Argentic oxide mediated N-dearylation of β-lactams

Article abstract of DOI:10.1016/j.tetlet.2011.01.022

A method is described for the N-dearylation of N-(4-methoxy- or 4-ethoxyphenyl)-2-azetidinones with argentic oxide. The yields are good-to-excellent and the reaction is simple, efficient, and fast.

Full text of DOI:10.1016/j.tetlet.2011.01.022

Tetrahedron Letters 52 (2011) 1192–1194
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Argentic oxide mediated N-dearylation of b-lactams
a
b,
⇑
Maaroof Zarei , Aliasghar Jarrahpour
a
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A method is described for the N-dearylation of N-(4-methoxy- or 4-ethoxyphenyl)-2-azetidinones with
argentic oxide. The yields are good-to-excellent and the reaction is simple, efficient, and fast.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 24 October 2010
Revised 9 December 2010
Accepted 7 January 2011
Available online 13 January 2011
Keywords:
N-unsubstituted 2-azetidinone
b-Lactam
N-dearylation
Argentic oxide
Oxidation
Argentic oxide (AgO) is used as an oxidizing agent in chemical
reactions. Soluble nitrate, perchlorate, sulfate, and fluoride salts
productive in large scale reactions because of the high equivalent
weight of CAN (548). In recognition of these drawbacks, Corley
reported an electrochemical procedure for the oxidative N-dearyla-
1
of silver yield AgO quantitatively, when oxidized with alkaline
2
13
solutions of sodium or potassium persulfate. Argentic oxide is also
tion of 2-azetidinones. However, electrochemical reactions are
3
commercially available.
poorly amenable to scale-up, requiring specialised equipment.
According to the standard reduction potential table,14 Ag(II)
[Ag(II) + e = Ag(I), 1.98 V] has a larger potential than that of Ce(IV)
[Ce(IV) + e = Ce(III), 1.72 V]. In this Letter we describe the use of
AgO for the oxidative N-dearylation of b-lactams for the first time.
First, we examined the oxidation of 2-azetidinone 1a using AgO.
When 2-azetidinone 1a was mixed with AgO in aqueous 1,4-diox-
ane at room temperature, no reaction was observed after 10 h.
When a mineral acid was added, the reaction took place immedi-
ately to give N-unsubstituted 2-azetidinone 2a. Hence, various
mineral acids were tested to find the optimum. According to Table
1, nitric acid was the most efficient and, at least 3 equiv each of
Oxidative cleavage of hydroquinone ethers with argentic oxide
has been reported previously.4 Weinreb5 and co-workers have
described the oxidative O-deprotection of p-methoxyphenyl ethers
using AgO.
b-Lactams are very important pharmacophores in compounds
6
for treatment of diseases caused by bacterial infections. In addi-
tion, b-lactams have been recently shown to possess other relevant
7
biological activities. Also, the 2-azetidinone ring has been em-
ployed successfully in a large variety of synthetic methods toward
various nitrogen-containing target compounds.8
N-Unsubstituted 2-azetidinones offer major synthetic opportu-
nities in the synthesis of b-lactam antibiotics such as the carbapen-
ems, penams, monobactams, nocardicins, and the glutamine
3
HNO and AgO were needed. The lower yield when using phospho-
3 4
ric acid (entry 4) is due to precipitation of Ag PO during the
9
4a
synthetase inhibitor, tabtoxin. The application of N-unsubstituted
reaction.
2
-azetidinones in the semi-synthesis of the anticancer agents Taxol
Next, optimization of the reaction conditions was investigated
by consideration of the effects of solvent, temperature, molar
ratio of reagents, and time (Table 2). The best result was obtained
in 1,4-dioxane with 3 equiv of AgO at room temperature over
5 min.
Using the optimized reaction conditions, 4-methoxyphenyl and
4-ethoxyphenyl b-lactams 1a–l were converted into the
corresponding NH-b-lactams 2a–l in good-to-excellent yields
10
and Taxotere has also been reported. Several protecting groups
are often used for N1-protection of b-lactams and can be cleaved
1
1
by various methods to give N-unsubstituted b-lactams. Cur-
rently, most reports describe oxidative removal of an alkoxyphenyl
group with ceric ammonium nitrate (CAN),12 but appear to neglect
the serious disadvantages associated with this procedure. Usually,
a large excess of CAN (3 equiv) is required and its use is not
(Scheme 1).
⇑
Corresponding author. Tel.: +98 711 228 4822; fax: +98 711 228 0926.
E-mail addresses: jarrah@susc.ac.ir, aliasghar6683@yahoo.com (A. Jarrahpour).
We also compared this new procedure with oxidative N-deary-
lation using CAN (Table 3). According to Table 3, the isolated
1
5
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.022

