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Cite this: Chem. Commun., 2014, 50, 978 Received 8th October 2013, Accepted 13th November 2013
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Highly enantioselective hydrogenation of 2-substituted-2-alkenols catalysed by a ChenPhos–Rh complex† Quanjun Wang, Xueying Liu, Xian Liu, Bin Li, Huifang Nie, Shengyong Zhang* and Weiping Chen*
DOI: 10.1039/c3cc47727d www.rsc.org/chemcomm
Highly enantioselective hydrogenation of a variety of 2-substituted-2alkenols has been achieved using a ChenPhos–Rh complex as catalyst, giving Z99% ee for most substrates. Optically active antifungal agent amorolfine was first synthesised using hydrogenation as the key step.
Chiral 2-substituted alkanol derivatives are key building blocks in the syntheses of many important pharmaceuticals, bioactive compounds, natural products and polymers.1,2 However, generally, the Rh- and Ru-complexes of known phosphine ligands are not effective for the asymmetric hydrogenation of 2-substituted-2-alkenols3 since these catalysts usually require a coordinating functional group (CFG) (most common CFG: ester, carboxylic acid and amide) at the suitable position to anchor the substrate to the metal in order to achieve high enantioselectivity,4 and the hydroxyl group in 2-substituted-2alkenols does not serve as a typical CFG.2 A breakthrough has been made by Pfaltz who has demonstrated that Ir–PHOX complexes can catalyse the hydrogenation of various unfunctionalized olefins with very high enantioselectivities,5 subsequently followed by others.6 Although the asymmetric hydrogenation of 2-methyl-3-phenyl-2propenol catalysed by a variety of chiral Ir-complexes based on P,N- or C,N-ligands has been well studied,7 the enantioselective hydrogenation of other 2-substituted-2-alkenols is rare. Previously, we reported TriFer and ChenPhos as well as their high enantioselectivities in the Rh-catalysed asymmetric hydrogenation of a-substituted cinnamic acids.8 The key to our success for TriFer and ChenPhos is probably owing to a secondary electrostatic interaction between the dimethylamino group of the ligand and the carboxylate unit of the substrate. We envisioned that a hydrogen-bonding interaction between the substrate and the catalyst might form in the asymmetric hydrogenation of 2-substituted-2-alkenols catalysed by a ChenPhos–Rh complex (Scheme 1), leading to highly enantioselective and efficient hydrogenation.
School of Pharmacy, Fourth Military Medical University, 169 Changle West Road, Xi’an, 710032, P.R. China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Detailed procedure, NMR spectra and ee determination. See DOI: 10.1039/c3cc47727d
978 | Chem. Commun., 2014, 50, 978--980
Scheme 1 Asymmetric hydrogenation of 2-substituted-2-alkenols catalysed using a ChenPhos–Rh complex.
We initially chose the most studied 2-methyl-3-phenyl-2-propenol 1a as a model substrate. To our delight, the ChenPhos–Rh complex exhibited excellent enantioselectivity for the asymmetric hydrogenation of 1a. Thus, hydrogenation of 1a in the presence of the ChenPhos–Rh complex, generated in situ from [Rh(NBD)2]BF4 (1.0 mol%; NBD = 2,5-norbornadiene) and ChenPhos (1.05 equivalent with respect to Rh), in dichloromethane (DCM) under 25 atm of hydrogen pressure at room temperature, gave (S)-2a with unprecedented enantioselectivities of up to >99% ee (Table 1, entry 1). The choice of solvent plays a critical role in this hydrogenation. An almost racemic product was obtained using polar protic solvents MeOH, EtOH and i-PrOH (entries 2–4). Polar aprotic solvents THF and EtOAc improved the enantioselectivities, but the results were unsatisfactory (Table 1, entries 5 and 6). Nonpolar solvent toluene gave 90% ee, but the activity was very low (entry 7). High activity was achieved using polar chlorinated solvents but the enantioselectivity was still somewhat low utilising CHCl3 (entry 8). Dichloromethane (DCM) or dichloroethane (DCE) gave perfect results (entries 1 and 9), and is the solvent of choice for the catalyst system. Importantly, for reactions at higher substrate concentrations, substrate-to-catalyst (S/C) ratios, hydrogen pressure and temperature seem to have no significant effect on ee values (Table 1, entries 10–14).
