A straightforward approach to 2-azetidinones from imines and carboxylic acids using dimethyl sulfoxide and acetic anhydride

Article abstract of DOI:10.1016/j.tetlet.2014.07.089

The direct synthesis of 2-azetidinones from imines and carboxylic acids under mild conditions is developed. Dimethyl sulfoxide (DMSO) can be activated by acetic anhydride and the resulting active species is used for the in situ generation of ketenes from

Full text of DOI:10.1016/j.tetlet.2014.07.089

Tetrahedron Letters xxx (2014) xxx–xxx
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A straightforward approach to 2-azetidinones from imines
and carboxylic acids using dimethyl sulfoxide and acetic anhydride
⇑
Maaroof Zarei
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct synthesis of 2-azetidinones from imines and carboxylic acids under mild conditions is
developed. Dimethyl sulfoxide (DMSO) can be activated by acetic anhydride and the resulting active
species is used for the in situ generation of ketenes from carboxylic acids. This method is cheap, simple,
convenient, and efficient and the products are easily isolated.
Received 24 April 2014
Revised 25 June 2014
Accepted 23 July 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
2-Azetidinone
Staudinger reaction
b-Lactam
Activated DMSO
Schiff base
Ketene
As examples of very important heterocyclic compounds,
b-lactams (2-azetidinones) have been considered as privileged
structures in chemical, pharmaceutical, and materials industries.1
The b-lactam antibiotics, including penicillins, cephalosporins,
monobactams, and carbapenems, are often administered because
of their wide spectrum of activity, safety, and reliable clinical effi-
cacy.2 Unfortunately, resistance against the common b-lactam
antibiotics has increased,3 and interest in creating new b-lactam
antibiotics and new methods for the synthesis of b-lactams is
rising. 2-Azetidinones have been shown to possess a wide variety
of pharmacological activities,4 for example, ezetimibe is used
clinically due to its cholesterol absorption inhibitor property.5 In
addition, 2-azetidinones are used as intermediates in the synthesis
of many classes of compounds6 and in the semi-synthesis of taxol
O
O
S
O
O
+
OAc
Me2S-O-C-Me
Me
Me
Me
O
Me
1
Scheme 1.
molecules.12 2-Azetidinones can also be synthesized by the one-
pot reaction of in situ activated carboxylic acids and imines.13
Low yields, harsh conditions, and chromatographic separations
are the disadvantages of some of these activated acids.
Dimethyl sulfoxide (DMSO) can be activated by acetic anhy-
dride and the resulting species 1 (Scheme 1) has been used for
the synthesis of nitriles from aldoximes14 and the oxidation of
alcohols.15
On this basis and following interest in the use of acid activators
for the synthesis of 2-azetidinones, herein a mild and efficient
alternative procedure for the conversion of imines and carboxylic
acids into the corresponding 2-azetidinones is reported.
derivatives.7
Many different methods have been developed for the formation
of the 2-azetidinone ring.8 Despite Staudinger reporting the
reaction between ketenes and imines in 1907,9 undoubtedly this
reaction is the most widely used route, which can be used for
the synthesis of several types of 2-azetidinones.10
At first, the reaction of imine 2a and phenoxyacetic acid in
DMSO in the presence of triethylamine at room temperature was
examined, but no reaction was observed after 13 h. When acetic
anhydride was added to this mixture at room temperature, TLC
monitoring showed that a reaction took place to give 2-azetidinone
4a (Table 1, entry 2) after purification by column chromatography.
Reaction in dichloromethane as the solvent at room temperature in
the absence of DMSO (entry 3) gave no reaction. These initial
Ketenes are typically generated by the reaction of acyl halides
with tertiary amines,11 but the preparation, isolation, and handling
of acid chlorides are difficult and they are unstable. Activation of
carboxylic acids for the formation of amide or ester bonds is a
key step in the synthesis of
a large number of bioorganic
⇑
Tel.: +98 761 766 0063; fax: +98 761 667 0714.
E-mail addresses: mzarei@hormozgan.ac.ir, maaroof1357@yahoo.com
http://dx.doi.org/10.1016/j.tetlet.2014.07.089
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zarei, M. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.07.089

2
M. Zarei / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
Next, the ability of DMSO and Ac2O to activate various acetic
acid derivatives was investigated for the synthesis of a range of
2-azetidinones (Scheme 2, Table 2).
