A mild and efficient route to 2-azetidinones using the cyanuric chloride-DMF complex

Article abstract of DOI:10.1055/s-0030-1289517

Efficient conversion of Schiff bases and carboxylic acids to -lactams can be carried out at room temperature in CH₂Cl₂, using a cyanuric chloride-N,N-dimethyl formamide complex. The complex is easily prepared by reaction of cyanuric

Full text of DOI:10.1055/s-0030-1289517

2572
LETTER
A Mild and Efficient Route to 2-Azetidinones Using the Cyanuric Chloride–
DMF Complex
A
Mild
and Efficient
R
a
oute to 2-A
a
zetidinone
r
s
oof Zarei,a Aliasghar Jarrahpour*b
a
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
Fax +98(711)228 0926; E-mail: jarrah@susc.ac.ir; E-mail: aliasghar6683@yahoo.com
b
Received 10 June 2011
Given the importance of b-lactams in heterocyclic and
medicinal chemistry, many different methods for the syn-
thesis of these compounds have been reported.22 The for-
mation of the 2-azetidinone ring via [2+2] cycloaddition
Abstract: Efficient conversion of Schiff bases and carboxylic acids
to b-lactams can be carried out at room temperature in CH2Cl2, us-
ing a cyanuric chloride–N,N-dimethyl formamide complex. The
complex is easily prepared by reaction of cyanuric chloride and
DMF, an inexpensive reagent, at room temperature. Optimization of of an imine with a ketene is termed the Staudinger reac-
tion.23 This method is generally accepted as the most ver-
conditions and comparison of yield with cyanuric chloride were
performed.
satile and efficient route for the construction of the b-
lactam skeleton.24 Several methods have been reported for
Key words: 2-azetidinone, b-lactam, Staudinger reaction, cyanuric
chloride, Schiff base
preparation of ketenes, but reaction of acyl halides with
tertiary bases is commonly used for in situ generation of
ketenes.25 Difficulty of preparation and handling, low
b-Lactams (2-azetidinones) have a long and illustrious availability and instability of acyl halides are some draw-
history in the field of antibacterial chemistry and are still backs of the latter method. Consequently, acid activators
the main drugs to treat infections caused by bacteria.1 have been reported in the synthesis of 2-azetidinones from
Amoxicillin, for example, remains one of the most pre- Schiff bases and acetic acid derivatives.26
scribed antibiotics in the United States, with approximate-
Cyanuric chloride (2,4,6-trichloro-1,3,5-triazine, TCT) is
ly 49.5 million prescriptions filled in 2009.2 Ezetimibe is
a stable, nonvolatile, inexpensive, commercially avail-
an example of a 2-azetidinone-containing drug, commer-
able, and easy-to-handle reagent. Over the past few years,
cialized for cholesterol absorption control, owing to its
there has been considerable interest in using TCT or its
potency for inhibiting cholesterol acyl transferase and was
derivatives in organic synthesis.27 An empirical observa-
marketed as Zetia in 2002.3 A literature survey reveals
tion is that monosubstitution of chlorine occurs below or
that 2-azetidinone and its derivatives possess a broad
at 0 °C.27c A search of the literature revealed that the use
spectrum of biological activities4 which include human
of TCT as an acid activator in the synthesis of 2-azeti-
cytomegalovirus (HCMV) inhibition,5 human leukocyte
dinones via ketene–imine cycloaddition has been pub-
elastase (HLE) inhibition,6 thrombin inhibition,7 porcine
lished,26l,28 although the procedure implied cooling the
pancreatic elastase (PPE) inhibition,8 HIV-1 protease in-
mixture below 0 °C.
hibition,9 cysteine protease inhibition,10 and anticancer,11
TCT and DMF (TCT–DMF adduct)29 have been used for
the conversion of primary alcohols to the corresponding
formate esters,30 Beckmann rearrangement of oximes,31
conversion of alcohols to alkyl chlorides,32 and prepara-
tion of a-glycosyl chlorides.33
antifungal,12 potential antimalarial,13 anti-influenza vi-
rus,14 antihyperglycemic,15 central nervous system
(CNS),16 neurological17 and antiproliferative activities.18
Besides their biological activities, the importance of b-
lactams as synthetic intermediates has been widely recog-
nized in the preparation of various heterocyclic com-
pounds of biological significance,19 for example, in the
semisynthesis of Taxol and Taxotere.20
On this basis, and as part of an ongoing program directed
to the development of efficient reagents for the synthesis
of b-lactams under mild conditions, we report herein a
mild and efficient procedure for the synthesis of b-lactams
from imines and acetic acid derivatives in the presence of
TCT–DMF adduct.
Microorganisms have built up resistance against the most
traditional b-lactam antibiotics due to excess use of anti-
biotics.21 The need for new b-lactam antibiotics and other
applications of 2-azetidinones has motivated chemists and
scientists to design new synthetic methods for the prepa-
ration of b-lactams.
The TCT–DMF adduct was prepared by reaction of DMF
and TCT following a reported procedure (Scheme 1).30–32
In a model study, a solution of 4-ethoxy-N-(4-methylben-
zylidene)aniline (1a) and 4-chlorophenoxyacetic acid