M. Zarei, A. Jarrahpour / Tetrahedron Letters 52 (2011) 1192–1194
1193
yields of N-unsubstituted 2-azetidinones 2a–k (entries 1–11) were
comparable with those obtained using CAN. 3-Chloro-2-azetidi-
none 1l (entry 12) was converted into the corresponding N-unsub-
stituted 2-azetidinone in lower yield with AgO than with CAN. The
N-dearylations of b-lactams 1a–l were faster using AgO than CAN.
The structures of N-unsubstituted b-lactams 2a–l were confirmed
1
2h–j,16
from spectroscopic data and elemental analyses.
The stereo-
chemistry of the starting b-lactams was retained in the products.
In conclusion, the use of AgO allowed us to develop a simple
and efficient synthetic method for obtaining N-unsubstituted b-
lactams via oxidative N-dearylation of N-alkoxyphenyl-b-lactams.
The reaction is rapid and high yields of products were obtained.
Table 1
a
N-dearylation of b-lactam 1a with AgO
MeO
MeO
Acknowledgments
MeO
PhO
MeO
PhO
The authors thank Shiraz University Research Council for the
financial support (Grant No. 88-GR-SC-23).
AgO
rt
N
NH
O
O
References and notes
OMe
Acid (mmol)
1
a
2a
1.
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1
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1
2
3
4
5
6
H
HNO
HClO
H PO
3 4
HNO
HNO
2
SO
4
(3 mmol)
(3 mmol)
(3 mmol)
(3 mmol)
(2 mmol)
(4 mmol)
63
88
69
54
59
83
3
Chem. 1971, 36, 3951–3960.
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1
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3
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Table 2
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a
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1
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1
2
3
4
5
6
7
8
9
1,4-Dioxane
rt
rt
rt
rt
0 °C
rt
rt
rt
rt
3
3
3
3
3
2
4
3
3
3
10
10
10
10
10
10
10
20
5
88
62
75
51
82
66
86
80
91
90
CH
3
CN
THF
DMF
1996; Vol. 1B, p 507.
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1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1
0
rt
3
a
3
Equimolar HNO and AgO were used for all reactions.
1
4, 2233–2239; (h) Marchand-Brynaert, J.; Dive, G.; Galleni, M.; Gerard, S.
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R3
O
R2
R1
R3
O
R2
NH
AgO
N
1,4-dioxane-H
O
2
8. (a) D’hooghe, M.; Mollet, K.; Dekeukeleire, S.; De Kimpe, N. Org. Biomol. Chem.
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a-l
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Scheme 1.
Table 3
Comparision of the N-dearylation of b-lactams 1a–l with AgO and CAN
Entry
R1
R2
R3
Stereochemistry
Product
Yield (%)
AgO
CANa
1
2
3
4
5
6
7
8
9
4-MeOC
4-MeOC
6
H
H
4
2,3-(MeO)
3,4-(MeO)
2
C
C
6
H
H
3
3
PhO
3-NO
PhO
PhthN
PhO
PhO
PhthN
2 6 3
2,4-Cl C H O
2-NaphthO
MeO
cis
cis
cis
cis
cis
cis
trans
cis
cis
cis
2a
2b
2c
2d
2e
2f
2g
2h
2i
91
86
83
88
85
87
85
82
87
83
89
78
85
84
81
90
78
82
80
79
6
4
2
6
2
PhthN
4-EtOC
4-EtOC
4-EtOC
6
6
6
H
H
H
4
4-MeOC
CH@CHPh
4-O NC
3,4-(MeO)
4-MeC
4-ClC
6 4
H
4
4
2
6 4
H
4-MeOC
6
H
4
2
C
6
H
3
4-EtOC
4-EtOC
4-EtOC
4-EtOC
6
6
6
6
H
H
H
H
4
4
4
4
6
H
4
H
6 4
4-O
4-O
2
NC
NC
6
H
H
4
1
0
2
6
4
2j
1
1
1
2
4-MeOC
4-MeOC
6
H
H
4
4-MeOC
4-MeOC
6
H
4
trans
cis
2k
2l
84
70
88
83
6
4
6
H
4
Cl
a
3
3
equiv of CAN in CH CN/H
2
O (3:1), 45 min, rt.

1
194
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1
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(10 mL) and all the organic layers were combined and washed successively
with 10% NaHSO SO . After
(2 Â 10 mL), brine (20 mL) and then dried over Na
filtration and evaporation of the solvent under reduced pressure, the crude
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2
O (10 mL) and
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2
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À1
6
) d
3.63 (OMe, s, 3H), 3.85 (H-3, dd, 1H, J = 2.4, 7.9), 4.90 (H-4, dd, 1H, J = 2.2, 2.4),
1
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4H), 8.76 (NH, br s, 1H); 13C NMR (62.9 MHz, DMSO-d
) d 56.2 (OMe), 64.6 (C-
3), 66.8 (C-4), 112.9, 115.5, 127.8, 137.2, 139.6, 157.5 (C@C, aromatic carbons),
6
1
(
+
2
161.1 (CO, b-lactam); GC–MS m/z = 203 [M ]; Anal. Calcd for C12H13NO : C,
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À1
methoxyphenyl)azetidin-2-one (2l): White solid. Mp 89–91 °C IR (KBr) cm
1759 (CO, b-lactam), 3424 (NH); 1H NMR (250 MHz, DMSO-d
3H), 4.51 (H-4, dd, 1H, J = 2.5, 5.1), 5.01 (H-3, d, 1H, J = 5.1), 6.78–7.23 (ArH, m,
4H), 8.91 (NH, br s, 1H); 13C NMR (62.9 MHz, DMSO-d
) d 55.8 (OMe), 62.7 (C-
4), 68.3 (C-3), 114.2, 127.9, 137.0, 154.6 (aromatic carbons), 162.9 (CO, b-
:
6
) d 3.66 (OMe, s,
1
990, 229–230; (j) Jarrahpour, A.; Zarei, M. Tetrahedron Lett. 2010, 51, 5791–
5
794.
6
1
2. (a) Green, T. W.; Wuts, P. G. M. Green’s Protective Group in Organic Synthesis, 4th
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+
37
+
35
lactam); GC–MS m/z = 213 [M ,
Cl], 211 [M ,
Cl]; Anal. Calcd for
C
10
H
10ClNO : C, 56.75; H, 4.76; N, 6.62. Found: C, 56.62; H, 4.85; N, 6.67.
2
16. Data for known compounds have been reported previously. See: (a) Jarrahpour,
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