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Table 1 Asymmetric hydrogenation of 2-methyl-3-phenylpropenol catalysed using a ChenPhos–Rh complexa
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Solvent DCM MeOH EtOH i-PrOH THF EtOAc Toluene CHCl3 DCE DCM DCM DCM DCM DCM
H2 (atm) 25 25 25 25 25 25 25 25 25 5 50 60 80 25
Temp. (1C) rt rt rt rt rt rt rt rt rt rt rt rt rt 40
a
Conv.b (%) 100 80 50 10 10 86 23 100 100 9 100 100 100 100
Asymmetric hydrogenation of 2-substituted-2-alkenola
eec (%)
Entry
R2, R1 (1)
Product
ee (%)
>99 0 5 6 40 71 90 85 97 >99 >99 >99 >99 98
1 2 3 4 5 6 7 8 9 10 11
Ph, Me (1a) 2-MeOC6H4, Me (1b) 3-MeOC6H4, Me (1c) 4-MeOC6H4, Me (1d) 4-MeC6H4, Me (1e) 4-(t-Bu)C6H4, Me (1f) 4-(t-Pentyl)C6H4, Me (1g) 4-FC6H4, Me (1h) 4-ClC6H4, Me (1i) 4-BrC6H4, Me (1j) 4-CF3C6H4, Me (1k)
2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k
>99 (S) 99 (S) >99 ( ) >99 (S) >99 ( ) 95 (S) 99 ( ) 98 ( ) 99 (S) 99 ( ) 93 ( )
2l
97 ( )
12 1
Reaction conditions: 0.2 mmol scale, [substrate] = 0.1 mol L , solvent = 2 mL, 1.0 mol% of catalyst. b Determined by 1H NMR analysis. c Determined by chiral HPLC analysis.
Some well-known diphosphine ligands were tested in the hydrogenation as well (see ESI†). The appropriately oriented dimethylamino group in the ligand seems to be crucial for achieving high enantioselectivity. Most of the ligands tested showed low activity and enantioselectivity except for TriFer that contains an almost identical dimethylamino group to ChenPhos. Under the optimized conditions of 25 atm of hydrogen pressure, 1.0 mol% of ChenPhos–Rh complex, dichloromethane as solvent, room temperature and 20 h of reaction time, a series of 2-substituted-2-alkenols were hydrogenated successfully. As shown in Table 2, the hydrogenation appears to be insensitive to the position and the steric properties of the substituent on the aromatic ring as well as the substituent at the 2-position, giving almost perfect enantioselectivities of Z99% ee for most substrates (Table 2, entries 1–10 and 12–15), but the electron-withdrawing group seems to reduce the enantioselectivity somewhat (entry 11). Importantly, heteroaromatic ring substituted substrates afforded extremely high enantioselectivities (entries 16–18). More importantly, the (E)- and (Z)-alkenols afforded products with the same configuration albeit the enantioselectivity of the (Z)-isomer was somewhat lower (entry 2 vs. entry 19). In addition to 2-substituted-2-alkenols, 3-substituted-2alkenols geraniol and its cis-isomer nerol were also tested in this catalyst system. Interestingly, geraniol provided optically pure (S)-citronellol while nerol gave (R)-citronellol in 92.0% ee (entries 20 and 21).9 Notably, the ChenPhos–Rh complex is highly active for the hydrogenation as well, giving full conversion in >99% ee with 0.1 mol% of catalyst loading in the hydrogenation of 2-methyl-3phenyl-2-propenol 1a (Table 2, entry 22). It is worth noting that the ChenPhos–Rh complex is inactive for the hydrogenation of some similar substrates without a hydrogen-bonding donor, such as 2-methyl-1-phenyl-1-butene, (E)-ethyl 2-methyl-3-phenylacrylate and (E)-2-methyl-3-phenylallyl acetate. In the chiral Ir-complex catalysed asymmetric hydrogenation of 2-methyl-3-phenyl-2-propenol, most catalysts showed
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Table 2
13 14 15 16 17 18
4-MeOC6H4, Et (1m) C6H5, nPentyl (1n) Ph, Ph (1o) 2-Thiophenyl, Me (1p) 2-Furanyl, Me (1q) 2-Furanyl, iPr (1r)
2m 2n 2o 2p 2q 2r
97 (+) 99 ( ) >99 (R) >99 (S) >99 (S) >99 (S)
19
2b
92 (S)
20b
2t
>99 (S)
21b
ent-2t
22c
Ph, Me (1a)
2a
92 (R)
>99 (S)
a
The reaction conditions and analysis were the same as those in Table 1, entry 1. Full conversions were obtained in all cases. b Only C2QC3 double bond was hydrogenated. c S/C = 1000.
the enantioselectivities of o95% ee, and some impressive results have been achieved using o-Tol-PHOX (98% ee),5 SimplePHOX (97% ee),7a phoshine thiazole ligands (up to 99% ee),7b,c,f CabPHOX (up to 96% ee)7e and QUINAP (95% ee).7d Thus, the ChenPhos–Rh complex is the most enantioselective catalyst system for the asymmetric hydrogenation of a broad range of 2-substituted-2-alkenols reported so far. Although we are unable to clarify the exact mechanism for the outstanding catalytic performance of the ChenPhos–Rh complex in the hydrogenation presently, the experimental facts seem to be in support of our hypothesis: a hydrogen-bonding interaction between a substrate and a catalyst might form, leading to highly enantioselective and efficient hydrogenation. Firstly, the distinct solvent effects on the catalytic outcome observed in Table 1 provide circumstantial evidence for the involvement of H-bonding interactions in the hydrogenation.
