Tosylimidazole-mediated one-pot synthesis of 2-azetidinones

Article abstract of DOI:10.3184/174751916X14683354026584

Cyclocondensation of Schiff bases and substituted acetic acid with tosylimidazole afforded 2-azetidinones in good to excellent yields. This reaction works reliably well for monocyclic and spirocyclic 2-azetidinones. This reaction is green and efficient an

Full text of DOI:10.3184/174751916X14683354026584

532 RESEARCH PAPER
VOL. 40 SEPTEMBER, 532–534
JOURNAL OF CHEMICAL RESEARCH 2016
Tosylimidazole-mediated one-pot synthesis of 2-azetidinones
a
b
a
Saleheh Zavar , Maaroof Zarei * and Mahnaz Saraei
a
Department of Chemistry, Payame Noor University, PO Box 19395-3697, Tehran, Iran
Department of Chemistry, Faculty of Sciences, University of Hormozgan, Bandar Abbas 71961, Iran
b
Cyclocondensation of Schiff bases and substituted acetic acid with tosylimidazole afforded 2-azetidinones in good to excellent yields.
This reaction works reliably well for monocyclic and spirocyclic 2-azetidinones. This reaction is green and efficient and the products can
be purified by simple crystallisation.
Keywords: β-lactam, 2-azetidinone, Staudinger reaction, tosylimidazole, ketene, imine
N-(p-Toluenesulfonyl)imidazole (tosylimidazole, TsIm; Fig. 1)
is a highly efficient, cheap and stable reagent for the one-pot
conversion of alcohols to alkyl azides and alkyl nitriles, and for
Table 1 Reaction conditions in the synthesis of 2-azetidinone 3
Ph
PhO
TsIm
1
N
PhN=CHPh + PhOCH COOH
esterification. Although this reagent is commercially available,
2
Et N
2
3
O
Ph
it can also be prepared by a reported method.
1
2
3
Owing to the wide-ranging and important biological activities
3
of 2-azetidinones and their application in the synthesis of non-
Entry Solvent
Temperature/°C Tosylimidazole /mmol Yield/%
4
β-lactam products, several methods have been developed for
1
2
3
4
5
6
7
8
9
benzene
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
40
r.t.
r.t.
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.3
1.5
51
76
73
41
49
55
67
70
91
88
5
–7
the synthesis of the 2-azetidinone ring.
CH Cl2
2
A well-established method for 2-azetidinone synthesis is the
CHCl3
THF
8
–10
[2 + 2] ketene–imine cycloaddition (Staudinger reaction).
Ketenes can be generated in situ by reaction of acyl chlorides
CH CN
11,12
3
with triethylamine.
However, owing to their instability and
DMF
the lack of availability of acyl chlorides and sometimes the low
yield of products, direct generation of ketenes from carboxylic
2
2
2
CH Cl2
12–20
CH Cl2
acids using acid activators has been considered.
Here, we
CH Cl2
report the use of tosylimidazole as a coupling reagent for the
one-pot synthesis of 2-azetidinones from carboxylic acids and
imines.
10
2
CH Cl2
O
S N
O
H C
3
N
Table 2 Synthesis of 2-azetidinones 3–13 using TsIm
Fig. 1 Tosylimidazol, TsIm.