Optimization of the reaction conditions for the synthesis of 2-azetidinone 4a
PhO
C6H4-4-OMe
Et3N
PhOCH2CO2H
+
4-MeO-C6H4-N=CH-C6H4-4-OMe
As can be seen from Table 2, this method was applied for the
conversion of a range of carboxylic acids and imines into the
corresponding 2-azetidinones in good to excellent yields.16
2-Azetidinones 4j–l which contain aliphatic substituents can also
be synthesized by this method. The lower stability of alkyl-substi-
tuted imines compared to aryl-substituted imines led to lower
yields of 2-azetidinones 4k–l. In particular, 2-azetidinone 4l was
obtained in a poor yield because of the lower stability of the imine
derived from an aliphatic amine and an aldehyde. Heteroaromatic-
substituted 2-azetidinone 4m was also prepared in good yield
using activated DMSO. Activated DMSO was successfully employed
for the synthesis of C-3 spiro-2-azetidinones 4n–p by the cycload-
dition reaction of xanthene-9-carboxylic acid with Schiff bases in
the presence of activated DMSO.
N
O
C6H4-4-OMe
2a
3a
4a
Entry
Reagent (mmol)
Solvent
Temp
Yield (%)
1
2
3
4
5
6
7
8
9
—
DMSO
DMSO
CH2Cl2
CH2Cl2
CH3CN
THF
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
rt
rt
rt
rt
rt
—
43
—
Ac2O (1.0)
Ac2O (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.3)
1 (1.5)
1 (2.0)
1 (1.5)
61
29
37
45
83
91
89
85
rt
rt
10
11
0 °C
2-Azetidinones 4a–p were purified by crystallization from EtOAc
after simple aqueous work-up. This reaction is very simple and clean
because the by-products of the reaction are highly water soluble and
can be easily removed by aqueous work-up. The structures of
b-lactams 4a–p were confirmed from spectroscopic data and ele-
mental analyses. The cis/trans stereochemistry was assigned by the
comparison of the H-3 and H-4 coupling constants (J3,4 >4.0 Hz) for
the cis stereoisomer and (J3,4 6 3.0 Hz) for the trans stereoisomer.8e
This reaction is amenable for the gram scale synthesis. When
N-(4-methoxybenzylidene)-4-methoxyaniline (3.0 g, 12.4 mmol)
was treated with phenoxyacetic acid (2.8 g, 18.6 mmol), DMSO
(1.3 mL, 18.6 mmol), Et3N (8.6 mL, 62.0 mmol), and acetic anhydride
(1.8 mL, 18.6 mmol) 2-azetidinone 4a was obtained in 89% yield
(4.1 g).
The synthesis of 2-azetidinone 4a was also performed in the
presence of other acid activators for comparison (Table 3). It is
noteworthy that 2-azetidinone 4a was obtained in high yield when
activated DMSO or the Mukaiyama reagent was used as the acid
activator at room temperature. The cost of the Mukaiyama reagent
and its by-product are disadvantages of this reagent.
R2
R3
O
1, Et3N
CH2Cl2, rt
R3CH2COOH
R1N=CHR2
+
N
R1
2
3
4a-p
Scheme 2.
results show that DMSO and acetic anhydride together activate the
carboxylic acid. Treatment of imine 2a, phenoxyacetic acid, and
triethylamine in the presence of Ac2O and DMSO at room temper-
ature in dry dichloromethane afforded the corresponding 2-azetid-
inone in 61% yield. Hence, different conditions were examined in
order to find the optimum parameters and the results are summa-
rized in Table 1.
The best result was obtained using DMSO and Ac2O (1.5 mmol)
in CH2Cl2 at room temperature in the presence of Et3N (91% yield,
entry 9).
Table 2
Synthesis of 2-azetidinones 4a–p using activated DMSO
Entry
R1
R2
R3
cis/trans
Product
Isolated yield (%)
mp (°C) (Lit.)
