Solid-solid phase and solvent-free oxidative removal of N-(4-alkoxyphenyl) groups of monocyclic β-lactams with ceric ammonium nitrate as a cheap, simple, and efficient method

Article abstract of DOI:10.1080/00397910801981326

Five N-(4-methoxyphenyl)- and five N-(4-ethoxyphenyl)-β-lactams were prepared by ketene-imine [2+2] cycloaddition (Staudinger reaction). Then these 2-azetidinones were N-dearylated by grinding together with ceric ammonium nitrate without hazardous solvent

Full text of DOI:10.1080/00397910801981326

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Solid‐Solid Phase and Solvent‐Free Oxidative
Removal of N‐(4‐Alkoxyphenyl) Groups of
Monocyclic β‐Lactams with Ceric Ammonium
Nitrate as a Cheap, Simple, and Efficient
Method
Aliasghar Jarrahpour a & M. Zarei a
a Department of Chemistry, College of Sciences , Shiraz University , Shiraz,
Iran
Published online: 09 May 2008.
To cite this article: Aliasghar Jarrahpour & M. Zarei (2008) Solid‐Solid Phase and Solvent‐Free Oxidative
Removal of N‐(4‐Alkoxyphenyl) Groups of Monocyclic β‐Lactams with Ceric Ammonium Nitrate as a Cheap,
Simple, and Efficient Method, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 38:11, 1837-1845, DOI: 10.1080/00397910801981326
To link to this article: http://dx.doi.org/10.1080/00397910801981326
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Synthetic Communicationsw, 38: 1837–1845, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801981326
Solid-Solid Phase and Solvent-Free
Oxidative Removal of N-(4-Alkoxyphenyl)
Groups of Monocyclic b-Lactams with Ceric
Ammonium Nitrate as a Cheap, Simple, and
Efficient Method
Aliasghar Jarrahpour and M. Zarei
Department of Chemistry, College of Sciences, Shiraz University,
Shiraz, Iran
Abstract: Five N-(4-methoxyphenyl)- and five N-(4-ethoxyphenyl)-b-lactams were
prepared by ketene-imine [2 þ 2] cycloaddition (Staudinger reaction). Then these
2-azetidinones were N-dearylated by grinding together with ceric ammonium nitrate
without hazardous solvents in good to excellent yields. The solid-solid phase N-dear-
ylation is easier, simpler, and more efficient than the general method in solution. The
pure N-unsubstituted b-lactams obtained by a nontedious workup and without further
purification.
Keywords: 2-Azetidinones, ceric ammonium nitrate, solvent-free, solid-solid phase,
N-unsubstituted b-lactam
INTRODUCTION
It is remarkable that chemists still carry out their reactions in solution.
Recently chemists have found that many reactions proceed efficiently in the
solid state or solvent-free conditions.[1] The solid-state reactions[2] or
solvent-free[3] reactions have many advantages: reduced pollution, low
costs, and simplicity in process and handling. These factors are especially
Received August 6, 2007
Address correspondence to Aliasghar Jarrahpour, Department of Chemistry,
College of Sciences, Shiraz University, Shiraz 71454, Iran. E-mail: jarrah@susc.ac.ir
or aliasghar6683@yahoo.com
1837

