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Parallel Screening of Asymmetric Bidentate Ligands in Zinc Catalyzed Transfer Hydrogenation.

Byline: Tariq Zaman, Habib Nasir and Enda Bergin

Summary: Development in the field of asymmetric catalysis is driven by the importance of stereochemically pure compounds in the field of pharmaceutical industry, agrochemicals and flavors. The unpredictable results given by new catalysts make the design of effective ones a long and costly work. Combinatorial asymmetric catalysis is efficient tools for finding best catalysts and it helps for many catalytic systems to be screened in a short period of time to decide about their effectiveness in synthesizing stereospicific products. This work describes rapid screening of chiral asymmetric oxazoline, imine, aminal and bisimine bidentate ligands and their in situ use for catalytic transfer hydrogenation of ketone in the presence of zinc.

The ligands thus prepared in situ gave nearly same results with that of the purified version. The ligands which gave more than 70% ee with excellent conversions (90%) were readily identified. Thus ligands with excellent results can be purified in bulk to save time and money.

Keywords: Combinatorial synthesis, fast screening, asymmetric catalysis, transfer hydrogenation, diethyl zinc, instant ligand libraries.

Introduction

Stereochemically pure compounds are required in the field of pharmaceutical industry, agrochemicals and flavors which can be synthesized by asymmetric catalysis [1]. The synthesis of molecules containing one or more chiral centers is remained active in the field of catalysis for chemists, [2] which are generally extracted from plants or by the separation of racemic mixtures [3]. According to W. S. Knowles the final structure cannot be predicted theoritically due to the small difference of energy (-2kcal/mol for 95% ee) between two diastereomeric transition states [4]. Finding new catalytic system is not an efficient way during classical method by running long columns which is also time consuming [5]. High throughput screening is a new way for the search of different catalytic systems by creating a number of different libraries, which is then screened for their potential [6].

The first comparison was made by De Vries by introducing instant libraries of MonoPhose [7, 8] during which chiral ligands were synthesized both in situ and in pure giving results with slightly difference. Inspite of the advances in the field, Bidentate ligands remains a problem that require purification of resulting ligands [9, 10] for which solid phase [11-13] and supramolecular [14-17] methods have been employed so for. Due to the greater synthetic difficulties [18] of bidentate ligands, its use in combinatorial screening was stopped until E. Bergin and co-workers used it with appreciable enantiomeric excesses [19, 20]. Herein we present a library of bidentate ligands for the in situ transfer hydrogenation of ketones and the comparison of results with the purified version.

Results and Discussions

In the beginning equimolar of aldehyde and amine were allowed to react together for 24 hours in toluene with 4A o molecular sieves and luckily a pure ligand was obtained after column chromatography. The beauty of this method is the available variation in both starting materials and the formation of by product (water, HCl) which can easily be removed with the help of molecular sieves. Four families of ligands imines, aminals, oxazolines and bisimines were synthesized and used in situ. These ligands were easily obtained by combining aldehyde with amine [21], diamine [21, 22] and amino alcohol [23, 24] respectively (scheme-1).

The structural variations and cheap availability of the above mentioned compounds helped us the synthesis of a library of ligands to be tested both in situ and in pure form (Fig. 1). At first we compare the results of ligands prepared in situ with that of purified one and found almost same results, 69% vs 68% ee and 91% vs 89% conversion for 5 (Table 1, entries 1 and 2) which encouraged us for the evaluation of other ligands by using one pot synthesis without the need of column chromatography i.e.; we made a small library and tested it in transfer hydrogenation of acetophenone (Table-1, Fig. 1). Such ligands could be carried out in modular and parallel way that could easily be produced overnight.

Substituents on the aldehyd had positive effect on both the conversion and selectivity (Table 1, entries 8 versus 10, 13 versus 14 and 16 versus 17) due to presence of methyl group aiding the availability to metal atom while bisimine having the methoxy and phenyl group give positive effect due to resonance (Table 1, entries 19 versus 20 and 21). Oxazoline ligands were both used in situ and in the purified form and maximum ee 66% and conversion 87% (Table 1, entry 27) were recorded for 29.

