One-step synthesis of β-lactams using cyanuric fluoride

Article abstract of DOI:10.3184/174751912X13545429290478

Cyanuric fluoride works as an efficient acid activator reagent for the direct [2+2] ketene-imine cycloaddition of substituted acetic acids and imines in a one-pot synthesis under mild conditions. The yields are good to excellent and the reaction condition

Full text of DOI:10.3184/174751912X13545429290478

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 25
JANUARY, 25–27
One-step synthesis of β-lactams using cyanuric fluoride
Maaroof Zarei*
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
Cyanuric fluoride works as an efficient acid activator reagent for the direct [2+2] ketene–imine cycloaddition of sub-
stituted acetic acids and imines in a one-pot synthesis under mild conditions. The yields are good to excellent and
the reaction conditions are mild, simple and efficient.
Keywords: β-lactam, 2-azetidinone, Staudinger reaction, cyanuric fluoride, ketene, imine
Table 1 Optimisation of reaction condition in the synthesis of
2,4,6-Trifluoro-1,3,5-triazine 1 with the common name
cyanuric fluoride, was prepared from cyanuric chloride and a
fluorinating agent.1 It is also commercially available. Cyanuric
fluoride is used for the mild and direct conversion of carbox-
ylic acids to acyl fluorides.1
4a
Entry
Solvent
Temp/°C Cyanuric fluoride Yield/%
/mmol
1
2
3
4
5
6
7
CH2Cl2
Dioxane
DMF
rt
rt
rt
rt
0
rt
rt
1.0
1.0
1.0
1.0
1.0
1.5
2.0
72
44
52
47
69
89
86
THF
CH2Cl2
CH2Cl2
CH2Cl2
β-Lactam antibiotics remain the main drugs to treat infections
caused by bacteria. These molecules disturb the final step of
bacterial cell wall biosynthesis by inhibiting penicillin binding
proteins (PBPs) involved in the cross linking of peptidoglycan
strands.2 Ezetimibe is a new drug, which has the 2-azetidinone
skeleton and selectively inhibits the absorption of cholesterol.3
Besides the antibacterial and cholesterol absorption inhibitory
activities, β-lactams show various other biological activities.4
They are also used as intermediates and synthons in the
synthesis of several organic compounds.5
Many synthetic methods have been developed for the prepa-
ration of the β-lactam ring.6 The Staudinger reaction ([2+2]
ketene–imine cycloaddition reaction)7 is regarded as one of the
most fundamental and versatile methods for the synthesis of
structurally diverse 2-azetidinone derivatives.8–12
Scheme 1 Synthesis of 2-azetidinones 4a–m.
the presence of Et3N at room temperature. After 18 hours, 2-
azetidinone 4a was obtained in 72% yield as a white solid after
crystallisation from EtOAc. Spectral data confirmed the struc-
ture of 4a. The reaction was easy, clean and simple aqueous
workup removed the byproduct salts.
Commonly, ketenes are prepared in situ by reaction of acyl
halides with tertiary amines.13–15 However, the application of
acyl halides for the preparation of ketenes has some disadvan-
tages such as low availability, instability and difficulty of prep-
aration. To solve these problems, acid activators have been
used for the one-pot synthesis of 2-azetidinones from imines
and carboxylic acids.16–22
In the present work, cyanuric fluoride is investigated as an
acid activator in the synthesis of 2-the azetidinone ring by the
ketene–imine cycloaddition.
Schiff bases were synthesised by reaction of the correspond-
ing amines and aldehydes in refluxing ethanol or by stirring
overnight in the presence of anhydrous Na2SO4 in dry CH2Cl2.
In a model study, the solution of 4-methoxy-N-(4-methylbenz
ylidene)aniline 2a (1.0 mmol) and 4-methoxyacetic acid 3a
(1.0 mmol) in dry CH2Cl2 was treated with cyanuric fluoride in
Previously cyanuric chloride has been used for activation of
acids in the synthesis of 2-azetidinones, although generally
this method requires the cooling of the mixture below 0 °C23,24
and the yields using cyanuric chloride above 0 °C are low.25
However, synthesis of 2-azetidinones using cyanuric fluoride,
unlike cyanuric chloride and some other acid activators, was
performed at room temperature with high yield of products
under simple and mild conditions.
After this successful result, the effects of solvents, tempera-
ture of reaction and quantity of reagent in the synthesis of 4a
were investigated. According to Table 1, among the dry
solvents examined, CH2Cl2 showed the best results. It was also
found that the yields were almost identical at 0 °C and room
temperature. The amounts of methoxyacetic acid and the
reagent were used for optimisation of the quantity of reagent.
