One-pot sequence synthesis of azetidin-2-one using diethyl chlorophosphate

Article abstract of DOI:10.3184/174751912X13282660033937

A simple and convenient synthesis of 2-azetidinone derivatives from the reaction of a pre-mixture of amines and aldehydes with carboxylic acids in the presence of diethyl chlorophosphate by [2+2] cycloaddition reaction is described. Separation and purification of imines as intermediates were not required. The methodology is convenient and good to excellent yields of products were obtained with simple purification.

Full text of DOI:10.3184/174751912X13282660033937

118 RESEARCH PAPER
FEBRUARY, 118–120
JOURNAL OF CHEMICAL RESEARCH 2012
One-pot sequence synthesis of azetidin-2-one using diethyl
chlorophosphate
Maaroof Zarei
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
A simple and convenient synthesis of 2-azetidinone derivatives from the reaction of a pre-mixture of amines and
aldehydes with carboxylic acids in the presence of diethyl chlorophosphate by [2+2] cycloaddition reaction is
described. Separation and purification of imines as intermediates were not required. The methodology is convenient
and good to excellent yields of products were obtained with simple purification.
Keywords: β-lactam, 2-azetidinone, Staudinger reaction, diethyl chlorophosphate, ketene, imine
The 2-azetidinone (β-lactam) unit is a crucial structural feature
of β-lactam antibiotics. It forms the structural component
of the widely used penicillin, cephalosporin, thienamycine,
nocardicin, aztreonam and carumonam.1–2 Ezetimibe, new
cholesterol absorption inhibitor drug, has a β-lactam skeleton.3
In addition, there are many other biological activities of β-
lactams.4,5 2-Azetidinones (β-lactams) can be employed as
useful intermediates in organic synthesis in the synthesis of
several compounds (β-lactam synthon method) and as side-
chain equivalents for the synthesis of Taxol and Taxotere.6–9
Because of these applications and the growing resistance
of bacteria against β-lactam antibiotics, it is necessary to
synthesise new β-lactams.
Among many synthetic methods for the formation of the
β-lactam ring10,11 the [2+2] cycloaddition of ketenes and imines
(Staudinger reaction) is the simplest and most convenient.12–13
This reaction has very broad applications in the preparation of
β-lactams. The convenience of the Staudinger cycloaddition
arises from not only the mild reaction conditions but also the
general availability of imines and ketenes. Also ketenes can
be simply prepared by the treatment of acyl chlorides with
triethylamine before the reaction or in situ.14–24
Because of instability and difficulty in the preparation of
acyl chloride, the Staudinger [2+2] cycloaddition has been
extensively modified. These modifications include the applica-
tion of a variety of acid-activating agents for the generation of
ketenes from carboxylic acids in situ.25–39
The high cost, unavailability, pollution and low yields are
disadvantages of some of these acid activators. Furthermore in
some cases, heating or cooling of the reaction is necessary and
purification of imines in most cases has been performed.
In this work, the one-pot sequence synthesis of β-lactams by
the Staudinger reaction using diethyl chlorophosphate as a
cheap and convenient method is described.
resulting solution containing N-(4-isopropylbenzylidene)-
4-ethoxyaniline 1a (without isolation) was transferred to
a round-bottomed flask equipped with a magnetic stirring
bar and a calcium chloride tube. Then phenoxyacetic acid
(1.0 mmol), dry triethylamine (3.0 mmol) and diethyl chloro-
phosphate (1.0 mmol) was added to the mixture at room
temperature and the mixture was stirred overnight. After the
usual work-up and purification by crystallisation from ethyl
acetate the pure cis-1-(4-ethoxyphenyl)-4-(4-isopropylphenyl)-
3-phenoxyazetidin-2-one 2a was obtained as a white solid in
68% yield (Scheme 1). The 2-azetidinone 2a was characterised
by its spectral data. The cis stereochemistry was assigned
by the comparison of the coupling constant H-3 and H-4
(J3,4 = 4.8 Hz).
