Chiral Pincer Ruthenium and Osmium Complexes for the Fast and

Jul 23, 2010 - †Dipartimento di Scienze e Tecnologie Chimiche, Universit`a di Udine, Via Cotonificio 108, I-33100 Udine,. Italy, and §Dipartimento ...
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Organometallics 2010, 29, 3563–3570 DOI: 10.1021/om1004918

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Chiral Pincer Ruthenium and Osmium Complexes for the Fast and Efficient Hydrogen Transfer Reduction of Ketones Walter Baratta,*,† Fabio Benedetti,§ Alessandro Del Zotto,† Lidia Fanfoni,§ Fulvia Felluga,§ Santo Magnolia,† Elisabetta Putignano,† and Pierluigi Rigo† †

Dipartimento di Scienze e Tecnologie Chimiche, Universit a di Udine, Via Cotonificio 108, I-33100 Udine, Italy, and §Dipartimento di Scienze Chimiche, Universit a di Trieste, Via L. Giorgieri 1, I-34127 Trieste, Italy Received May 19, 2010

A series of chiral HCNN ligands ((S)-1b-g) (S)-2-(1-aminoethyl)-6-(aryl)pyridine (aryl = 4-MeOphenyl, 1b; 4-CF3-phenyl, 1c; 3,5-di-Me-phenyl, 1d; 3,5-di-CF3-phenyl, 1e; 1-naphthyl, 1f; 2-naphthyl, 1g) were synthesized starting from commercial 2-acetyl-6-bromopyridine (2), by a chemoenzymatic method involving the dynamic kinetic resolution of the corresponding secondary alcohol (rac-3). The conversion of the resulting (R)-3, obtained in 98% ee, into the homochiral amine ((S)-6), followed by Suzuki coupling with the appropriate arylboronic acids 7b-g, gave access to (S)-1b-g, isolated in 97% ee, with an overall yield up to 50%. The in situ generated pincer complexes [MCl(CNN)(PP)] (M = Ru, Os; PP = Josiphos diphosphine), prepared from [MCl2(PPh3)3], (R,S)-Josiphos diphosphines, and the ligands (S)-1b-g, were found to efficiently catalyze the asymmetric transfer hydrogenation of acetophenone in 2-propanol at 60 °C and in the presence of NaOiPr. On the basis of these data, the 2-naphthyl ruthenium and osmium derivatives [RuCl(CNN)((R,S)-Josiphos*)] (8) (HCNN = (S)-1g) and [OsCl(CNN)(PP)] (PP = (R,S)-Josiphos, 9, and (R,S)-Josiphos*, 10) were isolated from [MCl2(PPh3)3], (R,S)Josiphos diphosphines, and the ligand (S)-1g. Complexes 8 and 10, displaying the correctly matched chiral PP and CNN- ligands, are highly active and productive catalysts for the transfer hydrogenation of alkyl aryl ketones and methyl pyridyl ketones with TOF = 105-106 h-1, using 0.005 mol % of catalysts and achieving up to 99% ee. The comparison of the catalytic activity of these pincer complexes shows that Ru and Os derivatives display similar rate and enantioselectivity. Introduction Asymmetric reduction of ketones to secondary alcohols is a core reaction for the synthesis of chiral alcohols. A number of homogeneous catalytic systems based on Ru, Rh, Ir, and more recently Os complexes have been developed for the ketone hydrogenation1 and transfer hydrogenation (TH)2 reactions. One of the most significant breakthroughs in this field was the work of Noyori and co-workers, which led to the systems trans-[RuCl2(PP)(1,2-diamine)] (PP = diphosphine) *To whom correspondence should be addressed. E-mail: inorg@ uniud.it. (1) (a) Shang, G.; Li, W.; Zhang, X. In Catalytic Asymmetric Synthesis, 3rd ed.; Ojima, I., Ed.; John Wiley & Sons: Hoboken, 2010; Chapter 7. (b) The Handbook of Homogeneous Hydrogenation, Vols. 1-3; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007. (c) Transition Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; WileyVCH: Weinheim, 2004; p 29. (d) Asymmetric Catalysis on Industrial Scale; Blaser, H.-U., Schmidt, E., Eds.; Wiley-VCH: Weinheim, 2004. (2) (a) Morris, R. H. Chem. Soc. Rev. 2009, 38, 2282. (b) Baratta, W.; Rigo, P. Eur. J. Inorg. Chem. 2008, 4041. (c) Wang, C.; Wu, X.; Xiao, J. Chem. Asian J. 2008, 3, 1750. (d) Morris, D. J.; Wills, M. Chim. OggiChem. Today 2007, 25, 11. (e) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300. (f) Samec, J. S. M.; B€ackvall, J. E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 35, 237. (g) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35, 226. (h) Ikariya, T.; Murata, K.; Noyori, R. Org. Biomol. Chem. 2006, 4, 393. (3) (a) Doucet, H.; Ohkuma, T.; Murata, K.; Yokozawa, T.; Kozawa, M.; Katayama, E.; England, A. F.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1998, 37, 1703. (b) Haack, K. J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285. r 2010 American Chemical Society