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It is not difficult to understand that the H-bonding interactions might be retained in the solvents without a H-bonding donor or receptor such as DCM and DCE but in the protic solvents such as MeOH, EtOH and i-PrOH or the solvents with a H-bonding receptor such as THF and EtOAc, this kind of hydrogen bonding could be destroyed by the solvents and consequently decrease the enantioselectivity and activity. Secondly, in accord with the postulate of a hydrogen-bonding secondary interaction, the ChenPhos–Rh complex is inactive for the hydrogenation of the similar substrates without a hydrogen-bonding donor, and, among the tested eight diphosphine ligands, only the ligands containing appropriately oriented dimethylamino groups (H-bonding receptors) show high enantioselectivity in the hydrogenation of 2-methyl-3-phenyl-2propenol 1a. Hydrogen-bonding interactions have been utilised to account for some metal-catalysed asymmetric transformations,10 but are rare in the enantioselective hydrogenation.11 This strategy might prove to be useful in the development of novel catalysts for the asymmetric hydrogenation of some challenging substrates. The application of the enantioselective hydrogenation was demonstrated in the first asymmetric synthesis of antifungal agent ( )-amorolfine (see ESI†). In summary, a highly enantioselective hydrogenation of a variety of 2-substituted-2-alkenols catalysed by a ChenPhos–Rh complex has been developed. To the best of our knowledge, the ChenPhos–Rh complex is the most enantioselective catalyst system for the asymmetric hydrogenation of a broad range of 2-substituted-2alkenols reported so far, probably due to a hydrogen-bonding secondary interaction of the dimethylamino unit of the ligand with the hydroxyl group of the substrate. Optically active antifungal agent amorolfine was first synthesised using the enantioselective hydrogenation as the key step. Further studies to explore the application of this methodology in the synthesis of bioactive compounds are underway in our lab. We thank Prof. Q.-L. Zhou’s group in Nankai University for sharing the hydrogenation facilities, Solvias AG for providing the Ligand Kit, and the National Natural Science Foundation of China (21272271, 21172262, 21002122) for financial support.
Notes and references 1 For some representative applications of chiral 2-substituted alkanols, see: (a) T. Troxler, K. Hurth, K. H. Schuh, P. Schoeffter, D. Langenegger, A. Enz and D. Hoyer, Bioorg. Med. Chem. Lett., 2010, 20, 1728; (b) H. Kurata, K. Kusumi, K. Otsuki, R. Suzuki, M. Kurono, N. Tokuda, H. Habashita, Y. Takada, H. Shioya, H. Mizuno, T. Komiya, T. Ono, H. Hagiya, M. Minami and S. Nakade, Bioorg. Med. Chem. Lett., 2012, 22, 144; (c) U. B. Kim, D. P. Furkert and M. A. Brimble, Org. Lett., 2013, 15, 658; (d) J. Wang, B.-F. Sun, K. Cui and G.-Q. Lin, Org. Lett., 2012, 14, 6354; (e) C. R. G. Grenier, S. J. George, T. J. Joncheray, E. W. Meijer and J. R. Reynolds, J. Am. Chem. Soc., 2007, 129, 10694. 2 For the difficulty of 2-substituted-2-alkenols in the Rh- and Ru-complex catalysed asymmetric hydrogenation, see: (a) Y. Zhu and K. Burgess, Acc. Chem. Res., 2012, 45, 1623; (b) J. Zhou and K. Burgess, Angew.
980 | Chem. Commun., 2014, 50, 978--980
Communication
3
4 5 6
7
8
9
10
11