* Correspondent. E-mail: maaroof1357@yahoo.com;
mzarei@hormozgan.ac.ir

26 JOURNAL OF CHEMICAL RESEARCH 2013
As shown in Table 1, 1.5 mmol of cyanuric fluoride was needed
to complete the reaction (TLC monitoring of disappearance
of the imine) in CH2Cl2 at room temperature. The yield of
2-azetidinone 4a did not increase when 2.0 mmol of cyanuric
fluoride and methoxyacetic acid were used
Based on the above results, 2-azetidinones 4a–m were syn-
thesised by treatment of 1.0 mmol of the corresponding Schiff
bases 2, 1.5 mmol of acetic acid derivatives 3 and 1.5 mmol
cyanuric fluoride in the presence of triethylamine in dry CH2Cl2
(Scheme 1, Table 2). Purification of β-lactams 4a–m was
performed by crystallisation from EtOAc. All products were
characterised by spectroscopic data and elemental analyses.
The indicated cis and trans stereochemistry of the products
was judged from the coupling constants of H-3 and H-4 of
β-lactam ring in 1H NMR (J ≥ 4.0 for the cis and J ≤ 3.0 for the
trans stereoisomer).
acid.20 It is suggested that the reaction is performed by in situ
generation of a ketene from the activated ester (Scheme 2),
then nucleophile attack of the imine followed by ring closure
of the zwitterionic intermediate to the β-lactam. The relative
(cis/trans) stereoselectivity is generated as a result of the com-
petition between the direct ring closure and the isomerisation
of the imine moiety in the zwitterionic intermediate.16,20
This paper describes the use of cyanuric fluoride to activate
the substituted acetic acids in the synthesis of 2-azetidinones
via a ketene–imine cycloaddition reaction. The remarkable
versatility of this method is the mild condition reactions, avail-
ability of the reagents, easy purification and high yield of the
products.
Experimental
The stereochemistry is mainly dominated by the electronic
effect and the steric hindrance of the ketene and imine substi-
tutents.26 The mechanism is similar to our previously reported
mechanism for the Staudinger reaction from acetic acid deriva-
tives and imines using methoxymethylene-N,N-dimethylimin-
ium salt via formation of an activated form of a carboxylic
All required chemicals were purchased from Merck, Fluka, andAcros.
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 spectrometer
(1H NMR 300 MHz, 13C NMR 75 MHz) using tetramethylsilane as an
internal standard and coupling constants are given in cycles per second
Table 2 Synthesis of 2-azetidinones 4a–m with cyanuric fluoride
Entry
R1
R2
R3
Stereochemistry
Product
Yield/%
1
2
4-MeOC6H4
4-MeONaphthyl
C6H5CH2
4-EtOC6H4
C6H5
4-MeOC6H4
C6H5
4-MeC6H4
4-MeC6H4
4-NO2C6H4
4-MeOC6H4
4-NO2C6H4
4-NO2C6H4
4-ClC6H4
MeO
PhO
cis
cis
4a
4b
4c
4d
4e
4f
89
92
84
90
93
94
91
85
82
87
85
93
90
3
PhO
cis
4
2-naphthO
2-naphthO
2,4-Cl2C6H3O
2,4-Cl2C6H3O
PhthN
cis
5
cis
6
cis
7
cis
4g
4h
4i
8
4-EtOC6H4
4-EtOC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
trans
trans
cis
9
PhthN
10
11
12
13
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
MeS
4j
4-EtOC6H4
4-MeONaphthyl
4-MeOC6H4CH2
MeS
cis
4k
4l
MeO
cis
4-NO2C6H4
2,4-Cl2C6H3O
cis
4m
Scheme 2

JOURNAL OF CHEMICAL RESEARCH 2013 27
(Hz). Elemental analyses were run on a Vario EL III elemental ana-
lyser. TLC was carried out on silica gel 254 analytical sheets obtained
from Fluka. Spectral data for 4a–f and 4h–j have been previously
reported.14,16,20,27,28
(OMe), 62.3 (C-4), 83.4 (C-3), 110.2, 110.9, 111.8, 112.4, 116.5,
120.2, 122.6, 128.2, 131.3, 132.7, 134.9, 144.0, 150.1, 155.3 (aroma-
tic carbons), 163.7 (CO, β-lactam); Anal. Calcd for C21H18ClNO3: C,
68.57; H, 4.93; N, 3.81. Found: C, 68.64; H, 5.06; N, 3.88%.
