Facile synthesis of β-lactam derivatives by the Staudinger reaction using 3,6-dichlorotetrazine

Article abstract of DOI:10.3184/174751915X14473416848163

A versatile and convenient method for synthesis of β-lactams using 3,6-dichlorotetrazine as an acid activator in the ketene-imine cycloaddition is reported. Monocyclic and spirocyclic β-lactams are obtained in good to excellent yields. Easy purification o

Full text of DOI:10.3184/174751915X14473416848163

698 RESEARCH PAPER
VOL. 39 DECEMBER, 698–700
JOURNAL OF CHEMICAL RESEARCH 2015
Facile synthesis of ß-lactam derivatives by the Staudinger reaction using
3,6-dichlorotetrazine
Maaroof Zarei* and Aflatoon Salehinezhad
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
A versatile and convenient method for synthesis of β-lactams using 3,6-dichlorotetrazine as an acid activator in the ketene–imine
cycloaddition is reported. Monocyclic and spirocyclic β-lactams are obtained in good to excellent yields. Easy purification of the products
can be performed by aqueous workup and then crystallisation from ethyl acetate.
Keywords: β-lactam, 2-azetidinone, Staudinger reaction, 3,6-dichlorotetrazine, ketene, imine
β-Lactam antibiotics are a group of drugs used to counter
infections caused by bacteria. Unfortunately, bacteria resistant
to them are now widespread with the irregular use of the
β-lactam antibiotics as one of the reasons for this resistance.1
Biologically active substrates, based on the β-lactam
(2-azetidinone) structure, have been reported recently such as
ezetimibe which acts as a cholesterol absorption inhibitor, a
new clinical use of 2-azetidinones.2 β-Lactams have also been
used as synthetic intermediates in organic synthesis and in the
semisynthesis of taxol derivatives.3
Many synthetic methods have been reported for the synthesis
of the 2-azetidinone ring because of the tremendous importance
of these β-lactams.4,5 The Staudinger reaction ([2+2] ketene–
imine cycloaddition) is the most commonly used method for
the synthesis of 2-azetidinones.6,7 Also, the reaction of acyl
chlorides with triethyamine has been used for the generation of
the ketenes.8
Acyl chlorides are unstable in the presence of moisture, some
of them are not commercially available and their synthesis
and purification can be difficult. Activation of a carboxylic
acid with acid activator reagents followed by treatment with
a base is another method for ketene generation without using
acid halides.9-18 Unfortunately, some of these acid activators are
difficult to access and require harsh conditions and purification
of the products is problematical.
CH2Cl2, CHCl3, THF and DMF were considered (Table 1).
Among the solvents, dichloromethane was found to be the
optimal, but low temperatures decreased the yield. As shown in
Table 1, the highest yield of 4a was obtained when 1.5 mmol of
3,6-dichlorotetrazine 1 and 1.5 mmol carboxylic acid 3a react
with 1.0 mmol of Schiff base 2a in dry dichloromethane at
room temperature(RT) (entry 8).
Using the optimal conditions, various β-lactams have been
synthesised through cycloaddition of Schiff bases with ketenes
(Scheme 1, Table 2). As can be seen from Table 2, different
carboxylic acids and Schiff bases can all be converted into the
corresponding 2-azetidinones using 3,6-dichlorotetrazine 1 in
good to excellent yields and with high purity.
The purification of β-lactams 4a–l was performed by
crystallisation from EtOAc after simple aqueous work-up.
