Synthesis of Novel N-(4-ethoxyphenyl) Azetidin-2-ones and Their Oxidative N-deprotection by Ceric Ammonium Nitrate

It is shown that the N-(p-ethoxyphenyl) group on β-lactams can be oxidatively removed by ceric ammonium nitrate in good yield. Fourteen new N-(p-ethoxyphenyl)-2-azetidinones 8a-n were synthesized through standard [2+2] ketene-imine cycloadditions (Staudinger reaction). Treatment of these compounds with ceric ammonium nitrate yielded the N-dearylated 2-azetidinones 9a-n in good to excellent yields. The effects of solvent, molar equiv of CAN and different temperatures have been investigated and optimum conditions were established.


Introduction
Protection of the amide-NH is an area of protective group chemistry that has received little attention, and as a consequence, few good methods exist for amide-NH protection [1].β-Lactam antibiotics can be synthesized by various routes, but the preparation of N-unsubstituted (NH) β-lactams is a common feature [2].N-Unsubstituted β-lactams play a central role as key intermediates in the synthesis of several biologically active antibiotics [3].The importance of these types of compounds for the semi-synthesis of the novel anticancer agents Taxol and Taxotere is also well documented [4].Benzyl [5], allyl [6], silyl [7], p-methoxyphenyl [8], 4-methoxybenzyl [9], (α-thiophenyl)benzyl [10], 4-(methoxymethoxy)phenyl [11], 2,4-dimethoxybenzyl [12], 3,4-dimethoxybenzyl [13], benzyloxyaniline linker [14], Rink resin [15], methyl-p-tolyl-amine [16] and pyrrolidinomethyl [17] groups are often used for N 1 -protection of β-lactams and can be deprotected using different methods to give Nunsubstituted β-lactams.With few exceptions the yields are poor.Furthermore, some methods require expensive or hard to find starting materials.Toxic and unsafe byproducts which are obtained in some cases and difficulties in the purification of the main products are other common problems.Among these methods, oxidative cleavage by ceric ammonium nitrate of a p-methoxyphenyl moiety attached to the β-lactam ring nitrogen offers the most direct synthesis of N-unsubstituted β-lactams [18].This reaction involves oxidation of the aromatic ring to benzoquinone with the release of 1 mole equiv of MeOH and 1 mole equiv of product amide [19].In this paper, we report the utility of the p-ethoxyphenyl (PEP) group as a new protecting group for the protection of N 1 -2-azetidinones.The oxidative removal of this group by ceric ammonium nitrate (CAN) to yield N-unsubstituted β-lactams is also reported.

Results and Discussion
To test the feasibility of using the p-ethoxyphenyl (PEP) group, we first examined separately the reactions of hydroquinone diethyl ether (5) and p-ethoxyaniline (p-phenetidine, 6) with CAN.Thus, compounds 5 and 6 were oxidatively transformed into p-benzoquinone at room temperature in 66% and 43% yield, respectively (Scheme 1).Scheme 1. Reaction of hydroquinone diethyl ether 5 and p-ethoxyaniline 6 with CAN.For our subsequent studies the starting Schiff bases 7a-f were readily obtained in excellent yields by stirring a mixture of p-phenetidine and the corresponding aldehydes in refluxing ethanol.Cycloaddition reactions of imines 7a-f with phthalimidioacetyl chloride and phenoxyacetyl chloride in the presence of triethylamine (Method A) or of imines 7a-b with 2-naphthoxyacetic acid, 2,4-dichlorophenoxyacetic acid and methoxyacetic acid in the presence of p-toluenesulfonyl chloride and triethylamine (Method B) gave cis/trans 2-azetidinones 8a-k and 8l-n, respectively, in good to excellent yields (Scheme 2, Table 1).The mechanism of the ketene-imine cycloaddition reaction involves initial nucleophilic attack of the imine nitrogen on the ketene carbonyl to form a zwitterionic intermediate, which cyclizes to form the β-lactam [21].
Next we decided to find the optimum condition for N-dearylation of the above 2-azetidinones.First, N-(p-ethoxyphenyl)-β-lactams 8a-n were treated by CAN (3 eq.) in two different solvents (MeCN and THF) at 0°C for the times mentioned in Table 2.As shown in Table 2, acetonitrile was a better solvent than THF.Although the solubility of some substrates (especially 3-phthalimido-2azetidinones 8a-e) was not good, the yield was better.The optimum time for these reactions was 30 min, as seen from the table.TLC of the reaction mixtures confirmed the presence of p-benzoquinone, which was easily eliminated by forming the corresponding bisulfite adduct that could be washed out with water after workup with aqueous NaHSO 3 solution.Removal of the p-ethoxyphenyl (PEP) residue generally resulted in a shift at the β-lactam carbonyl function to a higher field and the appearance of NH peaks in the IR spectra (see the Experimental section).The formation of NH-β-lactams 9a-n was also confirmed by mass spectra and elemental analyses.The 1 H-NMR spectra exhibited the NH signals at about 8.41-9.19ppm as a broad peak in DMSO-d 6 , which was eliminated by shaking vigorously with D 2 O.
The mechanism of CAN deprotection of the p-ethoxyphenyl group from amides has not been fully studied.However experiments on the oxidation of 1,4-dimethoxybenzenes (similar to 1,4-diethoxy benzenes) to the corresponding quinones have shown that cleavage of the aryl-oxygen bonds requires two eq. of CAN [20].Thus, it is found that at least two mol equiv of CAN are needed for the oxidation of N-(4-ethoxyphenyl)-2-azetidinones 8a-n to N-unsubstituted-2-azetidinones 9a-n.According to Table 3, it is shown that 2.8 mol eq. of CAN is sufficient for completing the oxidative N-dearylation of N-(4-ethoxyphenyl)-2-azetidinones 8a-n (except for 8e).Deprotection of compound 8e needed three eq. of CAN to complete conversion to 9e in 82% yield.The effect of different temperatures on this oxidation was studied next.2-Azetidinones 8a-n were treated separately with CAN for 30 min in aqueous acetonitrile at -10°C, 0°C and room temperature (RT).As shown in Table 4, nearly identical yields of NH-β-lactams 9a-n were obtained at 0°C and RT.The lower yield of N-unsubstituted β-lactams in aqueous acetonitrile at -10 o C may be attributed to the low solubility of 2-azetidinones 8a-n at that temperature.
According to a reported mechanism for the cleavage of p-methoxyphenyl group [21], following mechanism shown in Scheme 4 is suggested for the oxidative cleavage of p-ethoxyphenyl moiety.

