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LIGAND DESIGN FOR ASYMMETRIC TRANSFER HYDROGENATIONS
IN AQUEOUS MEDIUM
Jacqueline Bitai
INTRODUCTION
ASYMMETRIC TRANSFER HYDROGENATION IN AQUEOUS MEDIA
REFERENCES
CONCLUSION
LIGAND DESIGN
[1] Sheldon, R.; Arends, I.; Hanefeld, U. Industrial Catalysis: A practical approach, Second Edition; Wiley-VCH Verlag
GmbH & Co. KGaA: Weinheim, Germany, 2006.
[2] Vasiloiu, M.; Gaertner, P.; Zirbs, R.; Bica, K. Eur. J. Org. Chem. 2015, 2374 – 2381.
[3] Guduguntla, S.; Hornillos, V.; Tessier, R.; Fañanás-Mastral, M.; Feringa, B. L. Org. Lett. 2016, 18, 252–255.
For a successful application in aqueous asymmetric transfer
hydrogenation, a ligand has to meet the following basic requirements:
Increasing environmental awareness calls for greener processes in industry and laboratory applications. Within the 12 principles of
green chemistry, the use of innocuous solvents is one important goal. As such, water is attracting increasing attention. It offers many
beneficial properties: it is cheap, non-toxic, environmentally benign, abundant, non-flammable and far less volatile than common
organic solvents.
Another important goal in green chemistry is the implementation of catalytic transformations. Within catalytic processes, the
stereoselective reduction of carbonyls to chiral alcohols plays an important role. Common catalytic reductions involve the use of
hydrogen gas H2 as hydrogen donor, which is accompanied by major safety risks. H2 is easily inflammable and the reactions are
generally conducted under high pressure.
To avoid those hazards, an alternative reaction protocol has emerged – transfer hydrogenations (TH). Therein, a small organic
molecule is used instead of H2. Moreover, a transfer hydrogenation reaction is ideally suited for using water as the solvent, as it
allows for the use of the salt sodium formate NaCOOH as hydrogen donor. To enhance water solubility of the catalyst, adaptations
of the ligands in the catalyst complex to these conditions are crucial.[1]
We herein present the design and synthesis of highly coordinating hydrophilic chiral ionic ligands to obtain water soluble chiral
catalysts. We demonstrate the successful application of those catalysts in the ruthenium catalysed asymmetric transfer
hydrogenation of aromatic ketones in water.
Entry[a] Time [h] Temperature [°C] Ligand % Conv. [b] % ee[c]
1
24 40
L1a 90 49 (S)
2 L2 19 12 (S)
3 L3 20 46 (R)
4 L4 100 90 (R)
Herein, we presented the synthesis of highly coordinating chiral ionic ligands based on a chiral β-amino alcohol and a chiral diamine structural motive. The
obtained chiral ionic ligands were successfully applied in Ru-catalysed asymmetric transfer hydrogenation in water. The BOC protected diamine ligand L4
showed activities and selectivities compareable to the State of the Art System. The applicability of the new ligand L4 was further demonstrated by the
enantioselective reduction of different aromatic ketones.
[a] Performed with acetophenone (2 mmol), sodium formate (10 mmol), chiral ionic ligand (12 mol%), [Ru(p-
cymene)Cl2]2 (5 mol%). [b] Conversion determined by HPLC analysis. [c] Determined by HPLC analysis using a
DAICEL Chiralcel IB column.
To evaluate our newly designed chiral ionic ligands, we investigated the
Ru-catalysed asymmetric transfer hydrogenation of acetophenone to
1-phenylethanol in aqueous media, using sodium formate as hydrogen donor.
Starting from commercially available chiral
amino alcohols (1S,2R)-2-amino-1,2-diphenyl-
ethanol 1a and (1R,2R)-2-amino-1,2-diphenyl-
ethanol 1b and chiral diamine (1R,2R)-1,2-
diphenylethylenediamine 2 the targeted
hydrophilic coordinating chiral ionic ligands
could be obtained in 2 to 5 steps, respectively.
SYNTHESISIonic ligand precursor
Bidentate chiral
ligand as
structural motive
Selective alkylation
We also investigated the influence of ligand stereochemistry on product
stereochemistry. The results indicate that the stereocenters at C1 are
determining the product stereochemistry. However, dimethylation of the
heteroatom at C1 in L2 will lead to the inversion of product stereochemistry,
since the otherwise less favoured complex diastereomer will form.
Coordinating chiral
ionic ligand
Vienna University of Technology
Institute of Applied Synthetic Chemistry
Supervisor: Ass.Prof. Dipl.-Ing. Dr.techn. Katharina Schröder
Master Thesis Presentation
Master Program:
Technical Chemistry
Bidentate ligand structure for
coordination to metal centre
Primary / secondary amine
functionality to enable
transition state
Additional ionic
functionality to tune
catalyst solubility
Based on these prerequisites, a
general synthesis strategy could
be proposed.[2]
CIL L1a L1b L2 L3 L4Ligand
configuration (1S,2R) (1R,2R) (1R,2R) (1R,2R) (1R,2R)
Product configuration (S) (R) (S) (R) (R)
With the best performing ligand L4, different aromatic ketones were reduced
to evaluate the ligand performance in aqueous asymmetric transfer
hydrogenation.
68% yield
82% ee (R)
82% yield
97% ee (R)
74% yield
39% ee (R)
76% yield
81% ee (R)
73% yield
93% ee (R)
Chiral backbone for
chiral induction
Reagents and conditions: (L1a, L1b)[2]: (i) 1a or 1b, pyridine-3-carboxaldehyde, MS, NaBH4, MeOH; (ii) n-butylbromide, T; (L2): (i) phthalic anhydride, p-TsOH, MS, Toluene, rf;[3] (ii) HCHO,
HCOOH, rf;[4] (iii) hydrazine monohydrate, EtOH, rf;[3] (iv) pyridine-3-carboxaldehyde, MS, NaBH4, MeOH; (v) n-butylbromide, T; (L3): (i) HCl in MeOH, (BOC)2O;[5] (ii) pyridine-3-carboxaldehyde,
MS, NaBH4, MeOH; (iii) n-butylbromide, T; (iv) HBr in HAc, CH2Cl2;[6]; (L4): L3 (i) – (iii);
Performed with ketone (2 mmol), sodium formate (10 mmol), chiral ionic ligand (12 mol%), [Ru(p-cymene)Cl2]2 (5
mol%) at 25 °C for 24 h. Isolated yields after column chromatography. Enantiomeric excess determined by HPLC
analysis using a DAICEL Chiralcel IB column.
[4] Vasiloiu, M.; Leder, S.; Gaertner, P.; Mereiter, K.; Bica, K. Org. Biomol. Chem., 2013, 11, 8092–8102.
[5] Lee, D. W.; Ha, H.; Lee, W. K. Synth. Commun. 2007, 37, 737–742.
[6] Tiffner, M.; Novacek, J.; Busillo, A.; Gratzer, K.; Massa, A.; Waser, M. RSC Adv. 2015, 5, 78941–78949.
Catalysis
Water as
Solvent