This reaction is efficient and clean because the by-product
of tetrazine and the resulting salts are water soluble and are
easily removed by simple aqueous workup. All products were
characterised by their spectral data and elemental analyses. The
stereochemistry was judged by the comparison of the coupling
constants H-3 and H-4 (J3,4> 4.0 Hz) for the cis stereoisomer
and (J3,4≤ 3.0 Hz) for the trans stereoisomer.21
Table 1 Reaction condition in the synthesis of 2-azetidinone 4a
Ph
PhO
3,6-dichloro
tetrazine
3,6-Dichlorotetrazine
1 is a highly electron-deficient
heterocycle and, therefore, undergoes nucleophilic substitution
reactions. This reagent has been used previously for the
synthesis of bis(triazidomethyl)methoxytetrazine19 and in the
synthesis of a tripodal s-tetrazine.20
PhN=CHPh
+
PhOCH2COOH
N
Et3N
Ph
O
2a
4a
3a
Entry
Solvent
Toluene
THF
CH2Cl2
CHCl3
DMF
CH2Cl2
CH2Cl2
CH2Cl2
Temp/oC
RT
RT
RT
RT
RT
0
RT
RT
Quantity of reagent/mmol
Yield/%
55
39
63
61
51
36
79
90
To the best of our knowledge, β-lactams have not been
synthesised using 3,6-dichlorotetrazine. We now present our
synthesis of β-lactams from imine and carboxylic acids using
3,6-dichlorotetrazine through ketene–imine cycloaddition.
Schiff bases were synthesised by refluxing equimolar amounts
of aldehydes and amines in 95% ethanol. Acid activator 1 was
added to a solution of the Schiff base 2a, carboxylic acid 3a and
triethylamine in dry toluene at room temperature. After usual
work-up and crystallisation from ethyl acetate, 2-azetidinone 4a
was obtained in 55%. Therefore, this reaction was considered
as the optimum model. Several dry solvents such as toluene,
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.3
1.5
N N
R2
Cl
Cl
R3
N N
R3
2
R1
CH2COOH
N
N
N
N
+
N=CHR
N
rt
,
2
CH Cl
2
Cl
Cl
R1
O
Et3N
3
2
4a-l
1
Scheme 1 Synthesis of 2-azetidinones 4a–l.
* Correspondent. E-mail: maaroof1357@yahoo.com; mzarei@hormozgan.ac.ir

JOURNAL OF CHEMICAL RESEARCH 2015 699
tetramethylsilane as an internal standard and coupling constants (J) are
given in Hz. Elemental analyses were run on a Vario EL III elemental
analyser. TLC was carried out on silica gel 254 analytical sheets
obtained from Fluka. Spectral data for 4a–c have been previously
reported23-25 and β-lactams 4d–l and 6a–b are new compounds.
Table 2 Synthesis of 2-azetidinones 4a–l using 3,6-dichlorotetrazine
Entry R1
R2
R3
cis/ Product Isolated
trans
cis
yield /%
90
1
2
3
4
5
6
7
8
C6H5
C6H5
PhO
4a
4b
4c
4d
4e
4f
4-MeOC6H4 4-ClC6H4 PhO
cis
87
Synthesis of 2-azetidinones (4a–l and 6a–b); general procedure
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4 PhO
cis
86
3,6-Dichlorotetrazine (1.5 mmol) was added to solutions of substituted
acetic acids (1.5 mmol), imines (1.0 mmol) and triethylamine
(5.0 mmol) in dry CH2Cl2 (15 mL) at room temperature and the mixture
was stirred overnight. The reaction 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 to give the
crude product, which was purified by crystallisation from EtOAc to
give pure β-lactams 4a–l and 6a–b.
4-ClC6H4 4-ClC6H4O
cis
75
4-ClC6H4 2,4-Cl2C6H4O cis
71
4-ClC6H4 MeO
4-ClC6H4 PhthNa
cis
87
trans 4g
89
4-(Me2CH) PhO
C6H4
cis
4h
93
9
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-(Me2CH) 4-ClC6H4O
C6H4
4-(Me2CH) 2,4-Cl2C6H4O cis
C6H4
4-(Me2CH) MeO
C6H4
4-(Me2CH) PhthNa
C6H4
cis
4i
91
83
81
75
3-Phenoxy-1,4-diphenyl-2-azetindione (4a): M.p 191–193 °C (lit.23
193–195 °C).
4-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-phenoxyazetidin-2-one
(4b): M.p. 181–183 °C (lit.24 180–182 °C).
10
11
12
4j
cis
4k
1,4-bis(4-Chlorophenyl)-3-phenoxyazetidin-2-one
234–236 °C (lit.25 246 °C).