and [(η6-arene)RuCl(Tsdpen)] for the efficient ketone hydrogenation and TH reactions, respectively.3 The presence of the N-H functionality has been shown to be crucial in enhancing the activity of both systems. Evidence has been provided that during catalysis the cis-RuH/-NH2 motif plays a fundamental role through a concerted delivery of a N-H proton and a Ru-H hydride, via an outer-sphere mechanism (metal-ligand bifunctional catalysis).4 Inspired by this pioneering work, a large number of transition metal complexes containing N-H ligands have been designed and found to efficiently catalyze the enantioselective ketone reduction.1,2 It is worth noting that TH has emerged as a valuable tool to obtain optically active alcohols, this procedure being a complement/ alternative to the pressure hydrogenation, particularly for small- to medium-scale production. Recently, we found that the complexes cis-[RuCl2(PP)(ampy)], containing the mixed bidentate nitrogen ligand 2-aminomethylpyridine (ampy) instead of a 1,2-diamine, display high catalytic activity for the TH of ketones in basic 2-propanol.5 A more efficient catalyst is the pincer complex [RuCl(CNN)(Ph2P(CH2)4PPh2)],6 (4) (a) Alonso, D. A.; Brandt, P.; Nordin, S. J. M.; Andersson, P. G. J. Am. Chem. Soc. 1999, 121, 9580. (b) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466. (c) Petra, D. G. I.; Reek, J. N. H.; Handgraaf, J. W.; Meijer, E. J.; Dierkes, P.; Kamer, P. C. J.; Brussee, J.; Schoemaker, H. E.; van Leeuwen, P. W. N. M. Chem.;Eur. J. 2000, 6, 2818. (5) (a) Baratta, W.; Herdtweck, E.; Siega, K.; Toniutti, M.; Rigo, P. Organometallics 2005, 24, 1660. (b) Baratta, W.; Chelucci, G.; Herdtweck, E.; Magnolia, S.; Siega, K.; Rigo, P. Angew. Chem., Int. Ed. 2007, 46, 7651. Published on Web 07/23/2010

