Transfer hydrogenation of activated ketones using novel chiral Ru(II)-N-arenesulfonyl-1,2-diphenylethylenediamine complexes

Article abstract of DOI:10.1016/j.tetlet.2003.10.201

A series of α-keto esters and α,α,α- trifluoromethyl ketones were reduced in high yields and excellent enantioselectivities under Ru-catalysed transfer hydrogenation using novel chiral N-arenesulfonyl-1,2-diphenylethylenediamine ligands.

Full text of DOI:10.1016/j.tetlet.2003.10.201

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 535–537
Transfer hydrogenation of activated ketones using novel chiral
Ru(II)-N-arenesulfonyl-1,2-diphenylethylenediamine complexes
a
Damjan Sterk, Massoud S. Stephan and Barbara Mohar
b
a,
*
ꢀ
aLaboratory of Organic and Medicinal Chemistry, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia
bPhosPhoenix SARL, 115 rue de l’Abbeꢁ Groult, F-75015 Paris, France
Received 28 September 2003; revised 27 October 2003; accepted 31 October 2003
Abstract—A series of a-keto esters and a,a,a-trifluoromethyl ketones were reduced in high yields and excellent enantioselectivities
under Ru-catalysed transfer hydrogenation using novel chiral N-arenesulfonyl-1,2-diphenylethylenediamine ligands.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Chiral a-hydroxy esters are important pharmaceutical
intermediates and can be obtained through bioreduction
or catalytic hydrogenation of the corresponding
ketones.1 Few literature examples of their preparation
involving asymmetric transfer hydrogenation have been
described.2
catalysed transfer hydrogenation of a series of a-keto
esters and a,a,a-trifluoromethyl ketones.
Chiral Ru(II)-complexes were prepared in situ at 80 ꢁC
in DMF10 by reacting [RuCl2(p-cymene)]2 with (1S,2S)-
N-ArSO2-DPEN ligands 1a–f, which were prepared in
turn in DCM from the corresponding arenesulfonyl
chloride and (1S,2S)-DPEN followed by chromato-
graphic purification. These catalysts were used to reduce
a variety of activated ketones12 at room temperature
using the formic acid–triethylamine azeotrope (Fig. 1,
Table 1).
Asymmetric transfer hydrogenation using chiral Ru(II)-
complexes with nitrogen-based chiral ligands proved to
be a powerful method for the preparation of optically
active a-arylated and a,b-acetylenic alcohols.3 Such
technology uses stable organic molecules such as 2-pro-
panol or the formic acid–triethylamine azeotrope as
hydrogen source. Amongst the various types of chi-
ral nitrogen-based ligands, N-sulfonyl 1,2-diphenyl-
ethylenediamines (RSO2-DPENs) with R ¼ Ar,4–8 RF,9
or R02N10 in combination with Ru(II)Cl(g6-arene) exi-
hibit high enantiofacial discrimination ability. As pro-
posed by Noyori and co-workers, the reduction takes
place via a pericyclic mechanism involving an Ru
hydride.11 The RSO2 functionality in the DPEN series is
crucial in the reduction affecting the nucleophilicity of the
neighbouring nitrogen and of the NH2 in the Ru com-
plex.
Methyl mandelate was obtained within 4 h in up to 96%
ee using 0.5 mol % of the Ru-precursor and ligand 1e or
1f compared to 59% ee using Ts-DPEN. Similar results
were obtained for ethyl mandelate. Whether in the
presence of a Ru/ligand ratio of 1:1 or 2:1, complex of 1f
led to equivalent results. Ethyl 40-fluoromandelate was
Ts-DPEN: R= p-Me-C H
6
4
a: R= o-NO -C H
2
6
4
4
b: R= p-NO -C H
Ph
Ph
NHSO R
2
2
6
c: R= 2,4,6-Cl -C H
3
6 2
d: R= 2,4,6-(MeO) -C H
3
6 2
We disclose herein the preparation of a novel series of
chiral ArSO2-DPEN ligands and their use in the Ru(II)-
NH
i
2
e: R= 2,4,6- Pr -C H
6 2
3
(S,S)-1a-f
f: R=
(S,S)-DPEN-SO
2
g: R= o-NH -C H
6 4
Keywords: Asymmetric catalysis; Ketones; Ligands; Ruthenium;
Transfer hydrogenation.
2
Figure 1. Novel series of (1S,2S)-N-arenesulfonyl-1,2-diphenylethyl-
enediamine ligands based on Ts-DPEN.
* Corresponding author. Tel.: +386-14760250; fax: +386-14760300;
e-mail: barbara.mohar@ki.si
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.201

