Synthesis of β-lactams via Staudinger reaction using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline as a carboxylic acid activator

Article abstract of DOI:10.1080/00397911.2016.1244691

N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) has been used as an efficient and convenient reagent for the one-pot synthesis of β-lactams by [2+2] ketene–imine cycloaddition (Staudinger reaction). Cleanliness, simplicity of method, and good to exc

Full text of DOI:10.1080/00397911.2016.1244691

Synthesis of β-lactams via Staudinger reaction using N-ethoxycarbonyl-2-ethoxy-
,2-dihydroquinoline as a carboxylic acid activator
1
1
2
1
Saleheh Zavar , Maaroof Zarei , Mahnaz Saraei
1
2
Department of Chemistry, Payame Noor University, Tehran, Iran, Department of
Chemistry, Faculty of Sciences, University of Hormozgan, Bandar Abbas, Iran
Corresponding author: E-mail: mzarei@hormozgan.ac.ir, maaroof1357@yahoo.com
Abstract
N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) has been used as an efficient
and convenient reagent for the one-pot synthesis of β-lactams by [2+2] ketene-imine
cycloaddition (Staudinger reaction). Clean, simplicity of method and good to excellent
yield of products are some advantages of this method.
GRAPHICAL ABSTRACT
KEYWORDS: β-Lactam, 2-Azetidinone, Staudinger reaction, EEDQ, Ketene, Imine
INTRODUCTION
2
-Azetidinones, generally referred as β-lactams, show a unique ring system, with
1
interesting chemistry and great biological activities. The 2-azetidinone ring system is the
key of antibacterial activity in β-lactam antibiotics which have been widely used as
2,3
chemotherapeutic agents for treating microbial diseases. Antibiotic resistance is a
1

growing problem of modern medicine and some patients die annually from infection due
4
to antibiotic resistance. In addition, β-lactams possess many other pharmacological
activities such as human cytomegalovirus protease inhibitors, LHRH antagonists,
cholesterol absorption inhibitors, anticancer agents, antihyperglycemic, antimalarial, anti-
5
HIV, anti-inflammatory and analgesic activities. Furthermore, the considerable variety
of transformations related to the selective bond cleavage (enhanced by the ring strain) of
the 2-azetidinone core has suggested a systematic use of the β-lactam skeleton as a
6
,7
synthon in organic synthesis. Then many synthetic methods have been developed for
8
,9
10
the formation of the β-lactam ring. The Staudinger reaction is most common method
11–13
which applied for the synthesis of β-lactams.
1
4–16
A number of methods for generation of ketenes have been reported,
but reaction of
1
7–18
acyl chlorides with triethylamine is the most approach.
However, sometimes
application of acyl chlorides gave inadequate results and low yield of products. Also
stability of acyl chlorides is low and preparation, isolation, and handling of acid chlorides
are difficult. Recently some coupling reagents as carboxylic acid activator have been
19
20
used in the Staudinger reaction such as Vilsmeier reagent, cyanuric fluoride, 1,1-
2
1
22
carbonyldiimidazole, 2-fluoro-1-methylpyridinium p-toluenesulfonate,
23
24
propylphosphonic anhydride (T3P), phosphonitrilic chloride and
2
5
diphosphorustetraiodide. But some of them is expensive, need to control of
temperatures and painful chromatographic separations of products. N-Ethoxycarbonyl-2-
ethoxy-1,2-dihydroquinoline (EEDQ) is a highly specific reagent for activation of
26
carboxyl groups in the coupling of amino acids in high yield and without racemization.
2

27
28
Also applications of EEDQ for conversion of carboxylic acids to esters and amides
have been reported.
To the best of our knowledge, 2-ethoxy-l-(ethoxycarbonyl)-l,2-dihydroquinoline (EEDQ)
has not been used as a reagent for the synthesis of β-lactams ring. In this paper, we wish
to report that EEDQ can be successfully utilized as a convenient reagent for the synthesis
of β-lactams ring from imines and substituted acetic acids.
RESULTS AND DISCUSSION
Initially, a mixture of equimolar aldehydes and amines in ethanol was refluxed for 3
hours. After cooling, resulting precipitate were separated by filtration, and then were
washed with cold ethanol to give pure corresponding Schiff bases (Scheme 1).
Reaction of phenoxyacetic acid, N-(4-methoxyphenyl)-1-phenylmethanimine with EEDQ
in the presence of triethylamine in dry dichloromethane gave β-lactam 5a after
crystallization from ethanol. Among the dry solvents, the best yield was obtained using
dichloromethane. When cold media or refluxing dichloromethane was used, decrease of
yield was observed. According to table 1, the highest yield was obtained when 1.3 mmol
phenoxyacetic acid and 1.3 mmol EEDQ were reacted with 1.0 mmol of imine in dry
dichloromethane at room temperature (Table 1, Entry 8).
After optimization of reaction condition, β-lactams 5a-i were synthesized by this method
(Scheme 2, Table 2). Also, spiro-β-lactams 5j-m were prepared using EEDQ from
xanthene-9-carboxylic acid or fluorene-9-carboxylic acid. The progress of all reactions
3

