Vimal Parekh*, Ian Lennon,2 James Ramsden2 and Martin Wills1
1. Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, UK
2. CPS Chirotech, Dr Reddy’s Laboratories, Unit 162 Cambridge Science Park, Cambridge, CB4 OGH, UK
Introduction
Synthesis of the catalyst
Asymmetric 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:
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.
-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.
Scheme 1. General scheme
for the asymmetric transfer
hydrogenation
of quinolines.
Results and Discussion
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%.
In this project our aim was to carry out ATH of quinolines using ‘tethered’ and untethered
Ru (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)
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.
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.
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
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.
Reductions carried out on various quinoline
substrates using catalyst (7) and (10)
Table 1. Shows the reduction of 2-methylquinoline using different solvents.
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.
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
Table 2. Shows the reduction of 2-methylquinoline at different temperatures.
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.
Reductions using different Ru (II) catalysts
Figure 1. Shows the different Ru (II) and Rh
(III) catalysts used.
1
2
3
4
5
6
7
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Temp
(°C)
60
60
60
60
60
60
60
Catalyst
(7) dimer
(3) monomer
(4) monomer
(8) dimer
(6) dimer
(5) monomer
(6) monomer
HCO2H:
Et3N ratio
5:2
5:2
5:2
5:2
5:2
5:2
5:2
Substrate:
catalyst ratio
400:1
200:1
200:1
400:1
400:1
200:1
200:1
Imine
Solvent
1
12
13
14
15
16
17
18
19
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Dichloromethane
Methanol
Temp
(°C)
28
28
28
28
28
28
28
28
28
HCO2H:
Et3N ratio
5:2
5:2
5:2
5:2
5:2
5:2
5:2
5:2
5:2
Substrate:
catalyst ratio
400:1
400:1
400:1
400:1
400:1
400:1
400:1
400:1
400:1
Time
(hrs)
24
168
48
30
144
144
48
48
48
Conversion (%)
96
68
57
95
94
93
90
86
93
Enantiomeric excess
(%)
46
73
0
41
42
41
50
47
67
Configuration
R
S
R
R
R
R
R
R
Table 4. Shows the reduction of substrates (1, 12-19) using Ru (II) catalyst (7).
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.
Entry Solvent
Figure 3. Shows the different quinoline
substrates used for ATH.
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 moderategood ee.
Time (hrs)
24
24
24
24
24
24
24
Conversion
(%)
96
17
66
87
62
27
59
Enantiomeric Configuration
excess (%)
43
R
80
R
29
R
44
R
43
S
68
R
43
R
Table 3. Shows the reduction of 2-methylquinoline at 60°C using different catalysts.
References
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, 13901392. (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.
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.
Imine
Solvent
1
12
13
14
15
16
17
18
19
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
Dichloromethane
Methanol
Temp
(°C)
28
28
28
28
28
28
28
28
28
HCO2H:
Et3N ratio
5:2
5:2
5:2
5:2
5:2
5:2
5:2
5:2
5:2
Substrate:
catalyst ratio
200:1
200:1
200:1
200:1
200:1
200:1
200:1
200:1
200:1
Time
(hrs)
24
48
48
48
48
48
48
48
48
Conversion (%)**
68 (85)
30 (35)
16 (43)
67 (76)
65 (73)
64 (76)
57 (65)
30 (29)
58 (69)
Enantiomeric excess
(%)
93
86
0
91
90
92
93
81
94
Configuration
R
S
R
R
R
R
R
R
Table 5. Shows the reduction ofsubstrates (1, 12-19) using Rh (III) catalyst (10).
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.
Acknowledgements
I 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.