IntroductionAsymmetric reduction of C=N bonds represents a powerful method for the asymmetric formation of chiral amines.1 Whilst many methods exist for the asymmetric reduction of isolated C=N groups, their reduction when they are a part of an aromatic ring represents a more challenging objective. Tetrahydroquinoline derivatives have attracted considerable attention owing to their importance as: -Synthetic intermediates for drugs, -Agrochemicals, and-Dyes2

A number of reports on the pressure hydrogenation of quinolines have been published3

mostly using Ir based catalysts. Reductions using Ru based catalysts have also been reported using pressure hydrogenation, but Ir based catalysts are by far more active for quinoline reductions. My poster presentation will describe the use of asymmetric transfer hydrogenation (ATH) of quinolines using tethered and untethered Ru (II) catalysts.

Results and Discussion

Entry Solvent Temp

(°C)

Catalyst HCO2H:

Et3N ratio

Substrate: catalyst ratio

Time (hrs)

Conversion (%)

Enantiomeric excess (%)

Configuration

1 Methanol 28 (7) 5:2 400:1 24 96 46 R

2 Methanol 40 (7) 5:2 400:1 24 94 44 R

3 Methanol 50 (7) 5:2 400:1 24 94 43 R

4 Methanol 60 (7) 5:2 400:1 24 96 43 R

Entry Solvent Temp

(°C)

Catalyst HCO2H:

Et3N ratio

Substrate: catalyst ratio

Time (hrs)

Conversion (%)

Enantiomeric excess (%)

Configuration

1 Methanol 28 (7) 5:2 400:1 24 96 46 R

2 Acetonitrile 28 (7) 5:2 400:1 24 79 36 R

3 Water 28 (7) 5:2 400:1 24 23 32 R

4 Ethanol 28 (7) 5:2 400:1 24 96 37 R

5 Dichloromethane 28 (7) 5:2 400:1 24 92 25 R

6 Diethyl ether 28 (7) 5:2 400:1 24 98 17 R

7 Acetone 28 (7) 5:2 400:1 24 8 8 R

8 Toluene 28 (7) 5:2 400:1 24 73 22 R

9 2-Propanol 28 (7) 5:2 400:1 24 98 31 R

10 Ethyl acetate 28 (7) 5:2 400:1 24 74 18 R

Vimal Parekh*, Ian Lennon,2 James Ramsden2 and Martin Wills1

1. Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, UK2. CPS Chirotech, Dr Reddy’s Laboratories, Unit 162 Cambridge Science Park, Cambridge, CB4 OGH, UK

Reductions using different solvents

ATH of quinolines was carried out using different solvents, and from the results obtained it was quite clear that overall methanol gave the best conversion and ee.

In this project our aim was to carry out ATH of quinolines using ‘tethered’ and untetheredRu (II) catalysts. The results obtained from preliminary studies showed that the 4C ‘tethered’catalyst (7) was far more active than the untethered catalyst (3) for the reduction of quinolines, which was why optimization of conditions to give high e.e. and conversion was carried out using catalyst (7) as a starting point along with the least bulkier quinoline, 2-methylquinoline (1). (Scheme 1)

AcknowledgementsI would like to thank Martin Wills and the Wills group for their support and encouragement during this project. I would also like to thank my industrial supervisors James Ramsden and Ian Lennon and the EPSRC and Dr Reddy’s for the financial support.

1. (a) Noyori, R. Adv. Synth. Catal., 2003, 345, 15-32. (b) Noyori, R.; Sandoval, C. A.; Muniz, K.; Ohkuma, T. Phil. Trans. R. Soc. A 2005, 363, 901-912. (c) Noyori, R.; Kitamura, M.; Ohkuma, T. Proc. Nat. Acad. Sci. 2004, 101, 5356-5362. (d) Noyori, R.; Ohkuma, T. Angew. Chem. Int. Ed. 2006, 40, 40-73. 2. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031, and references cited therein.3. (a) Xu, L.; Lam, K. H.; Ji, J.; Wu, J.; Fan, Q.-H.; Lo, W.-H. Chem. Commun. 2005, 1390-1392. (b) Zhou, H.; Li, Z.; Wang, Z.; Wang, T.; Xu, L.; He, Y.; Fan, Q.-H.; Pan, J.; Gu, L.; Chan, A. S. C. Angew. Chem. Int. Edn. 2008, 47, 8464-8467.4. Hayes, A. M.; Morris, D. J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2005, 127, 7318.5. Parekh, V.; Ramsden, J. A.; Wills, M. Tetrahedron: Asymmetry, 2010, 21, 1549-1556.