Chem., Int. Ed., 2007, 46, 1129; (c) J. Zhou, J. W. Ogle, Y. Fan, V. Banphavichit, Y. Zhu and K. Burgess, Chem.–Eur. J., 2007, 13, 7162. For examples of Rh- and Ru-complex catalysed asymmetric hydrogenation of 2-substituted-2-alkenols, see: (a) K. Iseki, Y. Kuroki, T. Nagai and Y. Kobayashi, Chem. Pharm. Bull., 1996, 44, 477; ¨nziger, J. Cercus, H. Hirt, K. Laumen, C. Malan, (b) M. Ba F. Spindler, F. Struber and T. Troxler, Tetrahedron: Asymmetry, 2003, 14, 3469; (c) F. Spindler, C. Malan, M. Lotz, M. Kesselgruber, U. Pittelkow, A. Rivas-Nass, O. Briel and H.-U. Blaser, Tetrahedron: Asymmetry, 2004, 15, 2299; (d) J. Wassenaar, M. Kuil and J. N. H. Reek, Adv. Synth. Catal., 2008, 350, 1610; (e) M. Qiu, D.-Y. Wang, X.-P. Hu, J.-D. Huang, S.-B. Yu, J. Deng, Z.-C. Duan and Z. Zheng, Tetrahedron: Asymmetry, 2009, 20, 210. (a) W. Tang and X. Zhang, Chem. Rev., 2003, 103, 3029; (b) W. Zhang, Y. Chi and X. Zhang, Acc. Chem. Res., 2007, 40, 1278. A. Lighfoot, P. Schnider and A. Pfaltz, Angew. Chem., Int. Ed., 1998, 37, 2897. For recent reviews on the Ir-complex catalysed asymmetric hydrogenation, see: (a) S. J. Roseblade and A. Pfaltz, Acc. Chem. Res., 2007, 40, 1402; (b) T. L. Church and P. G. Andersson, Coord. Chem. Rev., 2008, 252, 513; `mies, (c) X. Cui and K. Burgess, Chem. Rev., 2005, 105, 3272; (d) O. Pa ´guez, Chem.–Eur. J., 2010, 16, 14232; P. G. Andersson and M. Die (e) D. H. Woodmansee and A. Pfaltz, Chem. Commun., 2011, 47, 7912. For some representative examples of the asymmetric hydrogenation of 2-methyl-3-phenyl-2-propenol catalysed by chiral Ir-complexes, see: (a) S. P. Smidt, F. Menges and A. Pfaltz, Org. Lett., 2004, 6, 2023; (b) K. Kaellstroem, C. Hedberg, P. Brandt, A. Bayer and P. G. Andersson, J. Am. Chem. Soc., 2004, 126, 14308; (c) C. Hedberg, K. Kaellstroem, P. Brandt, L. K. Hansen and P. G. Andersson, J. Am. Chem. Soc., 2006, 128, 2995; (d) X. Li, L. Kong, Y. Gao and X. Wang, Tetrahedron Lett., 2007, 48, 3915; (e) J.-D. Lee, T. C. Thanh, T.-J. Kim and O. K. Sang, Synlett, 2009, 771; ( f ) J. Mazuela, A. Paptchikhine, `mies, P. G. Andersson and M. Die ´guez, Chem.–Eur. J., 2010, O. Pa 16, 4567; ( g) A. Franzke and A. Pfaltz, Chem.–Eur. J., 2011, 17, 4131; (h) A. Franzke, F. Voss and A. Pfaltz, Tetrahedron, 2011, 67, 4358; `mies, M. Die ´guez, P.-O. Norrby and P. G. (i) J. Mazuela, O. Pa Andersson, J. Am. Chem. Soc., 2011, 133, 13634; ( j) A. Franzke and A. Pfaltz, Chem.–Eur. J., 2011, 17, 4131; (k) G. Chelucci, M. Marchetti, A. V. Malkov, F. Friscourt, P. Kocovsky and M. E. Swarbrick, Tetra`mies, M. Die ´guez, hedron, 2011, 67, 5421; (l ) J. Margalef, O. Pa M. Lega and F. Ruffo, Tetrahedron: Asymmetry, 2012, 23, 945; ¨l, W. Kimpe, J. L. Goeman and J. Van der Eycken, (m) K. Bert, T. Noe Org. Biomol. Chem., 2012, 10, 8539; (n) D. Rageot and A. Pfaltz, Helv. `mies and M. Die ´guez, Chim. Acta, 2012, 95, 2176; (o) M. Coll, O. Pa `mies and Adv. Synth. Catal., 2013, 355, 161; (p) J. Mazuela, O. Pa ´guez, Eur. J. Inorg. Chem., 2013, 2139. M. Die (a) W. Chen, P. J. McCormack, K. Mohammed, W. Mbafor, S. M. Roberts and J. Whittall, Angew. Chem., Int. Ed., 2007, 46, 4141; (b) W. Chen, F. Spindler, B. Pugin and U. Nettekoven, Angew. Chem., Int. Ed., 2013, 52, 8652. High enantioselectivities of up to 98% ee were achieved in the BINAP-Ru complex catalysed asymmetric hydrogenation of geraniol and nerol, see: H. Takaya, T. Ohta, N. Sayo, H. Kumobayashi, S. Akutagawa, S. Inoue, I. Kasahara and R. Noyori, J. Am. Chem. Soc., 1987, 109, 1596. For H-bonding in metal-catalyzed reactions, see: (a) M. Sawamura and Y. Ito, Chem. Rev., 1992, 92, 857; (b) T. Ikariya, K. Murata and R. Noyori, Org. Biomol. Chem., 2006, 4, 393; (c) A. H. Hoveyda, P. J. Lombardi, R. V. O’Brien and A.-R. Zhugralin, J. Am. Chem. Soc., 2009, 131, 8378; (d) S. Morikawa, K. Michigami and H. Amii, Org. Lett., 2010, 12, 2520; (e) Z.-Y. Ding, F. Chen, J. Qin, Y.-M. He and Q.-H. Fan, Angew. Chem., Int. Ed., 2012, 51, 5706; ( f ) W. Tang, S. Johnston, J. A. Iggo, N. G. Berry, M. Phelan, L. Lian, J. Bacsa and J. Xiao, Angew. Chem., Int. Ed., 2013, 52, 1668. Recently, Zhang et al. reported bifunctional ferrocene-based bisphosphine-thiourea for Rh-catalysed asymmetric hydrogenation of nitroalkenes. Q. Zhao, S. Li, K. Huang, R. Wang and X. Zhang, Org. Lett., 2013, 15, 4014.