(2a) in dry CH2Cl2 was treated with TCT–DMF adduct at
–15 °C. Then the mixture was stirred overnight at room
temperature to give 3-(4-chlorophenoxy)-1-(4-ethoxy-
phenyl)-4-p-tolylazetidin-2-one (3a) in high yield as a
SYNLETT 2011, No. 17, pp 2572–2576
x
x
.x
x
.2
0
1
1
Advanced online publication: 06.10.2011
DOI: 10.1055/s-0030-1289517; Art ID: D17811ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Mild and Efficient Route to 2-Azetidinones
2573
Me
R2
Me
+
N
Me
Cl–
R3
Me
+
N
Et3N
Cl
R3CH2COOH
R1N=CHR2
+
Me
Me
O–
N
N
Cl
H
CH2Cl2
O
O
R1
+
N
N
N
N
N
O
2
3a–k
1
N
N
Cl
N
Cl
Scheme 2
N
Scheme 1
dinones was also compared to the TCT method at –15 °C
and room temperature.
white solid after crystallization from EtOAc. The reaction
was very simple and clean, because the triazine byproduct
was removed by a simple aqueous workup. After this suc-
cess, we investigated the effect of solvent, temperature,
and quantity of reagent (based on mmol of TCT) in the
synthesis of 3a. In all reactions, triethylamine was used as
the base. According to Table 1, CH2Cl2 and DMF showed
the best results, but the workup from CH2Cl2 was much
easier than DMF. It was also found that the yields were al-
most identical at –15 °C, 0 °C, and room temperature;
whereas the yield decreased at –63 °C. The molar optimi-
zation of the reagent was also examined. As it is shown in
the Tables 1, 1.2 mmol of TCT–DMF was needed to com-
plete the reaction (TLC monitoring for disappearance of
the imine) in CH2Cl2 at room temperature.
The data in Table 2 confirm that the yields using TCT–
DMF adducts are higher than using TCT on its own, and
the yields are almost identical at –15 °C and at room tem-
perature using TCT–DMF. However, in the case of TCT,
the yields increased at lower temperature. In particular,
this method is useful for the synthesis of b-lactams 3j,k
with electron-withdrawing groups at C-3. When chloro-
acetic acid and azidoacetic acid were used as starting ma-
terials, no b-lactam formation was observed using TCT at
room temperature. 3-Azido b-lactam 3k was obtained in
13% yield using TCT at –15 °C. But 3-chloro- and azido
b-lactams 3j,k were prepared in better yield with TCT–
DMF adducts, although the yields increased at lower tem-
perature.
The mechanism is similar to our previously reported
mechanism for the Staudinger reaction from acetic acid
derivatives and imines using methoxymethylene-N,N-
dimethyliminium salt via formation of an activated form
of carboxylic acid.26c,d
Table 1 Reaction Conditions in the Synthesis of 3a
Entry
Solvent
Temp (°C)
TCT–DMF Yield
(mmol)
(%)
89
86
58
45
85
90
59
87
90
81
1
2
CH2Cl2
DMF
–15
–15
–15
–15
0
1.5
In conclusion, the procedure reported here for the first
time is a simple, high-yielding, and clean TCT–DMF one-
pot synthesis of b-lactams from imines and substituted
acetic acid under very mild conditions using inexpensive
and readily available starting materials. In this method, no
corrosive or toxic materials such as SOCl2 or Me2SO4 are
used, and the purification procedure was simple because
an aqueous workup removes the triazine byproduct.
Moreover, this method is convenient for the synthesis of
2-azetidinones from acetic acid derivatives that are a-sub-
stituted with electon-withdrawing substituents.
1.5
3
toluene
THF
1.5
4
1.5
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1.5
6
r.t.
1.5
7
–63
r.t.
1.5
8
1.3
9
r.t.
1.2
10
r.t.
1.0
General Procedure
DMF (0.30 mL, 4.0 mmol) was added to TCT (0.22 g, 1.2 mmol),
and the resulting suspension was stirred at r.t. for 5 min. The requi-
site Schiff base (1.0 mmol) and substituted AcOH (1.2 mmol) in dry
CH2Cl2 solution (7 mL) were added to the TCT–DMF suspension
followed by addition of dry Et3N (0.6 mL, 4.0 mmol). The reaction
mixture was stirred at r.t. overnight. The solution was washed suc-
cessively with sat. NaHCO3 (7 mL) and brine (7 mL), dried over
Na2SO4, and filtered. The solvent was evaporated under reduced
pressure to give the crude product. b-Lactams 3a–i were purified by
recrystallization from EtOAc and b-lactams 3j,k by short-column
chromatography (hexane–EtOAc = 9:1).
Based on the above results, 2-azetidinones 3a–k were
synthesized by treatment of 1.0 mmol of the correspond-
ing Schiff bases, 1.2 mmol of acetic acid derivatives, and
1.2 mmol TCT–DMF adduct in the presence of triethyl-
amine in dry CH2Cl2 (Scheme 2, Table 2). The b-Lactams
3a–i were purified by recrystallization from EtOAc and b-
lactams 3j,k by short column chromatography. All prod-
ucts were characterized by spectroscopic data and ele-
mental analyses. The indicated cis stereochemistry of the
products was judged from the coupling constants of H-3
and H-4 of the b-lactam ring in their 1H NMR spectra (J >
4.0 Hz). This new procedure for the synthesis of 2-azeti-
3-(4-Chlorophenoxy)-1-(4-ethoxyphenyl)-4-p-tolyl-azetidin-2-
one (3a)
Yield 90%; mp 178–180 °C. IR (KBr): 1759 (CO, b-lactam) cm–1.
1H NMR (250 MHz, CDCl3): d = 1.31 (Me, t, 3 H, J = 7.0 Hz), 2.33
(Me, s, 3 H), 4.02 (OCH2, q, 2 H, J = 7.0 Hz), 5.18 (H-4, d, 1 H,
Synlett 2011, No. 17, 2572–2576 © Thieme Stuttgart · New York