After this successful result, the optimisation of the reaction
conditions was investigated by consideration of the effects of
temperature and molar ratio of the reagent in the synthesis of
β-lactam 2a at dry CH2Cl2 (Table 1).
As shown in Table 1, the yield of 2a increases when
1.5 mmol of diethyl chlorophosphate and 1.5 mmol of carbox-
ylic acid react with 1.0 mmol of the mixture of amine and alde-
hyde instead of 1.0 or 1.3 mmol of diethyl chlorophosphate.
Also the yields were better at room temperature than at 0 °C.
The yield was not increased when the reaction stirred at 0 °C
for 48 hours.
On the basis of above results, the 2-azetidinones 2a–k were
synthesised by treatment of 1.0 mmol of the corresponding
amines and 1.0 mmol of the corresponding aldehydes in the
presence of anhydrous sodium sulfate in dry dichloromethane
for 24 hours, followed by addition of 1.5 mmol of substituted
acetic acids, 1.5 mmol of diethyl chlorophosphate and
5.0 mmol triethylamine to the previous solution at room tem-
perature and they were purified by crystallisation from EtOAc
(Table 2). All products were obtained in good to excellent
yields and were characterised by their spectral data and
elemental analyses. The cis stereochemistry of all products
was judged from the comparison of the coupling constant H-3
and H-4 (J3,4> 4.4 Hz).
First, the condensation of 4-ethoxyaniline (1.0 mmol)
and 4-isopropylbenzaldehyde (1.0 mmol) in dry CH2Cl2 in
the presence of excess of anhydrous sodium sulfate was
performed. After 24 hours, sodium sulfate was filtered and the
Scheme 1
* Correspondent. E-mail: maaroof1357@yahoo.com;
mzarei@hormozgan.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2012 119
Table 1 Optimisation of conditions in the synthesis of β-lactam
1.35 (Me, t, 3H, J = 6.8), 2.82 (CH, septet, 1H), 3.92 (OCH2, q, 2H,
J = 6.8), 5.30 (H-4, d, 1H, J = 5.0), 5.69 (H-3, d, 1H, J = 5.0), 6.82–
7.86 (ArH, m, 13H); 13C NMR (75 MHz, CDCl3) δ 14.3 (Me), 21.7
(Me), 32.5 (CH), 60.8 (OCH2), 63.3 (C-4), 81.5 (C-3), 113.3, 117.3,
119.5, 122.1, 124.3, 125.9, 127.1, 127.9, 136.3, 144.8, 147.2, 158.2
(aromatic carbons), 161.9 (CO, β-lactam). Anal. Calcd for C26H27NO3:
C, 77.78; H, 6.78; N, 3.49. Found: C, 77.89; H, 6.92; N, 3.41%.
3-(2,4-Dichlorophenoxy)-1-(4-ethoxyphenyl)-4-(4-isopropylphenyl)
azetidin-2-one (2b): White solid; m.p. 155–157 °C. IR (KBr) cm−1:
1746 (CO, β-lactam); 1H NMR (300 MHz, CDCl3) δ 1.27 (2Me, d, 6H,
J = 7.0), 1.31 (Me, t, 3H, J = 6.7), 2.74 (CH, septet, 1H), 4.00 (OCH2,
q, 2H, J = 6.7), 5.47 (H-4, d, 1H, J = 5.1), 5.65 (H-3, d, 1H, J = 5.1),
6.88–7.73 (ArH, m, 11H); 13C NMR (75 MHz, CDCl3) δ 14.8 (Me),
23.3 (Me), 34.1 (CH), 61.4 (OCH2), 63.1 (C-4), 82.9 (C-3), 111.3,
112.8, 116.0, 117.8, 120.6, 124.0, 126.2, 126.6, 129.3, 132.9, 137.1,
141.6, 145.8, 155.9 (aromatic carbons), 163.1 (CO, β-lactam). Anal.
Calcd for C26H25Cl2NO3: C, 66.39; H, 5.36; N, 2.98. Found: C, 66.45;
H, 5.348; N, 3.06%.
