J. CHEM. SOC. PERKIN TRANS. I 1995 Asymmetric Reduction of Prochiral Aromatic Ketones by Borane-Amine Complexes in the Presence of Chiral Amine-BF, Catalysts Mariappan Periasamy," J. V. Bhaskar Kanth and Ch. Kishan Reddy School of Chemistry, University of Hyderabad, Central University PO, Hyderabad 500 134, India The borane complexes of (S)-(-)-N,N-dibenzyl-I -phenylethylamine 1, (S,S)-(-)-N,N-bis(1-phenylethy1)-I -phenylethylamine 2, (-)-2-phenyl-1 -(I -phenylethyl)pyrrolidine 3, (-)-7-(I -phenylethyl) -4.5-dihydro-3H-dinaphth 2,3-~;2',3'-eazepine 4 and 1-(1-phenylethyl-3,4-diphenyl-pyrrolidine 5 have been prepared and used to reduce prochiral aromatic ketones to alcohols in 10-57 e.e. in the presence of BF,-OEt,. The complex 4*BF, catalyses asymmetric reduction of acetophenone by N,N'-diethylaniline-BH, to give 1-phenylethyl alcohol in 51 e.e.A transition state consisting of a chiral amine.BF,.BH, complex and the ketone is proposed to explain the transformation. Chiral amine-BH, complexes are promising reagents for asymmetric reduction of prochiral compounds since the chiral amine can be readily recovered and recycled.' -3Although (R)-(+ ) and (S)-(-)-I-phenylethylamine-borane complexes reduce prochiral ketones to alcohols at reflux temperatures the latter are obtained in only low (1-3) enantiomeric exce~s.~ In contrast. borane complexes of 1-phenylethylamine and N,N-dimethyl-1-phenylamine fail to reduce ketones at room temperaturc in benzeneq5 although in the presence of 1 equiv. of BF,.OEt, they do so in 0.5 h at 0 "C, to give the alcohols in up to 13 ex.' More recently, the chiral bis(1-phenylethy1)-amineBH ,complex has been reported to reduce acetophenone with 427e.e.in the presence of BF,.0Et,.6 Here we describe a detailed investigation of this transformation undertaken both in order to understand its mechanism and also to select a chiral amine system that would give good results. Results and Discussion Svnthesir of the Chiral Aniines 1-5.-The parent amines of 1 and 2 have been prepared by following closely related procedures.',' The amines 3, 4 and 5 have been prepared as outlined in Scheme l.9-'2 1 2 The amine-borane derivatives of (S)-1, (S,S)-2 and (-)-3 prepared using (S)-(-)-1-phenylethylamine, (-)-4 prepared using (R)-(+)-I -phenylethylamine and ( -)-5 prepared using (S)-(-)-1-phenylethylamine (Scheme 1) were utilized for reductions.Initially, we carried out the investigations utilizing the amine system (-)-4. The borane complex of the chiral 3 amine (-)-4 was prepared by bubbling an excess of diborane gas through a benzene solution of (-1-4, the IR spectrum of which showed strong BH absorption at 2400 cm-'. Attempted reduction of acetophenone using this borane complex in benzene gave recovery of acetophenone even after the mixture had been stirred for 24 h at room temperature. A similar reaction conducted in the presence of BF,.OEt, gave 1-phenylethanol in 51 e.e. (Scheme 2). Results for the reduction of other ketones with this complex in the presence of BF,.OEt, are summarized in Table I.The configurations of the products are consistently R with the optical induction decreasing with increasing chain length of the alkyl moiety. Although the role of BF,.OEt, in these reductions is not understood, Grundon et a/. suggested a mechanism involving hydrogen-transfer followed by fluorine-transfer (Scheme 3).5 We have carried out further investigations in order to understand the role of BF,.OEt, in this reaction. It is known that BF,.OEt, liberates diborane from amine-BH, and, also, that diborane does not displace BF, from amineBF, adducts.' Accordingly, the formation of an amine-BF, complex as an intermediate cannot be ruled out. In any case, it was of interest to prepare the amine-BF, complex and examine whether it would catalyse the asymmetric reduction of acetophenone by an achiral Lewis base-borane complex such as N,N-diethyl- aniline-borane.The chiral amineSBF, complex was prepared by the addition of a stoichiometric