Scheme-1: Synthesis of bidentate ligands

Table-1: Asymmetric transfer hydrogenation in water.

The phenyl group seems to be an important feature since replacement of this with cyclohexyl group showed a significant drop in enantioselectivity (Entry 11, 14 and 12 vs 15 table 1).

Steric effect played an important role in complex formation and achieving good ees as the enantiomeric excess of 1-phenylethanol obtained was maximum 81% for 8 (Entry 5 table 1), which helped us to access structure of the ligands in easy way. Honestly speaking none of our ligand is able to give product with exemplary conversion and ee, but we were able to improve the literature by combining easily available raw materials for synthesizing a small library of four classes of ligands and which can directly be used for combinatorial asymmetric syntheses.

Furthermore, it is not necessary in the beginning to synthesize ligands in bulk quantities and thorough purification which waste time and money but can easily be tested in microlitre ranges of the two fragments and thus reducing cost, and time. Once finding a hit for the best ligand it can be synthesized and purified easily on large scale. Studies to find optimum conditions for the successful ligands are underway in our group.

Experimental

The NMR spectra were recorded on a Bruker DPX-400 Advance spectrometer. The assignments were made on the basis of 1 H and 13 C NMR and the shifts are reported with TMS and the internal solvents CDCl 3 (1H: Delta 7.26 ppm, 13C: Delta 77.0 ppm) or D 2 O (1H: Delta 4.79 ppm) were used. All chemicals were obtained from commercial sources and used as received. Flash chromatography was carried out using (0.04-0.063 mm) silica gel and the progress were followed by TLC. Visualisation was by UV light (254 nm) or I 2 staining. Chiral HPLC was performed using chiral column Chiralpak IB (4.6 mm x 25 cm) columns.

Mass spectra were recorded on a Mass Lynx NT V 3.4 with carrier solvents water, methanol or ethanol. Electrothermal IA9000 digital melting point apparatus were used for determining of melting points. Infrared spectra were recorded on a Mattson Genesis II FTIR spectrometer equipped with Universal ATR sampling accessory. Toluene was refluxed over CaH 2 while THF was distilled from sodium/benzophenone and both were dried over 4A 0 molecular sieves.

Fig. 1: Ligands employed in this study.

A vial was charged with anhydrous toluene (0.2 ml), aldehyde (0.085 mmol) and amine (0.085mmol) along with 4A molecular sieves and was then stirred at 70degC overnight.1H-NMR (400 MHz, CDCl 3 ) Delta 8.60 (d, 1H, J = 4.5 Hz), 8.51 (s, 1H), 8.10 (d, 1H, J = 7.2 Hz), 7.65 (ap t, 1H), 7.50-7.45 (m, 2H), 7.40-7.30 (m, 2H), 7.25-7.17 (m, 2H), 4.63 (q, 1H, J = 6.6 Hz), 1.63 (d, 3H, J = 6.6 Hz), 13C- NMR (100MHz, CDCl 3 ) Delta 160.0, 154.3, 148.9, 144.1, 136.1, 128.1, 126.6, 126.3, 124.3, 121.0, 69.2, 24.2. Consistent with literature values [19]

Imine 6 Prepared via the above procedure, 1H-NMR (400 MHz, CDCl 3 ) Delta 8.48 (s, 1H, CH=N), 7.95 (d, 1H, J = 7.7 Hz, Ar), 7.62-7.68 (m, 1H, Ar), 7.42-7.51 (m, 2H, Ar), 7.33-7.40 (m, 2H, Ar), 7.20 (d, 1H, J = 7.7 Hz, Ar), 4.65 (q, 1H, J = 6.7 Hz, CHCH 3 ), 2.61 (s, 3H, PyrCH 3 ), 1.63 (d, 3H, J = 6.7 Hz, CHCH 3 ). 13C-NMR (100MHz, CDCl 3 ) Delta 160.4 (CH=N), 157.5, 153.8, 144.1, 136.3, 128.0, 126.5, 126.3, 125.4, 123.9, 117.9, 69.1 (CH), 24.1 (CH 3 ), 23.9 (CH 3 ). IR (NaCl-disk) v/cm -1 3388, 3061, 2971, 2926, 2861, 1711, 1645, 1591, 1453. HRMS calcd for C 15 H 16 N 2 [M + H] + , 225.1392, found 225.1395, Consistent with literature values [25].