1-(4-Ethoxyphenyl)-4-(4-isopropylphenyl)-3-(naphthalen-2-yloxy)
azetidin-2-one (2c): White crystalline solid; m.p. 182–184 °C. IR
(KBr) cm−1: 1744 (CO, β-lactam); 1H NMR (300 MHz, CDCl3) δ 1.24
(2Me, d, 6H, J = 7.2), 1.39 (Me, t, 3H, J = 7.0), 2.66 (CH, septet, 1H),
4.06 (OCH2, q, 2H, J = 7.0), 5.38 (H-4, d, 1H, J = 4.4), 5.59 (H-3, d,
1H, J = 4.4), 6.81–7.84 (ArH, m, 15H); 13C NMR (75 MHz, CDCl3) δ
14.9 (Me), 25.1 (Me), 32.8 (CH), 60.1 (OCH2), 63.6 (C-4), 84.0 (C-3),
113.7, 115.1, 117.0, 117.4, 119.6, 122.3, 123.7, 124.1, 126.0, 126.9,
127.7, 131.4, 135.8, 139.2, 143.6, 144.0, 148.1, 157.4 (aromatic
carbons), 162.3 (CO, β-lactam). Anal. Calcd for C30H29NO3: C, 79.80;
H, 6.47; N, 3.10. Found: C, 79.74; H, 6.59; N, 3.03%.
2a
Entry
Temp /°C Diethyl chlorophosphate
/mmol
Yield /%a
1
2
3
4
5
rt
rt
1.0
1.3
1.5
2.0
1.5
68
75
88
85
76
rt
rt
0 °C
a All reactions were stirred for 24 hours.
In conclusion, we have developed a simple procedure for the
synthesis of 2-azetidinones in good to excellent yields by acti-
vated carboxylic acids using diethyl chlorophosphate and a
mixture of amines and aldehydes at room temperature. All the
steps of reaction are sequential and isolation and purification
of imines is not required. The reaction has the advantages
of mild conditions, simple purification, easy handling of the
starting materials and high yields.
Experimental
All chemicals were purchased from Merck, Fluka and Acros. 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 spectropho-
tometer (1H NMR 300 MHz, 13C NMR 75 MHz) using tetramethylsi-
lane as an internal standard and coupling constants are given in Hz.
Elemental analyses were run on a Vario EL III elemental analyser.
TLC was carried out on silica gel 254 analytical sheets obtained from
Fluka. Spectral data for 2i–k have been previously reported.31,40
2-(1-(4-Ethoxyphenyl)-2-(4-isopropylphenyl)-4-oxoazetidin-3-yl)
isoindoline-1,3-dione (2d): Light-yellow solid; m.p. 178–180 °C. IR
1
(KBr) cm−1: 1738, 1751 (CO, phth), 1774 (CO, β-lactam); H NMR
(300 MHz, CDCl3) δ 1.20 (2Me, d, 6H, J = 7.0), 1.33 (Me, t, 3H,
J = 7.2), 2.61 (CH, septet, 1H), 4.12 (OCH2, q, 2H, J = 7.2), 5.19 (H-4,
d, 1H, J = 4.6), 5.57 (H-3, d, 1H, J = 4.6), 6.79-7.63 (ArH, m, 12H);
13C NMR (75 MHz, CDCl3) δ 15.1 (Me), 24.6 (Me), 31.5 (CH), 60.9
(OCH2), 62.7 (C-4), 65.3 (C-3), 114.8, 118.2, 121.1, 125.9, 126.4,
127.3, 128.3, 135.5, 138.2, 147.1, 155.8 (aromatic carbons), 162.4
(CO, phth), 164.0 (CO, β-lactam). Anal. Calcd for C28H26N2O4: C,
73.99; H, 5.77; N, 6.16. Found: C, 74.11; H, 5.90; N, 6.24%.
