NOH C R1 R2 + TBSCl DMF, imidazole 64–88% N C R1 R2 OTBS (1) X R N OTBS 1 i, BH3–THF ii, HCl iii, NaOH X R NH2 2 N X H 3 R + 10 J. CHEM. RESEARCH (S), 1998 J. Chem. Research (S), 1998, 10–11 J. Chem. Research (M), 1998, 0151–0168 The Reduction of O-(tert-Butyldimethylsilyl) Aldoximes and Ketoximes and Electronic Effect Studies on the Novel Rearrangement that occurs with a Borane–Tetrahydrofuran Complex Margarita Ortiz-Marciales,* Elmer Cruz, Ileana Alverio, Dyliana Figueroa, Jos�e F.Cordero, Jos�e Morales, Jos�e A. Soto, Hiresh Dashmana and Carlos Burgos Department of Chemistry, University of Puerto Rico, Humacao University College, CUH Station, Hunacao, Puerto Rico 00791 The reduction of aromatic and cyclic O-(tert-butyldimethylsilyl) oximes with various reducing reagents, such as NaBH4, LiAlH4, 9-BBN, Li(Me3Si)2NBH3 and BH3–THF, was investigated. Since the fundamental work of Feuer and Vincent,1 it has been well established that borane and boron hydrides reduce oximes, oxime ethers and acyl oximes affording N-monosubstituted hydroxylamines or primary amines, depending on the structure and reaction conditions.In 1985, Itsuno et al.16 first enantioselectively reduced O-trimethylsilylacetophenone oxime with borane complexed to 1,3,2-oxazaborolidine formed in situ by the reaction of the chiral amino alcohol, (S)-(µ)-2-amino-3-methyl-1,1-diphenylbutan-1-ol and borane. Although the O-(trimethylsilyl)oximes are readily prepared, 19 they are very susceptible to hydrolysis.20 We developed a new and convenient method for the large scale synthesis of O-(tert-butyldimethylsilyl) oximes,21 that were also envisioned as novel intermedites for the synthesis of chiral primary amines,22 and other organic compounds.23,24 Tillyer et al.27 reported the enantioselective reduction of keto O-TBS oxime ethers by Corey’s reagent,28 for the synthesis of cyclic amino alcohols.However, they observed a lower yield for the 6-methoxy-substituted aromatic ring.Similarly, Liu and co-workers29 found recently only 5% of hydroxylamine along with an unidentified compound, when 6-benzyloxy- 2,3-dihydrobenzofuran 3-O-trimethylsilyloxime was reduced with borane and norephedrine. For the O-TBS analogue, it was reported that no reaction took place. In this paper, we describe our studies on the reduction of O-(tert-butyldimethylsilyl) oximes with various reducing reagents and the role that electronic effects play on the reaction pathways.Representative aromatic and aliphatic O-TBS oximes were prepared in excellent yield by the reaction of the corresponding oxime with tert-butyldimethylchlorosilane, DMF and imidazole, [eqn. (1)], using a modification of our previously reported method.21 Initially, we found that the O-TBS moiety hinders the aromatic oximes from reduction with NaBH4, LiAlH4, 9-BBN, Li(Me3Si)2NBH3 nd BH3–THF at room temperature.24 Afterwards, we investigated the reduction of O-TBS oximes with BH3–THF under more vigorous reaction conditions. The results of the reductions of the corresponding silylated aryl oximes are summarized in Table 1.Benzylamine (2a) was obtained in excellent yield from the reduction of the O-TBS benzaldoxime (1a) with BH3–THF complex after 3 h under reflux conditions. Borane reduction of the acetophenone O-TBS oxime at reflux temperature for 4 h afforded 21% of the expected a-methylbenzylamine (2b), 49% yield of N-ethylaniline (3b) and a minor amount of N-monosubstituted *To receive any correspondence (e-mail: M_Ortiz@cuhad.upr.clu.edu). Table 1 Reduction of aryl O-TBS ketoximes with borane Starting material Yield 1 X R Reaction conditions (%)a 2:3b aaa bbbccc def HHHHHH Me Me Me MeO NO2 Cl HHH Me Me Me Me Me Me Me Me Me 2BH3–THF, heat, 5 h 2BH3–THF, 1 MgBr2–Et2O, 5 h 3BH3–THF, 1.5 MgBr2–Et2O, 5 h 1BH3–THF, heat, 6 h 2BH3–THF, heat, 4 h 2BH3–THF, heat, 4 h, MgBr2–Et2O 2BH3–THF, 25 °C, 9 days 2BH3–THF, heat, 4 h 3BH3–THF, heat, 4 h 2BH3–THF, heat, 8 h 2BH3–THF, heat, 8 h 2BH3–THF, heat, 8 h 83c 80 88 65 86 88 24(12)e 80 70 75 74 55 a99:1 97:3 90:10 45:55d 31:69 43:57 21:79 36:64d 30:70 25:75 a99:1 63:36 aIsolated overall yields.Product purity determination by GC–MS and by 300 MHz 1H and 13C NMR. bDetermined by capillary GC. cComparison with authentic samples. dRatio of isolated products by column chromatography. eIsolated hydroxylamine.N OTBS [ ] n n = 1,2 NH2 [ ] n i, BH3–THF, heat ii, HCl iii, NaOH (2) J.CHEM. RESEARCH (S), 1998 11 hydroxylamine. Reduction with 3 mol. equiv. of or a longer reaction time gave no hydroxylamine. Only the isomeric amines 2b and 3b were isolated and characterized by their spectroscopic data. As illustrated in entries 2, 3 and 6, the addition of magnesium bromide–diethyl ether promotes the rearrangement of the silylated benzaldoxime and acetophenone oxime, probably owing to the coordination of magnesium to the oxygen, making the silyloxy moiety a better leaving group.Moreover, entries 8 and 10 clearly show that the yield of the reductive rearranged product increases with an increase in the electron- releasing ability of the para-substituent, while a strong electron-withdrawing group such as NO2 (entry 11) favours formation of the primary amine. Although the formation of secondary anilines from the borane reduction of aromatic oximes and oxime ethers is unprecedented in the literature, borane can act as a Lewis acid promoting a reductive type of rearrangement for O-TBS oximes.In the case of aliphatic cyclic O-TBS oximes, [eqn. (2)], we observed that O-TBS cyclopentanone and cyclohexanone oximes, when treated with BH3–THF under reflux, generated only cyclopentyl- and cyclohexyl-amine in a 70 and 68% yield, respectively. Techniques used: IR, 1H NMR, 13C NMR, GC–MS References: 49 Received, 4th August 1997; Accepted, 17th September 1997 Paper E/7/05622B References cited in this synopsis 1 H.Feuer and B. F. Vincent, J. Am. Chem. Soc., 1962, 84, 3771. 16 S. Itsuno, M. Nakano, K. Miyazaki, H. Masuda and K. Ito, J. Chem. Soc., Perkin Trans. 1, 1985, 2039. 17 Y. Sakito, Y. Yoneyoshi and G. Suzukamo, Tetrahedron Lett., 1988, 29, 233. 19 A. Singh, V. D. Gupta, G. Srivastova and R. C. Mehrota, J. Organomet. Chem., 1974, 64, 145. 20 E. W. Colvin, Silicon in Organic Synthesis, Butterworths, London, 1981. 21 M. Ortiz-Marciales, J. F. Cordero, S. Pinto and I. Alverio, Synth. Commun., 1994, 24, 409. 22 C. Burgos, J. Sato, M. DeJesus and M. Ortiz-Marciales, 211th ACS National Meeting, New Orleans, 1966. 23 M. Ufret, E. Cruz and M. Ortiz-Marciales, 203th ACS National Meeting, San Francisco, 1992. 24 M. Ortiz-Marciales, E. Cruz, I. Alverio, H. Dhasmana and D. Velazquez, 206th ACS National Meeting, Chicago, 1993. 27 R. D. Tillyer, C. Boudreau, D. Tschaen, U. H. Dolling and P. J. Reider, Tetrahedron Lett., 1995, 36, 4337. 28 E. J. Corey and R. K. Bakshi, J. Am. Chem. Soc., 1987, 109, 5551. 29 J. T. Dougherty, J. R. Flisak, J. Hayes, I. Lantos, L. Liu and L. Tucker, Tetrahedron: Asymmetry, 1997, 8