Imine 7 Prepared via the above procedure, 1H-NMR (400 MHz, CDCl 3 ) Delta 8.33 (s, 1H, CH=N), 7.90 (d, 1H, J = 7.8Hz, Py), 7.63 (ap t, 1H, Py-4-H), 7.17 (d, 1H, J = 7.6 Hz, Py), 3.07 (q, 1H J = 6.5Hz, CH), 2.60 (s, 3H, ArCH 3 ), 1.17 (d, 3H, J = 6.5Hz, CH 3 ), 0.94 (s, 9H, C(CH 3 ) 3 ). 13C-NMR (100MHz, CDC l3 ) Delta 159.4, 157.3, 154.1, 136.2, 123.5, 117.5, 74.8, 33.8, 26.17, 23.8. IR (NaCl-disk) v/cm-1 2964, 2868, 1653, 1647, 1591, 1575, 1457, 1363, 1120, 783. [Alpha] 20 D = +51.1 (c 0.6, CHCl 3 ). HRM calcd for C 13 H 20 N 2 [M + Na] + 227.1524, found 227.1517. Consistent with literature values [19].

Aminal 10 A vial was charged with aldehyde (0.085 mmol)and diamine (0.085mmol) and anhydrous toluene (0.2 mL). To this was added 4A molecular sieves and the vial was sealed. The reaction was then stirred at 70 degC overnight. The ligand was purified through flash chromatography using a ratio of 5:1 (n- hexane:ethyl acetate)1H-NMR (400 MHz, CDCl 3 ) Delta 8.40 (d, J = 4.5 Hz, 1H, Py-6-H), 7.53 (td, J = 7.6, 1.6 Hz, 1H, Ar), 7.37 (d, J = 7.8 Hz, 1H, Ar), 7.23-7.02 (m, 11H, Ar), 4.74 (s, 1H, N-CH-N), 3.82 (d, J = 13.8 Hz, Ph-CHH), 3.50 (d, J = 14.5 Hz, Ph-CHH), 3.01 (d, J = 14.5 Hz, Ph-CHH), 3.05-2.95 (m, 1H, CHN), 2.59-2.45 (m, 1H, CHN), 1.90-1.61 (m, 4H, 2 x CH 2 ), 1.40-1.06 (m, 4H, 2 x CH 2 ).

13C-NMR (100 MHz, CDCl 3 ) Delta 161.1 (Py-6-C), 147.7, 140.4, 138.7, 134.9, 128.5, 127.5, 127.3, 127.2, 126.0, 125.8, 123.57, 121.5, 87.0 (N-C-N), 68.4 (benzyl), 67.0 (benzyl), 56.0 (CHN), 52.4 (CHN), 29.8, 29.7, 24.1. IR (NaCl- disk) v/cm-1 3027, 2929, 2857, 1637, 1588, 1452, 1434, 736. HRMS calcd for C 26 H 29 N 3 [M + H] + 384.2448, found 384.2440. Consistent with literature values [26].

Bisimine 22 . O-anisaldehyde solution (6.00 mmol) was added dropwise to a solution of Cyclohexane-1, 2 diamine (3.00 mmol) in 6 mL of toluene at 0degC with stirring over 15 min. The resulting mixture was then stirred for another 3 hours at RT. The two layers were then separated by adding Water (10 mL) and diethyl ether (30 mL). The upper layer (organic) was collected and the lower layer (aqueous) was washed with a further 30 mL of ether twice. The layers were then combined and dried over MgSO 4 after which the solvent was removed under reduced pressure to give of reddish oil (2.63 mmol, 87.6% yield).1H-NMR (400 MHz, CDCl 3 ) Delta 8.55 (d, 2H, J = 4.8 Hz, Py-6- H), 8.32 (s, 2H, CH=N), 7.88 (d,2H, J = 7.9 Hz, Py- 3-H), 7.65 (ap t, 2H, Py), 7.25-7.20 (m, 2H, Py), 3.60-3.49 (m, 2H), 1.95-1.75 (m, 6H), 1.55-1.46 (m, 2H). 13C-NMR (100MHz, CDC l3 ) Delta 161.4, 154.5 (q), 149.2, 136.4, 124.4, 121.33, 73.5 (CH), 32.7 (CH 2 ), 24.3 (CH 2 ). IR (NaCl-disk) v/cm-1 2928, 2842, 1714, 1644, 1587, 1467, 992.