1
2
3
cis/
trans
Isolated
yield/%
Entry R
R
R
Product
Results and discussion
1
2
3
4
5
6
7
8
9
C6H5
4-MeOC6H4 2,4-Cl C H
6 3
C6H5
PhO
PhO
PhthN
cis
cis
trans
3
4
5
6
7
8
9
10
11
91
94
85
77
91
85
80
81
76
Aldehydes and amines were refluxed in 95% ethanol for 2 h
to give the corresponding Schiff bases. Then treatment of
N-benzylideneaniline 1, phenoxyacetic acid and tosylimidazole
in dry benzene in the presence of triethylamine afforded
-azetidinone 3 in 51% yield. This reaction was considered as a
model reaction to permit the optimisation of the method. Several
dry solvents, such as benzene, THF, DMF, CHCl , CH Cl and
CH CN, were examined (Table 1). It was found that the best
yield was with CH Cl (Table 1, entry 2). Also temperature and
2
4-MeOC6H4 2,4-Cl C H
2
6 3
4-MeOC6H4 3,4,5-(MeO) C H 2,4-Cl C H O cis
4-MeOC6H4 3,4,5-(MeO) C H PhthN
3
6
2
2 6 2
trans
cis
3
6 2
2
4-EtC6H
4
2,4-Cl C H
2 6 3
PhO
4-EtC6H
4
2,4-Cl C H
2
6
3
2,4-Cl C H O cis
2 6 2
3
2
2
4-EtC6H
4
3,4,5-(MeO) C H 2,4-Cl C H O cis
3
6
2
2 6 2
3
4-EtC6H
4
3,4,5-(MeO) C H PhthN
3 6 2
trans
2
2
equimolar amounts of reagents were tested. The results showed
that the highest yield of 2-azetidinone 3 was obtained when 1.3
mmol phenoxyacetic acid and 1.3 mmol TsIm were reacted with
Cl
O
1
0
Cl
–
12
13
72
70
1
.0 mmol of Schiff base 1 in dry CH Cl at room temperature
N
2
2
O
(
Table 1, entry 9).
After determining the optimum reaction conditions, several
OCH3
monocyclic 2-azetidinones were synthesised using this method.
Simple aqueous work-up and purification by recrystallisation
from ethanol afforded pure 2-azetidinones 3–11 (Scheme 1 and
Table 2). All products were characterised from their spectra and
physical data. The stereochemistry of products was deduced
by the comparison of the coupling constant H-3 and H-4
OCH3
OCH3
O
OCH3
11
–
N
O
(J3,4 > 4.0 Hz) for the cis stereoisomer and (J3,4 ≤ 3.0 Hz) for the
C
H
2 5
*
Correspondent. E-mail: maaroof1357@yahoo.com; mzarei@hormozgan.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2016 533
R3
O
R2 59.80 (OMe), 60.7 (C-4), 80.3 (C-3), 104.1, 113.4, 115.0, 115.9, 117.9,
122.9, 126.2, 126.3, 129.0, 129.2, 137.3, 150.3, 152.2, 155.7 (aromatic
carbons), 160.5 (CO, β-lactam). Anal. calcd for C H Cl NO : C,
TsIm, Et N
2
1
3
3
R HC=NR
R CH CO H
2 2
N
25 23
2
6
CH Cl , r.t.
2
2
R1
59.54; H, 4.60; N, 2.78; found: C, 59.62; H, 4.69; N, 2.71.
2- (1- (4-Methoxyphenyl)-2-oxo-4- (3,4,5-trimethoxyphenyl)
overnight
1
2
3–13
azetidin-3-yl)isoindoline-1,3-dione (7): White solid; m.p. 118–120 °C;
Scheme 1 Synthesis of 2-azetidinones 3–13.
−1
1
IR (KBr) (cm ): 1767 (CO, β-lactam), 1751, 1720 (CO, phth); H NMR
CDCl ): δ 3.62 (s, 3H, OMe), 3.70 (s, 6H, 2 OMe), 3.81 (s, 3H, OMe),
(
3
21
trans stereoisomer. This method was extended to the synthesis
of 3-spirocyclic-2-azetidinones 12 and 13 (Table 2, entries 10
and 11).
5.34 (d, 1H, J = 3.0, H-4), 5.62 (d, 1H, J = 3.0, H-4), 6.49–7.69 (m,
13
10H, ArH); C NMR (CDCl ): δ 54.4, 55.1, 58.3 (OMe), 59.32 (C-4),
3
60.2 (C-3), 102.0, 113.3, 117.6, 122.3, 122.8, 126.7, 130.2, 133.3,
136.8, 152.1, 155.5 (aromatic carbons), 159.1 (CO, phth), 165.9 (CO,
The stereochemistry of 2-azetidinones in the Staudinger
reaction depends on reaction temperature, solvent, electronic
effect and the steric hindrance of the ketene and imine
β-lactam). Anal. calcd for C H N O : C, 66.39; H, 4.95; N, 5.73;
27 24
2
7
found: C, 66.48; H, 5.03; N, 5.79.
4-(2,4-Dichlorophenyl)-1-(4-ethylphenyl)-3-phenoxyazetidin-
2
2,23
substituents.