was followed by TLC monitoring. After simple aqueous work-up, all products were
purified by crystallization from ethanol. β-Lactams 5a-m were characterized by spectral
data. The reaction was performed in mild reaction condition with good to excellent yield
of products.
The stereochemistry of β-lactams 5a-i were determined by the comparison of the
coupling constant H-3 and H-4 (J3,4> 4.0 Hz) for the cis stereoisomer and (J3,4≤ 3.0 Hz)
2
9
for the trans stereoisomer.
Temperature, solvent, electronic effects, and the steric hindrance of the ketene and imine
substituents affect the stereochemistry of β-lactams in the Staudinger reaction. 3-
Phthalimido-β-lactams 5c, 5g and 5i were obtained as trans stereoisomer because ketenes
derived from phthalimidoacetic acid have more steric hindrance than aryloxyketenes.
3
0-31
Proposed mechanism according to a reported mechanism for the Staudinger reaction
32
and for carboxylic acid activation using EEDQ, was represented in scheme 3 via
formation of a mixed anhydride which in situ generated of ketene.
CONCLUSIONS
In summary, we have developed a simple synthesis of monocyclic and spiro- β-lactams
by one-pot [2+2] ketene-imine cycloaddition of imines and substituted acetic acids using
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ). Due to the mild reaction
4

condition, good yields, and easily accessible starting material, we think that this new
synthetic approach has the potential in the synthesis of various β-lactams.
EXPERIMENTAL
Melting points were measured by the capillary tube method with an opti-melt MPA100
1
13
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.
3
Chemical shifts were reported in ppm (δ) and coupling constants (J) were reported in Hz.
IR spectra were recorded from KBr disk on the Shimadzu FT IR-8400S. Elemental
analyses were run on a Thermo Finnigan Flash EA–1112. Commercial aluminum-backed
plates of silica gel 60 F254 was used to monitor the progress of reactions by thin layer
chromatography (TLC).
General Procedure For The Synthesis Of 2-Azetidinones (5a-M)
EEDQ (1.3 mmol) was added to a solution of the substituted acetic acid (1.3 mmol), the
Schiff base (1.0 mmol) and Et
and the mixture was stirred overnight. The mixture was washed successively with
4
saturated NaHCO (15 mL) and brine (15 mL). The organic layer was dried (Na SO ),
3 2 2
N (5.0 mmol) in dry CH Cl (15 mL) at room temperature,
3
2
filtered and the solvent was removed under reduced pressure. The crude residue was
purified by crystallization from 95% EtOH.
4
-(2,4-Dichlorophenyl)-1-(4-Methoxyphenyl)-3-Phenoxyazetidin-2-One (5b)
5

o
-1
1
3
White solid. m.p. 132-135 C, IR (KBr) cm : 1755 (CO, β-lactam), H NMR (CDCl ) δ:
3
1
1
.69 (s, 3H, OMe) , 5.52 (d, 1H, J=4.9, H-4), 5.71 (d, 1H, J=4.9, H-3), 6.75-7.29 (m,
1
3
2H, ArH); C NMR (CDCl
21.5, 124.8, 126.3,127.7,128.2, 128.7, 128.9, 133.2, 133.9, 155.7, 155.9 (aromatic
NO : C, 63.78; H, 4.14; N,
3
) δ: 54.4 (OMe), 57.0 (C-4),80.3 (C-3), 113.5, 114.8, 117.6,
carbons), 161.3 (CO, β-lactam), Anal. Calcd for C22
.38. Found: C, 63.87; H, 4.28; N, 3.43.
H
17Cl
2
3
3
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
Financial support from Payame noor University Research Council is gratefully
acknowledged.
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9

Table 1. Reaction condition in the synthesis of β-lactams
Entry
Solvent
CH Cl
THF
Temp
mmol EEDQ
Yield (%)
1
2
3
4
5
6
7
2
2
rt
rt
rt
rt
rt
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.3
1.5
69
23
52
47
60
48
53
88
87
Toluene
DMF
CHCl
3
o
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
2
2
2
0 C
o
40 C
rt
rt
1
0

Table 2. Synthesis of β-lactams 5a-m using EEDQ
Entr
Yield
(%)
88
1
2
3
R
R
R
cis/trans Product
y
1
4-MeOC
6
6
6
6
H
H
H
H
4
4
4
4
Ph
PhO
cis
5a
5b
5c
5d
5e
5f
4
4
4
4
4
4
4
4
-MeOC
-MeOC
-MeOC
2,4-Cl
2
2
C
6
H
H
3
3
PhO
cis
96
2,4-Cl
C
6
PhthN
trans
cis
71
3,4,5-(MeO)
3
C
6
H
2
2,4-Cl
2
C
C
6
6
H
H
2
2
O
O
93
-EtC
-EtC
-EtC
-EtC
-EtC
6
6
6
6
6
H
H
H
H
H
4
2,4-Cl
2,4-Cl
2,4-Cl
2
2
2
C
6
C
6
C
6
H
H
H
3
3
3
PhO
cis
83
4
4
4
4
2,4-Cl
2
cis
91
PhthN
PhO
trans
cis
5g
5h
5i
89
3,4,5-(MeO)
3,4,5-(MeO)
3
3
C
6
6
H
H
2
2
83
C
PhthN
trans
88
-
-
-
5j
5k
5l
80
84
48
1
1
1
2
1
1

1
3
-
5m
53
1
2

Scheme 1. Preparation of Schiff bases.
1
3

Scheme 2. Preparation of β-lactams.
1
4

Scheme 3. Proposed mechanism.
1
5