DOI: 10.1002/chem.201304770

Communication

& Synthetic Methods

Selective Transfer Hydrogenation and Hydrogenation of Ketones Using a Defined Monofunctional (P^N(Bn)^N(Bn)^P)–RuII Complex Shih-Fan Hsu and Bernd Plietker*[a] Abstract: A defined (P^N^N^P)–Ru complex possessing tertiary amines within the ligand backbone proved to be highly active both in transfer hydrogenations and hydrogenations of a variety of ketones. As compared to the existing catalytic systems, no bifunctional activation of H2 or of the substrate by the metal center and a secondary amine within the ligand backbone is required to obtain high activities at catalyst loadings of down to 10 ppm.

The selective hydrogenation of carbonyl compounds is one of the most important transformations in organic chemistry.[1] Hence a plethora of active catalysts for the selective reduction of carbonyl compounds to the corresponding alcohols has been reported up to date.[1, 2] When it comes to activity and selectivity, Noyori’s groundbreaking investigations still resemble the benchmark within this field of catalysis.[3] However, certain limitations (e.g., reduction of aliphatic ketones, aldehydes, imines, etc.) do exist and thus there is an ongoing interest in identifying more active catalysts that are able to address some of the limitations. With regard to catalyst loadings, the use of tetradentate (P^N ^N^P) ligands has recently moved into the center of research.[2e, 4, 5] Important contributions by the groups of Mezzetti[6] and Noyori[7]/Morris,[4b, 8] indicated (P^N^N^P) complexes to maintain their structure throughout the catalytic cycle. Ligand dissociation processes are usually not observed. Catalyst aging and hence a decrease of the activity with ongoing conversion is significantly reduced. Interestingly, both the Mezzetti and the Morris system rely on either preformed secondary amines or on bisimines within the ligand backbone.[9] The use of tertiary amines as part of the ligand backbone was reported to decrease catalyst activity.[10] Recently, our group was able to show that a defined (N^N^N^N)–Ru complex is a potent catalyst for hydrogen autotransfer reactions.[11] At the same time we reported a defined (P^N^N^P)–RuII complex to catalyze the selective oxidation of

benzylic C H bonds under mild conditions.[12] Both tetradentate ligands possess tertiary amines within the ligand backbone that were shown to bind to the metal center. As compared to the existing (P N N P)–Ru-type complexes this structural motif is unusual and we became interested in investigating the potential of our monofunctional (P^N^N^P)–RuII complex as a hydrogenation catalyst. At the outset of our investigations, we choose the transfer hydrogenation as a starting point. Different solvents and additives were tested in the reduction of benzophenone 2 under transfer hydrogenation conditions (Table 1). Already initial results indicated complex 1 to possess a high activity (Table 1). In the presence of only 0.5 mol % catalyst and 2.5 mol % Kt-amyl as a base, almost quantitative yield of alcohol 3 were obtained within just 1.5 h. Further optimization concentrated on a reduction of the catalyst loading. Complex 1 showed a remarkable activity in the test reaction. Even at

[a] S.-F. Hsu, Prof. Dr. B. Plietker Institut fr Organische Chemie Universitt Stuttgart Pfaffenwaldring 55 70569 Stuttgart (Germany) Fax: (+ 49) 711-68564285 E-mail: [email protected]

Entry

1 [mol %]

Kt-amyl [mol %]

Solvent

t [h]

Yield [%][b]

1 2 3 4 5 6 7 8 9 10 11 12

0.5 0.5 0.5 0.25 0.125 0.075 0.05 0.025 0.01 0.01 0.005 0.0025

2.5 2.5 2.5 1.25 0.625 0.375 0.25 0.125 0.05 0.20 0.20 0.20

iPrOH EtOH MeOH iPrOH iPrOH iPrOH iPrOH iPrOH iPrOH iPrOH iPrOH iPrOH

1.5 1.5 1.5 1.5 18 18 18 18 18 18 18 18

98 (97)[c] 11 1< 79 97[d] 98[d] 99[e] 98[e] 40[f] 87[f] 87[f] 75[f]

[a] The reactions were performed on a 1 mmol scale under a N2-atmosphere if not otherwise specified. [b] Determined by 1H NMR analysis using mesitylene as internal standard. [c] Isolated yield. [d] 5 mmol of ketone. [e] 15 mmol of ketone. [f] 50 mmol of ketone.

