Synthesis of N-unsubstituted β-lactams from N-alkoxyphenyl-β- lactams with cobalt(III) fluoride

Article abstract of DOI:10.1016/j.tetlet.2010.08.101

Mild and efficient oxidative N-dearylation of N-alkoxyphenyl-β-lactams with cobalt(III) fluoride proceeded in good to excellent yields to afford the corresponding N-unsubstituted β-lactams. Optimization of the solvent, molar ratio of reagents, time, and t

Full text of DOI:10.1016/j.tetlet.2010.08.101

Tetrahedron Letters 51 (2010) 5791–5794
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Tetrahedron Letters
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Synthesis of N-unsubstituted b-lactams from N-alkoxyphenyl-b-lactams
with cobalt(III) fluoride
Maaroof Zarei a, Aliasghar Jarrahpour b,
⇑
a Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
b Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2010
Revised 26 July 2010
Accepted 31 August 2010
Available online 6 September 2010
Mild and efficient oxidative N-dearylation of N-alkoxyphenyl-b-lactams with cobalt(III) fluoride pro-
ceeded in good to excellent yields to afford the corresponding N-unsubstituted b-lactams. Optimization
of the solvent, molar ratio of reagents, time, and temperature are described.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
2-Azetidinone
N-unsubstituted b-lactam
Cobalt(III) fluoride
Oxidative N-dearylation
2-Azetidinones (b-lactams) are of interest to synthetic and
medicinal chemists, as they are biologically significant.1 In addi-
tion, 2-azetidinones show many important non-antibiotic biologi-
cal activities.2 They are also being used increasingly as valuable
starting materials to develop new synthetic methodologies.3
N-unsubstituted b-lactams have been used as intermediates in
the synthesis of b-lactam antibiotics4 such as nocardicins and
monobactams, and the glutamine synthase inhibitor, tabtoxin.5
The importance of N-unsubstituted b-lactams for the semisynthe-
sis of the novel anticancer agents Taxol and Taxotere is also well
documented.6 N-unsubstituted b-lactams have been prepared by
several methods,7 but N-deprotection of N-alkoxyphenyl-b-lac-
tams is an established method in b-lactam chemistry (Scheme 1).8
Ceric ammonium nitrate (CAN) is the most frequently used reagent
for this purpose.9
We report herein the first example of oxidative N-dearylation of
b-lactams using CoF3 under mild conditions.
2-Azetidinone 1a was selected as a model compound. According
to the procedure for N-dearylation of b-lactams with CAN, 3 equiv
of CoF3 were added, at room temperature, to 2-azetidinone 1a in
1,4-dioxane. Next, water was added and the reaction mixture
was stirred vigorously for 2 h at room temperature. The corre-
sponding N-unsubstituted 2-azetidinone 2a was obtained in 64%
yield after purification by recrystallization from diethyl ether. To
find the optimum reaction conditions, we firstly evaluated the
influence of the solvent and reaction time using 3 equiv of CoF3
at room temperature (Table 1). As shown in Table 1, acetonitrile
proved to be the best solvent and 1 h was required to complete
the reaction.
The effect of the oxidant/substrate molar ratio and different
temperatures on this oxidation was next studied in CH3CN–H2O
(3:1) for 1 h (Table 2). The solubility of several substrates was
not good at 0 °C and the best results were obtained when the reac-
tions were performed at room temperature. It was found that
3.5 equiv of CoF3 were needed for the complete consumption of 1a.
Due to the high molecular weight of CAN (548) and the use of
three equivalents per mole of substrate, it has some disadvantages
especially when the reaction is run on a large scale.10
Cobalt(III) fluoride (CoF3) has been used for oxidative couplings
to give biaryls.11 Nakata and co-workers reported oxidative
demethylation of hydroquinone dimethyl ethers to quinones with
CoF3.12 According to the standard reduction potential table,13
Co(III) has a larger value than that of Ce(IV). Furthermore, the
hydrogen fluoride liberated, as the reaction proceeds, is a weak
acid and hence a milder medium would be anticipated throughout
the reaction.12 The toxicity of CAN and CoF3 is almost comparable.
R1
O
R2
O
R1
O
R2
+
+ ROH
N
NH
O
OR
⇑
Corresponding author. Tel.: +98 711 228 4822; fax: +98 711 228 0926.
E-mail addresses: jarrah@susc.ac.ir, aliasghar6683@yahoo.com (A. Jarrahpour).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.101