1
2
3
4
4-MeOC6H4
4-MeOC6H4
4-MeONaphth-1-yl
4-MeONaphth-1-yl
4-MeOC6H4
4-ClC6H4
4-MeOC6H4
4-ClC6H4
PhO
PhO
PhO
PhO
cis
cis
cis
cis
4a
4b
4c
4d
91
93
91
89
176–178 (177–178)13j
180–182 (181–183)13d
169–171
161–163
S
5
4-MeOC6H4
PhO
cis
4e
86
159–161
N
6
7
8
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
PhthN
PhthN
PhthN
trans
trans
trans
4f
4g
4h
88
84
85
196-198
4-MeOC6H4
4-MeONaphth-1-yl
225-227 (228-230)13m
180-182
S
9
4-MeOC6H4
PhthN
trans
4i
83
168-170
N
C6H5
Me
Me
4-MeOC6H4
10
11
12
13
4-NO2C6H4
4-NO2C6H4
C6H5CH2
2-Furyl
MeO
PhO
MeO
PhO
cis
cis
cis
cis
4j
4k
4l
89
78
65
87
122–124 (124–126)17c
93-95 (91–93)17c
colorless oil
4m
151-153 (154-155)13o
OMe
O
14
—
4n
86
162-164 (161–163)13d
N
O
OMe
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M. Zarei / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 2 (continued)
Entry
R1
R2
R3
cis/trans
Product
Isolated yield (%)
mp (°C) (Lit.)
Cl
O
15
—
4o
82
157-159
N
O
OMe
Cl
O
16
—
4p
81
155-157
N
S
O
N
Table 3
References and notes
Comparison of acid activators for the synthesis of 2-azetidinone 4a
1. Li, W.; Liu, C.; Zhang, H.; Ye, K.; Zhang, G.; Zhang, W.; Duan, Z.; You, S.; Lei, A.
Angew. Chem., Int. Ed. 2014, 53, 2443–2446.
2. Wang, F.-D.; Lin, M.-L.; Lee, W.-S.; Liu, C.-Y. Int. J. Antimicrob. Agents 2004, 23,
590–595.
3. Marumo, K.; Tekeda, A.; Nakamura, Y.; Nakaya, K. J. Antimicrob. Chemother.
1999, 43, 187–193.
4. (a) Arya, N.; Jagdale, A. Y.; Patil, T. A.; Yeramwar, S. S.; Holikatti, S. S.; Dwivedi,
J.; Shishoo, C. J.; Jain, K. S. Eur. J. Med. Chem. 2014, 74, 619–656; (b) Mehta, P. D.;
Sengar, N. P. S.; Pathak, A. K. Eur. J. Med. Chem. 2010, 45, 5541–5560; (c)
Veinberg, G.; Vorona, M.; Shestakova, I.; Kanepe, I.; Lukevics, E. Curr. Med.
Chem. 2003, 10, 1741–1757.
Entry
Acid activator
Temp
Yield (%)
1
2
3
4
5
6
DMSO/Ac2O
POCl3
Me2S/Br2
Cyanuric chloride
Cyanuric chloride
Mukaiyama reagent
rt
rt
rt
rt
0 °C
rt
91
62
67
44
71
83
5. Xu, X.; Fu, R.; Chen, J.; Chen, S.; Bai, S. Bioorg. Med. Chem. Lett. 2007, 17, 101–
104.
Activated DMSO 1 can activate carboxylic acids to give an
activated ester and then generate a ketene in situ in the presence
of Et3N. Finally, the ketene reacts with an imine to produce the
b-lactam, according to the reported mechanism for the Staudinger
synthesis.17 Many different experimental factors, such as reaction
temperature, solvent, electronic effects, and the steric hindrance
of the ketene and imine substituents may affect the stereochemis-
try of b-lactams produced via the Staudinger synthesis.
Phthalimidoketene has more steric hindrance than phenoxy- and
methoxyketene, and gave rise to 3-phthalimido-2-azetidinones
4f–i as trans isomers.
6. For a review, see: (a) Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev. 2007,
107, 4437–4492; (b) Alcaide, B.; Almendros, P. Curr. Med. Chem. 2004, 11, 1921–
1949; (c) Deshmukh, A. R. A. S.; Bhawal, B. M.; Krishnaswamy, D.; Govande, V.