3-(2,4-Dichlorophenoxy)-1-(4-methoxybenzyl)-4-(4-nitrophenyl)-
Synthesis of 2-azetidinones (4a–m); general procedure
Cyanuric fluoride (1.5 mmol) was added to a solution of substituted
acetic acids (1.5 mmol), imines (1.0 mmol) and triethylamine
(5.0 mmol) in dry CH2Cl2 (20 mL) at room temperature and the mix-
ture was stirred overnight. The reaction mixture was washed succes-
sively with saturated NaHCO3 (20 mL) and brine (10 mL). The organic
layer was dried (Na2SO4), filtered and the solvent was removed to give
the crude product, which was purified by crystallisation from EtOAc
to give pure β-lactams 4a–m.
azetidin-2-one (4m): Light-yellow solid; m.p. 84–86 °C. IR (KBr)
1
cm−1: 1344, 1557 (NO2), 1751 (CO, β-lactam); H NMR (300 MHz,
CDCl3) δ 3.60 (OMe, s, 3H), 3.81, 4.75 (CH2-benzyl, 2d, 2H,
J = 14.7), 4.93 (H-4, d, 1H, J = 5.0), 5.45 (H-3, d, 1H, J = 5.0), 6.77–
8.08 (ArH, m, 11H); 13C NMR (75 MHz, CDCl3) δ 45.9 (CH2), 55.6
(OMe), 63.1 (C-3), 82.7 (C-4), 113.5, 114.6, 116.0, 117.2, 119.5,
120.3, 125.8, 126.2, 128.0, 128.9, 133.6, 147.5, 152.1, 155.8 (aroma-
tic carbons), 163.6 (CO, β-lactam); Anal. Calcd for C23H18Cl2N2O5: C,
58.37; H, 3.83; N, 5.92. Found: C, 58.49; H, 3.97; N, 5.98%.
1-(4-Methoxyphenyl)-3-methoxy-4-p-tolylazetidin-2-one (4a): White
solid; m.p. 152–154 °C (lit.20 151–153 °C).
Financial support from Hormozgan University Research
Centre is gratefully acknowledged.
1-(4-Methoxynaphthalen-1-yl)-3-phenoxy-4-p-tolyl-azetidin-2-one
(4b): White crystalline solid; m.p. 180–182 °C (lit.27 182–184 °C).
1-Benzyl-4-(4-nitrophenyl)-3-phenoxyazetidin-2-one (4c): White
solid; m.p. 127–129 °C (lit.20 130–32 °C).
1-(4-Ethoxyphenyl)-4-(4-methoxyphenyl)-3-(naphthalen-2-yloxy)-
azetidin-2-one (4d): White solid; m.p. 163–165 °C (lit.20 162–164 °C).
3-(Naphthalen-2-yloxy)-4-(4-nitrophenyl)-1-phenyl-azetidin-2-one
(4e): Light-yellow solid; m.p. 188–190 °C (lit.16 189–191 °C).
3-(2,4-Dichlorophenoxy)-1-(4-methoxyphenyl)-4-(4-nitro-phenyl)-
azetidin-2-one (4f): White crystalline solid; m.p. 188–190 °C (lit.20
187–189 °C).
Received 30 September 2012; accepted 1 November 2012
Paper 1201547 doi: 10.3184/174751912X13545429290478
Published online: 15 January 2013
References
1
2
G.A. Olah, M. Nojima and I. Kerekes, Synthesis, 1973, 487.
H. Ceric, M. Sindler-Kulyk, M. Kovacevic, M. Peric and A. Zivkovic,
Bioorg. Med. Chem., 2010, 18, 3053.
4-(4-Chlorophenyl)-3-(2,4-dichlorophenoxy)-1-phenylazetidin-2-
one (4g). White solid; m.p. 195–197 °C. IR (KBr) cm−1: 1750 (CO,
β-lactam); 1H NMR (300 MHz, CDCl3) δ 5.21 (H-4, d, 1H, J = 4.8),
5.53 (H-3, d, 1H, J = 4.8), 6.86–7.52 (ArH, m, 12H); 13C NMR
(75 MHz, CDCl3) δ 64.5 (C-4), 82.9 (C-3), 113.7, 115.0, 118.3,
122.9, 126.6, 127.1, 127.9, 130.3, 130.7, 131.4, 131.7, 136.4, 150.8,
155.8 (aromatic carbons), 162.7 (CO, β-lactam); Anal. Calcd for
C21H14Cl3NO2: C, 60.24; H, 3.37; N, 3.35. Found: C, 60.37; H, 3.52;
N, 3.28%.
3
4
D.A. Burnett, Curr. Med. Chem., 2004, 11, 1873.
P.D. Mehta, N.P.S. Sengar and A.K. Pathak, Eur. J. Med. Chem., 2010, 45,
5541.
B. Alcaide, P. Almendros and C. Aragoncillo, Chem. Rev., 2007, 107,
4437.
N. Fu and T.T. Tidwell, Tetrahedron, 2008, 64, 10465.
H. Staudinger, Liebigs Ann. Chem., 1907, 356, 51.
A. Jarrahpour, M. Motamedifar, M. Zarei and M. Mimouni, Phosphorus
Sulfur Silicon, 2010, 185, 287.