5792
M. Zarei, A. Jarrahpour / Tetrahedron Letters 51 (2010) 5791–5794
Table 1
Table 2
Solvent and reaction time optimization
Moles of CoF3 and temperature optimization in the synthesis of 2a
NO2
Entry
Temp (°C)
CoF3 (mmol)
Yield (%)
NO2
1
2
3
4
5
6
7
8
9
0
0
0
0
2
2.5
3
3.5
4
2
2.5
3
3.5
4
20
22
35
43
53
40
59
78
86
85
PhO
PhO
O
CoF3
rt
N
NH
O
0
rt
rt
rt
rt
rt
OEt
1a
Solvent
2a
Entry
1
Time (h)
Yield (%)
10
1,4-Dioxane–H2O (3:1)
0.5
1
51
66
64
43
58
61
60
78
75
47
51
55
2
2
3
4
5
DMF–H2O (3:1)
0.5
1
Encouraged by this success, we next investigated the oxidative
N-dearylation of several N-alkoxyphenyl-b-lactams 1a–k to obtain
NH-b-lactams 2a–k. In all the reactions, 3.5 equiv of CoF3 were
used in aqueous acetonitrile at room temperature for 1 h, and
the yields were compared with those obtained using CAN
(Table 3).14
Although a larger quantity of the reagent was required in the
case of CoF3, the isolated yields of the NH-b-lactams 2a–j (entries
1–10) were comparable to those obtained with CAN. In the case
of 3-chloro-2-azetidinone 1k (entry 11), the oxidative N-dearyla-
tion to 2k using CAN was superior. All NH-b-lactams 2a–k were
characterized from spectral data and by elemental analyzes.15
2
CH3CN–H2O (3:1)
THF–H2O (3:1)
0.5
1
2
0.5
1
2
a
CH2Cl2–H2O (19:1)
0.5
1
—
—
a
2
0b
a
Not determined.
No product was observed.
b
Table 3
N-dearylation of 2-azetidinones 1a–k
Entry
Substrate
Product
Yield (%)
CoF3
CANa
NO2
NO2
PhO
O
PhO
O
1
83
81
N
NH
OEt
2a
1a
MeO
MeO
OMe
OMe
PhO
O
PhO
O
2
80
83
NH
N
2b
OMe
OMe
1b
OMe
PhO
O
PhO
O
3
81
79
NH
N
2c
OEt
1c
O
O
N
N
4
78
83
O
O
N
NH
O
O
2d
OEt
1d

M. Zarei, A. Jarrahpour / Tetrahedron Letters 51 (2010) 5791–5794
5793
Table 3 (continued)
Entry
Substrate
Product
Yield (%)
CoF3
CANa
NO2
NO2
O
O
OMe
OMe
OMe
OMe
N
N
O
5
85
87
O
O
NH
N
O
2e
OMe
Cl
1e
O
O
Cl
N
N
6
80
74
O
O
O
O
NH
N
2f
OEt
1f
Me
Me
MeO
O
MeO
O
7
76
77
82
79
80
76
N
NH
2g
OMe
1g
NO2
NO2
O
O
O
8
N
NH
O
2h
OEt
1h
NO2
NO2
Cl
Cl
O
O
O
Cl
Cl
9
N
NH
O
2i
OMe
1i
Cl
Cl
O
O
N
N
O
O
10
80
71
81
88
NH
N
O
O
2j
OMe
1j
Cl
O
Cl
O
N
NH
11
OMe
2k
1k
a
CAN (3 equiv) in CH3CN/H2O (3:1) for 1 h.
In conclusion, the use of CoF3 for the oxidative N-dearylation of
N-alkoxyphenyl-b-lactams under mild conditions has been re-
ported. The method is simple and versatile. The solvents, molar ra-
tio of reagent, time, and temperature have been optimized.
Acknowledgments
The authors thank the Shiraz University Research Council for
the financial support (Grant No. 88-GR-SC-23).

