Ind. Eng. Chem. Res. 2005, 44, 1625-1626
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APPLIED CHEMISTRY Highly Efficient, Low-Cost, and Simple Protocol for the Preparation of O-(Phenylmethyl)hydroxylamine Paolo Strazzolini* and Andrea Pavsler Department of Chemical Sciences and Technologies, University of Udine, via del Cotonificio 108, I-33100 Udine (UD), Italy
A simple, economically convenient, and ecocompatible two-step process for the preparation of large amounts of the valuable intermediate O-(phenylmethyl)hydroxylamine has been developed, starting from N-hydroxyphthalimide and (chloromethyl)benzene. Introduction
Scheme 1
O-(Phenylmethyl)hydroxylamine (O-benzylhydroxylamine, 1) is a commercially available reagent, in the form of its hydrochloride, with many important uses in organic synthesis. In fact, 1 has been successfully employed in the derivatization of ketones for gas chromatographic analysis,1 in the production of analogues of β-lactam antibiotics,2 as well as of hydroxylamines and hydroxamates,3 and in the synthesis of N-hydroxypeptides4 and R-hydroxybenzylamines.5 In the course of our studies concerning the preparation of new hydroxyamino derivatives of R-amino acids, we needed large amounts of 1 to be produced at low cost and with high efficiency. The most convenient preparation available6 appeared to be a two-step process (Scheme 1), starting from the commercially available 2-hydroxy-1,3-dihydroisoindol-1,3-dione (N-hydroxyphthalimide, 2), initially O-alkylated to give the corresponding phenylmethyl derivative 3 and subsequently cleaved, affording 1. The initial alkylation step producing the intermediate 2 has been reported and duplicated by us, in moderate to fairly good yields, under a variety of conditions. Usually, the less convenient (bromomethyl)benzene was employed as the alkylating agent, in the presence of triethylamine as the base, in CHCl3,7 CH3CN,8 or dimethylformamide (DMF);9 alternatively, 1,8-diazabicyclo[5.4.0]undec-7-ene10 or NaH11 in DMF has been used. (Chloromethyl)benzene was used in some instances in combination with K2CO3 in dimethyl sulfoxide,12 or with NaHCO3 in the system CH2Cl2-H2O, under phase-transfer conditions.13 In one report,14 2 and benzenemethanol (benzyl alcohol) have been coupled in tetrahydrofuran under Mitsunobu conditions, involving the unstable diethyl azodicarboxylate. The second step, concerning the conversion of the intermediate 2 into the desired 1, has been performed under acidic hydrolytic conditions (6 N aqueous HClAcOH, 1 h, reflux)12,13 or, more efficiently, by hydrazinolysis, in EtOH (1-4 h, reflux).6,8,12,14,15 It must be pointed out that, for safety and economical reasons, tha * To whom correspondence should be addressed. Tel.: +390432-558870. Fax: +39-0432-558803. E-mail: strazzolini@ dstc.uniud.it.
Scheme 2
latter reaction should be preferably carried out using NH2NH2 in its hydrated form and 95% EtOH as the solvent. Results and Discussion With the aim of developing an unambiguous, straightforward, and environmentally compatible synthetic protocol for producing large amounts of 1, at lower cost and minimizing the amounts of toxic wastes and byproducts, we decided to prepare the suitable intermediate 3 by performing the alkylation on the sodium salt of 2, operating in an easily recyclable solvent, and selecting (chloromethyl)benzene as the alkylating species. Therefore, compound 2 was treated with NaH in DMF, followed by a slight excess of (chloromethyl)benzene, and the resulting mixture heated at 90 °C overnight (Scheme 2). After filtration of NaCl, the reaction mixture was treated with H2O and solid 3 that separated was collected by filtration, dried, and obtained in practically quantitative yield. It was suitable for the subsequent step without further purification. No difference was observed when (bromomethyl)benzene was used as the alkylating agent. The second step was easily performed by treating the intermediate 3 with a stoichiometric amount of hydra-
