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Cu(II)-Catalyzed asymmetric boron conjugate addition to a,b-unsaturated imines in water† Taku Kitanosono, Pengyu Xu, Satoshi Isshiki, Lei Zhu and Shu¯ Kobayashi*
Received 27th May 2014, Accepted 24th June 2014 DOI: 10.1039/c4cc04062g www.rsc.org/chemcomm
Enantioselective conjugate addition of bis(pinacolato)diboron to a,b-unsaturated imines proceeds smoothly in water in the presence of a chiral copper(II) complex consisting of Cu(OAc)2 and chiral 2,20 -bipyridine. The corresponding b-boryl imines, which were oxidized to b-hydroxy imines, further leading to c-amino alcohols, were obtained in high yields and high enantioselectivities.
Enantiopure b-hydroxy imines are useful precursors of optically active g-amino alcohols, and compounds with backbones composed of the latter are often observed in natural products including antibiotics1 as well as in chiral auxiliaries2 and chiral ligands3 for asymmetric synthesis. Asymmetric synthesis of g-amino alcohols has received much attention in recent years because of the versatility of such compounds in chemical transformations and because of their anticipated pharmacology in areas such as development of ‘‘secondgeneration’’ serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants4 and m-opioid receptor agonist analgesics.5 Intensive work over the past decade on developing efficient protocols to furnish enantioenriched g-amino alcohols has led to the emergence of asymmetric catalysts for the construction of suitable precursors. A widely implemented technique is based on asymmetric synthesis of precursors such as b-hydroxy imines,6,7 b-amino carbonyl compounds,8 and isoxazolidines,9 or other cyclic compounds,10 followed by appropriate selective reduction. A limited number of reports on b-hydroxy imines have been published7,11 where chiral Cu(I) catalysts were used for asymmetric b-borylation of electrondeficient alkenes.12 These protocols entailed the use of air-sensitive phosphine ligands as well as the addition of strong bases such as sodium tert-butoxide to activate bis(pinacolato)diboron.13 On the other hand, organic reactions in water are now of great interest. Water is a safe, inexpensive, and environmentally benign solvent. While most organic reactions tend to be carried
Deparment of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan. E-mail: [email protected]; Fax: +81-3-5684-0634; Tel: +81-3-5841-4790 † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc04062g
9336 | Chem. Commun., 2014, 50, 9336--9339
out in organic solvents, it is becoming apparent that some reactions proceed smoothly in water and that unique reactivity and selectivity can be induced in reactions in water compared with the same reactions in organic solvents. In general, organic reactions in water are less explored and much less information is available on reactions in aqueous medium compared with reactions in organic solvents. In this context, we have recently disclosed Cu(II)-catalyzed asymmetric boron conjugate additions to a,b-unsaturated ketones, esters, and amides in water.14 While boron conjugate addition reactions have previously been reported, in most cases Cu(I) catalysts have been used in organic solvents and, to our knowledge, no asymmetric examples of the reaction in water have been disclosed before our report. Because unique reactivities and selectivities can be obtained in asymmetric catalysis in water, we became interested in the application of such chiral Cu(II) catalysis to other aqueous systems. We were particularly intrigued by the use of imines in water. While imines (Schiff bases) are versatile intermediates in organic transformations, their use in water is very limited because they readily decompose in the presence of even a small amount of water. We now report Cu(II)-catalyzed asymmetric boron conjugate additions to a,b-unsaturated imines in water. Remarkably, the reactions proceed smoothly without decomposition of the imines, to afford the desired b-boryl imines, which were oxidized to b-hydroxy imines, in high yields and with high enantioselectivities.15 At the outset, Cu(OH)2 with chiral 2,20 -bipyridine16 was applied to the reaction of benzalacetone-derived imines with bis(pinacolato)diboron in water (Table 1). As reported previously,14a,d despite the insolubility of all materials (both substrates, Cu(OH)2 and chiral ligand) in water, the reaction of benzalacetone proceeded smoothly to afford the desired product in high yield with moderate enantioselectivity after subsequent oxidation (entry 1). We then examined the reaction of a,b-unsaturated imines. Whereas the reactions of a,b-unsaturated imines derived from isopropylamine or aniline gave low yields with low enantioselectivities (entries 2 and 3), the use of the a,b-unsaturated imines derived from benzylamine resulted in high reactivity and excellent enantioselectivity (entry 4).