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M. Zarei, A. Jarrahpour / Tetrahedron Letters 51 (2010) 5791–5794
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14. General procedure: To a solution of 2-azetidinone 1a–k (1.0 mmol) in 16 mL of
CH3CN–H2O (3:1), CoF3 (0.41 g, 3.5 mmol) was added at room temperature.
The reaction mixture was stirred for 1 h, then water (10 mL) was added and the
mixture was extracted with EtOAc (3 Â 10 mL) and the combined organic layer
washed with 10% aqueous (NaHCO3) (20 mL). The aqueous layer of NaHCO3
was extracted again with EtOAc (10 mL) and all the organic layers were
combined and washed successively with 10% NaHSO3 (2 Â 10 mL) and brine
(20 mL), and then dried over Na2SO4. After filtration and evaporation of the
solvent in vacuo, the crude product was purified by recrystallization from Et2O.
4-(4-Chlorophenyl)-3-(5-norbornene-2,3-dicarboxyloylimido)-azetidin-2-one
(2j): White solid. Yield: (80%), mp: 225–227 °C IR (KBr) cmÀ1: 1743, 1770 (CO,
imide), 1787 (CO, b-lactam), 3424 (NH); 1H NMR (250 MHz, DMSO-d6) d 1.46,
1.64 (H-11, d, 2H, J = 8.5), 3.22 (H-5, d, 1H, J = 7.7), 3.30 (H-10, d, 1H, J = 7.7),
3.42–3.51 (H-6 and H-9, m, 2H), 4.71 (H-4, dd, 1H, J = 2.3, 3.5), 5.12 (H-3, d, 1H,
J = 2.3), 6.06–6.21 (H-7 and H-8, m, 2H), 6.53–7.13 (ArH, m, 4H), 8.94 (NH, br s,
1H); 13C NMR (62.9 MHz, DMSO-d6) d 40.0, 40.9 (C-5, C-10), 43.7, 44.4 (C-6, C-
9), 50.6 (C-11), 58.1 (C-4), 63.5 (C-3), 117.3-151.1 (C@C, aromatic carbons),
163.8 (CO, b-lactam), 177.9, 178.4 (CO, imide); GC-MS m/z = 344 [M+, 37Cl], 342
[M+, 35Cl]. Anal. Calcd for C18H15ClN2O3: C, 63.07; H, 4.41; N, 8.17. Found: C,
62.91; H, 4.55; N, 8.03. 3-Chloro-4-phenylazetidin-2-one (2k): White solid.
Yield: (71%), mp: 71–73 °C IR (KBr) cmÀ1: 1767 (CO, b-lactam), 3417 (NH); 1H
NMR (250 MHz, DMSO-d6) d 4.33 (H-4, d, 1H, J = 4.7), 4.87 (H-3, dd, 1H, J = 2.2,
4.7), 6.63–7.09 (ArH, m, 5H), 9.03 (NH, br s, 1H); 13C NMR (62.9 MHz, DMSO-
d6) d 58.6 (C-4), 69.4 (C-3), 111.7–150.3 (aromatic carbons), 161.4 (CO, b-
lactam); GC-MS m/z = 183 [M+, 37Cl], 181 [M+, 35Cl]. Anal. Calcd for C9H8ClNO:
C, 59.52; H, 4.44; N, 7.71. Found: C, 59.60; H, 4.62; N, 7.65.
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