5
6
7
8
9
A. Jarrahpour and M. Zarei, Tetrahedron Lett., 2009, 50, 1568.
2-(1-(4-Ethoxyphenyl)-2-oxo-4-p-tolylazetidin-3-yl)isoindoline-
1,3-dione (4h): Light-yellow solid; m.p. 205–207 °C (lit.14 202–
204 °C).
2-(2-(4-Chlorophenyl)-1-(4-ethoxyphenyl)-4-oxoazetidin-3-
yl)isoindoline-1,3-dione (4i): Light-yellow solid; m.p. 211–213 °C
(lit.14 211–213 °C).
10 A. Jarrahpour and M. Zarei, Tetrahedron Lett., 2007, 48, 8712.
11 A. Jarrahpour, M.M. Doroodmand and E. Ebrahimi, Tetrahedron Lett.,
2012, 53, 2797.
12 R.S. Keri and K.M. Hosamani, Monatsh. Chem., 2010, 141, 883.
13 R.S. Keri, K.M. Hosamani, R.V. Shingalapur and H.R.S. Reddy, Eur. J.
Med. Chem., 2009, 44, 5123.
14 A. Jarrahpour and M. Zarei, Molecules, 2007, 12, 2364.
15 A. Jarrahpour and M. Zarei, Molecules, 2006, 11, 49.
16 M. Zarei, Bull. Chem. Soc. Jpn, 2012, 85, 360.
17 M. Zarei, J.Chem. Res., 2012, 36, 118.
18 A. Jarrahpour and M. Zarei, Synlett, 2011, 2572.
19 A. Jarrahpour, A. Fadavi and M. Zarei, Bull. Chem. Soc. Jpn., 2011, 84,
320.
20 A. Jarrahpour and M. Zarei, Tetrahedron, 2010, 66, 5017.
21 A. Jarrahpour and M. Zarei, Tetrahedron, 2009, 65, 2927.
22 B.K. Banik, I. Banik and F.F. Becker, Eur. J. Med. Chem., 2010, 45, 846.
23 M.S. Manhas, A.K. Bose and M.S. Khajavi, Synthesis, 1981, 209.
24 W. Hinz and G. Just, Can. J. Chem., 1987, 65, 1503.
25 J.M. Van der Veen, S.S. Bari, L. Krishnan, M.S. Manhas and A.K. Bose,
J. Org. Chem., 1989, 54, 5758.
26 Y. Wang, Y. Liang, L. Jiao, D.-M. Du and J. Xu, J. Org. Chem., 2006, 71,
6983.
27 M. Zarei, A. Jarrahpour, E. Ebrahimi, M. Aye and S.A. Torabi Badrabady,
Tetrahedron, 2012, 68, 5505.
1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-3-(methylthio)azetidin-
2-one (4j): White solid; m.p. 64–66 °C (lit.28 64–66 °C).
1-(4-Ethoxyphenyl)-4-(4-methoxyphenyl)-3-(methylthio)azetidin-
2-one (4k): White solid; m.p. 63–65 °C. IR (KBr) cm−1: 1743 (CO,
1
β-lactam); H NMR (300 MHz, CDCl3) δ 1.27 (Me, t, 3H, J = 7.0),
2.23 (S-Me, s, 3H), 3.55 (OMe, s, 3H), 4.05 (OCH2, q, 2H, J = 7.0),
4.67 (H-4, d, 1H, J = 4.5), 5.17 (H-3, d, 1H, J = 4.5), 6.64–8.01 (ArH,
m, 8H); 13C NMR (75 MHz, CDCl3) δ 15.0 (Me), 15.9 (S-Me), 56.4
(OMe), 61.3 (OCH2), 62.9 (C-3), 63.7 (C-4), 110.1, 116.9, 122.0,
122.6, 133.9, 142.4, 149.7, 155.9 (aromatic carbons), 161.3 (CO, β-
lactam). Anal. Calcd for C19H21NO3S: 66.45; H, 6.16; N, 4.08; S, 9.34.
Found: C, C, 66.38; H, 6.29; N, 4.14; S, 9.27%.
4-(4-Chlorophenyl)-3-methoxy-1-(4-methoxynaphthalen-1-
yl)azetidin-2-one (4l): White solid; m.p. 148–150 °C. IR (KBr) cm−1:
1746 (CO, β-lactam); 1H NMR (300 MHz, CDCl3) δ 3.37, 3.60
(2OMe, s, 6H), 4.71 (H-4, d, 1H, J = 4.9), 5.33 (H-3, d, 1H, J = 4.9),
6.80–7.94 (ArH, m, 10H); 13C NMR (75 MHz, CDCl3) δ 55.8, 57.6
28 M. Zarei and M. Mohamadzadeh, Tetrahedron, 2011, 67, 5832.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.