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Table 1
ChemComm
Comparative reaction of benzalacetone and the corresponding imines
Entry
R
Yielda (%)
eeb (%)
1c 2 3 4 5 6
— i Pr Ph Bn OH NHPh
84 20 19 65 43 Trace
65 32 35 499 17 —
a Isolated yield. b Determined by HPLC analysis. c Performed with 5 mol% catalyst loading at 5 1C; ref. 14d.
Besides steric hindrance, the exocyclic CQN double bonds as well as CQC bonds tend to undergo the isomerization,17 exerting an influence on the stereochemical outcomes. The reactions of a,b-unsaturated oxime or hydrazone produced poor results, presumably because of the strong coordination between copper and the substrates (entries 5 and 6). In previous reports,14a,b,d b-borylation reactions of multifarious unsaturated compounds were efficiently catalyzed by chiral Cu(II) complexes formed from Cu(OH)2 or Cu(OAc)2 and chiral 2,2 0 -bipyridine, irrespective of whether the catalyst was homogeneous or heterogeneous. The use of Cu(OH)2 renders the catalysis heterogeneous, whereas Cu(OAc)2 is homogeneous. The effect of Cu(II) salts on the outcome of the reaction was then examined (Table 2). The addition of one equivalent of AcOH to Cu(OH)2 increased the reactivity slightly while retaining excellent enantioselectivity (entry 2). The catalytic system became homogeneous under these conditions, which implied an exchange of one hydroxide with an acetate group. Catalytic use of Cu(II)
Table 2
Effect of Cu salts
Entry
Cu salt
Yielda (%)
eeb (%)
1 2c 3 4d 5e 6 7 8 9
Cu(OH)2 Cu(OH)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 CuCl2 CuSO4 Cu(OTf)2 Cu(acac)2
65 69 83 86 67 10 43 5 80
499 499 499 499 94 45 85 499 499
a Isolated yield. b Determined by HPLC analysis. c 10 mol% of AcOH was added as an additive. d 5 mol% of catalyst loading. e 1 mol% of catalyst loading.
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Scheme 1
Enantioselective b-borylation of a,b-unsaturated imines.
acetate resulted in higher yield of the desired product, which was formed with 499% ee (entry 3). Whereas a similar result was obtained by decreasing the catalyst loading from 10 to 5 mol%, the yield and the enantioselectivity decreased slightly when 1 mol% catalyst was used (entries 4 and 5). Copper salts with more nucleophilic counteranions such as Cl and SO42 exhibited lower enantioselectivity compared with Cu(OTf)2, and the use of Cu(OTf)2 gave a poor yield (entries 6–8). Performing the reaction with Cu(II) acetylacetonate afforded similar results to those obtained with Cu(II) acetate (entry 9). A range of a,b-unsaturated imines underwent Cu(II)-catalyzed enantioselective b-borylation to afford the desired enantioenriched b-hydroxy imines in high yields with excellent enantioselectivities (Scheme 1). It is noteworthy that imines bearing chalcone and benzalacetone backbones gave b-hydroxy imines with outstanding enantioselectivities (499% ee). The use of a substrate with an electron-withdrawing substituent at the b-position resulted in lower enantioselectivity. The reaction profile of Cu(OAc)2-catalyzed b-borylation of an a,b-unsaturated imine was compared with that of the reaction of the corresponding ketone (Scheme 2, top). Although the b-borylation of the a,b-unsaturated imine was slightly slower than that of the corresponding ketone, the relatively rapid completion of the reaction implied sufficient and efficient activation of the a,b-unsaturated imine by Cu(OAc)2. On the other hand, when a 1 : 1 mixture of chalcone and the corresponding imine was added to the catalyst solution, chalcone was consumed almost quantitatively and the competitive b-borylation of the imine was clearly hampered (Scheme 2, bottom). Considering decomposition of the imine in water, the amounts of the recovered imine and the ketone are reasonable. The preferential consumption of the a,b-unsaturated ketone over the corresponding imine under Cu(II) catalysis is interesting, considering the preferential activation of an aldimine over an aldehyde by a Cu(II) salt.18 We assume that the asymmetric boron conjugate addition to a,b-unsaturated imines in water follows the catalytic cycle shown in Scheme 3. In situ formation of a borylcopper(II) species 2 was confirmed by ESI-MS analysis, and this intermediate was assumed to be a key component in the Cu(II) catalysis.14b,d
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Scheme 2 Competitive reactivity against the a,b-unsaturated ketone and the corresponding imine as an independent system (above) and as a mixed system (below).