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Cite this: Chem. Commun., 2014, 50, 978 Received 8th October 2013, Accepted 13th November 2013
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Highly enantioselective hydrogenation of 2-substituted-2-alkenols catalysed by a ChenPhos–Rh complex† Quanjun Wang, Xueying Liu, Xian Liu, Bin Li, Huifang Nie, Shengyong Zhang* and Weiping Chen*
DOI: 10.1039/c3cc47727d www.rsc.org/chemcomm
Highly enantioselective hydrogenation of a variety of 2-substituted-2alkenols has been achieved using a ChenPhos–Rh complex as catalyst, giving Z99% ee for most substrates. Optically active antifungal agent amorolfine was first synthesised using hydrogenation as the key step.
Chiral 2-substituted alkanol derivatives are key building blocks in the syntheses of many important pharmaceuticals, bioactive compounds, natural products and polymers.1,2 However, generally, the Rh- and Ru-complexes of known phosphine ligands are not effective for the asymmetric hydrogenation of 2-substituted-2-alkenols3 since these catalysts usually require a coordinating functional group (CFG) (most common CFG: ester, carboxylic acid and amide) at the suitable position to anchor the substrate to the metal in order to achieve high enantioselectivity,4 and the hydroxyl group in 2-substituted-2alkenols does not serve as a typical CFG.2 A breakthrough has been made by Pfaltz who has demonstrated that Ir–PHOX complexes can catalyse the hydrogenation of various unfunctionalized olefins with very high enantioselectivities,5 subsequently followed by others.6 Although the asymmetric hydrogenation of 2-methyl-3-phenyl-2propenol catalysed by a variety of chiral Ir-complexes based on P,N- or C,N-ligands has been well studied,7 the enantioselective hydrogenation of other 2-substituted-2-alkenols is rare. Previously, we reported TriFer and ChenPhos as well as their high enantioselectivities in the Rh-catalysed asymmetric hydrogenation of a-substituted cinnamic acids.8 The key to our success for TriFer and ChenPhos is probably owing to a secondary electrostatic interaction between the dimethylamino group of the ligand and the carboxylate unit of the substrate. We envisioned that a hydrogen-bonding interaction between the substrate and the catalyst might form in the asymmetric hydrogenation of 2-substituted-2-alkenols catalysed by a ChenPhos–Rh complex (Scheme 1), leading to highly enantioselective and efficient hydrogenation.
School of Pharmacy, Fourth Military Medical University, 169 Changle West Road, Xi’an, 710032, P.R. China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Detailed procedure, NMR spectra and ee determination. See DOI: 10.1039/c3cc47727d
978 | Chem. Commun., 2014, 50, 978--980
Scheme 1 Asymmetric hydrogenation of 2-substituted-2-alkenols catalysed using a ChenPhos–Rh complex.
We initially chose the most studied 2-methyl-3-phenyl-2-propenol 1a as a model substrate. To our delight, the ChenPhos–Rh complex exhibited excellent enantioselectivity for the asymmetric hydrogenation of 1a. Thus, hydrogenation of 1a in the presence of the ChenPhos–Rh complex, generated in situ from [Rh(NBD)2]BF4 (1.0 mol%; NBD = 2,5-norbornadiene) and ChenPhos (1.05 equivalent with respect to Rh), in dichloromethane (DCM) under 25 atm of hydrogen pressure at room temperature, gave (S)-2a with unprecedented enantioselectivities of up to >99% ee (Table 1, entry 1). The choice of solvent plays a critical role in this hydrogenation. An almost racemic product was obtained using polar protic solvents MeOH, EtOH and i-PrOH (entries 2–4). Polar aprotic solvents THF and EtOAc improved the enantioselectivities, but the results were unsatisfactory (Table 1, entries 5 and 6). Nonpolar solvent toluene gave 90% ee, but the activity was very low (entry 7). High activity was achieved using polar chlorinated solvents but the enantioselectivity was still somewhat low utilising CHCl3 (entry 8). Dichloromethane (DCM) or dichloroethane (DCE) gave perfect results (entries 1 and 9), and is the solvent of choice for the catalyst system. Importantly, for reactions at higher substrate concentrations, substrate-to-catalyst (S/C) ratios, hydrogen pressure and temperature seem to have no significant effect on ee values (Table 1, entries 10–14).