1838
A. Jarrahpour and M. Zarei
important in industry. Furthermore, in many cases, solid-state reactions
proceed much faster than the solution reaction, probably because the solid-
state reaction is a very high concentration reaction.[4] b-Lactam compounds
really are “evergreen” bioactive molecules.[5] N-Unsubstituted b-lactams
are intermediates in the synthesis of monocyclic and bicyclic b-lactam anti-
biotics.[6] Monocyclic b-lactams such as nocardicins 1 and monobactams 2
are of interest as they have been found to exhibit antibiotic properties.[7]
These compounds can be synthesized by various routes, though the prep-
aration of an N-unsubstituted b-lactam is a common feature.[8]
The importance of N-unsubstituted b-lactams for the semisynthesis of the
novel anticancer agents Taxol and Taxotere is also well documented.[9]
Several protecting groups are often used for N1-protection of b-lactams and
can be deproteced by different methods to give N-unsubstituted b-lactams.[10]
Generally, the selection of Nl-protective groups in b-lactam synthesis is based
on the ease of selective removal of these groups at the appropriate stage.[11] In
solution-phase syntheses, ceric ammonium nitrate (CAN) has been utilized to
remove the 4-methoxyphenyl,[12] 4-methoxybenzyl,[13] 4-(methoxymethoxy)-
phenyl,[14] and benzloxy-aniline linker[15] group from the amide nitrogen of
b-lactams to generate their N-unsubstituted analogs. Generally aqueous aceto-
nitrile is used as solvent in these deprotection reactions.[16] However, these
methods have some drawbacks that limit their applications: toxicity, high cost,
and tedious workup. Acetonitrile is a toxic and expensive solvent. Because of
the low partition coefficient between ethyl acetate and water, a large amount
of the former is used repeatedly for workup.[17]
Our aim was to develop a simple and efficient synthetic strategy for the prep-
aration of N-unsubstituted 2-azetidinones. In this study, we report the conversion
of N-(4-alkoxyphenyl)-2-azetidinones to N-unsubstituted 2-azetidinones with
ceric ammonium nitrate (CAN) in solid-solid phase and solvent-free medium.
RESULTS AND DISCUSSION
3,4-Disubstituted-2-azetidinones 3a–j were prepared as described in
Scheme 1. [2 þ 2]-Ketene-imine cycloaddition reaction (Staudinger
reaction) of corresponding acylchlorides and Schiff bases in the presence of
triethylamine at 210 8C resulted in cis and trans 2-azetidinones 3a–j in
excellent yields. Subsequent treatment with ceric ammonium nitrate (CAN)
converted b-lactams 3a–j into the N-unsubstituted b-lactams 4a–j
(Scheme 1 and Table 1). The powdered b-lactams 3a–j and CAN were
mixed in a mortar. Then 2–3 drops of distilled cold water were added and
ground into the mixture for 1 min at room temperature.
The reaction usually starts immediately with formation of the colored
p-benzoquinone. The change of the color was a good indicator of its
formation. The presence of water is necessary, and the reported mechanism[18]
confirms it. After 15 min, the mortar was fully colored. Ethyl acetate was

Removal of N-(4-Alkoxyphenyl) Groups
1839
Scheme 1. N-Dearylation of 2-azetidinones 3a–j in solid-solid phase.
added to the reaction mixture, shaken well, and then filtered. The resulted
solution was washed with 10% NaHSO3 and brine. The released quinone was
removed by forming the bisulfite adduct, which can be washed out with water.[19]
Removal of water by Na2SO4 and evaporation of the solvent in vacuo
resulted in pure N-unsubstituted b-lactams 4a–j in good to excellent yields.
Both N-(4-methoxyphenyl)-2-azetidinones 3a–e and N-(4-ethoxyphenyl)-2-
azetidinones 3f–j were dearylated rapidly and selectively with satisfactory
purity without need for column chromatography or recrystallization.
The structures of the NH-b-lactams 4a–j were confirmed by spectro-
scopic data and elemental analyses. The carbonyl function of these dearylated
b-lactams was shifted to higher wave numbers in IR spectra. 1H NMR spectra
definitely showed the NH signals and H-4 as a doublet of doublets peak. The
mass spectra showed the molecular ion for all synthesized molecules. This
method is more convenient, more efficient, cheaper, and safer than the
general reported methods.
In summary, we have developed a simple and green procedure for the
synthesis of N-unsubstituted b-lactams. For the first time, a solvent-free
method for N-dearylation of 2-azetidinones in solid-solid phase by grinding
with CAN has been reported by us. Cleavage of the electron-rich aryl
groups with CAN occurs rapidly in mild and green conditions.
EXPERIMENTAL
Typical Experimental Procedure for the Solid-Solid Phase
N-Dearylation of b-Lactams 3a–j
All solid–solid reactions were performed by grinding together 1.0 mmol of the
pure 2-azetidinones 3a–j with 3.5 mmol of CAN in the presence of 2–3 drops
of cold water in a mortar for 1 min and keeping the mixture at room temperature
for 15 min. Then the reaction mixture was poured into EtOAc, shaken well, and