V.; Shinkre, B. A.; Jayanthi, A. Curr. Med. Chem. 2004, 11, 1889–1920; (d) Ojima,
I.; Delaloge, F. Chem. Soc. Rev. 1997, 26, 377–386; (e) Palomo, C.; Aizpurua, J. M.;
Ganboa, I.; Oiarbide, M. Synlett 2001, 1813–1826; (f) Palomo, C.; Oiarbide, M. In
Topics in Heterocyclic Chemistry; Banik, B. K., Ed.; Springer: Berlin, 2010; Vol. 22,
pp 211–259; (g) Alcaide, B.; Almendros, P. Chem. Rec. 2011, 11, 311–330.
7. (a) Hodge, M.; Chen, O.-H.; Bane, S.; Sharma, S.; Loew, M.; Banerjee, A.; Alcaraz,
A. A.; Snyder, J. P.; Kingston, D. G. I. Bioorg. Med. Chem. Lett. 2009, 19, 2884–
2887; (b) Suffness, M. Taxol Science and Applications; CRC Press: Boca Raton
Florida, USA, 1995.
8. For a review, see: (a) Alcaide, B.; Almendros, P. Prog. Heterocycl. Chem. 2011, 22,
85–107; see also: (b) Aranda, M. T.; Perez-Faginas, P.; Gonzalez-Muniz, R. Curr.
Org. Synth. 2009, 6, 325–341; (c) Fu, N.; Tidwell, T. T. Tetrahedron 2008, 64,
10465–10496; (d) Vankoten, D.; Van der Steen, F. H. Tetrahedron 1991, 47,
7503–7524; (e) Georg, G. I. The Organic Chemistry of b-Lactams; Verlag Chemie:
New York, 1993; (f) Xu, J. Tetrahedron 2012, 68, 10696–10747; (g) Kamath, A.;
Ojima, I. Tetrahedron 2012, 68, 10640–10664.
O
+
C
SMe2
R3H2C
O
activated ester
9. Staudinger, H. Liebigs Ann. Chem. 1907, 356, 51–123.
In conclusion, a practical and efficient one-step synthesis of
2-azetidinones has been developed. The one-pot reaction of imines
and substituted acetic acid with dimethyl sulfoxide and acetic
anhydride [activated DMSO (1)] in the presence of triethylamine
afforded 2-azetidinones in high yields. DMSO and Ac2O are inex-
pensive and this reagent system is useful for both large and small
scale reactions. This method is very convenient and the water-
soluble by-products are removed by simple aqueous work-up.
10. (a) Fodor, L.; Csomos, P.; Holczbauer, T.; Kalman, A.; Csampai, A.; Sohar, P.
Tetrahedron Lett. 2011, 52, 224–227; (b) Zarei, M.; Karimi-Jaberi, Z.; Movahedi,
A. Synth. Commun. 2013, 43, 728–734; (c) Keri, R. S.; Hosamani, K. M.;
Shingalapur, R. V.; Reddy, H. R. S. Eur. J. Med. Chem. 2009, 44, 5123–5130; (d)
Zarei, M.; Jarrahpour, A. Synlett 2011, 2572–2576; (e) Zarei, M.;
Mohamadzadeh, M. Tetrahedron 2011, 67, 5832–5840.
11. (a) Qi, H.; Yang, Z.; Xu, J. Synthesis 2011, 723–730; (b) Tidwell, T. T. Ketenes II;
John Wiley & Sons: New Jersey, 2006. pp 55–192.
12. (a) Kaminski, Z. J.; Kolesinska, B.; Kolesinska, J.; Sabatino, G.; Chelli, M.; Rovero,
P.; Błaszczyk, M.; Głowka, M. L.; Papini, A. M. J. Am. Chem. Soc. 2005, 127,
16912–16920; (b) Unsworth, W. P.; Kitsiou, C.; Taylor, R. J. K. Org. Lett. 2013,
15, 258–261; (c) Unsworth, W. P.; Gallagher, K. A.; Jean, M.; Schmidt, J. P.;
Diorazio, L. J.; Taylor, R. J. K. Org. Lett. 2013, 15, 262–265.
Acknowledgments
13. (a) Smith, S. R.; Douglas, J.; Prevet, H.; Shapland, P.; Slawin, A. M. Z.; Smith, A. D.
J. Org. Chem. 2014, 79, 1626–1639; (b) Darvishi, A.; Zarei, M.; Akhgar, M. R. Lett.
Org. Chem. 2013, 10, 645–650; (c) Jarrahpour, A.; Zarei, M. Tetrahedron Lett.