−
1
2
-one (8): White solid; m.p. 129–131 °C; IR (KBr) (cm ): 1758 (CO,
In summary, the use of tosylimidazole for the one-pot
synthesis of 2-azetidinones from Schiff bases and carboxylic
acids under mild conditions is reported. The solvents, molar
ratio of reagent, time and temperature have been optimised.
The method is efficient and versatile.
1
β-lactam); H NMR (CDCl ): δ 1.94 (t, 3H, J = 7.6, CH ), 2.59 (q,
H, J = 7.6, CH ), 5.58 (d, 1H, J = 4.9, H-4), 5.80 (d, 1H, J = 4.9, H-3),
2
3
3
2
6
5
1
13
.86–7.37 (m, 12H, ArH); C NMR (CDCl ): δ 14.5 (CH ), 27.3 (CH ),
3
3
2
8.9 (C-4), 80.2 (C-3), 114.9, 116.3, 121.5, 126.3, 127.7, 128.3, 128.8,
29.0, 133.2, 133.2, 133.5, 133.9, 140.1, 155.9 (aromatic carbons), 161.7
(
CO, β-lactam). Anal. calcd for C H Cl NO : C, 67.00; H, 4.65; N,
Experimental
Melting points were measured by the capillary tube method with an
opti-melt MPA100 apparatus. H NMR and C NMR spectra were
recorded on a Bruker Spectrospin Advance 400 spectrometer using
TMS as an internal standard and CDCl as a solvent. Chemical shifts
were reported in ppm (δ) and coupling constants (J) were reported in
Hz. IR spectra were recorded from KBr disks using the Shimadzu FT
IR-8400S. Elemental analyses were recorded using a Thermo Finnigan
Flash EA–1112. Commercial aluminium-backed plates of silica gel
23 19 2 2
3
.40; found: C, 67.12; H, 4.73; N, 3.35.
- (2,4-Dichlorophenoxy) - 4- (2,4-dichlorophenyl) -1- (4-
ethylphenyl)azetidin-2-one (9): White solid; m.p. 148–150 °C; IR
3
1
13
−1
1
(
KBr) (cm ): 1762 (CO, β-lactam); H NMR (CDCl ): δ 1.20 (t, 3H, J =
3
3
7.6, CH ), 2.61 (q, 2H, J = 7.6, CH ), 5.56 (d, 1H, J = 5.1, H-4), 5.81 (d,
1
(
1
3
2
13
H, J = 5.1, H-3), 7.14–7. 44 (m, 10H, ArH); C NMR (CDCl ): δ 14.5
3
CH ), 27.4 (CH ), 56.8 (C-4), 80.5 (C-3), 115.7, 116.4, 123.2, 126.4,
3
2
26.6, 126.75, 127.8, 128.0, 128.4, 128.7, 128.9, 133.1, 133.3, 134.1,
40.4, 150.4 (aromatic carbons), 160.9 (CO, β-lactam). Anal. calcd for
1
6
0 F254 were used to monitor the progress of reactions by thin-layer
C H Cl NO : C, 57.41; H, 3.56; N, 2.91; found: C, 57.36; H, 3.66; N,
2
3
17
4
2
chromatography.
2
.85.
- (2,4-Dichlorophenoxy) -1- (4-ethylphenyl) - 4- (3,4, 5-
trimethoxyphenyl)azetidin-2-one (10): White solid; m.p. 145–151 °C;
3
Synthesis of 2-azetidinones (3–13); general procedure
A mixture of Schiff base (1.0 mmol), triethylamine (5.0 mmol),
carboxylic acid (1.3 mmol) and tosylimidazole (1.3 mmol)
−1
1
IR (KBr) (cm ): 1720 (CO, β-lactam); H NMR (CDCl ): δ 1.19
3
(t, 3H, J = 7.5, CH ), 2.59 (q, 2H, J = 7.5, CH ), 3.77 (s, 6H, 2 OMe),
3
2
in dry CH Cl2 (20 mL) was stirred at room temperature
2
3.82 (s, 3H, OMe), 5.30 (d, 1H, J = 4.9, H-4), 5.53 (d, 1H, J = 4.9,
H-4), 6.57–7.32 (m, 9H, ArH); C NMR (CDCl ): δ 14.5 (CH ), 27.3
(CH ), 55.2, 59.8 (OMe), 60.6 (C-4), 80.2 (C-3), 104.2, 115.1, 116.6,
1
1
overnight. The mixture was washed successively with saturated
13
3
3
NaHCO (20 mL) and brine (15 mL). The organic layer was
3
2
dried and the solvent was removed to give the crude product,
which was purified by crystallisation from EtOH to give pure
23.0, 126.3, 126.4, 126.6, 127.5, 129.1, 133.5, 137.4, 140.1, 150.3,
52.2 (aromatic carbons), 160.9 (CO, β-lactam). Anal. calcd for
2
-azetidinones 3–13.
