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