2009, 50, 1568–1570; (d) Jarrahpour, A.; Zarei, M. Tetrahedron 2009, 65, 2927–
2934; (e) Nahmany, M.; Melman, A. J. Org. Chem. 2006, 71, 5804–5806; (f)
Jarrahpour, A.; Zarei, M. Molecules 2007, 12, 2364–2379; (g) Bose, A. K.; Kapur,
J. C.; Sharma, S. D.; Manhas, M. S. Tetrahedron Lett. 1973, 2319–2320; (h)
Jarrahpour, A.; Zarei, M. Tetrahedron Lett. 2007, 48, 8712–8714; (i) Zarei, M. J.
Chem. Res. 2013, 37, 25–27; (j) Matsui, S.; Hashimoto, Y.; Saigo, K. Synthesis
1998, 1161–1166; (k) Palomo, C.; Aizpurua, J. M.; Urchegui, R.; Iturburu, M.; de
Retana, A. O.; Cuevas, C. J. Org. Chem. 1991, 56, 2244–2247; (l) Zarei, M.
Thanks are due to the Iran National Science Foundation
(INSF-91059658) and Hormozgan University Research Council for
the financial support to this study.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.07.089.
Please cite this article in press as: Zarei, M. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.07.089

4
M. Zarei / Tetrahedron Letters xxx (2014) xxx–xxx
Monatsh. Chem. 2013, 144, 1021–1025; (m) Zarei, M. Tetrahedron 2013, 69,
residue was purified by crystallization from EtOAc. 2-Azetidinone 4l was
purified by short column chromatography (hexane/EtOAc 8:2). 1-
6620–6626; (n) Zigheimat, F.; Islami, M. R.; Nourmohammadian, F. Synlett
2014, 229–232; (o) Arrieta, A.; Lecea, B.; Palomo, C. J. Chem. Soc., Perkin Trans. 1
1987, 845–850.
(Benzo[d]thiazol-2-yl)-4-(4-methoxyphenyl)-3-phenoxy-azetidin-2-one
(4e):
Light-yellow solid. mp 159–161 °C IR (KBr) cmÀ1: 1636 (C@N), 1751 (CO, b-
lactam); 1H NMR (250 MHz, CDCl3) d 3.68 (OMe, s, 3H), 4.59 (H-4, d, 1H,
J = 4.8), 5.45 (H-3, d, 1H, J = 4.8), 6.88-7.97 (ArH, m, 13H); 13C NMR (62.9 MHz,
CDCl3) d 55.5 (OMe), 62.0 (C-3), 81.6 (C-4), 111.9, 121.7, 123.5, 123.9, 124.3,
126.8, 127.5, 129.0, 129.4, 129.6, 132.7, 141.4, 149.1, 152.4 (aromatic carbons),
161.7 (C@N), 163.3 (CO, b-lactam); Anal. Calcd for C23H18N2O3S: C, 68.64; H,
4.51; N, 6.96. Found: C, 68.71; H, 4.64; N, 7.02.
14. Song, Y.; Shen, D.; Zhang, Q.; Chen, B.; Xu, G. Tetrahedron Lett. 2014, 55, 639–
641.
15. (a) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2416–2423; (b)
Katagiri, N.; Akatsuka, H.; Haneda, T.; Kaneko, C.; Sera, A. J. Org. Chem. 1988, 53,
5464–5470.
16. General procedure: Ac2O (1.5 mmol) was added to a solution of substituted
acetic acid (1.5 mmol), Schiff base (1.0 mmol), DMSO (1.5 mmol), and Et3N
(5.0 mmol) in dry CH2Cl2 (10 mL) at room temperature, and the mixture was
stirred overnight. The mixture was washed successively with saturated
NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4),
filtered and the solvent was removed under reduced pressure. The crude
17. (a) Wang, Y.; Liang, Y.; Jiao, L.; Du, D.-M.; Xu, J. J. Org. Chem. 2006, 71, 6983–
6990; (b) Jarrahpour, A.; Zarei, M. Tetrahedron 2010, 66, 5017–5023; (c) Zarei,
M. Bull. Chem. Soc. Jpn. 2012, 85, 360–368; (d) Manhas, M. S.; Amin, S. G.;
Glazer, R. D. Synthesis 1979, 210–213.
Please cite this article in press as: Zarei, M. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.07.089