(4c):
M.p.
trans 4l
3-(4-Chlorophenoxy)-1,4-bis(4-chlorophenyl)azetidin-2-one
(4d): White solid; m.p. >220 °C. IR (KBr) cm−1: 1744 (CO, β-lactam);
1H NMR (CDCl3) δ 5.34 (H-4, d, 1H, J = 4.9), 5.65 (H-3, d, 1H, J =
4.9), 6.87–7.35 (ArH, m, 12H); 13C NMR δ 62.1 (C-4), 79.83 (C-3),
116.9, 120.6, 126.6, 128.3, 128.5, 128.6, 128.7, 128.8, 129.5, 136.1,
137.8, 156.0 (aromatic carbons), 162.4 (CO, β-lactam). Anal. calcd for
C21H14Cl3NO2: C, 60.24; H, 3.37; N, 3.35; found: C, 60.32; H, 3.46; N,
3.30%.
O
a PhthN = phthalimido group =
N
O
Many different experimental factors, such as reaction
temperature, solvent, electronic effect and the steric
hindrance of the ketene and imine substituents may affect the
stereochemistry of the β-lactams in the Staudinger reaction.22
Ketenes generated from alkoxyacetic acids lead to cis β-lactam
but ketenes derived from pththalimidoacetic acid (β-lactams
4g and 4l) lead to the trans isomer because of the greater
steric hindrance of pththalimidoketene relative to that in
alkoxyketenes.
1,4-bis(4-Chlorophenyl)-3-(2,4-dichlorophenoxy)azetidin-2-one
(4e): Cream colour solid; m.p. >240 °C IR (KBr) cm−1: 1743 (CO,
1
β-lactam); H NMR (CDCl3) δ 5.29 (H-4, d, 1H, J = 5.0), 5.66 (H-3,
d, 1H, J = 5.0 ), 6.91–7.43 (ArH, m, 11H); 13C NMR δ 61.1 (C-4), 81.8
(C-3), 119.3, 120.6, 126.8, 128.2, 128.3, 128.4, 128.5, 128.6, 131.3,
133.4, 135.8, 136.1, 137.8, 152.2, 161.1 (aromatic carbons), 161.1 (CO,
β-lactam). Anal. calcd for C21H13Cl4NO2: C, 55.66; H, 2.89; N, 3.09;
found: C, 55.79; H, 3.01; N, 3.01%.
1,4-bis(4-Chlorophenyl)-3-methoxyazetidin-2-one (4f): White
solid; m.p. 160–162 °C. IR (KBr) cm−1: 1754 (CO, β-lactam); 1H NMR
(CDCl3) δ 3.40 (OMe, s, 3H), 5.04 (H-4, d, 1H, J = 4.6), 5.25 (H-
3, d, 1H, J = 4.6), 7.12–7.33 (ArH, m, 8H); 13C NMR δ 58.5 (OMe),
62.9 (C-4), 82.0 (C-3), 120.6, 128.3, 128.5, 128.6, 128.8, 130.1, 131.9,
133.4, 137.8 (aromatic carbons), 163.8 (CO, β-lactam). Anal. calcd for
C16H13Cl2NO2: C, 59.65; H, 4.07; N, 4.35; found: C, 59.75; H, 4.19; N,
4.42%.
2-(1,2-bis(4-Chlorophenyl)-4-oxoazetidin-3-yl)isoindoline-1,3-
dione (4g): Pale-yellow solid; m.p. 140–142 °C. IR (KBr) cm-1: 1736,
1773 (CO, phth), 1784 (CO, β-lactam); 1H NMR (CDCl3) δ 5.45 (H-3,
d, 1H, J = 2.5), 5.55 (H-4, d, 1H, J = 2.5), 7.18–7.59 (ArH, m, 12H);
13C NMR δ 61.2 (C-3), 62.3 (C-4), 120.2, 125.3, 128.8, 129.1, 129.4,
130.1, 131.2, 132.4, 133.1, 137.8, 137.9 (aromatic carbons), 165.5 (CO,
phth), 167.8 (CO, β-lactam). Anal. calcd for C23H14Cl2N2O3: C, 63.17;
H, 3.23; N, 6.41; found: C, 63.12; H, 3.29; N, 6.36%.