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Table 1 Asymmetric hydrogenation of 2-methyl-3-phenylpropenol catalysed using a ChenPhos–Rh complexa
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Solvent DCM MeOH EtOH i-PrOH THF EtOAc Toluene CHCl3 DCE DCM DCM DCM DCM DCM
H2 (atm) 25 25 25 25 25 25 25 25 25 5 50 60 80 25
Temp. (1C) rt rt rt rt rt rt rt rt rt rt rt rt rt 40
a
Conv.b (%) 100 80 50 10 10 86 23 100 100 9 100 100 100 100
Asymmetric hydrogenation of 2-substituted-2-alkenola
eec (%)
Entry
R2, R1 (1)
Product
ee (%)
>99 0 5 6 40 71 90 85 97 >99 >99 >99 >99 98
1 2 3 4 5 6 7 8 9 10 11
Ph, Me (1a) 2-MeOC6H4, Me (1b) 3-MeOC6H4, Me (1c) 4-MeOC6H4, Me (1d) 4-MeC6H4, Me (1e) 4-(t-Bu)C6H4, Me (1f) 4-(t-Pentyl)C6H4, Me (1g) 4-FC6H4, Me (1h) 4-ClC6H4, Me (1i) 4-BrC6H4, Me (1j) 4-CF3C6H4, Me (1k)
2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k
>99 (S) 99 (S) >99 ( ) >99 (S) >99 ( ) 95 (S) 99 ( ) 98 ( ) 99 (S) 99 ( ) 93 ( )
2l
97 ( )
12 1
Reaction conditions: 0.2 mmol scale, [substrate] = 0.1 mol L , solvent = 2 mL, 1.0 mol% of catalyst. b Determined by 1H NMR analysis. c Determined by chiral HPLC analysis.
Some well-known diphosphine ligands were tested in the hydrogenation as well (see ESI†). The appropriately oriented dimethylamino group in the ligand seems to be crucial for achieving high enantioselectivity. Most of the ligands tested showed low activity and enantioselectivity except for TriFer that contains an almost identical dimethylamino group to ChenPhos. Under the optimized conditions of 25 atm of hydrogen pressure, 1.0 mol% of ChenPhos–Rh complex, dichloromethane as solvent, room temperature and 20 h of reaction time, a series of 2-substituted-2-alkenols were hydrogenated successfully. As shown in Table 2, the hydrogenation appears to be insensitive to the position and the steric properties of the substituent on the aromatic ring as well as the substituent at the 2-position, giving almost perfect enantioselectivities of Z99% ee for most substrates (Table 2, entries 1–10 and 12–15), but the electron-withdrawing group seems to reduce the enantioselectivity somewhat (entry 11). Importantly, heteroaromatic ring substituted substrates afforded extremely high enantioselectivities (entries 16–18). More importantly, the (E)- and (Z)-alkenols afforded products with the same configuration albeit the enantioselectivity of the (Z)-isomer was somewhat lower (entry 2 vs. entry 19). In addition to 2-substituted-2-alkenols, 3-substituted-2alkenols geraniol and its cis-isomer nerol were also tested in this catalyst system. Interestingly, geraniol provided optically pure (S)-citronellol while nerol gave (R)-citronellol in 92.0% ee (entries 20 and 21).9 Notably, the ChenPhos–Rh complex is highly active for the hydrogenation as well, giving full conversion in >99% ee with 0.1 mol% of catalyst loading in the hydrogenation of 2-methyl-3phenyl-2-propenol 1a (Table 2, entry 22). It is worth noting that the ChenPhos–Rh complex is inactive for the hydrogenation of some similar substrates without a hydrogen-bonding donor, such as 2-methyl-1-phenyl-1-butene, (E)-ethyl 2-methyl-3-phenylacrylate and (E)-2-methyl-3-phenylallyl acetate. In the chiral Ir-complex catalysed asymmetric hydrogenation of 2-methyl-3-phenyl-2-propenol, most catalysts showed
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Table 2
13 14 15 16 17 18
4-MeOC6H4, Et (1m) C6H5, nPentyl (1n) Ph, Ph (1o) 2-Thiophenyl, Me (1p) 2-Furanyl, Me (1q) 2-Furanyl, iPr (1r)
2m 2n 2o 2p 2q 2r
97 (+) 99 ( ) >99 (R) >99 (S) >99 (S) >99 (S)
19
2b
92 (S)
20b
2t
>99 (S)
21b
ent-2t
22c
Ph, Me (1a)
2a
92 (R)
>99 (S)
a
The reaction conditions and analysis were the same as those in Table 1, entry 1. Full conversions were obtained in all cases. b Only C2QC3 double bond was hydrogenated. c S/C = 1000.
the enantioselectivities of o95% ee, and some impressive results have been achieved using o-Tol-PHOX (98% ee),5 SimplePHOX (97% ee),7a phoshine thiazole ligands (up to 99% ee),7b,c,f CabPHOX (up to 96% ee)7e and QUINAP (95% ee).7d Thus, the ChenPhos–Rh complex is the most enantioselective catalyst system for the asymmetric hydrogenation of a broad range of 2-substituted-2-alkenols reported so far. Although we are unable to clarify the exact mechanism for the outstanding catalytic performance of the ChenPhos–Rh complex in the hydrogenation presently, the experimental facts seem to be in support of our hypothesis: a hydrogen-bonding interaction between a substrate and a catalyst might form, leading to highly enantioselective and efficient hydrogenation. Firstly, the distinct solvent effects on the catalytic outcome observed in Table 1 provide circumstantial evidence for the involvement of H-bonding interactions in the hydrogenation.