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activators in water, resulting in potentially base-free conditions. Given the instability of the d9–p interaction due to its unpaired electron, a nucleophilic addition would take place to produce an N-enolate intermediate 3. The polarization of the Cu–B bond toward the boron could facilitate the interaction. Steric bulk of the two tert-butyl groups in the ligand may give rise to enantiofacial preference toward the more accessible Si face, which is consistent with the observed sense of chiral induction. Because the proton-transfer rate in water is known to be in the order of picoseconds, rapid protonation subsequent to the nucleophilic addition would afford the product in water, lowering the activation energy and facilitating the catalytic turnover.21 It was found that a chiral Cu(II) complex formed with chiral 2,2 0 -bipyridine was suitable for use in the b-borylation of a,b-unsaturated imines in water. The use of Cu(OAc)2 as the Cu(II) source gave superior performance, affording enantioenriched b-hydroxy imines after oxidation, which are known to be useful precursors of g-amino alcohols. Excellent stereocontrol was achieved with a range of substrates. In contrast to the known Cu(I) catalyses in organic solvents, this Cu(II) protocol in water is expedient and free from the use of air-sensitive phosphine ligands and strong bases. The use of unstable imines in water is also remarkable. This work was partially supported by a Grant-in-Aid for Science Research from the Japan Society for the Promotion of Science (JSPS), Global COE Program, The University of Tokyo, MEXT, Japan, Japan Science Technology Agency (JST). T.K. thanks the JSPS for a Research Fellowship for Young Scientists.
Notes and references
Scheme 3
Proposed mechanism of Cu(II) catalysis.
Crystallographic investigations showed that the CuBr2–ligand complex adopted a square pyramidal structure in which two nitrogen atoms and one of the oxygen atoms of the ligand were attached to Cu(II) in a tridentate manner.19 In contrast to Cu(I) catalysis,20 which demands a strong base to activate diboron, counteranions of Cu(II) salts or noncoordinating hydroxy groups of the chiral ligand (1) were expected to function as
9338 | Chem. Commun., 2014, 50, 9336--9339
1 (a) F. Benedetti and S. Norbedo, Chem. Commun., 2001, 203–204; (b) S. Knapp, Chem. Rev., 1995, 95, 1859–1876. 2 (a) S. M. Lait, D. A. Rankic and B. A. Keay, Chem. Rev., 2007, 107, ´s, J. Nieto and S. Del Pozo, J. Org. 767–796; (b) R. Pedrosa, C. Andre Chem., 2003, 68, 4923–4931; (c) D. W. L. Sung, P. Hodge and P. W. Stratford, J. Chem. Soc., Perkin Trans. 1, 1999, 1463–1472; ´s, J. Nieto, R. Pedrosa and M. Vicente, J. Org. Chem., (d) C. Andre 1998, 63, 8570–8573. 3 For recent examples, see: (a) L. Zhan and S. Ma, Angew. Chem., Int. ´. Bala ´zs, T. A. Martinek and Ed., 2008, 47, 258–297; (b) Z. Szakonyi, A ¨p, Tetrahedron: Asymmetry, 2006, 17, 199–204; (c) M. Panda, ¨lo F. Fu P.