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Figure 1

obtained by orthometalation of the ampy-type ligand 2-(1-aminomethyl)-6-(4-metylphenyl)pyridine (HCNN), which afforded extremely high TOF7 and TON values (Figure 1). The chiral pincer complexes [RuCl(CNN)(PP)], prepared from chiral Josiphos diphosphines and racemic HCNN ligands, have proven to catalyze the ketone TH with both high enantioselectivity and productivity.8 Interestingly, the analogous osmium complexes [OsCl2(PP)(ampy)] and [OsCl(CNN)(PP)] display very high catalytic activity in the enantioselective ketone TH (Figure 1).9 In addition, the osmium pincer compounds9b,10a and the trans-[OsCl2(PP)(1,2-diamine)]10b derivatives were found to be efficient catalysts in the asymmetric hydrogenation of ketones. It is worth noting that only a few Os catalysts have been described for the asymmetric reduction of ketones via TH,11 whereas no example for hydrogenation had been reported before our work on [OsCl(CNN)(PP)]. As a matter of fact, osmium is thought to give more stable complexes and less active catalysts compared to ruthenium, as a consequence of the stronger bonding.12 On account of the high performance of the pincer complexes,13 this class of compounds appears attractive for obtaining robust catalysts,14 relevant for industrial applications. The high stability and productivity of [MCl(CNN)(PP)] complexes arise from the presence of the σ metal-carbon bond, which prevents ligand dissociation, retarding catalyst deactivation. In this context, we were inter(6) (a) Baratta, W.; Chelucci, G.; Gladiali, S.; Siega, K.; Toniutti, M.; Zanette, M.; Zangrando, E.; Rigo, P. Angew. Chem., Int. Ed. 2005, 44, 6214. (b) Baratta, W.; Bosco, M.; Chelucci, G.; Del Zotto, A.; Siega, K.; Toniutti, M.; Zangrando, E.; Rigo, P. Organometallics 2006, 25, 4611. (c) Baratta, W.; Ballico, M.; Del Zotto, A.; Herdtweck, E.; Magnolia, S.; Peloso, R.; Siega, K.; Toniutti, M.; Zangrando, E.; Rigo, P. Organometallics 2009, 28, 4421. (7) Turnover frequency (moles of ketone converted into alcohol per mole of catalyst per hour) at 50% conversion. (8) Baratta, W.; Chelucci, G.; Magnolia, S.; Siega, K.; Rigo, P. Chem.;Eur. J. 2009, 15, 726. (9) (a) Baratta, W.; Ballico, M.; Del Zotto, A.; Siega, K.; Magnolia, S.; Rigo, P. Chem.;Eur. J. 2008, 14, 2557. (b) Baratta, W.; Ballico, M.; Chelucci, G.; Siega, K.; Rigo, P. Angew. Chem., Int. Ed. 2008, 47, 4362. (c) Baratta, W.; Ballico, M; Baldino, S.; Chelucci, G.; Herdtweck, E.; Siega, K.; Magnolia, S.; Rigo, P. Chem.;Eur. J. 2008, 14, 9148. (10) (a) Baratta, W.; Fanfoni, L.; Magnolia, S.; Siega, K.; Rigo, P. Eur. J. Inorg. Chem. 2010, 1419. (b) Baratta, W.; Barbato, C.; Magnolia, S.; Siega, K.; Rigo, P. Chem.;Eur. J. 2010, 16, 3201. (11) (a) Schl€ unken, C.; Esteruelas, M. A.; Lahoz, F. J.; Oro, L. A.; Werner, H. Eur. J. Inorg. Chem. 2004, 2477. (b) Carmona, D.; Lamata, M. P.; Viguri, F.; Dobrinovich, I.; Lahoz, F. J.; Oro, L. A. Adv. Synth. Catal. 2002, 344, 499. (c) Faller, J. W.; Lavoie, A. R. Org. Lett. 2001, 3, 3703. (12) (a) Morris, R. H. In The Handbook of Homogeneous Hydrogenation; de Vries, J. G., Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007; Vol. 1, p 45. (b) Esteruelas, M. A.; L opez, A. M.; Olivan, M. Coord. Chem. Rev. 2007, 251, 795. (c) Sanchez-Delgado, R. A.; Rosales, M.; Esteruelas, M. A.; Oro, L. A. J. Mol. Catal. A: Chem. 1995, 96, 231. (13) (a) Leis, W.; Mayer, H. A.; Kaska, W. C. Coord. Chem. Rev. 2008, 252, 1787. (b) Benito-Garagorri, D.; Kirchner, K. Acc. Chem. Res. 2008, 41, 201. (c) van der Boom, M. E.; Milstein, D. Chem. Rev. 2003, 103, 1759. (d) Albrecht, M.; van Koten, G. Angew. Chem., Int. Ed. 2001, 40, 3750. (e) Albrecht, M. Chem. Rev. 2010, 110, 576.

Figure 2. Chiral HCNN ligands (S)-1a-g.