2574
M. Zarei, A. Jarrahpour
LETTER
Table 2 Comparison of the Synthesis of 2-Azetidinones 3a–k with TCT and TCT–DMF Adduct
Product
R1
R2
R3
Temp (°C)
Yield (%)
TCT
TCT–DMF adduct
3a
3b
3c
3d
3e
3f
4-EtOC6H4
4-EtOC6H4
4-MeOC6H4
4-MeOC6H4
4-EtOC6H4
4-EtOC6H4
Bn
4-MeC6H4
3,4-diMeOC6H3
CH=CHPh
4-MeC6H4
4-O2NC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-O2NC6H4
Ph
4-ClC6H4O
PhO
–15
r.t.
72
60
89
90
–15
r.t.
77
80
82
86
PhthN
–15
r.t.
70
51
88
86
MeO
–15
r.t.
74
69
87
91
2,4-diClC6H3O
2-NaphthO
PhO
–15
r.t.
63
48
85
84
–15
r.t.
83
71
90
91
3g
3h
3i
–15
r.t.
86
75
89
92
Me
PhthN
–15
r.t.
53
39
67
62
PhN=NC6H4
4-MeOC6H4
Ph
2-NaphthO
Cl
–15
r.t.
79
69
90
93
3j
–15
r.t.
0
0
55
42
3k
Ph
N3
–15
r.t.
13
0
69
45
J = 5.1 Hz), 5.40 (H-3, d, 1 H, J = 5.1 Hz), 6.84–7.61 (ArH, m, 12
H). 13C NMR (62.9 MHz, CDCl3): d = 14.2 (Me), 22.5 (Me), 59.6
(OCH2), 61.6 (C-4), 63.0 (C-3), 117.4, 119.1, 122.9, 123.3, 124.0,
125.6, 128.9, 129.2, 141.8, 142.5, 152.7, 156.3 (arom. C), 165.9
(CO, b-lactam). Anal. Calcd for C24H22ClNO3: C, 70.67; H, 5.44; N,
3.43. Found: C, 70.58; H, 5.53; N, 3.38.
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Acknowledgment
The authors thank Shiraz University Research Council for financial
support (Grant No. 89-GR-SC-23).
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