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It is not difficult to understand that the H-bonding interactions might be retained in the solvents without a H-bonding donor or receptor such as DCM and DCE but in the protic solvents such as MeOH, EtOH and i-PrOH or the solvents with a H-bonding receptor such as THF and EtOAc, this kind of hydrogen bonding could be destroyed by the solvents and consequently decrease the enantioselectivity and activity. Secondly, in accord with the postulate of a hydrogen-bonding secondary interaction, the ChenPhos–Rh complex is inactive for the hydrogenation of the similar substrates without a hydrogen-bonding donor, and, among the tested eight diphosphine ligands, only the ligands containing appropriately oriented dimethylamino groups (H-bonding receptors) show high enantioselectivity in the hydrogenation of 2-methyl-3-phenyl-2propenol 1a. Hydrogen-bonding interactions have been utilised to account for some metal-catalysed asymmetric transformations,10 but are rare in the enantioselective hydrogenation.11 This strategy might prove to be useful in the development of novel catalysts for the asymmetric hydrogenation of some challenging substrates. The application of the enantioselective hydrogenation was demonstrated in the first asymmetric synthesis of antifungal agent ( )-amorolfine (see ESI†). In summary, a highly enantioselective hydrogenation of a variety of 2-substituted-2-alkenols catalysed by a ChenPhos–Rh complex has been developed. To the best of our knowledge, the ChenPhos–Rh complex is the most enantioselective catalyst system for the asymmetric hydrogenation of a broad range of 2-substituted-2alkenols reported so far, probably due to a hydrogen-bonding secondary interaction of the dimethylamino unit of the ligand with the hydroxyl group of the substrate. Optically active antifungal agent amorolfine was first synthesised using the enantioselective hydrogenation as the key step. Further studies to explore the application of this methodology in the synthesis of bioactive compounds are underway in our lab. We thank Prof. Q.-L. Zhou’s group in Nankai University for sharing the hydrogenation facilities, Solvias AG for providing the Ligand Kit, and the National Natural Science Foundation of China (21272271, 21172262, 21002122) for financial support.
Notes and references 1 For some representative applications of chiral 2-substituted alkanols, see: (a) T. Troxler, K. Hurth, K. H. Schuh, P. Schoeffter, D. Langenegger, A. Enz and D. Hoyer, Bioorg. Med. Chem. Lett., 2010, 20, 1728; (b) H. Kurata, K. Kusumi, K. Otsuki, R. Suzuki, M. Kurono, N. Tokuda, H. Habashita, Y. Takada, H. Shioya, H. Mizuno, T. Komiya, T. Ono, H. Hagiya, M. Minami and S. Nakade, Bioorg. Med. Chem. Lett., 2012, 22, 144; (c) U. B. Kim, D. P. Furkert and M. A. Brimble, Org. Lett., 2013, 15, 658; (d) J. Wang, B.-F. Sun, K. Cui and G.-Q. Lin, Org. Lett., 2012, 14, 6354; (e) C. R. G. Grenier, S. J. George, T. J. Joncheray, E. W. Meijer and J. R. Reynolds, J. Am. Chem. Soc., 2007, 129, 10694. 2 For the difficulty of 2-substituted-2-alkenols in the Rh- and Ru-complex catalysed asymmetric hydrogenation, see: (a) Y. Zhu and K. Burgess, Acc. Chem. Res., 2012, 45, 1623; (b) J. Zhou and K. Burgess, Angew.
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3
4 5 6
7
8
9
10
11