-W. Phuan and M. C. Kozlowski, J. Org. Chem., 2003, 68, 564–571; ´s and R. Pedrosa, (d) M. J. Vilaplana, P. Molina, A. Arques, C. Andre Tetrahedron: Asymmetry, 2002, 13, 5–8; (e) T. Mino, S. Hata, K. Ohtaka, M. Sakamoto and T. Fujita, Tetrahedron Lett., 2001, 42, 4837–4839; ( f ) G. Palmieri, Tetrahedron: Asymmetry, 2000, 11, 3361–3373; (g) S. R. Davies, M. C. Mitchell, C. P. Cain, P. G. Devitt, R. J. Taylor and T. P. Kee, J. Organomet. Chem., 1998, 550, 29–57. 4 J. Wang, D. Liu, Y. Liu and W. Zhang, Org. Biomol. Chem., 2013, 11, 3855–3861. 5 A. Pohland and H. R. Sullivan, J. Am. Chem. Soc., 1953, 75, 4458–4459. 6 T. Kashiwagi, S. Kotani, M. Sugiura and M. Nakajima, Tetrahedron, 2011, 67, 531–539. ´, E. Ferna ´ndez and 7 (a) A. D. J. Calow, A. S. Batsanov, A. Pujol, C. Sole ´, A. Whiting, Org. Lett., 2013, 15, 4810–4813; (b) A. D. J. Calow, C. Sole ´ndez, ChemCatChem, 2013, 5, 2233–2239; A. Whiting and E. Ferna ´ndez, C. Sole ´ and (c) A. D. J. Calow, A. S. Batsanov, E. Ferna ´, A. Whiting, Chem. Commun., 2012, 11401–11403; (d) C. Sole ´s and A. Bonet, A. H. M. de Vries, J. G. de Vries, L. Lefort, H. Gulya ´ndez, Organometallics, 2012, 31, 7855–7861; (e) C. Sole ´, E. Ferna ´s and E. Ferna ´ndez, Adv. Synth. Catal., 2011, A. Whiting, H. Gulya ´, A. Tatla, J. A. Mata, A. Whiting, H. Gulya ´s 353, 376–384; ( f ) C. Sole ´ndez, Chem. – Eur. J., 2011, 17, 14248–14257. and E. Ferna
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Communication 8 (a) R. Abonia, D. Arteaga, J. Castillo, B. Insuasty, J. Quiroga and A. Ortı´z, J. Braz. Chem. Soc., 2013, 24, 1396–1402; (b) C. Appayee, A. J. Fraboni and S. E. Brenner-Moyer, J. Org. Chem., 2012, 77, 8828–8834; (c) F. A. Davis, P. M. Gaspari, B. M. Nolt and P. Xu, J. Org. Chem., 2008, 73, 9619–9626. 9 (a) Y. Xie, K. Yu and Z. Gu, J. Org. Chem., 2014, 79, 1289–1302; ´rinot, S. Reymond and J. Cossy, J. Org. Chem., (b) J. Cornil, A. Gue 2013, 78, 10273–10287; (c) K. V. Gothelf and K. A. Jørgensen, Chem. ¨ger, V. Buß and W. Schwab, Rev., 1998, 98, 863–909; (d) V. Ja Tetrahedron Lett., 1978, 19, 3133–3136. 10 (a) G. T. Rice and M. C. White, J. Am. Chem. Soc., 2009, 131, 11707–11711; (b) J.-L. Liang, S.-X. Yuan, J.-S. Huang, W.-Y. Yu and C.-M. Che, Angew. Chem., Int. Ed., 2002, 41, 3465–3468. ´, H. Gulya ´s and 11 For racemic examples, see: (a) A. Bonet, C. Sole ´ndez, Chem. – Asian J., 2011, 6, 1011–1014; (b) C. Sole ´ and E. Ferna ´ndez, Chem. – Asian J., 2009, 4, 1790–1793. E. Ferna 12 A number of Cu(I)-catalysed protocols for the enantioselective construction of a-chiral boranes were explored: (a) H. Ito, H. Yamanaka, J.-I. Tateiwa and A. Hosomi, Tetrahedron Lett., 2000, 41, 6821–6825; (b) K. Takahashi, T. Ishiyama and N. Miyaura, J. Organomet. Chem., 2001, 625, 47–53; (c) K. Takahashi, T. Ishiyama and N. Miyaura, Chem. Lett., 2000, 982–983; (d) X. Feng and J. Yun, Chem. – Eur. J., 2010, 16, 13609–13612; (e) X. Feng and J. Yun, Chem. Commun., 2009, 6577–6579; ( f ) H. Chea, H.-S. Sim and J. Yun, Adv. Synth. Catal., 2009, 351, 855–858; (g) H.