ested in the design of new chiral pincer ligands of the HCNN type (Figure 2), with different steric and electronic properties for the development of highly productive catalysts for asymmetric organic transformations. The synthesis of pyridyl ligands with a chiral center directly attached to the heterocyclic part is a challenging topic that has widely been explored.15 Biocatalytic procedures employing isolated enzymes have emerged as a reliable alternative to chemical methods16-18 for the synthesis of a variety of chiral building blocks with a high degree of selectivity, under mild reaction conditions.19 In particular, lipases have been frequently used as the biocatalysts for the enantioselective acylation of secondary alcohols.20 Lipases are very flexible enzymes, for their wide acceptance of structurally different substrates and their ability to retain their activity and selectivity also in nonconventional media such as organic solvents20a,21a and ionic liquids.21b Specifically, lipase B from Candida antarctica (CAL-B) has shown a quite general enantioselectivity toward linear and benzylic secondary (14) (a) Liu, F.; Pak, E. B.; Singh, B.; Jensen, C. M.; Goldman, A. S. J. Am. Chem. Soc. 1999, 121, 4086. (b) Dani, P.; Karlen, T.; Gossage, R. A.; Gladiali, S.; van Koten, G. Angew. Chem., Int. Ed. 2000, 39, 743. (c) Gibson, S.; Foster, D. F.; Eastham, G. R.; Tooze, R. P.; Cole-Hamilton, D. J. Chem. Commun. 2001, 779. (d) Conner, D.; Jayaprakash, K. N.; Cundari, T. R.; Gunnoe, T. B. Organometallics 2004, 23, 2724. (e) Amoroso, D.; Jabri, A.; Yap, G. P. A.; Gusev, D. G.; dos Santos, E. N.; Fogg, D. E. Organometallics 2004, 23, 4047. (15) For pioneering work on chiral pyridine ligands, see: (a) Botteghi, C.; Caccia, G.; Chelucci, G.; Soccolini, F. J. Org. Chem. 1984, 49, 4290. (b) Botteghi, C.; Chelucci, G.; Chessa, G.; Delogu, G.; Gladiali, S.; Soccolini, F. J. Organomet. Chem. 1986, 304, 217. (c) Chelucci, G. Tetrahedron: Asymmetry 1995, 6, 811. (d) Bolm, C.; Ewald, M. Tetrahedron Lett. 1990, 31, 5011. (e) Bolm, C.; Schlingloff, G.; Harms, K. Chem. Ber. 1992, 125, 1191. (16) (a) Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763. (b) Pu, L.; Yu, H. B. Chem. Rev. 2001, 101, 757, and references therein. (17) For reviews on the asymmetric reduction of the carbonyl group: Houben-Weyl Methods of Organic Chemistry, Stereoselective Synthesis; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Georg Thieme Verlag: Stuttgart, 1997; Vol. E21d. (18) (a) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763. (b) Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3, 1475. (c) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 5675. (d) Soai, K.; Niwa, S.; Kobayashi, T. J. Chem. Soc., Chem. Commun. 1987, 801. (e) Itsuno, S. Org. React. 1998, 52, 395. (19) Faber, K. Biotransformations in Organic Chemistry, 5th ed.; Springer-Verlag: Berlin, 2004. (20) (a) Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis: Regio and Stereoselective Biotransformations, 2nd ed.; WileyVCH: Weinheim, Germany, 2005. (b) Schmid, R. D.; Verger, R. Angew. Chem., Int. Ed. 1998, 37, 1609. (21) (a) Koskinen, A. M. P.; Klibanov, A. M. Enzymatic Reactions in Organic Media; Blackie Ed.: London, 1996. (b) Itoh, T.; Akasaki, E.; Nishimura, Y. Chem. Lett. 2002, 154.

Article

Organometallics, Vol. 29, No. 16, 2010 Scheme 1a

a

Reaction conditions: (i) NaBH4, EtOH; (ii) Novozyme 435, p-chlorophenylacetate, 2% Shvo’s catalyst, toluene, 70 °C; (iii) K2CO3, MeOH/ H2O, room temperature; (iv) DPPA, DBU, toluene, 0 °C; (v) Ph3P, THF, H2O, rt; (vi) Pd(OAc)2, PPh3, K2CO3(aq), 1-propanol, reflux.

alcohols,22 and the origin of this behavior has been fully explained from the knowledge of the protein structure.23 In this context, we have recently developed a strategy for the stereoselective synthesis24 of enantiomerically pure 2-(1-aminoethyl)6-(phenyl)pyridine, based on a well-established biocatalytic protocol for the stereoselective synthesis of sec-alcohols.20,25 We report herein the synthesis of new chiral pincer HCNN ligands obtained through a chemoenzymatic approach. These compounds were used to prepare in situ Ru and Os pincer [MCl(CNN)(Josiphos)] catalysts for the TH of acetophenone in basic 2-propanol. On account of the high performance of the HCNN ligand containing the 2-naphthyl moiety, the corresponding Ru and Os complexes [MCl(CNN)(Josiphos)], showing the correctly matched chiral ligands, were isolated. These catalysts have proven to catalyze the enantioselective TH of alkyl aryl ketones with low loading (0.005 mol %), high rate (TOF ≈ 105-106 h-1), and up to 99% ee.