10.1021/ie049410c CCC: $30.25 © 2005 American Chemical Society Published on Web 02/12/2005
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Ind. Eng. Chem. Res., Vol. 44, No. 6, 2005
zine hydrate in 95% EtOH and heating the obtained solution at 80 °C for 6 h (Scheme 2). After cooling, the reaction mixture was filtered in order to separate solid phthalazine (4), desolvented and, after simple workup, afforded crude 1 in almost quantitative yield. Pure 1 was obtained after fractional distillation at reduced pressure in 87% overall yield. In conclusion, the procedure described above represents, in terms of simplicity, economicity, and ecocompatibility, an efficient and straightforward method for the synthesis of large amounts of the valuable intermediate 1. Experimental Section Unless otherwise specified, reagents and solvents were commercially available. IR spectra were recorded on a Nicolet FTIR Magna 550 spectrophotometer using the KBr technique. 1H and 13C NMR spectra were recorded in CDCl3 on a Bruker AC-200 spectrometer at 200 and 50 MHz, respectively, using TMS (δ ) 0) as the internal standard. Mass spectrometry measurements were performed with a Fisons TRIO-2000 apparatus, working in the positive-ion electron impact mode (70 eV), by direct introduction (DI) of the sample into the ion source, and heating from 50 up to 300 °C. The 10 most intense peaks and the molecular peak are reported. 2-(Phenylmethoxy)-1H-isoindole-1,3(2H)-dione (NBenzyloxyphthalimide, 3). In a typical experiment, a solution of 2 (0.20 mol) in DMF (140 mL) was added dropwise and under an inert atmosphere (N2) into a well-stirred, ice-cooled suspension of NaH (8.40 g, 0.21 mol, 60% dispersion in mineral oil) in DMF (100 mL), resulting in hydrogen evolution and developing a characteristic red color. After the end of the addition, the reaction mixture was heated at 55 °C for 30 min; then, the temperature was raised to 90 °C and (chloromethyl)benzene (26.6 g, 0.21 mol) added dropwise during 30 min. The resulting suspension was stirred at 90 °C overnight, undergoing complete decoloration, and subsequently poured into water (1200 mL, stirred). The resulting colorless precipitate was filtered, washed with H2O (50 mL), collected, and dried in a desiccator for 60 min over P2O5, at 80 °C, and under reduced pressure (1 mmHg). Product 3 was obtained in quantitative yield; an analitycal sample was prepared by crystallization from EtOH (88% yield) as a colorless solid. Mp: 142 °C (EtOH) [142-143 °C (EtOH)].9 IR (pellet): 3078, 2957, 1731, 1465, 1383, 1185, 1134, 1082, 1012, 976, 913, 878, 836, 789, 764, 700, 522 cm-1. 1H NMR:9 δ 7.9-7.7 (sym m, 4H, Ar-H), 7.6-7.5 (m, 2H, C6H5), 7.4-7.3 (m, 3H, C6H5), 5.2 (s, 2H, Ph-CH2). 13C NMR:13 δ 163.4 (CdO), 134.4, 133.6, 129.8, 129.3, 128.8, 128.5, 123.4, 79.8 (CH2). MS (30 °C) m/z: 253 [M+], 149, 148, 147, 105, 104, 92, 91, 90, 76, 39. The same result was obtained when (bromomethyl)benzene was employed instead of the corresponding chloro derivative. O-(Phenylmethyl)hydroxylamine (O-Benzylhydroxylamine, 1). A solution of 3 (50.6 g, 0.20 mol) in 95% EtOH (600 mL) was treated with hydrazine hydrate (10.0 mL, 0.206 mol) and the reaction mixture stirred at 80 °C for 6 h. After cooling to room temperature, the colorless suspension was filtered in order to remove the formed 4, and the clear filtrate was concentrated in a rotary evaporator (20 mmHg) to a small volume. The obtained residue was taken up with Et2O