References

Synthesis of the catalyst

The studies carried out showed that the 4C ‘tethered’ link is required for rapid conversion and functionality on the aromatic ring might be essential for a high ee, which was why the catalyst shown in Scheme 3 was synthesized.

Reductions carried out at different temperatures

Having determined the best solvent, the next task was to see whether changing the temperature had any effect on the conversion and ee.

The results clearly show that the fastest conversion was obtained at 60°C with only a drop of 3% ee. The next task was to carry out ATH reductions at 60°C using both untethered and ‘tethered’ Ru (II) catalysts.

Scheme 1. General scheme for the asymmetric transfer hydrogenationof quinolines.

Table 1. Shows the reduction of 2-methylquinoline using different solvents.

Table 2. Shows the reduction of 2-methylquinoline at different temperatures.

Table 3. Shows the reduction of 2-methylquinoline at 60°C using different catalysts.

Figure 1. Shows the different Ru (II) and Rh (III) catalysts used.

Reductions using different Ru (II) catalysts

ATH of quinolines was carried out using both untethered and ‘tethered’ catalysts (Figure 1), and results obtained clearly showed that the 4C ‘tethered’ link (7) is important for the rapid conversion of quinoline to tetrahydroquinolines, and functionality on the aromatic ring above the Ru on the untethered catalyst (3) is vital for obtaining a high ee.

Catalyst (9) was tested out with the conditions used previously (Table 3), and the reaction proved to be unsuccessful as only 29% conversion was obtained after 24hrs, with an ee of 42%.

Scheme 3. Shows the reaction scheme for the formation of the 4C ‘tethered’ catalyst (9) with added functionality on the aromatic ring about the Ru.

OHBr

OBr Si

Ph

PhO

SiPh

Ph

OHO

i)TBDPSCl

THF, Imidazole

i) tBuLi THF -78°C

ii) Br

i) Na/NH3 (l) EtOH -78°C

i) ClCOCOCl

DMSO/DCM ii) Et3N

i) TBAF in THF

THF

Step 1 Step 2

Step 3 Step 4 Step 5

Ph

Ph

NH

NH

Ts

RuTsN

N

PhPh

H

Cl2

MeMe

Ru

Cl Cl

2

H2N NHTs

PhPh

Cl

Me

Me

i) R,R-TsDPEN CH3CO2H MeOH

ii) NaBH3CN

i) HCl (2M in Et2O)DCM

ii) Ru (III) trichloride hydrate

EtOH, refluxStep 6 Step 7

OH

(9) dimer

31% Yield 70% Yield

91% Yield 91% Yield 96% Yield

37% Yield 25% Yield

Dimer (9) forming the

monomer insitu4

(9) monomer

Imine Solvent Temp(°C)

HCO2H:Et3N ratio

Substrate: catalyst ratio

Time (hrs)

Conversion (%) Enantiomeric excess (%)

Configuration

1 Methanol 28 5:2 400:1 24 96 46 R12 Methanol 28 5:2 400:1 168 68 73 S13 Methanol 28 5:2 400:1 48 57 0 -14 Methanol 28 5:2 400:1 30 95 41 R15 Methanol 28 5:2 400:1 144 94 42 R16 Methanol 28 5:2 400:1 144 93 41 R17 Methanol 28 5:2 400:1 48 90 50 R18 Dichloromethane 28 5:2 400:1 48 86 47 R19 Methanol 28 5:2 400:1 48 93 67 R

Entry Solvent Temp(°C)

Catalyst HCO2H:Et3N ratio

Substrate: catalyst ratio

Time (hrs) Conversion (%)