Results and Discussion Synthesis of the Chiral Pincer Ligands. The compound (S)1a was prepared from 2-(1-hydroxyethyl)-6-phenylpyridine via dynamic kinetic resolution, as previously described (Figure 2).24 According to the strategy outlined in Scheme 1, the HCNN ligands 1b-g in their S configuration and in excellent enantiomeric excess were obtained starting from the commercial 2-acetyl-6-bromopyridine (2). On the basis of the high enantioselectivity displayed in the acetylation of 2-pyridyl alcohols,26 Candida antarctica lipase B was used for the resolution of racemic 6-bromo-1-(2-pyridyl)ethanol, (()-3, obtained by NaBH4 reduction of 2. Exhibiting the usual enantiospecificity,27 CAL-B, here used in its immobilized form (Novozyme 435), converted (R)-3 selectively into (22) Orrenius, C.; Ohrner, N.; Rotticci, D.; Mattson, A.; Hult, K.; Norin, T. Tetrahedron: Asymmetry 1995, 6, 1217. (23) (a) Mccabe, R. W.; Rodger, A.; Taylor, A. Enzyme Microb. Technol. 2005, 36, 70. (b) Uppenberg, J.; Hansen, M. T.; Patkar, S.; Jones, T. A. Structure 1994, 2, 293. (c) Uppenberg, J.; Ohrner, N.; Norin, M.; Hult, K.; Kleywegt, G. J.; Patkar, S.; Waagen, V.; Anthonsen, T.; Jones, T. A. Biochemistry 1995, 34, 16838. (24) Felluga, F.; Baratta, W.; Fanfoni, L.; Pitacco, G.; Rigo, P.; Benedetti, F. J. Org. Chem. 2009, 74, 3547. (25) (a) Kroutil, W.; Mang, H.; Edegger, K.; Faber, K. Curr. Opin. Chem. Biol. 2004, 8, 120. (b) Nakamura, K.; Yamanaka, R.; Matsuda, T.; Harada, T. Tetrahedron: Asymmetry 2003, 14, 2659. (26) (a) Uenishi, J.; Nishiwaki, K.; Hata, S.; Nakamura, K. Tetrahedron Lett. 1994, 35, 7973. (b) Uenishi, J.; Hiraoka, T.; Hata, S.; Nishiwaki, K.; Yonemitsu, O.; Tsukube, H. J. Org. Chem. 1998, 63, 2481. (27) (a) Rotticci, D.; Hæffner, F.; Orrenius, C.; Norin, T.; Hult, K. J. Mol. Catal. B: Enzym. 1998, 5, 267. (b) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294.

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Table 1. Catalytic TH of Acetophenone (0.1 M) with the System [RuCl2(PPh3)3]/(R,S)-Josiphos*/HCNN ligand (Ru = 0.005 mol %) and NaOiPr (2 mol %) in 2-Propanol at 60 °C HCNN ligand

conv (%)a

time (min)

TOF (h-1)b

ee (%)a

(S)-1a (S)-1b (S)-1c (S)-1d (S)-1e (S)-1f (S)-1g

98 97 95 27 4 95 98

30 30 30 120 60 60 30

1.6  105 1.3  105 6.5  104

92 R 86 R 85 R 84 R

6.5  104 1.5  105

85 R 92 R

a Conversion and ee were determined by GC analysis. b Turnover frequency (moles of ketone converted to alcohol per mole of catalyst per hour) at 50% conversion.