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201304770. Chem. Eur. J. 2014, 20, 4242 – 4245

Table 1. The Ru-catalyzed transfer hydrogenation system development.[a]

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Communication a catalyst concentration of only 0.0025 mol % (25 ppm) using as little as 0.2 mol % of the base a 75 % yield after 18 h were observed (entry 12, Table 1). With these optimized reaction conditions in hand, we turned our attention toward an exploration of scope and limitation of this transfer hydrogenation protocol (Table 2). The reactions were performed using 0.01 mol % of catalyst 1 in order to reduce the reaction times, however the catalyst loadings can be reduced in a variety of cases down to

Table 2. Ru-catalyzed reduction of aldehydes/ketones under transfer hydrogenation conditions.[a]

Entry

R1

R2

1

C6H5

CH3

4

2

p-CH3C6H4

CH3

5

3

p-FC6H4

CH3

6

4 5 6

p-BrC6H4 p-IC6H4 p-CH3OC6H4

CH3 CH3 CH3

7 8 9

7

o-ClC6H4

CH3

10

8

o-CH3OC6H4

CH3

11

9

m-BrC6H4

CH3

12

10

m-CF3C6H4

CH3

13

11

C6H5

C6H5

3

12

C6H5

cyclopropyl

Product

14

Yield [%][b,c] 97 92 85 92 87 89 97 55 78 32 97 88 98 98 91 87 97 75 91 97

(18) (1.5)[d] (24) (1.5)[d] (24) (1.5)[d] (1.5)[d] (18)[d] (1.5)[d] (18) (3)[d] (3)[d] (18) (1.5)[d] (1.5)[d] (18) (1.5)[d] (18)[d] (24) (1.5)[d]

13

15

14

16

81 (8)[d]

15

17

71 (18)[d]

16

18

79 (8)[d]

17

19

81 (8)[d]

18

20

88 (3)[d]

19

21

78 (3)[d]

0.0025 mol % at the expense of a longer reaction time of about 24–36 h. Various aromatic or aliphatic ketones were reduced to the corresponding alcohols at low catalyst loadings. Aromatic compounds containing para-, meta- and ortho-substituted as well as cyclic ketones were reduced. Cyclopropyl, trifluoromethyl, furan, but also pyridine rings or even double and triple bonds are stable under the reaction conditions. As compared to the number of catalysts reported for transfer hydrogenation or hydrogenations, the number of complexes that are highly active for both reduction scenarios is comparably small.[13] With these encouraging results in the field of transfer hydrogenation in hand, we were wondering whether the complex might also be active in hydrogenation reaction. The reduction of acetophenone 22 was chosen as a model reaction. Various parameters in this transformation were systematically varied. Concentration, pressure, and temperature had a significant influence.[14] Under the optimized conditions the reduction of acetophenone 22 to 1-phenylethanol 4 can be performed in a 5 m iso-propanol solution using 10 ppm of catalyst 1 and 0.2 mol % of Kt-amyl as a base. The reaction is applicable to a variety of different substrates (Table 3). As observed in the transfer hydrogenation the direct H2-assisted hydrogenation proved to be applicable to various substrates. Aliphatic or aromatic ketones are reduced to the corresponding alcohols in good to excellent overall yields using only 50 ppm of catalyst 1. Importantly, olefins are not touched by this complex. Apart from ketones, aldehydes (Eq. [1], Scheme 1) and imines (Eq. [2], Scheme 1) are also reactive

Table 3. Ru-catalyzed hydrogenation system development.[a]

[a] The reactions were performed on a 30 mmol scale using 0.01 mol % Ru-catalyst (3.3 mg) and 0.2 mol % Kt-amyl (35.3 mL, 1.7 m in toluene) at 80 8C in dry iPrOH (120 mL). [b] Isolated yield. [c] The number in brackets refers to the reaction time. [d] The reactions were performed on a 1 mmol scale using 0.5 mol % Ru-catalyst (5.6 mg) and 2.5 mol % Kt-amyl (14.7 mL, 1.7 m in toluene) at 80 8C in dry iPrOH (2 mL).