C H Cl NO : C, 62.16; H, 5.02; N, 2.79; found: C, 62.25; H, 5.13; N,
2
6
25
2
5
2
4
3
-Phenoxy-1,4-diphenyl-2-azetindione (3): M.p. 190–192 °C (lit.
2
.84.
-(1-(4-Ethylphenyl)-2-(3,4,5-trimethoxyphenyl)-4-oxoazetidin-3-
yl)isoindoline-1,3-dione (11): White solid; m.p. 215–217 °C; IR (KBr)
191–193 °C).
2
4
-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)-3-phenoxyazetidin-
−1
−1
1
2
-one (4): White solid; m.p. 132–135 °C; IR (KBr) (cm ): 1755 (CO,
(cm ): 1767 (CO, β-lactam), 1718, 1759 (CO, phth); H NMR (CDCl ):
δ 1.19 (t, 3H, J = 7.5, CH ), 2.59 (q, 2H, J = 7.5, CH ), 3.81, 3.85 (2 s,
9H, 3 OMe), 5.28 (d, 2H, J = 2.5, H-4 and H-3), 6.57–7.87 (m, 10H,
3
1
β-lactam); H NMR (CDCl ): δ 3.69 (s, 3H, OMe), 5.52 (d, 1H, J = 4.9,
3
3
2
13
H-4), 5.71 (d, 1H, J = 4.9, H-3), 6.75–7.29 (m, 12H, ArH); C NMR
13
(
CDCl ): δ 54.4 (OMe), 57.0 (C-4), 80.3 (C-3), 113.5, 114.8, 117.6,
ArH); C NMR (CDCl ): δ 14.5 (CH ), 27.3 (CH ), 55.1, 59.8 (OMe),
3
3 3 2
121.5, 124.8, 126.3, 127.7, 128.2, 128.7, 128.9, 133.2, 133.9, 155.7,
60.6 (C-4), 61.7 (C-3), 101.8, 116.6, 122.8, 127.4, 130.5, 130.6, 133.6,
133.9, 137.3, 139.7, 152.9 (aromatic carbons), 160.93 (CO, phth), 165.8
(CO, β-lactam). Anal. calcd for C H N O : C, 69.12; H, 5.39; N, 5.76;
155.9 (aromatic carbons), 161.3 (CO, β-lactam). Anal. calcd for
C H Cl NO : C, 63.78; H, 4.14; N, 3.38; found: C, 63.87; H, 4.28; N,
2
2
17
2
3
28 26
2
6
3
.43.
-(2-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)-4-oxoazetidin-3-
yl)isoindoline-1,3-dione (5): White solid; m.p. 205–207 °C; IR (KBr)
found: C, 69.20; H, 5.51; N, 5.83.
2
2-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)spiro[azetidine-3,9’-
−1
xanthen]-4-one (12): White solid; m.p. 220–223 °C; IR (KBr) (cm ):
1757 (CO, β-lactam); H NMR (CDCl ): δ 3.81 (s, 3H, OMe), 5.28 (s,
1H, H-4), 6.72–8.89 (m, 15H, ArH); C NMR (CDCl ): δ 54.4 (OMe),
54.5 (C-4), 71.4 (C-3), 113.4, 113.6, 115.5, 117.8, 121.2, 123.0, 124.5,
126.5, 127.5, 128.2, 129.5, 133.2, 150.4, 150.9, 152.2, 155.7 (aromatic
carbons), 165.1 (CO, β-lactam); Anal. calcd for C H Cl NO : C,
−1
1
1
(cm ): 1772 (CO, β-lactam), 1762, 1726 (CO, phth); H NMR (CDCl ):
3
3
13
δ 3.77 (s, 3H, OMe), 5.59 (d, 1H, J = 3.0, H-4), 5.80 (d, 1H, J = 3.0,
H-3), 6.79–7.65 (m, 11H, ArH); C NMR (CDCl ): δ 56.71 (OMe),
3
13
3
57.86 (C-4), 60.6 (C-3), 113.5, 117.4, 122.6, 124.8, 126.0, 127.8, 128.9,
129.4, 130.1, 132.5, 133.4, 133.8, 155.6 (aromatic carbons), 159.7 (CO,
2
8
19
2
3
phth), 165.3 (CO, β-lactam). Anal. calcd for C H Cl N O : C, 61.69;
68.86; H, 3.92; N, 2.87; found: C, 68.94; H, 4.05; N, 2.95.