1-Benzyl-3-(4-chlorophenoxy)-4-(4-nitrophenyl)azetidin-2-one
(2e): Light-yellow solid; m.p. 123–125 °C IR (KBr) cm−1: 1332, 1522
(NO2), 1744 (CO, β-lactam); 1H NMR (300 MHz, CDCl3) δ 3.92, 4.80
(CH2-benzyl, 2d, 2H, J = 15.0), 4.91 (H-4, d, 1H, J = 4.8), 5.56 (H-3,
d, 1H, J = 4.8), 6.74-8.21 (ArH, m, 13H); 13C NMR (75 MHz, CDCl3)
δ 45.8 (CH2), 62.4 (C-3), 83.6 (C-4), 116.3, 120.6, 122.9, 127.8, 128.3,
129.4, 129.7, 131.0, 138.8, 140.2, 146.2, 155.3 (aromatic carbons),
163.7 (CO, β-lactam). Anal. Calcd for C22H17ClN2O4: C, 64.63; H,
4.19; N, 6.85. Found: C, 64.74; H, 4.32; N, 6.94%.
Synthesis of 2-azetidinones (2a-k); general procedure
To a stirred solution of corresponding aldehyde (1.0 mmol) in dry
CH2Cl2 (20 mL) at room temperature were successively added the cor-
responding amine (1.0 mmol) and a large excess of anhydrous sodium
sulfate (2.0 g). The resulting mixture was stirred for 24 hours at
room temperature. The mixture was filtered and the resulted solution
transferred to round-bottomed flask equipped with a magnetic stirring
bar and calcium chloride tube. Then corresponding substituted acetic
acids (1.5 mmol), dry triethylamine (5.0 mmol) and diethyl chloro-
phosphate (1.5 mmol) was added to the mixture at room temperature
and it was stirred overnight. Then the solution was washed succes-
sively with HCl 0.5 M (20 mL), saturated NaHCO3 (20 mL) and brine
(20 mL). The organic layer was dried (Na2SO4), filtered and the sol-
vent was removed under reduced pressure to give the crude products.
β-Lactams 2a–k were purified by crystallisation from ethyl acetate.
1-(4-Ethoxyphenyl)-4-(4-isopropylphenyl)-3-phenoxyazetidin-2-
one (2a): White solid; m.p. 161–163 °C. IR (KBr) cm−1: 1751 (CO,
β-lactam); 1H NMR (300 MHz, CDCl3) δ 1.22 (2Me, d, 6H, J = 7.3),
1-Benzyl-3-(4-chlorophenoxy)-4-(4-chlorophenyl)azetidin-2-one
(2f): White solid; m.p. 109–111 °C IR (KBr) cm−1: 1752 (CO,
β-lactam); 1H NMR (300 MHz, CDCl3) δ 3.85, 4.87 (CH2-benzyl, 2d,
2H, J = 14.8), 4.93 (H-4, d, 1H, J = 5.1), 5.41 (H-3, d, 1H, J = 5.1),
Table 2 Synthesis of 2-azetidinones 2a–k
Entry
R1
R2
R3
Product
Isolated yield/%
1
2
4-EtOC6H4
4-EtOC6H4
4-EtOC6H4
4-EtOC6H4
PhCH2
4-(Me2CH)C6H4
4-(Me2CH)C6H4
4-(Me2CH)C6H4
4-(Me2CH)C6H4
4-NO2C6H4
PhO
2,4-Cl2C6H3O
2-naphthO
PhthN
4-ClC6H4O
4-ClC6H4O
4-ClC6H4O
4-ClC6H4O
MeO
2a
2b
2c
2d
2e
2f
2g
2h
2i
88
84
82
79
87
80
82
76
83
79
88
3
4
5
6
PhCH2
4-ClC6H4
7
4-MeOC6H4CH2
4-MeOC6H4CH2
4-MeOC6H4
4-MeOC6H4
4-EtOC6H4
4-NO2C6H4
8
4-ClC6H4
9
4-MeC6H4
10
11
CH=CHPh
PhO
2-naphthO
2j
2k
4-MeOC6H4

120 JOURNAL OF CHEMICAL RESEARCH 2012
6.84-7.57 (ArH, m, 13H); 13C NMR (75 MHz, CDCl3) δ 43.7 (CH2),
60.5 (C-3), 81.9 (C-4), 114.2, 118.7, 121.0, 124.6, 126.3, 127.5, 128.9,
132.4, 134.1, 138.7, 141.3, 153.8 (aromatic carbons), 161.4 (CO,
β-lactam). Anal. Calcd for C22H17Cl2NO2: C, 66.34; H, 4.30; N, 3.52.