(200 mL) and the solution filtered in order to separate some additionally precipitated 4. The clear filtrate, after dilution with Et2O (200 mL) and washing with 10% aqueous Na2SO4 (2 × 200 mL), was dried over anhydrous Na2SO4 and the solvent distilled off. The pale yellow oily residue was finally fractionally distilled at reduced pressure (90 °C, oil bath), affording pure 1 in 87% isolated yield as a colorless liquid. Bp: 56 °C/210 Pa (58 °C/267 Pa).12 IR (neat):8 3309, 3033, 2921, 1683, 1591, 1494, 1454, 1362, 1188, 1079, 999, 918, 848, 822, 744, 703, 611, 483 cm-1. 1H NMR:8 δ 7.4-7.3 (m, 5 H, C6H5), 5.4 (br s, 2H, NH2), 4.7 (s, 2H, Ph-CH2). 13C NMR: δ 137.3, 128.4, 128.3, 127.9, 77.8 (CH2). MS (20 °C) m/z: 123 [M+], 91, 89, 77, 65, 63, 52, 51, 50, 39, 38. Acknowledgment We thank the University of Udine (FURD) for financial assistance. Literature Cited (1) (a) Thompson, R. M. Analysis of Mono- and Disaccharides by High-Performance Liquid Chromatography of the BenzyloximePerbenzoyl Derivatives. J. Chromatogr. 1978, 166, 201. (b) Magin, D. F. Preparation and Gas Chromatographic Characterization of Benzyloximes and p-Nitrobenzyloximes of Short-Chain (C1-C7) Carbonyls. J. Chromatogr. 1979, 178, 219. (2) Mattingly, P. G.; Miller, M. J. Chiral Syntheses of Protected 3-Amino-4-(alkoxycarbonyl)-2-azetidinones from β-Hydroxyaspartic Acid. J. Org. Chem. 1983, 48, 3556. (3) (a) Lee, B. H.; Miller, M. J. Natural Ferric Ionophores: Total Synthesis of Schizokinen, Schizokinen A, and Arthrobactin. J. Org. Chem. 1983, 48, 24. (b) Lee, B. H.; Miller, M. J. Constituents of Microbial Iron Chelators. The Synthesis of Optically Active Derivatives of δ-N-Hydroxy-l-ornithine. Tetrahedron Lett. 1984, 25, 927. (4) Akiyama, M.; Iesaki, K.; Katoh, A.; Shimizu, K. N-Hydroxy Amides. Part 5. Synthesis and Properties of N-Hydroxypeptides having Leucine Enkephalin Sequences. J. Chem. Soc., Perkin Trans. 1 1986, 851. (5) Ghosh, A. C.; Mckee, S. P.; Sanders, W. M. Stereoselective Reduction of R-Hydroxy Oxime Ethers: a Convenient Route to Cis1,2-Amino Alcohols. Tetrahedron Lett. 1991, 32, 711. (6) Rougny, A.; Daudon, M. Utilisation d’Imides N-Hydroxyles pour la Synthese d’Alkoxylamines Primaries. Bull. Soc. Chim. Fr. 1976, 833. (7) Hearn, M. T. W.; Ward, A. D. Hydroxamic Acids. VI. The Synthesis, Properties and Reactions of Amidic Hydroxamic Acid and Dihydroxamic Acid Derivatives. Aust. J. Chem. 1977, 30, 2031. (8) Welch, J. T.; Seper, K. W. Synthesis, Regioselective Deprotonation, and Stereoselective Alkylation of Fluoro Ketimines. J. Org. Chem. 1988, 53, 2991. (9) Bartovic, A.; Decroix, B.; Netchitailo, P. Synthesis of 1,2Oxazaheterocycles Containing an Isoindolone Moiety from NHydroxyphthalimide. J. Heterocycl. Chem. 2000, 37, 827. (10) Kim, J. N.; Kim, K. M.; Ryu, E. K. Improved Synthesis of N-Alkoxyphthalimides. Synth. Commun. 1992, 22, 1427. (11) Kim, S.; Lee, T. A.; Song, Y. Facile Generation of Alkoxy Radicals from N-Alkoxyphthalimides. Synlett 1998, 471. (12) Fujii, T.; Wu, C. C.; Yamada, S. Preparation and Nuclear Magnetic Resonance Spectra of Alkoxyamines. Chem. Pharm. Bull. 1967, 15, 345. (13) Bonaccorsi, F.; Giorgi, R. A Convenient, Large Scale Synthesis of O-Benzylhydroxylamine. Synth. Commun. 1997, 27, 1143. (14) Grochowski, E.; Jurczak, J. A New Synthesis of OAlkylhydroxylamines. Synthesis 1976, 682. (15) Alanine, A.; Bourson, A.; Bu¨ttelmann, B.; Gill, R.; Heitz, M.-P.; Mutel, V.; Pinard, E.; Trube, G.; Wyler, R. Bioorg. Med. Chem. Lett. 2003, 13, 3155.
Received for review July 5, 2004 Revised manuscript received January 12, 2005 Accepted January 14, 2005 IE049410C