2
4
16
2
2
4
H, 3.45; N, 5.99; found: C, 61.61; H, 3.54; N, 6.03.
-(2,4-Dichlorophenoxy)-4-(3,4,5-trimethoxyphenyl)-1-(4-
methoxyphenyl)azetidin-2-one (6): White solid; m.p. 154–156 °C; IR
1-(4-Ethylphenyl)-4-(3,4,5-trimethoxyphenyl)spiro[azetidine-3,9’-
−1
3
xanthen]-2-one (13): White solid; m.p. 148–149 °C; IR (KBr) (cm ):
1
1760 (CO, β-lactam); H NMR (CDCl ): δ 1.14 (t, 3H, J = 7.6, CH ),
3
3
−1
1
(
KBr) (cm ): 1755 (CO, β-lactam); H NMR (CDCl ): δ 3.76, 3.78,
2.54 (q, 2H, J = 7.6, CH ), 3.63, 3.68 (2s, 9H, 3OMe), 4.98 (s, 1H,
2
3
13
3
.80 (3 s, 12H, 4 OMe), 5.28 (d, 1H, J = 4.8, H-4), 5.53 (d, 1H, J = 4.8,
H-4), 6.84–7.48 (m, 14H, ArH); C NMR (CDCl ): δ 14.5 (CH ), 27.3
3
3
13
H-3), 6.49–7.69 (m, 9H, ArH); C NMR (CDCl ): δ 54.39, 55.14,
(CH ), 55.1, 59.8 (3 OMe), 63.2 (C-4), 73.1 (C-4), 102.9, 115.1, 115.7,
2
3

534 JOURNAL OF CHEMICAL RESEARCH 2016
1
16.1, 118.8, 122.8, 127.4, 127.5, 128.4, 128.7, 134.1, 139.8, 151.0, 151.2
7
8
9
Singh, G.S. Tetrahedron, 2003, 59, 7631.
M. Zarei and M. Mohamadzadeh, Tetrahedron, 2011, 67, 5832.
R.S. Keri, K.M. Hosamani, RV. Shingalapur and H.R.S. Reddy, Eur. J.
Med. Chem., 2009, 44, 5123.
(aromatic carbons), 164.8 (CO, β-lactam). Anal. calcd for C H NO :
32
29
5
C, 75.72; H, 5.76; N, 2.76; found: C, 75.81; H, 5.89; N, 2.81.
1
0
M. Zarei and F. Maaqooli, Synthetic Commun., 2016, 46, 523.
T.T. Tidwell, Ketenes II, John Wiley & Sons, New Jersey, 2006, pp. 55–192.
A. Jarrahpour, M. Motamedifar, M. Zarei and M. Mimouni, Phosphorus
Sulfur Silicon, 2010, 185, 287.
Financial support from Payame Noor University Research
Council is gratefully acknowledged.
1
1
12
Received 11 May 2016; accepted 3 June 2016
Paper 1604093 doi: 10.3184/174751916X14683354026584
Published online: 4 August 2016
13 A. Jarrahpour, A. Fadavi and M. Zarei, Bull. Chem. Soc. Jpn, 2011, 84, 320.
14 M. Zarei, J. Chem. Res., 2012, 36, 118.
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M. Zarei, Z. Karimi-Jaberi and A. Movahedi, Synthetic Commun., 2013,
3, 728.
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1
6
A. Khademi Shiraz and M. Zarei, Monatsh. Chem., 2015, 146, 941.
M. Zarei, Monatsh. Chem., 2013, 144, 1021.
M. Nahmany and A. Melman, J. Org. Chem., 2006, 71, 5804.
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