The use of 3,6-dichlorotetrazine 1 was successfully extended
to the synthesis of C-3 spiro-β-lactams. The treatment of
xanthene-9-carboxylic acid 5 with imines 2 in the presence
of reagent 1 and triethylamine afforded spiro-β-lactams 6a-b
which were purified by crystallisation from EtOAc (Scheme 2).
In conclusion, a simple and convenient method for one-pot
synthesis of β-lactams from carboxylic acids and imines using
3,6-dichlorotetrazine has been reported. Good to excellent
yields of the products, easy workup and purification, and the
mild condition reactions are some advantages of this method.
Experimental
All required chemicals were purchased from Merck, Fluka, and
Acros Chemical Companies. The melting points were determined
on a Buchi 535 apparatus. IR spectra were measured on a Shimadzu
FTIR 8300 spectrophotometer. NMR spectra were recorded on a
Bruker spectrometer (1H NMR 250 MHz, 13C NMR 62.9 MHz) using
1-(4-Chlorophenyl)-4-(4-isopropylphenyl)-3-phenoxyazetidin-
2-one (4h): White solid; m.p. >240 °C. IR (KBr) cm-1: 1757 (CO,
O
O
Et N
CH Cl
,
2
2
3
R2
2
R1
+
N=CHR
N N
N N
N
Cl
Cl
R1
O
O
OH
1
6a R 4-ClC H R2 4-ClC H
86%
87%
:
,
=
=
6
4
6
4
2
5
6b: R1 4-ClC H , R2 4-(Me CH) C H
=
=
6
4
2
6
4
Scheme 2

700 JOURNAL OF CHEMICAL RESEARCH 2015
1
β-lactam); H NMR (CDCl3) δ 1.34 (Me, d, 6H), 3.04 (CH, Sept,
1-(4-Chlorophenyl)-2-(4-isopropylphenyl)spiro[azetidine-3,9’-
xanthen]-4-one (6b): White solid; m.p. 156–158 °C. IR (KBr) cm-1:
1746 (CO, β-lactam); 1H NMR (CDCl3) δ 1.28(Me, d, 6H), 2.97
(CH, sept, 1H), 5.5 (H-4, s, 1H), 6.81–7.32 (ArH, m, 16H); 13C NMR
δ 22.9 (Me), 34.3 (CH), 63.0 (C-4), 77.0 (C-3), 117.4, 120.1, 122.1,
123.4, 124.6, 128.3, 129.0, 134.1, 135.3, 136.9, 137.3, 138.8, 145.8,
151.0 (aromatic carbons), 166.9 (CO, β-lactam). Anal. calcd for
C30H24ClNO2: C, 77.33; H, 5.19; N, 3.01; found: C, 77.42; H, 5.32; N,
3.09%.
1H), 5.51 (H-4, d, 1H, J = 4.9), 5.67 (H-3, d, 1H, J = 4.9), 6.92–7.36
(ArH, m, 13H); 13C NMR δ 23.3 (Me), 34.0 (CH), 62.1 (C-4), 82.2 (C-
3), 117.6, 120.6, 121.6, 125.5, 128.8, 128.9, 132.3, 133.2, 135.6, 137.8,
147.16, 157.9 (aromatic carbons), 162.0 (CO, β-lactam). Anal. calcd for
C24H22ClNO2: C, 73.56; H, 5.66; N, 3.57; found: C, 73.67; H, 5.73; N,
3.61%.
3-(4-Chlorophenoxy)-1-(4-chlorophenyl)-4-(4-isopropylphenyl)
azetidin-2-one (4i): Cream colour solid; m.p. >210 °C. IR (KBr)
cm-1: 1755 (CO, β-lactam); 1H NMR (CDCl3) δ 1.32 (Me, d, 6H), 3.01
(CH, Sept, 1H), 5.35 (H-4, d, 1H, J = 4.5), 5.66 (H-3, d, 1H, J = 4.5),
7.01–7.32 (ArH, m, 12H); 13C NMR δ 24.9 (Me ), 34.2 (CH), 62.7 (C-4),
80.68 (C-3), 115.9, 116.0, 120.6, 125.5, 127.4, 128.8, 129.4, 131.1, 133.3,
135.6, 147.2, 156.0 (aromatic carbons), 163.0 (CO, β-lactam). Anal.
calcd for C24H21Cl2NO2: C, 67.61; H, 4.96; N, 3.29; found: C, 67.70; H,
5.09; N, 3.23%.