HRMS calculated for C 18 H 20 N 4 [M + H] + 293.1766, found 293.1759. Consistent with literature values [27].

Bisimine 23 Prepared via the procedure above using Cyclohexane-1, 2 diamine (2.72 mmol) and cyclohexanecarbaldehyde (5.44 mmol) to give dark- yellow oil (0.698 g, 6.40 mmol, 78.4% yield) 10 The spectral data was consistent with that reported in the literature, 1H NMR (400MHz; CDCl 3 ) Delta 8.24 (2H, s, CH=N), 7.65 - 7.55 (4H, m, Ar-H), 7.40 - 7.25 (6H, m, Ar-H), 3.48 (2H, m, CH), 1.98 - 1.76 (6H, m, Cy), 1.64 - 1.43 (2H, m, Cy), 13C-NMR (100 MHz, CDCl 3 ) Delta 160.5, 135.9, 129.7, 127.9, 127.4, 73.3, 32,5, 24.0. Consistent with literature values [28].

Bisimine 24 Prepared via the procedure above using Cyclohexane-1, 2 diamine (0.321 g, 2.81 mmol) and cyclohexanecarbaldehyde (0.630 g, 630 mg 0.680 mL 5.62 mmol) to give pale-yellow oil (0.721 g, 7.32mmol, 75.8% yield)11. 1H NMR: (400MHz; CDCl 3 ) Delta 7.42 (2H, d,J = 5.65 Hz, CyCH=N), 3.05 - 2.95 (2H, m, Cy), 2.15 - 2.05 (2H, m, Cy), 1.82 - 1.51 (16H, m, Cy), 1.39 - 1.10 (14H, m, Cy). 13C- NMR (100 MHz, CDCl 3 ) Delta 168.2, 72.9, 42.9, 32.5, 29.5, 25.4, 24.9, 24.9, 24.0. Consistent with literature values [29]. ] Oxazoline 28 Imidate (0.085 mmol) and amino alcohol (0.085mmol) was added to anhydrous toluene (0.4 mL) in a vial with teflon septum along with 4A molecular sieves and was sealed. The reaction was then stirred for overnight at 70degC. The product was then extracted with DCM (3x20ml), dried over MgSO 4 and concentrated. The compound was then purified using flash chromatography (EtOAc:n- hexane:Et3N, 7:5:0.01) to yield a colourless oil (327 mg, 83%) [19].

1H-NMR (400 MHz, CDCl 3 ) Delta 8.74 (d,1H, J =4.2 Hz, o-CHpy), 8.09 (d,1H, J = 8.2 Hz, o-CHpy), 7.80 (t, 1H, J = 1.6 Hz, m-CHpy), 7.42 (dd, 1H, J = 4.7 Hz, J = 6.8 Hz, p-CHpy), 4.54 (t, 1H, J = 8.6 Hz, -CHN), 4.27-4.20(m,1H, -CH(CH 3 ) 2 ), 1.92- 1.88 (m, 2H,-CH 2 -O), 1.10-1.06 (m, 3H, -CH 3 ), 0.99- 0.96 (m, 3H, -CH 3 ).13C-NMR (100MHz, CDCl 3 ) Delta 162.1, 149.2, 146.4, 136.1, 125.0, 123.4, 72.4, 70.3, 32.3, 18.63, 17.7. IR (NaCl-disk) v/cm-1, HRMS calcd for C 11 H 14 N 2 O [M + H] + 191.1184, 239.1177. Consistent with literature values [19].