1840
A. Jarrahpour and M. Zarei
Table 1. Comparison of the yields by use of CAN in solution with solvent-free
N-dearylation of 2-azetidinones 3a–j
Yield (%) by isolation
Substrate
Products
Solution phasea Solid phaseb
83
81
88
80
77
85
75
76
79
82
80
83
(continued)

Removal of N-(4-Alkoxyphenyl) Groups
Table 1. Continued
1841
Yield (%) by isolation
Solution phasea Solid phaseb
Substrate
Products
76
79
84
85
78
83
74
78
aCH3CN/H2O (3:1) for 30–45 min.
b15 min.
filtered. The colored resulted solution was washed with 10% sodium bisulfite (until
the aqueous layer remained colorless) and brine and then dried over dry sodium
sulfate. After filtration and evaporation of solvent under reduced pressure, the
N-unsubstituted b-lactams 4a–j were obtained.
Data
4-(3,4-Dimethoxyphenyl)-3-phenoxyazetidin-2-one (4a). Yield: 88%. Mp:
140–142 8C. IR (KBr) cm21: 1777.7 (CO), 3418.9 (NH). 1H NMR

1842
A. Jarrahpour and M. Zarei
(250 MHz, DMSO-d6) d 3.58, 3.66 (2MeO, 2s, 6H), 5.03 (H-3, d, 1H,
J ¼ 4.0), 5.58 (H-4, dd, 1H, J ¼ 2.2, 4.0), 6.64–7.26 (ArH, m, 8H), 8.83
(NH, brs, 1H). 13C NMR (62.9 MHz, DMSO-d6) d 55.23, 55.25 (2OMe),
56.40 (C-4), 81.13 (C-3), 111.02–156.59 (aromatic carbons), 165.98 (CO,
b-lactam). GC-MS m/z ¼ 299 [Mþ]. Anal. calcd. for C17H17NO4: C,
68.21; H, 5.72; N, 4.68. Found: C, 68.31; H, 5.79; N, 4.73.
4-(4-Chlorophenyl)-3-phenoxyazetidin-2-one (4b). Yield: 80%. Mp: 188–
1
190 8C. IR (KBr) cm21: 1773.5 (CO), 3420.0 (NH). H NMR (250 MHz,
DMSO-d6) d 5.09 (H-3, d, 1H, J ¼ 4.5), 5.61 (H-4, dd, 1H, J ¼ 2.1, 4.5),
6.77–7.32 (ArH, m, 9H), 8.89 (NH, brs, 1H). 13C NMR (62.9 MHz,
DMSO-d6) d 56.91 (C-4), 82.26 (C-3), 114.98–156.34 (aromatic carbons),
165.90 (CO, b-lactam). GC-MS m/z ¼ 275 [Mþ, 37Cl], 273 [Mþ, 35Cl].
Anal. calcd. for C15H12ClNO2: C, 65.82; H, 4.42; N, 5.12. Found: C, 65.78;
