Preparation of 2-azetidinones by cyclocondensation of carboxylic acids and imines via diphosphorustetraiodide

Article abstract of DOI:10.1080/00397911.2016.1148165

One-pot mild synthesis of 2-azetidinones was carried out by the reaction of imines and carboxylic acids in dry dichloromethane at room temperature using diphosphorus tetraiodide. It was also applied for synthesis of 3-spiro-2-azetidinones. The synthesized

Full text of DOI:10.1080/00397911.2016.1148165

Synthetic Communications
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Preparation of 2-azetidinones by
Cyclocondensation of Carboxylic Acids and Imines
via Diphosphorustetraiodide
Maaroof Zarei & Fatemeh Maaqooli
To cite this article: Maaroof Zarei & Fatemeh Maaqooli (2016): Preparation of 2-azetidinones
by Cyclocondensation of Carboxylic Acids and Imines via Diphosphorustetraiodide, Synthetic
Communications, DOI: 10.1080/00397911.2016.1148165
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Date: 24 February 2016, At: 00:15

Preparation of 2-azetidinones by cyclocondensation of carboxylic acids and imines
via diphosphorustetraiodide
1
1
Maaroof Zarei , Fatemeh Maaqooli
1
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas,
Iran
Corresponding author Maaroof Zarei E-mail: mzarei@hormozgan.ac.ir,
maaroof1357@yahoo.com
Abstract
One pot mild synthesis of 2-azetidinones was carried out by the reaction of imines and
carboxylic acids in dry dichloromethane at room temperature using diphosphorus
tetraiodide. It was also applied for synthesis of 3-spiro-2-azetidinones. The synthesized
1
13
compounds were characterized by analytical and spectral (IR, H NMR, C NMR, and
elemental analysis) data.
KEYWORDS: β-Lactam, 2-Azetidinone, Staudinger reaction, Diphosphorustetraiodide,
Ketene, Imine
INTRODUCTION
Diphosphorus tetraiodide (P I ) is a well characterized, stable, crystalline solid which it is
2
4
1
useful reagent in organic synthesis. Although several methods has been reported for
2
-3
synthesis of diphosphorus tetraiodide but it is commercially available. It has been
4
introduced for the synthesis of alkyl halides from alcohols, amides from carboxylic acids
1

5
2
6
and amines, aldoximes from nitriles, nitriles from carboxylic acids and for
7
decarboxylative bromination.
The β-lactam (2-azetidinone) skeletal structure is the key component of the β-lactam
antibiotics which are the widespread antimicrobial agents. The β-lactam antibiotics
include penicillins, cephalosporins, penems, carbapenems, and monobactams, and
8
others. As a consequence of the antibiotic pressure, the emergence and dispersion of
resistant bacterial strains increase dramatically through mutation and β-lactamase gene
transfer, and then research efforts have to be devoted to the discovery of new
9
antibacterial agents. Recently, new interesting biologically active substrates, based on β-
1
0
lactam (2-azetidinone) structure, have been reported which cholesterol absorption
1
1
inhibitor in Ezetimibe is a new activity of 2-azetidinones for clinical use. In addition, 2-
azetidinones take place as intermediates in the synthesis of numerous organic
1
2-13
14
compounds,
for example, in the semi-synthesis of Taxol derivatives.
There are several methods for synthesis of 2-azetidinones because of their immense
1
5-16
importance to mankind.
The most frequently employed methodology for the synthesis
of the 2-azetidinone ring is the [2 + 2] ketene–imine cycloaddition (Staudinger
1
7-21
reaction).
Although a number of methods for preparation of ketenes have been
introduced, reaction of acyl halides with tertiary amines remains the most preparative and
2
2-23
useful approach because of the availability of starting material.
But, sometimes
application of acyl halides shows unfavorable results such as low stability, low yield of
product, and difficulties in handling and preparation.
2

Then for ketene generation without need to acid chlorides, activation of a carboxylic acid
2
4-
with acid activator reagents in the presence of a base have been reported.
4
2
Unfortunately some of these acid activators are unavailable and require harsh
conditions and diffucult purification of products. Need low or high temperatures,
inconvenient reaction conditions, and painful chromatographic separations for
purification of products are disadvantages of some of these acid activators.
We observed that diphosphorus tetraiodide could be used at room temperature for the
direct conversion of carboxylic acids and imines to the corresponding 2-azetidinones.
RESULTS AND DISCUSSION
For our initial studies, (4-methoxyphenyl)-1-phenylmethanimine 1a and phenoxyacetic
acidwas chosen as model substrates. A mixture of imine 1a, phenoxyacetic acid,
diphosphorus tetraiodide and triethylamine in anhydrous dichloromethane was stirred at
room temperature overnight. After work-up and purification by crystallization from ethyl
acetate, 2-azetidinone 3a was isolated in 78% yield.
The reactions were carried out in the presence of various anhydrous solvents and the
results are presented in Table 1 which dry dichloromethane showed the best result. When
o
this reaction performed at 0 C in dry dichlromethane, the yield of 2-azetidinoe decreased
to 51%. For optimization of quantity of reagent, 1.0 mmol of imine and 1.5 mmol of
phenoxyacetic acid have been used in entry 7-9. As it is shown in the table, the highest
3