Chem. Eur. J. 2014, 20, 4242 – 4245

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Entry

R1

R2

Product

Yield [%][b]

1 2 3 4 5

C6H5 C6H5 p-CH3C6H4 o-ClC6H4 m-BrC6H4

C6H5 CH3 CH3 CH3 CH3

3 4 5 10 12

99 94 99 23 99

6

17

66

7

18

74

8

20

99

9

21

99

[a] The reactions were performed on a 50 mmol scale using 0.005 mol % Ru-catalyst (2.8 mg) and 0.2 mol % Kt-amyl (58.8 mL, 1.7 m in toluene) at 80 8C in dry iPrOH (16.7 mL). [b] Determined by 1H NMR analysis using mesitylene as internal standard.

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Communication

Figure 1. Mechanistic proposal.

Scheme 1. Ru-catalyzed reduction of aldehydes, aldimines, and ketones.

under both hydrogenation and transfer hydrogenation conditions. The slightly basic conditions eventually result in undesired side reactions. In order to analyze such a scenario, ketoester 28 was subjected to both the transfer hydrogenation as well as to the hydrogenation conditions. Interestingly, the use of an alcoholic solvent led to both reduction of the carbonyl group but also to a transesterification giving product 27 in moderate yields.[15] Using the hydrogenation conditions in benzene as a solvent however led to a clean formation of compound 29 in high yield. Importantly, formation of polymers by polyesterification was not observed under the given conditions.[16] At the present state of research, we propose two different reduction mechanisms to be operative. The Ru-hydride species I which is formed from the corresponding precatalyst 1 undergoes a fast hydrometallation of the incoming carbonyl group to give to the alkoxo complex IV (Figure 1). Under transfer hydrogenation conditions the catalytic cycle is closed via a protodemetallation-b-hydride elimination sequence to give the product VI and catalyst I. Based upon Llobet’s recent report on Ru-catalyzed reduction of CO2, we propose that in the case of the H2-hydrogenation the metal alkoxide species IV undergoes a ligand exchange to form the h2-H2Ru species X in which the alkoxide IX is acting as a base that induces a heterolytic cleavage of the metal coordinated H Hbond. In this manuscript, we present a broadly applicable reduction of ketones, aldehydes and imines under both transfer hydrogenation as well as hydrogenation conditions. Importantly, the (P^N(Bn)^N(Bn)^P)–Ru precatalyst is highly active down to ppm amounts. The complex is lacking any active hydrogen Chem. Eur. J. 2014, 20, 4242 – 4245

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within the ligand core but resembles high activity and stability. In this regard we consider this complex to be complementary to existing (P2,N2)– or (PNNP)–Ru complexes and hope that it might open the way toward new catalytic applications. Future work is concentrating on the development of a stereoselective version of this transformation.

Acknowledgements Financial support from the Deutscher Akademischer Austauschdienst (DAAD, Ph.D.-grant for S. -F. H.) is gratefully acknowledged. Keywords: catalysis · hydrogenation · ligand · ruthenium · transfer hydrogenation