-S. Sim, X. Feng and J. Yun, Chem. – Eur. J., 2009, 15, 1939–1943; (h) J.-E. Lee and J. Yun, Angew. Chem., Int. Ed., 2008, 47, 145–147; (i) S. Mun, J.-E. Lee and J. Yun, Org. Lett., 2006, 8, 4887–4889; ( j) S. Radomkit and A. H. Hoveyda, Angew. Chem., Int. Ed., 2014, 53, 3387–3391; (k) J. M. O’Brien, K.-S. Lee and A. H. Hoveyda, J. Am. Chem. Soc., 2010, 132, 10630–10633; (l) I.-H. Chen, L. Yin, W. Itano, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 11664–11665; (m) J. K. Park, H. H. Lackey, M. D. Rexford, K. Kovnir, M. Shatruk and D. T. McQuade, Org. Lett., 2010, 12, 5008–5011and the authoritative reviews; (n) A. D. J. Calow and A. Whiting, Org. Biomol. Chem., 2012, 10, 5485–5497; (o) E. Hartmann, D. J. Vyas and M. Oestreich, Chem. ¨ther and Commun., 2011, 47, 7917–7932; (p) J. A. Schiffner, K. Mu M. Oestreich, Angew. Chem., Int. Ed., 2010, 49, 1194–1196.
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ChemComm 13 A base-free catalytic system comprising Cu2O was reported recently. See ref. 7b. 14 (a) T. Kitanosono, P. Xu and S. Kobayashi, Chem. – Asian J., 2014, 9, 179–188; (b) T. Kitanosono, P. Xu and S. Kobayashi, Chem. Commun., ˇ asar, Appl. Organomet. 2013, 49, 8184–8186; (c) G. Stavber and Z. C Chem., 2013, 27, 159–165; (d) S. Kobayashi, P. Xu, T. Endo, M. Ueno and T. Kitanosono, Angew. Chem., Int. Ed., 2012, 51, 12763–12766; For a racemic example, see: (e) S. B. Thorpe, J. A. Calderone and W. L. Santos, Org. Lett., 2012, 14, 1918–1921. 15 (a) S. Kobayashi, T. Busujima and S. Nagayama, J. Chem. Soc., Chem. Commun., 1998, 34, 19–20; (b) T. Hamada, K. Manabe and S. Kobayashi, Angew. Chem., Int. Ed., 2003, 42, 3927–3930; (c) I. Ibrahem and A. Cordova, Chem. Commun., 2006, 1760–1762. 16 (a) S. Ishikawa, T. Hamada, K. Manabe and S. Kobayashi, Synthesis, 2005, 2176–2182; (b) C. Bolm, M. Ewald, M. Felder and G. Schlingloff, Chem. Ber., 1992, 125, 1169–1190; (c) C. Bolm, M. Zehnder and D. Bur, Angew. Chem., Int. Ed. Engl., 1990, 29, 205–207. ¨rner and E. Fischer, J. Photochem. Photobiol., A, 1991, 57, 17 H. Go 235–246. 18 S. Kobayashi, T. Busujima and S. Nagayama, Chem. – Eur. J., 2000, 6, 3491–3494. 19 (a) M. Kokubo, T. Naito and S. Kobayashi, Tetrahedron, 2010, 66, 1111–1118; (b) C. Ogawa, M. Kokubo and S. Kobayashi, J. Synth. Org. Chem., Jpn., 2010, 68, 718–728; (c) M. Kokubo, T. Naito and S. Kobayashi, Chem. Lett., 2009, 38, 904–905. 20 This mechanism is supported by quantum-chemical calculations, see: L. Dang, Z. Lin and T. B. Marder, Organometallics, 2008, 27, 4443–4454. 21 For recent examples that demonstrate the profound correlation between unique catalyses exerted in water and the protonation event, see: (a) T. Kitanosono, T. Ollevier and S. Kobayashi, Chem. – Asian J., 2013, 8, 3051–3062; (b) T. Kitanosono and S. Kobayashi, Asian J. Org. Chem., 2013, 2, 961–966; (c) S. Kobayashi, T. Endo, T. Yoshino, U. Schneider and M. Ueno, Chem. – Asian J., 2013, 8, 2033–2045; (d) T. Kitanosono, M. Sakai, M. Ueno and S. Kobayashi, Org. Biomol. Chem., 2012, 10, 7134–7147.