amount of BF,.OEt, to the chiral amine (-)-4 in dry ether under nitrogen. The ether was pumped off under dry nitrogen to give the amine-BF, complex, to which N,N-diethylaniline-borane complex (1 equiv.) in dry benzene followed by acetophenone (1 equiv.) were added. Work-up gave the alcohol product in 51 e.e. The result is similar to that obtained following the earlier procedure, We carried out experiments using various amounts of chiral amine.BF, complex in the reduction of acetophenone by N,N-diethyl- anilineaBH, or triethylamineBH, the results for which are summarized in Table 2." They indicate that although the 428 J.CHEM. SOC. PERKIN TRANS. I 1995 OMe I,NaBHJlrlHF Me 7 3 4 Hd H Ph (3H-I NaBHamp;POC,2h phamp;H 0 THF. reflux H H-6+ ph6HOzC C02H PhxMephXph PhXM 6h PhxMe PhxMe 5 Scheme I Table 1 Reduction of prochiral ketones using amine (-)-4-borane complex" Product Substrate H OH Yield' E.e. RCOR' R (I r,y (c, solvent d, (Configuration) R = Ph, R' = Me 82 +23 (3, MeOH)' 51(R) R = Ph. R' = Et 81 +20(l, Me,CO)I 41(R) R = Ph, R' = Pr 80 t 5 (2, benzene) 1 1(R) R = I-naphthyl, R' = Me 78 t45 (2, MeOH)h 57(R) 'All reactions were carried out at 0 "C with 10 mmol each of amine.BH,, ketone and BF,.OEt, in benzene.The experiments were run at least twice in each case. Products were identified by analysis of spectral data (IR, 'H NMR) and comparison with the reported data. Yields are of isolated, chromatographed and distilled products. Optical rotations were measured with an Autopol-I1 automatic polarimeter (observed rotation accuracy 0.01). Throughout, .ID values are quoted in units of 10-' deg cm2 g-'. Based on the maximum -45.5 (c 3, MeOH) 16. Based on the maximum CN~' -47.03 (c 1, Me,CO) (R. H. Pickard and K. Kenyon, J. Chem. SOC.,1914, 105, 115). Based on the maximum .A5 t45.2 (c 3, benzene (see ref. in footnotef). Based on the maximum a:' -78.9 (c 3, MeOH).I3 Me' +-+ -hydrogentransfer i, PhCOMeJBF3.0Etz Phh=OBFJ + PhCH(Me)NH2BH3 c (-)4 I/,dll.HCI 51.le.e PhCH(Me)OBF3 + PhCH(Me)NG2BH2 f'uorine'ransfer-H2OScheme 2 PhCH(Me)OBF2 + PhCH(Me)Namp;BH2F -asymmetric inductions are decreased very little by a 50 iBH)iiIreduction in the concentration of chiral amine.BF, complex, PhCH(Me)OH + HZNCH(MejPh any further reduction has a significant effect. This may result from competitive uncatalysed reduction of the ketone by the Scheme 3 N,N-diethylaniline.BH, complex. We found that in the absence of amineSBF, acetophenone reacts with the N,N-diethyl-aniline.BH, complex at 0 "C over 3 h to give the corresponding It is clear from these results that the asymmetric inductions alcohol in 30 yield. are at best, modest. However, the mechanism of the catalytic In order to examine both whether such a catalytic process is a reduction by amineSBF, in intriguing since there is no free co- general one and its structural aspects, we have carried out ordination site available on the boron for further complexation similar experiments using amines 1, 2, 3 and 5.The results are with the ketone. The nature of the actual reactive species may summarized in the Table 3. be deduced from the results summarized in Tables 1-3. The J. CHEM. SOC. PERKIN TRANS. 1 1995 Table 2 Catalytic reduction of acetophenone in the presence of the chiral amine (-)-i.BF, complex" Ketone-amine-BF, Reaction External reducing Yieldb cai:: E.e. ' (mol. equiv.) time (h) agent (I (C3, CH,OH) 1:l 3 PhEt,N.BH, 81 +23 51.1 1:1 15 Et,N*BH, 80 +22 48.9 1 :0.75 3 PhEt,N.BH, 82 +23 1 :0.5 3 PhEt2N*BH3 80 +22 1 :0.5 15 EtxN.BH3 80 +22 I :0.4 3 PhEt,N*BH, 80 + 19 1 :0.25 3 PhEt,N.BH, 75 +9 51.1 48.9 48.9 42.2 20.0 Reactions were carried out with the ketone (10 mmol) and the amine-BH, (10 mmol) at 0 OC.The experiments were run at least twice in each case. Yields are of isolated, chromatographed and distilled products. 