Found: C, 66.29; H, 4.41; N, 3.46.
5
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7
8
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1-(4-Methoxybenzyl)-3-(4-chlorophenoxy)-4-(4-nitrophenyl)azetidin-
2-one (2g): Light-yellow solid; m.p. 92–94 °C. IR (KBr) cm−1: 1339,
1544 (NO2), 1745 (CO, β-lactam); 1H NMR (300 MHz, CDCl3) δ 3.71
(OMe, s, 3H), 3.93, 4.84 (CH2-benzyl, 2d, 2H, J = 14.9), 4.89 (H-4, d,
9
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1H, J = 4.8), 5.52 (H-3, d, 1H, J = 4.8), 6.71–8.24 (ArH, m, 12H). 13
C
NMR (75 MHz, CDCl3) δ 45.4 (CH2), 56.1 (OMe), 61.3 (C-3), 81.7
(C-4), 115.3, 116.8, 120.6, 124.0, 127.5, 128.2, 129.5, 130.3, 142.8,
145.1, 154.7, 157.9 (aromatic carbons), 162.7 (CO, β-lactam). Anal.
Calcd for C23H19ClN2O5: C, 62.95; H, 4.36; N, 6.38. Found: C, 63.08;
H, 4.46; N, 6.41%.
14 J. Xu, Arkivoc 2009, (ix), 21.
1-(4-Methoxybenzyl)-3-(4-chlorophenoxy)-4-(4-chlorophenyl)azetidin-
15 L. Fodor, P. Csomos, T. Holczbauer, A. Kalman, A. Csampai and P. Sohar,
2-one (2h): White solid; m.p. 83–85 °C. IR (KBr) cm−1: 1749 (CO,
Tetrahedron Lett., 2011, 52, 224.
1
16 K. Janikowska, N. Pawelska and S. Makowiec, Synthesis, 2011, 69.
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β-lactam); H NMR (300 MHz, CDCl3) δ 3.65 (OMe, s, 3H), 3.88,
4.78 (CH2-benzyl, 2d, 2H, J = 15.0), 4.85 (H-4, d, 1H, J = 4.5), 5.42
(H-3, d, 1H, J = 4.5), 6.63–7.59 (ArH, m, 12H). 13C NMR (75 MHz,
CDCl3) δ 45.9 (CH2), 55.7 (OMe), 62.4 (C-3), 81.1 (C-4), 114.8,
116.0, 118.3, 123.5, 126.9, 127.7, 129.1, 130.8, 136.4, 142.6, 153.1,
158.4 (aromatic carbons), 163.6 (CO, β-lactam). Anal. Calcd for
C23H19Cl2NO3: C, 64.50; H, 4.47; N, 3.27. Found: C, 64.57; H, 4.62;
N, 3.20%.
18 R.S. Keri, K.M. Hosamani, R.V. Shingalapur and H.R.S. Reddy, Eur. J.
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1-(4-Methoxyphenyl)-3-methoxy-4-p-tolylazetidin-2-one (2i): White
solid; m.p. 153-155 °C (lit.40 151–153 °C).
1-(4-methoxyphenyl)-3-phenoxy-4-styrylazetidin-2-one (2j): White
solid; m.p. 182–184 °C (lit.31 181–182 °C).
1-(4-Ethoxyphenyl)-4-(4-methoxyphenyl)-3-(naphthalen-2-yloxy)-
azetidin-2-one (2k):White solid; m.p. 161–163 °C (lit.40 162–164 °C).
Financial support from Hormozgan University Research center
is gratefully acknowledged.
Received 14 December 2011; accepted 19 January 2012
Paper 1101039 doi: 10.3184/174751912X13282660033937
Published online: 23 February 2012
34 J. Meshram, P. Ali and V. Tiwari, J. Het. Chem., 2010, 47, 1454.
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