Chem. Commun., 2014, 50, 9336--9339 | 9339
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Cu(II)-Catalyzed asymmetric boron conjugate addition to a,b-unsaturated imines in water† Taku Kitanosono, Pengyu Xu, Satoshi Isshiki, Lei Zhu and Shu¯ Kobayashi*
Received 27th May 2014, Accepted 24th June 2014 DOI: 10.1039/c4cc04062g www.rsc.org/chemcomm
Enantioselective conjugate addition of bis(pinacolato)diboron to a,b-unsaturated imines proceeds smoothly in water in the presence of a chiral copper(II) complex consisting of Cu(OAc)2 and chiral 2,20 -bipyridine. The corresponding b-boryl imines, which were oxidized to b-hydroxy imines, further leading to c-amino alcohols, were obtained in high yields and high enantioselectivities.
Enantiopure b-hydroxy imines are useful precursors of optically active g-amino alcohols, and compounds with backbones composed of the latter are often observed in natural products including antibiotics1 as well as in chiral auxiliaries2 and chiral ligands3 for asymmetric synthesis. Asymmetric synthesis of g-amino alcohols has received much attention in recent years because of the versatility of such compounds in chemical transformations and because of their anticipated pharmacology in areas such as development of ‘‘secondgeneration’’ serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants4 and m-opioid receptor agonist analgesics.5 Intensive work over the past decade on developing efficient protocols to furnish enantioenriched g-amino alcohols has led to the emergence of asymmetric catalysts for the construction of suitable precursors. A widely implemented technique is based on asymmetric synthesis of precursors such as b-hydroxy imines,6,7 b-amino carbonyl compounds,8 and isoxazolidines,9 or other cyclic compounds,10 followed by appropriate selective reduction. A limited number of reports on b-hydroxy imines have been published7,11 where chiral Cu(I) catalysts were used for asymmetric b-borylation of electrondeficient alkenes.12 These protocols entailed the use of air-sensitive phosphine ligands as well as the addition of strong bases such as sodium tert-butoxide to activate bis(pinacolato)diboron.13 On the other hand, organic reactions in water are now of great interest. Water is a safe, inexpensive, and environmentally benign solvent. While most organic reactions tend to be carried
Deparment of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan. E-mail: [email protected]; Fax: +81-3-5684-0634; Tel: +81-3-5841-4790 † Electronic supplementary information (ESI) available. See DOI: 10.1039/ c4cc04062g
9336 | Chem. Commun., 2014, 50, 9336--9339
out in organic solvents, it is becoming apparent that some reactions proceed smoothly in water and that unique reactivity and selectivity can be induced in reactions in water compared with the same reactions in organic solvents. In general, organic reactions in water are less explored and much less information is available on reactions in aqueous medium compared with reactions in organic solvents. In this context, we have recently disclosed Cu(II)-catalyzed asymmetric boron conjugate additions to a,b-unsaturated ketones, esters, and amides in water.14 While boron conjugate addition reactions have previously been reported, in most cases Cu(I) catalysts have been used in organic solvents and, to our knowledge, no asymmetric examples of the reaction in water have been disclosed