'Enantiomeric excess based on the maximum a;' -45.5 (c 3, MeOH). Table 3 Reduction of prochiral ketones using amine-borane complexes" Product OHSubstrate Amine-borane Yield E.e. () RCOR' complex R ()' (Config. all R) R = Ph, R' = Me (-1-1 R = Ph,R = Me 80 24 (-)-2 R = Ph,R =Me 82 48 ( -)-3 R = Ph,R =Me 73 53 (-1-5 R = Ph,R = Me 86 17 R = Ph, R' = Et (-1-1 R = Ph, R' = Et 87 22' ( -)-2 R = Ph, R' = Et 78 31 ( -)-3 R = Ph, R' = Et 70 41 ( -)-5 R = Ph, R' = Et 84 10 R = Ph, R' = Pr ( -)-I R = Ph, R' = Pr 80 6* ( -1-2 R = Ph, R' = Pr 75 10 ( -1-3 R = Ph, R' = Pr 65 15 R = I-naphthyl, R' = Me ( -1-1 R = 1-naphthyl, R' = Me 75 39 9 ( -)-2 R = I-naphthyl, R' = Me 70 52 ( -1-3 R = I-naphthy1,R' = Me 71 56 'All reactions were carried out at room temp.for 6 h with amine-BH, (10 mmol) ketone (10 mmol) and BF,-OEt, (10 mmol) in benzene. The experiments were run at least twice in each case. Products were identified by analysis of the spectral results (IR, 'H NMR) and comparison of these with those already reported. Yields are of isolated, chromatographed and distilled products.Based on the maximum XI;' -45.5 (c 3, MeOH). 'Based on the maximum alp -47.03 (c 1, Me2C0).14 IBased on the maximum .A5 +45.2 (c 3, benzene).16 4Based on the maximum ~6~-78.9 (c 3, MeOH) (see ref. in footnotef, Table I). reaction of R,N-BH, with BF,-OEt, is expected to give R,N.BF, and borane. Since the diborane is not liberated, the B-H unit must be present in an associated form along with the R,N.BF, to provide the reactive intermediate. Also, the same reactive intermediate would have been formed in the Scheme 4 reaction ofchiral R3N.BF3 with PhEt,N.BH, or Et,N-BH,. In order to gain further information about the reactive species, we ketone oxygen to give a reactive intermediate, the amine.BF, prepared chiral amineeBF, using the amine 4 as described should also catalyse other ketone reactions.For example, if this above. This was dissolved in dry benzene and diborane gas was arnineBF, species can activate an a$-unsaturated carbonyl bubbled through the solution. The IR spectrum of the solution group, it should catalyse certain Diels-Alder reactions. In the exhibits strong B-H absorption at 2450 ern-'. Since diborane event Diels-Alder additions of dienes and dienophiles cannot displace BF, from the R,N.BF, complex, the :B-H normally catalysed by a Lewis acid failed to react in the must be present in an associated form with R,N-BF,. Addition presence of the amineeBF, species. Since R3N.BF, catalyses, of triphenylphosphine to this gave, after work-up, a solid then, only borane reductions, the results can be best explained product along with the chiral amine.The llB NMR spectrum in terms of the transition state outlined in Fig. 1. In order to of this compound was found to be the same as that of PPh,. investigate this species, we carried out similar experiments BH,. The associated complex prepared in this way reduced with triethylamine which, although forming a strong complex acetophenone to the corresponding alcohol in 48.9 e.e. with borane, failed to reduce acetophenone at 0 OC. However, in (Scheme 4). the presence of BF,-OEt, (I equiv.) the reduction is complete Initially, it was thought that since this catalysis might be in 8 h at 0deg;C to give I-phenylethanol (85). Similarly, explained in terms of displacement of one of the fluorides by the acetophenone gave 1-phenylethanol(84). I--l Fig.1 Experimental The chiral amine 1 was prepared through benzylation of (S)-(-)-1-phenylethylamine in the presence of KOH, benzyl bromide and sodium iodide.' The amine 2 has been synthesized by benzylation of the corresponding secondary amine which can be readily prepared using (S)-(-)-1-phenylethylamine following a reported method.' The diastereoisomeric amines of 3 have been prepared from the dibromide 6 or the imine 7 as outlined in Scheme The diastereoisomeric amines 4 and 5 were also prepared as outlined in Scheme 1."-'* These diastereoisomers were separated by chromatography on neutral alumina column utilizing hexane-ethyl acetate as eluent.The amines eluted first in each case were obtained in pure form and utilized for this study (Tables 1-3). Reduction of Acetophenone with a Chiral Amine (-)-4-borane Complex in the Presence of BF,.OEt,.