H, 4.46; N, 5.08.
4-(4-Methoxyphenyl)-3-phenoxyazetidin-2-one (4c). Yield: 85%. Mp:
157–159 8C. IR (CHCl3) cm21: 1776.3 (CO), 3409.9 (NH). 1H NMR
(250 MHz, DMSO-d6) d 3.66 (MeO, s, 3H), 5.02 (H-3, d, 1H, J ¼ 4.3),
5.52 (H-4, dd, 1H, J ¼ 1.8, 4.3), 6.55–7.35 (ArH, m, 9H), 9.08 (NH, brs,
1H). 13C NMR (62.9 MHz, DMSO-d6) d 54.83 (OMe), 56.45 (C-4), 81.76
(C-3), 113.19–158.68 (aromatic carbons), 166.84 (CO, b-lactam). GC-MS
m/z ¼ 269 [Mþ]. Anal. calcd. for C16H15NO3: C, 71.36; H, 5.61; N, 5.20.
Found: C, 71.42; H, 5.66; N, 5.24.
2-(2-Oxo-4-styrylazetidin-3-yl)-isoindoline-1,3-dione (4d). Yield: 76%.
Mp: 168–170 8C. IR (CHCl3) cm21: 1726.2, 1768.6 (CO, phth), 1784.0
(CO, b-lactam), 3417.0 (NH). 1H NMR (250 MHz, DMSO-d6) d 4.72
(H-4, m, 1H), 5.60 (H-3, d, 1H, J ¼ 5.2), 6.25 (H-5, dd, 1H, J ¼ 7.6,
16.0), 6.70 (H-6, d, 1H, J ¼ 16.0), 7.22–7.92 (ArH, m, 9H), 8.85 (NH,
brs, 1H). 13C NMR (62.9 MHz, DMSO-d6) d 55.38 (C-4), 58.69 (C-3),
123.42–135.69 (C55C, aromatic carbons), 164.06 (CO, phth), 166.93
(CO, b-lactam). GC-MS m/z ¼ 318 [Mþ]. Anal. calcd. for
C19H14N2O3: C, 71.69; H, 4.43; N, 8.80. Found: C, 71.74; H, 4.49; N,
8.78.
2-[2-(3,4-Dimethoxyphenyl)-4-oxo-azetidin-3-yl]-4-nitroisoindole-1,3-dione
(4e). Yield: 82%. Mp. 117–119 8C. IR (KBr, cm21) 1735.0, 1770.2 (phth.,
CO), 1785.0 (CO, b-lactam), 3380.5 (NH). H NMR (250 MHz, DMSO-d6)
1
d 3.61, 3.75 (2 OMe, 2 s, 6H), 5.04 (H-4, dd, 1H, J ¼ 12.2, 3.5), 5.53 (H-3,
d, 1H, J ¼ 5.5), 6.55 (NH, br s, 1H), 6.97–8.63 (ArH, m, 6H). 13C NMR
(62.9 MHz, DMSO-d6) d 55.44, 55.85 (OMe), 60.81 (C-4), 63.16 (C-3),
110.08–150.07 (aromatic carbons), 163.36 (CO), 164.49 (CO, b-lactam).
GC-MS m/z ¼ 397 [Mþ]. Anal. calcd. for C19H15N3O7: C, 57.43; H, 3.81;
N, 10.58. Found: C, 57.37; H, 3.88; N, 10.55.