before our report. Because unique reactivities and selectivities can be obtained in asymmetric catalysis in water, we became interested in the application of such chiral Cu(II) catalysis to other aqueous systems. We were particularly intrigued by the use of imines in water. While imines (Schiff bases) are versatile intermediates in organic transformations, their use in water is very limited because they readily decompose in the presence of even a small amount of water. We now report Cu(II)-catalyzed asymmetric boron conjugate additions to a,b-unsaturated imines in water. Remarkably, the reactions proceed smoothly without decomposition of the imines, to afford the desired b-boryl imines, which were oxidized to b-hydroxy imines, in high yields and with high enantioselectivities.15 At the outset, Cu(OH)2 with chiral 2,20 -bipyridine16 was applied to the reaction of benzalacetone-derived imines with bis(pinacolato)diboron in water (Table 1). As reported previously,14a,d despite the insolubility of all materials (both substrates, Cu(OH)2 and chiral ligand) in water, the reaction of benzalacetone proceeded smoothly to afford the desired product in high yield with moderate enantioselectivity after subsequent oxidation (entry 1). We then examined the reaction of a,b-unsaturated imines. Whereas the reactions of a,b-unsaturated imines derived from isopropylamine or aniline gave low yields with low enantioselectivities (entries 2 and 3), the use of the a,b-unsaturated imines derived from benzylamine resulted in high reactivity and excellent enantioselectivity (entry 4).
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Table 1
ChemComm
Comparative reaction of benzalacetone and the corresponding imines
Entry
R
Yielda (%)
eeb (%)
1c 2 3 4 5 6
— i Pr Ph Bn OH NHPh
84 20 19 65 43 Trace
65 32 35 499 17 —
a Isolated yield. b Determined by HPLC analysis. c Performed with 5 mol% catalyst loading at 5 1C; ref. 14d.
Besides steric hindrance, the exocyclic CQN double bonds as well as CQC bonds tend to undergo the isomerization,17 exerting an influence on the stereochemical outcomes. The reactions of a,b-unsaturated oxime or hydrazone produced poor results, presumably because of the strong coordination between copper and the substrates (entries 5 and 6). In previous reports,14a,b,d b-borylation reactions of multifarious unsaturated compounds were efficiently catalyzed by chiral Cu(II) complexes formed from Cu(OH)2 or Cu(OAc)2 and chiral 2,2 0 -bipyridine, irrespective of whether the catalyst was homogeneous or heterogeneous. The use of Cu(OH)2 renders the catalysis heterogeneous, whereas Cu(OAc)2 is homogeneous. The effect of Cu(II) salts on the outcome of the reaction was then examined (Table 2). The addition of one equivalent of AcOH to Cu(OH)2 increased the reactivity slightly while retaining excellent enantioselectivity (entry 2). The catalytic system became homogeneous under these conditions, which implied an exchange of one hydroxide with an acetate group. Catalytic use of Cu(II)
Table 2
Effect of Cu salts
Entry
Cu salt
Yielda (%)
eeb (%)
1 2c 3 4d 5e 6 7 8 9
Cu(OH)2 Cu(OH)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 CuCl2 CuSO4 Cu(OTf)2 Cu(acac)2
65 69 83 86 67 10 43 5 80
499 499 499 499 94 45 85 499 499
a Isolated yield. b Determined by HPLC analysis. c 10 mol% of AcOH was added as an additive. d 5 mol% of catalyst loading. e 1 mol% of catalyst loading.
