5a. The IR spec-
R3
O
R2
1, Et3N
+ R3CH2COOH
R1N=CHR2
N
CH2Cl2, rt
R1
3
4
5a-5l
Scheme 2
trum contained the b-lactam carbonyl peak at 1,746 cm-1
.
In the 1H NMR spectrum of b-lactam 5a the coupling
constant of H-3 and H-4 is J = 4.8 Hz which is indicative
of its cis stereochemistry. In addition, 13C NMR spectro-
scopic data for b-lactam 5a contained the b-lactam
carbonyl peak at 161.7 ppm.
4, and 1.5 mmol reagent 1, in the presence of triethyl-
amine, in dry CH2Cl2 at room temperature (Scheme 2;
Table 2). The reactions are convenient and clean and
purification of b-lactams 5a–5l was performed by crystal-
lization from EtOAc after simple work up. The
stereochemistry of the products was determined from the
coupling constants of H-3 and H-4 of the 2-azetidinone
ring in 1H NMR spectra. Temperature, the electronic effect,
and steric hindrance by the ketene and imine substituents
affect the stereochemistry of ketene–imine cycloaddition
[40]. The ketene–imine cycloaddition reaction is a step-
wise, rather than concerted, reaction, and is initiated by
nucleophilic attack of the imine on the ketene, giving rise
to a zwitterionic intermediate. Conrotatory electrocyclic
ring closure of the zwitterionic intermediate finally pro-
duces the b-lactam product [41–43]. It is suggested that the
reaction is performed by in-situ generation of a ketene from
an activated ester. Thus the mechanism is similar to our
previously reported mechanism for the Staudinger reaction
of acetic acid derivatives and imines, using methoxym-
ethylene-N,N-dimethyliminium salt, via formation of an
activated carboxylic acid [35]. The relative (cis/trans)
stereoselectivity is generated as a result of the competition
Next, we decided to examine the effect of solvents and
reaction conditions on the synthesis of b-lactam 5a.
According to Table 1, among the dry solvents examined
(CHCl3, THF, DMF, CH2Cl2, toluene), CHCl3 and CH2Cl2
to gave the best yields. Because working with CH2Cl2 is
easier than with CHCl3, owing to its low boiling point and
safety, CH2Cl2 was chosen for subsequent reactions.
Moreover, the aqueous work up in THF and DMF was
much harder than in CHCl3, CH2Cl2, and toluene. The best
yields were obtained when 1.5 mmol 2-fluoro-1-meth-
ylpyridinium p-toluenesulfonate and phenoxyacetic acid
(4a) were used with 1.0 mmol imine 3a (Table 1, entry 6).
It was also found that yields at room temperature were
higher than those at 0 °C, thus cold media are not neces-
sary for this reaction.
On the basis of the successful synthesis of 2-azetidinone
5a, 2-azetidinones 5a–5l were synthesized by reaction of
1.0 mmol Schiff bases 3, 1.5 mmol substituted acetic acids
Scheme 1
Cl
PhO
1
MeO
N=CH
Cl
+
PhOCH2COOH
N
O
Et3N
4a
5a
3a
OMe
123

A convenient synthesis of 2-azetidinones via 2-fluoro-1-methylpyridinium p-toluenesulfonate
Table 2 Synthesis of 2-azetidinones 5a–5l by use of reagent 1 (Scheme 2)
1023
Product
R1
R2
R3
Stereo
Yield/%
Reference
5a
5b
5c
5d
5e
5f
4-MeOC6H4
4-MeOC6H4CH2
4-EtOC6H4
4-EtOC6H4
4-EtOC6H4
4-MeOC6H4
4-EtOC6H4
4-MeOC6H4
C6H5
4-ClC6H4
PhO
cis
92
87
81
83
84
95
90
91
88
92
89
88
[37]
[45]
[39]
[39]
[46]
[29]
[35]
[47]
[29]
[47]
[35]
–
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
Ph-CH = CH
4-MeOC6H4
4-MeOC6H4
4-MeC6H4
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
PhO
cis
PhthN
trans
trans
cis
PhthN
PhthN
2-NaphthO
2-NaphthO
MeO
cis
5g
5h
5i
cis
cis
MeO
cis
5j
4-EtOC6H4
C6H5CH2
2,4-Cl2C6H3O
2,4-Cl2C6H3O
2,4-Cl2C6H3O
cis
5k
5l
cis
4-MeOC6H4CH2
4-NO2C6H4
cis
Table 3 Synthesis of b-lactams
substituted at position 3 by
electron-withdrawing groups
Product
R1
R2
R3
Yield/% at rt
Yield/% at -10 °C
Reference
6a
6b
6c
7a
7b
7c
4-EtOC6H4
4-MeOC6H4
4-EtOC6H4
4-EtOC6H4
4-MeOC6H4
4-EtOC6H4
4-ClC6H4
4-MeOC6H4
C6H5
Cl
Cl
Cl
N3
N3
N3
18
24
19
48
57
54
51
59
58
68
73
68
[37]
[37]
–
4-NO2C6H4
4-ClC6H4
C6H5
[35]
[35]
–
between the direct ring closure and isomerization of the
imine moiety in the zwitterionic intermediate [34, 41].