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[1] a) T. Ohkuma, R. Noyori, in The Handbook of Homogeneous Hydrogenation (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH, Weinheim, 2007; Vol. 3, pp. 745 – 1244; b) T. Ohkuma, R. Noyori, in Transition Metals for Organic Synthesis 2nd ed. (Eds.: M. Beller, C. Bolm), Wiley-VCH, Weinheim, 2004, Vol. 2, pp. 29 – 113; c) T. Ohkuma, M. Kitamura, R. Noyori, in Catalytic Asymmetric Synthesis 2nd ed. (Ed.: I. Ojima), Wiley-VCH, New York, 2000, pp. 1 – 110. [2] For selected recent examples, see: a) S. Fleischer, S. Zhou, K. Junge, M. Beller, Angew. Chem. 2013, 125, 5224; Angew. Chem. Int. Ed. 2013, 52, 5120; b) S. Manzini, C. A. U. Blance, S. P. Nolan, Adv. Synth. Catal. 2012, 354, 3036; c) K. Junge, K. Schrçder, M. Beller, Chem. Commun. 2011, 47, 4849; d) T. Johnson, W. G. Totty, M. Wills, Org. Lett. 2012, 14, 5230; e) H. R. Morris, Chem. Soc. Rev. 2009, 38, 2282; f) Z.-R. Dong, Y.-Y. Li, J.-S. Chen, B.-Z. Li, Y. Xing, J.-X. Gao, Org. Lett. 2005, 7, 1043. [3] a) R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97; b) R. Noyori, T. Ohkuma, Angew. Chem. 2001, 113, 40; Angew. Chem. Int. Ed. 2001, 40, 40. [4] The beneficial influene of a (P2,N2)-ligand in Ru-catalyzed hydrogenations or transfer hydrogenations is well documented, for seminal contributions see: a) W. Baratta, E. Herdtweck, K. Siega, M. Toniutti, P. Rigo, Organometallics 2005, 24, 1660; b) V. Rautenstrauch, X. Hoang-Cong, R. Churland, K. Abdur-Rashid, R. H. Morris, Chem. Eur. J. 2003, 9, 4954.  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication [5] A. Mezzetti, Dalton Trans. 2010, 39, 7851. [6] a) J. Egloff, M. Ranocchiari, A. Schira, C. Schotes, A. Mezzetti, Organometallics 2013, 32, 4690; b) C. Schotes, M. Althaus, R. Aardoom, A. Mezzetti, J. Am. Chem. Soc. 2012, 134, 1331; c) C. Schotes, A. Mezzetti, Angew. Chem. 2011, 123, 3128; Angew. Chem. Int. Ed. 2011, 50, 3072. [7] J.-Y. Gao, T. Ikariya, R. Noyori, Organometallics 1996, 15, 1087. [8] a) A. A. Mikhailine, M. I. Maishan, A. J. Lough, R. H. Morris, J. Am. Chem. Soc. 2012, 134, 12266; b) D. E. Prokopchuk, J. F. Sonnenberg, N. Meyer, M. Z.-D. Iuliis, A. J. Lough, R. H. Morris, Organometallics 2012, 31, 3056; c) D. E. Prokopchuk, R. H. Morris, Organometallics 2012, 31, 7375; d) A. A. Mikhailine, M. I. Maishan, R. H. Morris, Org. Lett. 2012, 14, 4638; e) C. Sui-Seng, F. Freutel, A. J. Lough, R. H. Morris, Angew. Chem. 2008, 120, 954; Angew. Chem. Int. Ed. 2008, 47, 940. [9] The necessity of bifunctional catalysts in Ru-catalyzed reduction has been intensively investigated. For a recent example see: F. Jiang, K. Yuan, M. Achard, C. Bruneau, Chem. Eur. J. 2013, 19, 10343 (and literature (7) – (19) cited therein).

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[10] M. S. Rahman, P. D. Prince, J. W. Steed, K. K. Hii, Organometallics 2002, 21, 4927. [11] D. Weickmann, W. Frey, B. Plietker, Chem. Eur. J. 2013, 19, 2741. [12] S.-F. Hsu, B. Plietker, ChemCatChem 2013, 5, 126. [13] Although numerous examples for highly active Ru-complexes in both transfer hydrogenation and hydrogenation exist, cross-checking is still an exception, see also ref. [4b] [14] For details see the Supporting Information [15] The lower yield can be attributed to the decelerating effect of the methanol and KOMe formed within the transesterification process. [16] The polyesterification was suppressed when high quality Kt-amyl was used. Partial hydrolysis of the Kt-amyl leads to a reagent that facilitates the polyesterification.

Received: December 5, 2013 Published online on March 12, 2014

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Selective transfer hydrogenation and hydrogenation of ketones using a defined monofunctional (P^N(Bn)^N(Bn)^P)-Ru(II) complex.

A defined (P^N^N^P)-Ru complex possessing tertiary amines within the ligand backbone proved to be highly active both in transfer hydrogenations and hy...
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