This journal is © The Royal Society of Chemistry 2014
Scheme 1
Enantioselective b-borylation of a,b-unsaturated imines.
acetate resulted in higher yield of the desired product, which was formed with 499% ee (entry 3). Whereas a similar result was obtained by decreasing the catalyst loading from 10 to 5 mol%, the yield and the enantioselectivity decreased slightly when 1 mol% catalyst was used (entries 4 and 5). Copper salts with more nucleophilic counteranions such as Cl and SO42 exhibited lower enantioselectivity compared with Cu(OTf)2, and the use of Cu(OTf)2 gave a poor yield (entries 6–8). Performing the reaction with Cu(II) acetylacetonate afforded similar results to those obtained with Cu(II) acetate (entry 9). A range of a,b-unsaturated imines underwent Cu(II)-catalyzed enantioselective b-borylation to afford the desired enantioenriched b-hydroxy imines in high yields with excellent enantioselectivities (Scheme 1). It is noteworthy that imines bearing chalcone and benzalacetone backbones gave b-hydroxy imines with outstanding enantioselectivities (499% ee). The use of a substrate with an electron-withdrawing substituent at the b-position resulted in lower enantioselectivity. The reaction profile of Cu(OAc)2-catalyzed b-borylation of an a,b-unsaturated imine was compared with that of the reaction of the corresponding ketone (Scheme 2, top). Although the b-borylation of the a,b-unsaturated imine was slightly slower than that of the corresponding ketone, the relatively rapid completion of the reaction implied sufficient and efficient activation of the a,b-unsaturated imine by Cu(OAc)2. On the other hand, when a 1 : 1 mixture of chalcone and the corresponding imine was added to the catalyst solution, chalcone was consumed almost quantitatively and the competitive b-borylation of the imine was clearly hampered (Scheme 2, bottom). Considering decomposition of the imine in water, the amounts of the recovered imine and the ketone are reasonable. The preferential consumption of the a,b-unsaturated ketone over the corresponding imine under Cu(II) catalysis is interesting, considering the preferential activation of an aldimine over an aldehyde by a Cu(II) salt.18 We assume that the asymmetric boron conjugate addition to a,b-unsaturated imines in water follows the catalytic cycle shown in Scheme 3. In situ formation of a borylcopper(II) species 2 was confirmed by ESI-MS analysis, and this intermediate was assumed to be a key component in the Cu(II) catalysis.14b,d
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Scheme 2 Competitive reactivity against the a,b-unsaturated ketone and the corresponding imine as an independent system (above) and as a mixed system (below).
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activators in water, resulting in potentially base-free conditions. Given the instability of the d9–p interaction due to its unpaired electron, a nucleophilic addition would take place to produce an N-enolate intermediate 3. The polarization of the Cu–B bond toward the boron could facilitate the interaction. Steric bulk of the two tert-butyl groups in the ligand may give rise to enantiofacial preference toward the more accessible Si face, which is consistent with the observed sense of chiral induction. Because the proton-transfer rate in water is known to be in the order of picoseconds, rapid protonation subsequent to the nucleophilic addition would afford the product in water, lowering the activation energy and facilitating the catalytic turnover.21 It was found that a chiral Cu(II) complex formed with chiral 2,2 0 -bipyridine was suitable for use in the b-borylation of a,b-unsaturated imines in water. The use of Cu(OAc)2 as the Cu(II) source gave superior performance, affording enantioenriched b-hydroxy imines after oxidation, which are known to be useful precursors of g-amino alcohols. Excellent stereocontrol was achieved with a range of substrates. In contrast to the known Cu(I) catalyses in organic solvents, this Cu(II) protocol in water is expedient and free from the use of air-sensitive phosphine ligands and strong bases. The use of unstable imines in water is also remarkable. This work was partially supported by a Grant-in-Aid for Science Research from the Japan Society for the Promotion of Science (JSPS), Global COE Program, The University of Tokyo, MEXT, Japan, Japan Science Technology Agency (JST). T.K. thanks the JSPS for a Research Fellowship for Young Scientists.
Notes and references
Scheme 3
Proposed mechanism of Cu(II) catalysis.
Crystallographic investigations showed that the CuBr2–ligand complex adopted a square pyramidal structure in which two nitrogen atoms and one of the oxygen atoms of the ligand were attached to Cu(II) in a tridentate manner.19 In contrast to Cu(I) catalysis,20 which demands a strong base to activate diboron, counteranions of Cu(II) salts or noncoordinating hydroxy groups of the chiral ligand (1) were expected to function as
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