the corresponding acetate (R)-4 with excellent yield and ee.26a In order to improve the yield of the kinetic resolution, which is intrinsically limited to a maximum 50% in its classical version, we applied to the lipase-catalyzed transesterification of rac-3 the conditions developed by B€ ackvall for the dynamic kinetic resolution of sec-alcohols.28 When the acetylation of (()-3, with p-chlorophenylacetate as the acyl donor, was coupled to the in situ racemization of the slow reacting S enantiomer with the Ru-based redox catalyst [Ru2(CO)4(μ-H)(C4Ph4-COHOCC4Ph4)] (Shvo’s catalyst), the reaction reached complete conversion, enantioconverging to the acetate (R)-4, which was isolated in 98% ee and 70% yield after column chromatography (Scheme 1). Mild basic hydrolysis of the optically active ester (R)-4 gave the corresponding alcohol (R)-3 (98% ee, 70% from (()-3). To obtain the amine (S)-6, the homochiral alcohol (R)-3 was first converted into the corresponding azide (S)-5 with diphenylphosphoroazidate (DPPA) in the presence of DBU.29 To avoid epimerization, the reaction was run at 0 °C, leading to a clean SN2 process, which converted the alcohol (R)-3, having 98% ee, into the inverted azide (S)-5, without significant loss in the enantiomeric purity (97% ee). Transformation of the azide into the corresponding amine (S)-6 (97% ee) was carried out by treatment with Ph3P in refluxing THF/H2O.30 Finally, Suzuki coupling with the appropriate substituted phenyl and naphthyl boronic acids 7b-g gave the HCNN ligands (S)-1b-g in 70-95% yield (Scheme 1 and Figure 2). Asymmetric TH of Acetophenone with in Situ Generated Ru and Os Complexes. Previous studies with HCNN and the C1symmetric (R,S)-Josiphos ligands showed that an increase of enantioselectivity can be achieved by employment of the (R,S)Josiphos* diphosphine containing 4-OMe-3,5-Me2C6H2 instead of Ph. The in situ generated pincer complex [RuCl(CNN)((R,S)-Josiphos*)], obtained by refluxing a 2-propanol solution of [RuCl2(PPh3)3] with (R,S)-Josiphos* (1 h) and (S)-1a (1 h), promotes the asymmetric transfer hydrogenation of acetophenone in basic 2-propanol at 60 °C to give quantitatively (R)-1-phenylethanol in 30 min (eq 1) with high rate (TOF = 1.6  105 h-1) and with 92% ee (Table 1).

The use of (S,R)-Josiphos* in combination with (S)-1a led to (S)-1-phenylethanol, but with lower ee (75%), indicating (28) (a) Persson, B. A.; Larsson, A. L.; Le Ray, M.; B€ackvall, J.-E. J. Am. Chem. Soc. 1999, 121, 1645. (b) Larsson, A. L. E.; Persson, B. A.; B€ackvall, J.-E. Angew. Chem., Int. Ed. Engl. 1997, 36, 1211. (29) Thomson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D. J.; Grabowski, E. J. J. J. Org. Chem. 1993, 58, 5886. (30) Horner, L.; Gross, A. Liebigs Ann. Chem. 1955, 591, 117.

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Table 2. Catalytic TH of Acetophenone (0.1 M) with the System [OsCl2(PPh3)3]/(R,S)-Josiphos*/HCNN Ligand (Os = 0.005 mol %) and NaOiPr (2 mol %) in 2-Propanol at 60 °C HCNN ligand

conv (%)a

time (min)

TOF (h-1)b

ee (%)a

(S)-1a (S)-1b (S)-1c (S)-1d (S)-1e (S)-1f (S)-1g

96 96 76 39 8 70 96

30 30 120 120 60 120 30

1.5  105 1.2  105 6.0  104

83 R 85 R 83 R 75 R

6.6  104 1.5  105

81 R 87 R

RuCl2-(R,S)-Josiphos* system reacts with (S)-1g in toluene at reflux temperature, affording different species, which convert after 3 h to substantially only one set of resonances, attributable to a single stereoisomer. The isolation of the orange complex 8 (75% yield) has successfully been achieved by treatment of [RuCl2(PPh3)3] with 1.2 equiv of (R,S)-Josiphos* in toluene at 105 °C for 2 h and reaction with 1 equiv of (S)-1g in the presence of an excess of NEt3 in 2-propanol at reflux temperature for 3 h (eq 2).

a Conversion and ee were determined by GC analysis. b Turnover frequency (moles of ketone converted to alcohol per mole of catalyst per hour) at 50% conversion.