Chem., Int. Ed., 2007, 46, 1129; (c) J. Zhou, J. W. Ogle, Y. Fan, V. Banphavichit, Y. Zhu and K. Burgess, Chem.–Eur. J., 2007, 13, 7162. For examples of Rh- and Ru-complex catalysed asymmetric hydrogenation of 2-substituted-2-alkenols, see: (a) K. Iseki, Y. Kuroki, T. Nagai and Y. Kobayashi, Chem. Pharm. Bull., 1996, 44, 477; ¨nziger, J. Cercus, H. Hirt, K. Laumen, C. Malan, (b) M. Ba F. Spindler, F. Struber and T. Troxler, Tetrahedron: Asymmetry, 2003, 14, 3469; (c) F. Spindler, C. Malan, M. Lotz, M. Kesselgruber, U. Pittelkow, A. Rivas-Nass, O. Briel and H.-U. Blaser, Tetrahedron: Asymmetry, 2004, 15, 2299; (d) J. Wassenaar, M. Kuil and J. N. H. Reek, Adv. Synth. Catal., 2008, 350, 1610; (e) M. Qiu, D.-Y. Wang, X.-P. Hu, J.-D. Huang, S.-B. Yu, J. Deng, Z.-C. Duan and Z. Zheng, Tetrahedron: Asymmetry, 2009, 20, 210. (a) W. Tang and X. Zhang, Chem. Rev., 2003, 103, 3029; (b) W. Zhang, Y. Chi and X. Zhang, Acc. Chem. Res., 2007, 40, 1278. A. Lighfoot, P. Schnider and A. Pfaltz, Angew. Chem., Int. Ed., 1998, 37, 2897. For recent reviews on the Ir-complex catalysed asymmetric hydrogenation, see: (a) S. J. Roseblade and A. Pfaltz, Acc. Chem. Res., 2007, 40, 1402; (b) T. L. Church and P. G. Andersson, Coord. Chem. Rev., 2008, 252, 513; `mies, (c) X. Cui and K. Burgess, Chem. Rev., 2005, 105, 3272; (d) O. Pa ´guez, Chem.–Eur. J., 2010, 16, 14232; P. G. Andersson and M. Die (e) D. H. Woodmansee and A. Pfaltz, Chem. Commun., 2011, 47, 7912. For some representative examples of the asymmetric hydrogenation of 2-methyl-3-phenyl-2-propenol catalysed by chiral Ir-complexes, see: (a) S. P. Smidt, F. Menges and A. Pfaltz, Org. Lett., 2004, 6, 2023; (b) K. Kaellstroem, C. Hedberg, P. Brandt, A. Bayer and P. G. Andersson, J. Am. Chem. Soc., 2004, 126, 14308; (c) C. Hedberg, K. Kaellstroem, P. Brandt, L. K. Hansen and P. G. Andersson, J. Am. Chem. Soc., 2006, 128, 2995; (d) X. Li, L. Kong, Y. Gao and X. Wang, Tetrahedron Lett., 2007, 48, 3915; (e) J.-D. Lee, T. C. Thanh, T.-J. Kim and O. K. Sang, Synlett, 2009, 771; ( f ) J. Mazuela, A. Paptchikhine, `mies, P. G. Andersson and M. Die ´guez, Chem.–Eur. J., 2010, O. Pa 16, 4567; ( g) A. Franzke and A. Pfaltz, Chem.–Eur. J., 2011, 17, 4131; (h) A. Franzke, F. Voss and A. Pfaltz, Tetrahedron, 2011, 67, 4358; `mies, M. Die ´guez, P.-O. Norrby and P. G. (i) J. Mazuela, O. Pa Andersson, J. Am. Chem. Soc., 2011, 133, 13634; ( j) A. Franzke and A. Pfaltz, Chem.–Eur. J., 2011, 17, 4131; (k) G. Chelucci, M. Marchetti, A. V. Malkov, F. Friscourt, P. Kocovsky and M. E. Swarbrick, Tetra`mies, M. Die ´guez, hedron, 2011, 67, 5421; (l ) J. Margalef, O. Pa M. Lega and F. Ruffo, Tetrahedron: Asymmetry, 2012, 23, 945; ¨l, W. Kimpe, J. L. Goeman and J. Van der Eycken, (m) K. Bert, T. Noe Org. Biomol. Chem., 2012, 10, 8539; (n) D. Rageot and A. Pfaltz, Helv. `mies and M. Die ´guez, Chim. Acta, 2012, 95, 2176; (o) M. Coll, O. Pa `mies and Adv. Synth. Catal., 2013, 355, 161; (p) J. Mazuela, O. Pa ´guez, Eur. J. Inorg. Chem., 2013, 2139. M. Die (a) W. Chen, P. J. McCormack, K. Mohammed, W. Mbafor, S. M. Roberts and J. Whittall, Angew. Chem., Int. Ed., 2007, 46, 4141; (b) W. Chen, F. Spindler, B. Pugin and U. Nettekoven, Angew. Chem., Int. Ed., 2013, 52, 8652. High enantioselectivities of up to 98% ee were achieved in the BINAP-Ru complex catalysed asymmetric hydrogenation of geraniol and nerol, see: H. Takaya, T. Ohta, N. Sayo, H. Kumobayashi, S. Akutagawa, S. Inoue, I. Kasahara and R. Noyori, J. Am. Chem. Soc., 1987, 109, 1596. For H-bonding in metal-catalyzed reactions, see: (a) M. Sawamura and Y. Ito, Chem. Rev., 1992, 92, 857; (b) T. Ikariya, K. Murata and R. Noyori, Org. Biomol. Chem., 2006, 4, 393; (c) A. H. Hoveyda, P. J. Lombardi, R. V. O’Brien and A.-R. Zhugralin, J. Am. Chem. Soc., 2009, 131, 8378; (d) S. Morikawa, K. Michigami and H. Amii, Org. Lett., 2010, 12, 2520; (e) Z.-Y. Ding, F. Chen, J. Qin, Y.-M. He and Q.-H. Fan, Angew. Chem., Int. Ed., 2012, 51, 5706; ( f ) W. Tang, S. Johnston, J. A. Iggo, N. G. Berry, M. Phelan, L. Lian, J. Bacsa and J. Xiao, Angew. Chem., Int. Ed., 2013, 52, 1668. Recently, Zhang et al. reported bifunctional ferrocene-based bisphosphine-thiourea for Rh-catalysed asymmetric hydrogenation of nitroalkenes. Q. Zhao, S. Li, K. Huang, R. Wang and X. Zhang, Org. Lett., 2013, 15, 4014.
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