-Diborane gas (20 mmol) generated through the slow addition of I, (5.2 g, 20 mmol) in diglyme (25 cm3) to NaBH, (1.6 g, 40 mmol) in diglyme (I0 cm3) at room temperature, was bubbled slowly into a benzene solution of (-)-7-( 1-phenylethyl)-4,5-dihydro-3H-dinaphthazepine (3.99 g, 10 mmol) during 2 h. Acetophenone (1.2 g, 10 mmol) was added at 0 OC to the reaction mixture which was then stirred for 2 h at 0 "C. The reaction was quenched with water and the organic layer was separated, washed with brine, dried (MgSO,), and evaporated under reduced pressure.The amine present in the mixture was precipitated with BF,.OEt, in ether as a BF, salt. The ether layer was decanted and concentrated to give the crude alcohol product which was purified first by column chromatography on silica gel with hexane-ethyl acetate (90: 10) as eluent and then by distillation under reduced pressure; the product (1 .O g, 82) had b.p. 80 OC at 6 mmHg, {lit.,15 203 *C(at 760 mmHg),sr;' +23 (c 3, MeOH); lit.,I6 a;' -45.5 (c 3, MeOH)); v,,,(neat)/cm-' 3350, 3050 and 1600; 6,(100 MHz, CDCIJ 1.4 (d, 3 H), 2.9 (br s, 1 H), 4.8 (4, 1 H) and 7.3 (m, 5 H). Reduction of Acetophenone with a N,N-Diethylaniline-Borane Complex in the Presence of a Chiral Amine (-)-4BF, Complex as Lewis Acid Catalyst.-To a solution of the chiral amine 4 (3.99 g, 10 mmol) dissolved in dry ether (20 cm3) was added BF,.0Et2 (1.42 g, 10 mmol) at 0 "C.The chiral amineBF, complex was precipitated and the solvent was pumped off under J. CHEM. SOC. PERKIN TRANS. i 1995 nitrogen atmosphere. Into a two-necked septum flask N,N-diethylaniline (1.49 g, 10 mmol) was dissolved in benzene (40 cm3) and diborane gas (20 mmol) was bubbled into the solution at 10deg;C during 3 h. The N,N-diethylaniline-borane thus prepared was transferred to the flask containing the chiral amine-BF, complex under a nitrogen atmosphere and this was followed by acetophenone (1.2 g, 10 mmol) added at 0 "C. The mixture was stirred for 3 h after which the reaction was quenched with water (5 cm3).The organic layer was separated and washed with 3 mol dm-, HCI (3 x 10cm3) to remove N,N-diethylaniline after which the chiral amine was removed as its BF, complex to give the amine-free reduced product. The alcohol was purified by column chromatography over silica gel using hexane-ethyl acetate (90: 10) as eluent and by distilation under reduced pressure; the product (I .O g, 82) had r;' +23 (c 3, MeOH). Acknowledgements Support of this research work by DST and CSIR (New Delhi) is gratefully acknowledged. We also thank UGC (New Delhi) for special assistance and COSIST support. References 1 G.C. Andrews and T. C. Crawford, Tetrahedron Lett., 1980,693. 2 G. C. Andrews, Tetrahedron Lett., 1980, 687. 3 A.Pelter and K. Smith, Comprehensive Organic Chemistry, ed. D. Jones, Pergamon, Oxford, 1979,3,687. 4 R. F. Borch and S. R. Levitan, J. Org. Chem., 1972, 37, 2347. 5 M. F. Grundon, D. G. McCleery and J. W. Wilson, J. Chem. SOC., Perkin Trans. I, 198I, 23 I. 6 H. Hogeveen and,M. B. Elevald, Tetrahedron Lett., 1986,26,635. 7 W. G. Young, F. F. Caserio Jr. and D. P. Brandon Jr.,J. Am. Chem. SOC.,1960,82, 6163. 8 M. B. Elevald, H. Hogeveen and E. P. Schudde, J. Org. Chem., 1986, 51, 3635. 9 Ch. Kishan Reddy and M. Periasamy, unpublished results. 10 J. V. B. Kanth and M. Periasamy, J. Chem. SOC.,Chem. Commun., 1990, 1145. 11 J. V. B.Kanth, Ph.D. Thesis, University of Hyderabad, 1993. 12 A. S. B. Prasad, J. V. B. Kanth and M. Periasamy, Tetrahedron, 1993, 48,4623. 13 H. C. Brown, Y.M. Choi and S. Narasimham, J. Org. Chem., 1982, 47, 3153. 14 C. Narayana and M. Periasamy, J. Organomet. Chem., 1987, 323, 145. 15 K. Kawazu, T. Fujita and T. Matsui, J. Am. Chem. SOC.,1959,81, 933. 16 A. Hirao, S. Itsuno, V. Ito and S. Nakahama, J. Chem. SOC., Chem. Commun., 1983, 469. Paper 4/05336B Received 18th September 1994 Accepted 17th October 1994
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