that (R,S)-Josiphos* and (S)-1a are the correctly matched combination of the chiral ligands, in agreement with the results obtained with the related cis-[RuCl2(Josiphos)(R-ampy)]5b complexes. In order to investigate the stereoelectronic effects of the substituents of the pincer ligand in the asymmetric TH, we have prepared in situ ruthenium catalysts with the ligands (S)-1b-g, containing one or two electron-donating versus electron-withdrawing groups on the aryl moiety. With (S)-1b and (S)-1c with OMe and CF3 in the para position, respectively, we observed complete reduction of acetophenone (30 min) with TOF = 1.3  105 and 6.5  104 h-1 and 86 and 85% ee, suggesting that the electron-withdrawing CF3 group leads to a decrease of the activity of the catalyst. Employment of the 3,5-disubstituted Me and CF3 ligands (S)-1d and (S)-1e, respectively, gave 27% and 4% conversion, indicating that the presence of two groups in the 3 and 5 positions affords less active systems, possibly inhibiting the orthometalation. Interesting results were obtained with the ligands (S)-1f and (S)-1g, containing the 1-naphthyl and 2-naphthyl moieties bound to the pyridine ring, resulting in the quantitative conversion of acetophenone with TOF = 6.5  104 and 1.5  105 h-1 and 85 and 92% ee. These data suggest that in both cases orthometalation occurs, the 2-substituted ligand affording the best performance in terms of rate and enantioselectivity. The effect of the substituents on the ligands (S)-1a-g was investigated also with the osmium precursor [OsCl2(PPh3)3], and we observed a trend similar to that found for ruthenium. The in situ generated complexes, prepared by refluxing a 2-propanol solution of [OsCl2(PPh3)3] with (R,S)-Josiphos* (1.5 h) in combination with the pincer ligands (1 h), namely, the phenyl (S)-1a, the para-methoxyphenyl (S)-1b, and the 1-naphthyl (S)1f ligands, gave good values of rate (6.6  104 to 1.5  105 h-1) and enantioselectivity (81-85% ee) in the TH of acetophenone (Table 2). As for ruthenium, the 2-naphthyl ketone (S)-1g shows the best performance with TOF = 1.5  105 h-1 and 87% ee. The ligand (S)-1c, containing the electron-withdrawing group CF3, led to lower rate and conversion (76%) in 2 h, whereas the disubstituted methyl and CF3 ligands (S)-1d and (S)-1e gave incomplete conversion of acetophenone (39% and 8%, respectively) as observed for ruthenium, suggesting that also in this case the presence of two substituents in the 3,5 positions may hinder the orthometalated reaction. Synthesis and Characterization of [MCl(CNN)(PP)] (M = Ru, Os) Complexes. On account of the high activity and enantioselectivity achieved with the in situ prepared metal catalysts obtained from (R,S)-Josiphos* in combination with the 2-naphthyl ligand (S)-1g, the corresponding ruthenium and osmium complexes were isolated. A control 31P NMR experiment for ruthenium reveals that the in situ prepared

The 31P NMR spectrum of 8 shows two doublets at δ 67.1 and 37.6 with 2J(P,P) = 40.5 Hz. In the 1H NMR spectrum the singlet at δ 8.70 is for one naphthyl proton, whereas the 13 C NMR signal at δ 181.2 is for the orthometalated carbon, in agreement with the proposed naphthyl coordination mode. Attempts to obtain suitable crystals for X-ray analysis failed. The stereochemistry for the pincer complexes [RuCl(CNN)(Josiphos)] has been proposed on the basis of the structure of the related Josiphos ruthenium complexes with ampy-type ligand [RuCl(CNN)(PP)]6b and cis-[RuCl2(Josiphos)(R-ampy)]5b complexes. The orange-red pincer osmium complexes 9 and 10 (77% and 71% yield) containing (R,S)-Josiphos and (R,S)-Josiphos*, respectively, were obtained from [OsCl2(PPh3)3], the suitable diphosphine in combination with (S)-1g, according to the procedure for 8. The 31P NMR spectrum of 9 shows two doublets at δ 9.5 and -3.8 with 2J(P,P) = 22.4 Hz, whereas the 1H NMR spectrum reveals two singlets at δ 8.67 and 8.29 for the two protons of the orthometalated naphthyl ring. Similar spectroscopy data were obtained for the analogous derivative 10, containing the bulkier (R,S)-Josiphos* diphosphine. Asymmetric TH of Ketones with the Pincer Ru and Os Complexes. The ruthenium compound 8 and the osmium complexes 9 and 10 were found to efficiently catalyze the enantioselective reduction of alkyl aryl ketones with high rate and ee, using a low amount of catalyst. Thus, acetophenone 11 is rapidly and quantitatively converted into (R)-1-phenylethanol in 2-propanol at 60 °C using 8, 9, and 10 (0.005% mol) and in the presence of NaOiPr (2 mol %) (Scheme 2), achieving ee = 92%, 89%, and 91% and TOF = 1.2  105 to 3.2  105 h-1 (Table 3). These data show that under these catalytic conditions the osmium complexes 9 and 10 are faster compared to the ruthenium complex 8, indicating that the formation of the catalytically active osmium species is a rapid process. In addition, complex 10,