Removal of N-(4-Alkoxyphenyl) Groups
1843
4-(4-Nitrophenyl)-3-phenoxyazetidin-2-one (4f). Yield: 83%. Mp: 160–
1
162 8C. IR (KBr) cm21: 1774.4 (CO), 3247.9 (NH). H NMR (250 MHz,
DMSO-d6) d 5.33 (H-3, d, 1H, J ¼ 4.8), 5.77 (H-4, dd, 1H, J ¼ 2.2, 4.8),
6.77–8.20 (ArH, m, 9H), 9.10 (NH, brs, 1H). 13C NMR (62.9 MHz,
DMSO-d6) d 56.01 (C-4), 82.71 (C-3), 115.04–156.24 (aromatic carbons),
165.78 (CO, b-lactam). GC-MS m/z ¼ 284 [Mþ]. Anal. calcd. for
C15H12N2O4: C, 63.38; H, 4.25; N, 9.85. Found: C, 63.44; H, 4.30; N, 9.87.
3-Phenoxy-4-styrylazetidin-2-one (4g). Yield: 79%. Mp: 190–192 8C. IR
1
(KBr) cm21: 1775.7 (CO), 3310.0 (NH). H NMR (250 MHz, DMSO-d6) d
4.64 (H-4, m, 1H,), 5.51 (H-3, d, 1H, J ¼ 4.3), 6.18 (H-5, dd, 1H, J ¼ 7.4,
15.9), 6.65 (H-6, d, 1H, J ¼ 15.9), 6.90–7.33 (ArH, m, 9H), 8.96 (NH, brs,
1H). 13C NMR (62.9 MHz, DMSO-d6) d 60.67 (C-4), 87.47 (C-3), 120.30–
162.15 (C55C, aromatic carbons), 170.78 (CO, b-lactam). GC-MS
m/z ¼ 265 [Mþ]. Anal. calcd. for C17H15NO2: C, 76.96; H, 5.70; N, 5.28.
Found: C, 76.92; H, 5.77; N, 5.24.
3-Phenoxy-4-p-tolylazetidin-2-one (4h). Yield: 85%. Mp: 180–182 8C. IR
1
(KBr) cm21: 1773.9 (CO), 3300.0 (NH). H NMR (250 MHz, DMSO-d6) d
1.95 (Me, s, 3H), 4.81 (H-3, d, 1H, J ¼ 4.4), 5.32 (H-4, dd, 1H, J ¼ 2.2,
4.4), 6.54–6.98 (ArH, m, 9H), 8.60 (NH, brs, 1H). 13C NMR (62.9 MHz,
DMSO-d6) d 20.62 (Me), 56.52 (C-4), 82.34 (C-3), 115.07–156.66
(aromatic carbons), 166.14 (CO, b-lactam). GC-MS m/z ¼ 253 [Mþ].
Anal. calcd. for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.84;
H, 6.03; N, 5.48.
2-(2-Oxo-4-p-tolylazetidin-3-yl)isoindoline-1,3-dione (4i). Yield: 83%. Mp:
197–199 8C. IR (CHCl3) cm21: 1740.0, 1775.0 (CO, phth), 1785.0 (CO,
b-lactam), 3480.5 (NH). H NMR (250 MHz, DMSO-d6) d 2.35 (Me, s,
1
3H), 4.94 (H-4, dd, 1H, J ¼ 2.5, 3.5), 5.04 (H-3, d, 1H, J ¼ 2.5), 7.23–8.03
(ArH, m, 8H), 9.02 (NH, brs, 1H). 13C NMR (62.9 MHz, DMSO-d6) d
20.68 (Me), 55.43 (C-4), 62.63 (C-3), 123.39–137.27 (aromatic carbons),
164.56 (CO, phth), 166.71 (CO, b-lactam). GC-MS m/z ¼ 306 [Mþ]. Anal.
calcd. for C18H14N2O3: C, 70.58; H, 4.61; N, 9.15. Found: C, 70.62; H,
4.58; N, 9.21.
2-(2-(4-Chlorophenyl)-4-oxoazetidin-3-yl)-isoindoline-1,3-dione (4j). Yield:
78%. Mp: 196–198 8C. IR (CHCl3) cm21: 1733.9, 1777.0 (CO, phth), 1785.0
(CO, b-lactam), 3373.5 (NH). 1H NMR (250 MHz, DMSO-d6) d 4.92 (H-3, d,
1H, J ¼ 2.5), 5.04 (H-4, dd, 1H, J ¼ 2.5, 3.2), 7.41–7.92 (ArH, m, 8H),
9.01 (NH, brs, 1H). 13C NMR (62.9 MHz, DMSO-d6) d 54.96 (C-4), 62.53
(C-3), 123.37–138.08 (aromatic carbons), 164.48 (CO, phth), 166.70
(CO, b-lactam). GC-MS m/z ¼ 328 [Mþ, 37Cl], 326 [Mþ, 35Cl]. Anal.
calcd. for C17H11ClN2O3: C, 62.49; H, 3.39; N, 8.57. Found: C, 62.55; H,
3.43; N, 8.54.

1844
A. Jarrahpour and M. Zarei
ACKNOWLEDGMENT
The authors thank the Shiraz University Research Council for financial
support (Grant No. 86-GR-SC-23).
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