yield of 3a was obtained when 1.0 mmol of imine 1a react with 1.5 mmolphenoxyacetic
acid using 0.5 mmol of P I in dry dichloromethane at room temperature (Entry 9).
2
4
Encouraged by these results and optimization of reaction condition, we subjected various
carboxylic acids and imines to the reaction and the results are presented in Table 2. 2-
Azetidinones 3a-j were obtained in good to excellent yields under mild condition at room
temperature (Scheme 1, Table 2) which were purified by crystallization from EtOAc after
simple aqueous work-up.
The formation of 2-azetidinones were characterized by IR spectra, which show
–
1
characteristic C=O stretching vibration at 1739-1784 cm with the disappearance of
–1
1
vibration at about 1620 cm (C=N of imine). In the H NMR spectra, they show
appearance of peak due to proton on carbon 3 and 4 of the 2-azetidinone ring (H-3 and H-
4
) observed from 5.05-5.35 and 5.26-5.66 ppm, respectively. The stereochemistry of
them were assigned by the comparison of the coupling constant H-3 and H-4 (J > 4.0
3
,4
4
3-45
13
Hz) for the cis stereoisomer and (J ≤ 3.0 Hz) for the trans stereoisomer.
In C
3
,4
NMR, the peaks appeared at about 164 ppm due to carbonyl of 2-azetidinoe ring.
Diphosphorus tetraiodide was successfully employed for the synthesis of spiro-2-
azetidinones 5a-b. 2-Azetidinones 5a-b were easily obtained from xanthene-9-carboxylic
acid 4 and imines in the presence of triethylamineby this method and purified by
crystallization from EtOAc (Scheme 2).
4

CONCLUSIONS
In conclusion, a novel method has been developed for direct conversion of carboxylic
acids and imines to the corresponding 2-azetidinones using diphosphorus tetraiodide in
the presence of triethylamine in anhydrous dichloromethane at room temperature. The
method is mild and gave good to excellent yields of 2-azetidinones without need to
column chromatography.
EXPERIMENTAL
All required chemicals were purchased from Merck, Fluka, and Acros chemical
companies. The melting points were determined on a Buchi 535 apparatus. IR spectra
were measured on a Shimadzu FT-IR 8300 spectrophotometer. NMR spectra were
1
13
recorded on a Bruker spectrometer ( H NMR 250 MHz, C NMR 62.9 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. Data for new products have been reported in this paper.
General Procedure For The Synthesis Of 2-Azetidinones (3a-J And 5a-B)
Diphosphorus tetraiodide (0.5 mmol) was added to a solution of substituted acetic acids
(
1.5 mmol), imines (1.0 mmol) and triethylamine (5.0 mmol) in dry CH Cl (20 ml) at
2 2
room temperature and the mixture was stirred overnight. The reaction mixture was
washed successively with saturated NaHCO (15 ml) and brine (15 ml). The organic layer
3
5

was dried (Na SO ), filtered and the solvent was removed to give the crude product,
2
4
which was purified by crystallization from EtOAc to give pure β-lactams 3a-j and 5a-b.
3
-(4-Chlorophenoxy)-1-(4-Methoxyphenyl)-4-Phenylazetidin-2-One (3c)
-1
1
White solid.m.p: 177-179 °C. IR (KBr) cm : 1749 (CO, β-lactam). H NMR δ 3.79
(MeO, s, 3H), 5.35 (H-4, d, 1H, J = 4.4), 5.61 (H-3, d, 1H, J = 4.4), 6.86-7.28 (ArH, m,
1
3
1
3H); C NMR δ 56.0 (MeO), 63.0 (C-4), 80.6 (C-3), 114.4-156.3 (aromatic carbons),
63.0 (CO, β-lactam); Anal. Calcd for C H ClNO : C, 69.57; H, 4.78; N, 3.69. Found:
1
2
2
18
3
C, 69.70; H, 4.86; N, 3.74.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
Financial support from Hormozgan University Research center is gratefully
acknowledged.
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9

Table 1. Optimization of condition in the synthesis of 3a using P2I4
Entry Solvent Temp mmol PhOCH CO H mmol P I Isolated yield (%)
2
2
2 4
1
2
3
4
5
6
7
8
9
CH Cl rt
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.75
0.5
78
55
36
59
63
51
83
84
92
2
2
Toluene rt
THF rt
CH CN rt
3
DMF
rt
o
CH Cl 0 C 1.0
2
2
CH Cl rt
1.5
1.5
1.5
2
2
CH Cl rt
2
2
CH Cl rt
2
2
1
0

Table 2. 2-Azeidinones from imines and carboxylic acids using diphosphorus tetraiodide
1
2
3
Entry R
R
R
cis/trans Product Isolated yield (%)
1
2
3
4
5
6
7
8
9
1
4-MeOC H
C H
PhO
2,4-Cl C H O cis
cis
3a
3b
3c
3d
3e
3f
92
78
91
80
85
88
85
90
81
88
6
4
4
4
4
4
6
5
5
5
5
5
4-MeOC H
C H
6
6
2
6
3
4-MeOC H
C H
6
4-ClC H O
cis
6
6
4
4-MeOC H
C H
6
MeO
cis
6
4-MeOC H
C H
6
PhthN
PhO
trans
cis
6
4-ClC H
4-(NMe )C H
2 6
6
4
4
4
4
4
4
4
4
4
4
4-ClC H
4-(NMe )C H
2,4-Cl C H O cis
3g
3h
3i
6
2
6
2
6
3
4-ClC H
4-(NMe )C H
4-ClC H O
cis
6
2
6
6
4
4-ClC H
4-(NMe )C H
MeO
PhthN
cis
6
2
6
0
4-ClC H
4-(NMe )C H
trans
3j
6
2
6
1
1

Scheme 1. Synthesis of 2-azetidinones 3a-j
1
2

Scheme 2.
1
3