Financial support from the Hormozgan University Research
Center is gratefully acknowledged.
Received 2 October 2015; accepted 19 October 2015
Paper 1503634 doi: 10.3184/174751915X14473416848163
Published online: 1 December 2015
1- (4 - Ch lorop h e nyl) -3 - ( 2 , 4 - d ich lorop h e n ox y) - 4 - (4 -
isopropylphenyl)azetidin-2-one (4j): Cream colour solid; m.p.
196–198 °C. IR (KBr) cm-1: 1744 (CO, β-lactam); H NMR (CDCl3)
1
References
δ 1.32 (Me, d, 6H), 3.05 (CH, Sept, 1H), 5.35 (H-4, d, 1H, J = 4.7), 5.66
(H-3, d, 1H, J = 4.7), 7.01–7.39 (ArH, m, 11H); 13C NMR δ 22.2 (Me),
34.8 (CH),61.4 (C-4), 80.6 (C-3), 119.2, 120.5, 125.4, 126.4, 128.6,
132.3, 133.3, 135.5, 135.9, 137.3, 137.8, 138.2, 147.2, 152.2 (aromatic
carbons), 163.0 (CO, β-lactam). Anal. calcd for C24H20Cl3NO2: C,
62.56; H, 4.37; N, 3.04; found: C, 62.63; H, 4.45; N, 2.97%.
1-(4-Chlorophenyl)-4-(4-isopropylphenyl)-3-methoxyazetidin-2-
one (4k): White solid; m.p. 130–132 °C. IR (KBr) cm-1: 1745.3 (CO,
β-lactam); 1H NMR (CDCl3) δ 1.32 (Me, d, 6H), 3.02 (CH, Sept, 1H),
5.04 (H-4, d, 1H, J = 4.5), 5.66 (H-3, d, 1H, J = 4.5), 7.01–7.31 (ArH,
m, 8H); 13C NMR δ 23.0 (Me), 33.2 (CH), 57.9 (MeO), 63.4 (C-4), 83.0
(C-3), 120.6, 125.4, 128.7, 131.0, 133.3, 135.6, 137.3, 147.2 (aromatic
carbons), 164.5 (CO, β-lactam). Anal. calcd for C19H20ClNO2: C, 69.19;
H, 6.11; N, 4.25; found: C, 69.33; H, 6.25; N, 4.32%.
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1
cm-1: 1731, 1758 (CO, phth), 1774 (CO, β-lactam); H NMR (CDCl3)
δ 1.31 (Me, d, 6H), 3.04 (CH, Sept, 1H), 5.46 (H-3, d, 1H, J = 2.5), 5.55
(H-4, d, 1H, J = 2.5), 7.01–7.80 (ArH, m, 11H); 13C NMR δ 24.1 (Me),
34.7 (CH), 60.8 (C-3), 61.8 (C-4), 121.0, 125.2, 126.3, 128.7, 131.0,
131.9, 133.2, 134.8, 137.3, 138.2, 145.8 (aromatic carbons), 166.2 (CO,
phth), 167.5 (CO, β-lactam). Anal. calcd for C26H21ClN2O3: C, 70.19;
H, 4.76; N, 6.30; found: C, 70.28; H, 4.85; N, 6.34%.
1,2-bis(4-Chlorophenyl)spiro[azetidine-3,9’-xanthen]-4-one (6a):
White solid; m.p. 220–222 °C IR (KBr) cm-1: 1748 (CO, β-lactam);
1H NMR (CDCl3) δ 5.60 (H-4, S, 1H), 6.86–7.34 (ArH, m, 16H);
13C NMR δ 62.7 (C-4), 71.7 (C-3), 116.8, 119.9, 121.8, 122.9, 123.9,
123.8, 125.9, 127.8, 129.05, 133.2, 134.4, 136.9, 137.2, 150.8 (aromatic
carbons), 167.7 (CO, β-lactam). Anal. calcd for C27H17Cl2NO2: C,
70.75; H, 3.74; N, 3.06; found: C, 70.85; H, 3.83; N, 3.11%.