Article

Organometallics, Vol. 29, No. 16, 2010

3567

Table 4. Catalytic TH of Ketones (0.1 M) with the Ru System 8 (0.005 mol %) and NaOiPr (2 mol %) in 2-Propanol

Scheme 2

ketone

conv (%)a

T (°C)

time (min)

TOF (h-1)b

ee (%)a

12 13 14 15 16 16 17 18 19 19 20 21 22 23 24 25 26

90 98c 96 80c 99 99 99 96 97 97 99c,d 93 99d 99c,d 4 10 20

60 60 60 60 60 82 60 60 60 82 60 60 60 60 60 60 60

120 30 30 60 30 5 30 60 30 2 60 60 30 10 30 120 60

7.7  104 4.7  104 1.6  105 2.5  104 1.3  105 8.4  105 2.6  105 9.0  104 2.1  105 1.8  106 1.9  104 3.9  104 6.6  104 1.2  105

99 R 96 R 93 R 96 R 99 R 99 R 96 R 94 R 95 R 91 R 98 R 86 R 92 R 97 R

a Conversion and ee were determined by GC analysis. b Turnover frequency (moles of ketone converted to alcohol per mole of catalyst per hour) at 50% conversion. c Substrate/8/NaOiPr = 10 000/1/200. d In situ reaction.

Table 3. Catalytic TH of Acetophenone (0.1 M) with the Complexes 8-10 (0.005 mol %) and NaOiPr (2 mol %) in 2-Propanol at 60 °C complex

conv (%)a

time (min)

TOF (h-1)b

ee (%)a

8 9 10

95 96 97

30 30 30

1.2  105 2.5  105 3.2  105

92 R 89 R 91 R

a Conversion and ee were determined by GC analysis. b Turnover frequency (moles of ketone converted to alcohol per mole of catalyst per hour) at 50% conversion.

with the bulkier (R,S)-Josiphos* with respect to complex 9, shows both higher ee and rate. With 8 a number of ketones have quickly been reduced using 0.005 mol % of catalyst. Propiophenone 12 has been reduced to (R)-1-phenylpropan1-ol with 99% ee and TOF = 7.7  104 h-1, whereas the 1-acetonaphthone 13 and 2-acetonaphthone 14 are converted into the corresponding R-alcohols with 96% and 93% ee and TOF = 4.7  104 and 1.6  105 h-1, respectively (Table 4). The ortho methyl acetophenone 15 and the meta-substituted Cl, CF3, and OMe derivatives 16, 17, and 18 are promptly reduced to R-alcohols with both high TOF (2.5  104 to 2.6  105 h-1) and enantioselectivity (94-99% ee). The reduction of the ketone 16 at 82 °C occurs in 5 min with a remarkably high rate (TOF = 8.4  105 h-1) and without erosion of ee (99%). At 60 °C, also the 3,5-disubstituted ketones 19 and 20 have quickly been converted into R-alcohols with TOF up to 2.1  105 h-1 and 95% and 98% ee. At 82 °C the derivative 19 undergoes a rapid reduction (2 min) with very high TOF (1.8  106 h-1) and a decrease of ee (91%). Heterocyclic ketones, such as 2-, 3-, and 4-pyridyl methyl ketones 21-23, have been converted quantitatively at 60 °C into the (R)-pyridyl alcohols with TOF in the range 3.9  104 to 1.2  105 h-1 and 86%, 92%, and 97% ee, respectively. Attempts to reduce more sterically demanding ketones such as 2-methyl-1-phenylpropan-1-one (24) or dialkyl ketones, namely, 2-decanone 25 or 5-hexen-2-one 26, resulted in low alcohol conversion (