Oxazoline 29 Prepared via the procedure above and collected as colourless oil. (299 mg, 76%)24. 1H- NMR (400 MHz, CDCl 3 ) Delta 8.74 (d,1H, J =3.5 Hz, o- CHpy), 8.08 (d,1H, J = 8.0 Hz, o-CHpy), 7.82-7.78 (dd, 1H, J = 5.88 Hz, J = 15.5 Hz m-CHpy), 7.43- 7.40 (dd, 1H, J = 4.66 Hz, J = 8.74 Hz, p-CHpy), 4.70-4.60 (m, 1H, -CHN), 4.48-4.37 (m,1H, CH 2 -O), 4.15-4.05 (m,1H, CH 2 -O), 1.96-1.85(m, 2H,-CH 2 ), 1.78-1.68 (m, 2H, -CH 2 ), 1.45 (m, 1H, -CH), 1.00 (6H, d, J = 2.20 Hz, CH 3 ).13C-NMR (100MHz, CDCl 3 ) Delta 162.4, 149.6, 146.8, 136.5, 125.4, 123.8, 73.6, 65.3, 45.4, 25.3, 22.7. IR (NaCl-disk) v/cm-1. HRMS calcd for C 12 H 16 N 2 O [M + Na] + 227.1160, 227.1167.

Oxazoline 30 Prepared via the procedure above and collected as colourless oil. (350 mg, 89%)191H- NMR (400 MHz, CDCl 3 ) Delta 8.74 (d, 1H, J = 4.7 Hz, Py-6-H), 8.08 (d, 1H, J = 7.9 Hz, Py-3-H), 7.82-7.72 (m, 1H, Py-4-H), 7.40 (dd, 1H J = 7.5, 4.7 Hz, Py-5- H), 7.35-7.27 (m, 2H, Ph), 7.28-7.20 (m, 3H, Ph), 4.71-4.61 (m, 1H, CH, 4-H), 4.45 (ap t, 1H, CH, 5- H), 4.23 (ap t, 1H, CH, 5-H), 3.30 (dd, 1H, J = 13.8, 5.0 Hz, CH 2 ), 2.76 (dd, 1H, J = 13.8, 9.1 Hz, CH 2 ). 13C-NMR (100MHz, CDCl 3 ) Delta 162.6 (q), 149.3, 146.2 (q), 137.3 (q), 136.2, 128.7, 128.1, 126.1, 125.16, 123.49, 72.05 (CH 2 ), 67.68 (CH), 41.24 (CH 2 ). IR (NaCl-disk) v/cm-1 3084, 2860, 1641, 1469, 1440, 1363, 1099. HRMS calcd for C 15 H 14 N 2 O [M + H] + 239.1184, 239.1189. Consistent with literature values [19].

General procedure for asymmetric transfer hydrogenation In a vial 42 umol of the electrophile and nucleophile were added in toluene (0.4 mL) in the presence of molecular sieves. The reaction stirred at 70degC for 12 h. The ligands were obtained by evaporating solvent under reduced pressure. A mixture of the ligand (42 umol) and ZnEt 2 (12.4 mg, 21 umol) in absolute MeOH (20 mL) was stirred at 40degC overnight under N 2 . The solvent was removed to give the crude complex. A mixture of the crude complex and ketone (4.0 mmol) in degassed solution of HCOOH/HCOONa (30 mL, pH 3.5) was stirred vigorously at 40degC for 12 h under N 2 . The reaction mixture was extracted with ethyl acetate (2 x 15 mL). The upper layer (organic) was dried over MgSO 4 , and the products were obtained by evaporating solvents.

Conclusions ] In conclusion we have applied the instant library to the transfer hydrogenation of acetophenone with zinc in water. After the comparison of results obtained from purified vs. in-situ ligands it was found that the technique is suitable for rapid recognition of best catalytic system. Four different types of ligands were tested and the ee Greater than 60% was easily identified. The positive trend of the results was explained due to presence of phenyl group and substituent on aldehyde.

Acknowledgement We thank Science Foundation Ireland and Higher Education Commission, Pakistan for funding.

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1,2 Tariq Zaman , 1 Habib Nasir and 2 Enda Bergin 1 School of Chemical and Materials Engineering, NUST, H-12, Islamabad, 44000, Pakistan.

2 School of Chemistry, University of Dublin, Trinity College, Dublin 2, Ireland.

tariq@scme.nust.edu.pk
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Author:Zaman, Tariq; Nasir, Habib; Bergin, Enda
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