Conclusions
In conclusion, in this study it was shown that the p-ethoxyphenyl group can be introduced onto the 2-azetidinone skeleton as a suitable N-protective group.Furthermore it can easily be removed by CAN under mild conditions.It should be noted that the R 1 and R 2 substitution on the β-lactam ring and the stereochemistry of the ring remain intact during the course of reaction.In addition to good to excellent yields of the products, ethanol is formed in this oxidation reaction, which is a less toxic and friendlier byproduct for the environment than methanol.It is noteworthy that this oxidative cleavage is rapid and can be performed at room temperature.

General
All required chemicals were purchased from the Merck or Fluka chemical companies.Dichloromethane and triethylamine were dried by distillation over CaH 2 and then stored over 4Å molecular sieves.IR spectra were run on a Shimadzu FT-IR 8300 spectrophotometer. 1 H-and 13 C-NMR spectra were recorded in DMSO-d 6 or CDCl 3 using a Bruker Avance DPX instrument ( 1 H-NMR at 250 MHz, 13 C-NMR at 62.9 MHz, respectively).Chemical shifts are reported in ppm (δ) downfield from TMS.All the coupling constants (J) are given in Hertz.The mass spectra were recorded on a Shimadzu GC-MS QP 1000 EX instrument.Elemental analyses were run on a Thermo Finnigan Flash EA-1112 series.Melting points were determined in open capillaries with a Buchi 510 melting point apparatus and are not corrected.Thin-layer chromatography was carried out on silica gel 254 analytical sheets obtained from Fluka.Column chromatography was performed on Merck Kieselguhr (230-270 mesh).

General procedure for synthesis of Schiff bases 7a-f.
A mixture of p-ethoxyaniline (20.0 mmol) and corresponding aldehyde (20.0 mmol) was refluxed in EtOH for 2-4 hours.After cooling the solutions, the precipitate formed was filtered off and washed with ethanol to give pure Schiff bases 7a-f as colored solid or crystals in excellent yields.

Typical experimental procedure for the synthesis of 2-azetidinones 8a-n
Method A. A solution of the corresponding acyl chlorides (1.50 mmol) in dry CH 2 Cl 2 (10 mL) was slowly added to a solution of Schiff bases 7a-f (1.00 mmol) and triethylamine (3.00 mmol) in CH 2 Cl 2 (15 mL) at -10 o C. The reaction mixture was then allowed to warm to room temperature, stirred overnight and then it was washed successively with saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried (Na 2 SO 4 ) and the solvent was evaporated to give the crude product which was then purified by column chromatography or recrystalization from EtOAc.Method B. A solution of Schiff base 7a-b (1.0 eq.) was stirred with the corresponding substituted acetic acid (1.5 eq.), p-toluenesulfonyl chloride (1.5 eq.) and triethylamine (4-5 eq.) in dry CH 2 Cl 2 at room temperature.After 8 to 10 h, the mixture was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and the solvent was evaporated to give the crude product which was then purified by recrystalization from EtOAc, unless stated otherwise.

Typical experimental procedure for the synthesis of N-unsubstituted β-lactams 9a-n
A solution of (NH 4 ) 2 Ce(NO 3 ) 6 (CAN, 2.0-3.5 mmol) in water (15 mL) was added dropwise to a solution of the β-lactam 8a-n (1.00 mmol) in CH 3 CN or THF (30 mL) at the temperature mentioned in Table 3.The mixture was stirred at corresponding temperature for the mentioned time, then water (30 mL) was added and the mixture was extracted with EtOAc (3×20 mL) and washed with 10 % aqueous NaHCO 3 (40 mL).The aqueous layer of NaHCO 3 was extracted again with EtOAc (15 mL) and all organic layers were combined and washed successively with 10 % NaHSO 3 (2×30 mL), 10 % NaHCO 3 (20 mL) and brine (20 mL) and then dried over sodium sulfate.After filtration and evaporation of the solvent in vacuo, the crude product was purified by column chromatography or recrystalization from diethyl ether, as indicated.

Table 4 .
Deprotection of β-lactams 8a-n by 2.8 molar eq. of CAN for 30 min at different temperatures.