This method was also extended to synthesis of b-lactams
substituted at position 3 by electron-withdrawing groups
(reviewed elsewhere [44]). 3-Chloro-b-lactams 6a–6c and
3-azido-b-lactams 7a–7c were synthesized from the cor-
responding carboxylic acids and imines by using 2-fluoro-
1-methylpyridinium p-toluenesulfonate in the presence of
Et3N at room temperature. Yields of the products were
greater when the reactions were performed at -10 °C
rather than room temperature (Table 3). Purification of
3-chloro-b-lactams 6a–6c and 3-azido-b-lactams 7a–7c
was performed by short column chromatography on silica
gel.
Bu¨chi 535 apparatus. IR spectra were measured on a galaxy
series FT-IR 5000 spectrometer. NMR spectra were
recorded on a Bruker spectrometer (1H NMR 300 MHz,
13C NMR 75 MHz) using tetramethylsilane as internal
standard; coupling constants are given in Hz. Elemental
analyses were performed with a Vario EL III elemental
analyzer and results agreed favorably with calculated val-
ues. Thin-layer chromatography was performed on silica
gel 254 analytical sheets obtained from Fluka. Column
chromatography was performed on silica gel 60 (Merck,
70–230 mesh).
General procedure for synthesis of b-lactams 5a–5l,
6a–6c, and 7a–7c
In conclusion, use of 2-fluoro-1-methylpyridinium
p-toluenesulfonate to activate the substituted acetic acids in
the one-pot synthesis of 2-azetidinones via a ketene–imine
cycloaddition reaction has been described. This method has
the advantages of simplicity, efficiency, mild condition
reactions, availability of the reagents, easy purification, and
high yield of the products.
2-Fluoro-1-methylpyridinium p-toluenesulfonate (1.5 mmol)
was added to a solution of substituted acetic acid (1.5 mmol),
imine (1.0 mmol), and triethylamine (5.0 mmol) in 20 cm3
dry CH2Cl2 at the temperatures given in the tables.
The mixture was stirred at room temperature overnight
then washed successively with 20 cm3 saturated
NaHCO3 and 10 cm3 brine. The organic layer was dried
(Na2SO4), filtered, and the solvent was removed to give
the crude product, which was purified by crystallization
from EtOAc to give pure f-lactams 5a–5l or by short
column chromatography on silica gel for 3-chloro-b-
lactams 6a–6c and 3-azido-b-lactams 7a–7c. Spectral
Experimental
All the chemicals required were purchased from Merck,
Fluka, and Acros. Melting points were determined on a
123

1024
M. Zarei
CDCl3): d = 15.3 (Me), 60.6 (OCH2), 62.5 (C-3), 65.8 (C-
4), 113.2, 116.5, 119.3, 120.1, 125.8, 129.2, 136.4, 155.7
(aromatic carbons), 161.3 (CO, b-lactam) ppm.
data for 5a–5k, 6a, 6b, 7a, and 7b have been reported
elsewhere.
3-(2,4-Dichlorophenoxy)-1-(4-methoxybenzyl)-4-(4-nitro-
phenyl)azetidin-2-one (5l, C23H18Cl2N2O5)
Acknowledgments The author is grateful to Hormozgan University
Research Council for financial assistance.
Light-yellow solid; m.p.: 84–86 °C; Rf = 0.39 (petroleum
ether–EtOAc 8:2); IR (KBr): vꢀ = 1,344, 1,557 (NO2),
1
1,751 (CO, b-lactam) cm-1; H NMR (300 MHz, CDCl3):
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155.8 (aromatic carbons), 163.6 (CO, b-lactam) ppm.
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White solid; m.p.: 121–123 °C; Rf = 0.31 (petroleum
ether–EtOAc 7:3).
3-Chloro-1-(4-ethoxyphenyl)-4-phenylazetidin-2-one
(6c, C17H16ClNO2)
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;
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