Enantiomeric excess (%)

Configuration

1 Methanol 60 (7) dimer 5:2 400:1 24 96 43 R2 Methanol 60 (3) monomer 5:2 200:1 24 17 80 R3 Methanol 60 (4) monomer 5:2 200:1 24 66 29 R4 Methanol 60 (8) dimer 5:2 400:1 24 87 44 R5 Methanol 60 (6) dimer 5:2 400:1 24 62 43 S6 Methanol 60 (5) monomer 5:2 200:1 24 27 68 R7 Methanol 60 (6) monomer 5:2 200:1 24 59 43 R

Imine Solvent Temp(°C)

HCO2H:Et3N ratio

Substrate: catalyst ratio

Time (hrs)

Conversion (%)** Enantiomeric excess (%)

Configuration

1 Methanol 28 5:2 200:1 24 68 (85) 93 R12 Methanol 28 5:2 200:1 48 30 (35) 86 S13 Methanol 28 5:2 200:1 48 16 (43) 0 -14 Methanol 28 5:2 200:1 48 67 (76) 91 R15 Methanol 28 5:2 200:1 48 65 (73) 90 R16 Methanol 28 5:2 200:1 48 64 (76) 92 R17 Methanol 28 5:2 200:1 48 57 (65) 93 R18 Dichloromethane 28 5:2 200:1 48 30 (29) 81 R19 Methanol 28 5:2 200:1 48 58 (69) 94 R

Reductions carried out on various quinoline substrates using catalyst (7) and (10)

The reduction of a series of further quinolines, 12-19 (Figure 3) was examined using tethered catalyst 7 (Table 4). As this proved to be the most successful catalyst for conversion of quinolines to tetrahydroquinolines. Of these, the phenyl-substituted substrate 12 was reduced in the highest ee of the series, whilst the tBu derivative 13 was successfully reduced but only in racemic form. Other isoquinolines were reduced in high conversion but only moderate-good ee.

Better results, in terms of enantioselectivity, in several cases exceeding 90% ee, were achieved using the rhodium tethered catalyst 10, which has previous been used for ketone and imine reduction (Table 5). Using 0.5 mol% of 10, the reactions did not go to full conversion after 48 hours, although the use of a higher loading (2 mol%)** of catalyst increased the conversions in most cases. Further work is required to optimize the reductions by these catalysts.

Table 5. Shows the reduction ofsubstrates (1, 12-19) using Rh (III) catalyst (10).

Table 4. Shows the reduction of substrates (1, 12-19) using Ru (II) catalyst (7).

Conclusion

In conclusion, we have demonstated that tethered Ru(II) and Rh(III) complexes are effective catalysts for the ATH of substituted isoquinolines, which are generally regarded as challenging substrates for this application. To the best of our knowledge, this is the first report5 of the use of such catalysts in a solution of formic acid/triethylamine/methanol. As has been observed in ketone reduction, the increased reactivity of tethered complexes over the untethered ones appears to be key to their capacity to work as effective catalysts in this application.

N

N Ph

N

N N

N N

OMe

OMe

Br O

O

NN Ph(1) (12) (13) (14)

(15) (16) (17)

(18) (19)

5 (n=0)

6 (n=1)

RuTsN

NPh

Ph

H

Cl

4

Ph RuTsN

N

PhPh

H

Cl

n

7 (n=2)

8 (n=3)

9 (n=2)

RuTsN

N

Ph

Ph

H

Cl

n

RhTsN N

PhPh

H

Cl

10

RuTsN

NPh

Ph

H

Cl

3

H

N Me NH Me

1 2

H

0.5 % catalyst 3-10 HCO2H, Et3N

Cosolvent, rtsee Table 1-5. R-

Figure 3. Shows the different quinoline substrates used for ATH.

Reductions using different Ru (II) catalysts

The graph clearly shows that the 4C ‘tethered’ catalyst (7) proves to be the best Ru (II) catalyst for ATH of quinolines (Figure 2).

Figure 2. Shows the conversion vs time at 60°C for different catalysts.