ꢀ
536
D. Sterk et al. / Tetrahedron Letters 45 (2004) 535–537
Table 1. Asymmetric transfer hydrogenation of ketonesa
Ketone
Ligand
Substrate/catalyst ratio
Time (h)
Conversion (%)b
Ee (%)b
C6H5COCO2Me
Ts-DPEN
1a
200
200
200
200
200
200
4
4
4
4
4
4
100
90
59
85
71
93
76
96
1b
1c
100
100
100
100
1d
1e or 1f
p-F-C6H5COCO2Et
Ts-DPEN
1b
200
200
200
200
200
4
8
4
8
4
100
100
100
100
100
28
27
77
70
84
1c or 1f
1d
1e
p-MeO-C6H5COCO2Et
Ts-DPEN
200
200
200
24
24
24
34
44
58
73
75
95
1b
1c
Ts-DPEN
1b or 1e
1c or 1f
1d
40
40
40
40
36
36
36
36
100
100
100
100
82
84
94
87
O
COCO Et
2
C6H5(CH2)2COCO2Et
Ts-DPEN
1b
1c
40
40
40
40
24
24
24
24
100
100
100
100
80
76
68
74
1e or 1f
CH3COCO2Et
Ts-DPEN
1b
1c or 1e
40
40
40
40
40
24
24
24
24
24
100
100
100
85
86
86
78
74
83
1d
1f
100
(CH3)2CHCOCO2Etc
Ts-DPEN
200
200
200
24
24
24
100
100
100
9
20
44
1c
1f
MeO2C(CH2)2COCO2Me
Ts-DPEN
1b
200
200
200
200
200
4
4
4
4
4
100
100
100
50
65
63
60
65
58
1c or 1f
1d
1e
100
C6H5COCF3
Ts-DPEN
1a
1c or 1f
100
100
100
24
24
24
100
100
100
42
42
25
C6H5CH2COCF3
Ts-DPEN
1b or 1c
1d or 1e
1f
100
100
100
100
1
1
1
1
100
100
100
100
95
96
97
98
a Reactions were carried out with HCO2H/Et3N 5:2 in DMF at 25 ꢁC.
b Determined by GC analysis using Chirasil-DEX CB (25 m) unless otherwise stated.
c % Conversion and % ee determined by GC analysis using Chirasil-
L-Val (25 m).
obtained in up to 84% ee using 1e compared to 28% ee
using Ts-DPEN. With an electron-donating group on
the aromatic ring, the reduction was slower and ethyl
40-methoxymandelate was obtained in 95% ee using 1c
compared to 73% ee using Ts-DPEN. The reduction of
ethyl 2-furoylformate was sluggish requiring 2.5 mol %
of Ru catalyst and led, after 36 h, to the corresponding
a-hydroxyester in up to 94% ee using 1c or 1f compared
to 82% ee employing Ts-DPEN. An ACE inhibitor
intermediate, ethyl 2-hydroxy-4-phenylbutanoate, was
obtained in up to 76% ee compared to 80% ee using
Ts-DPEN. The same enantioselectivity (86% ee) was
obtained for ethyl lactate using 1b or Ts-DPEN. How-
ever, up to 44% ee was obtained in the reduction of ethyl
ketovalinate using 1f compared to 9% ee using Ts-
DPEN. Moderate enantioselectivity (65% ee) was
obtained in the reduction of dimethyl 2-oxoglutarate
using 1d or Ts-DPEN.
In the reduction of other activated ketones such as 2,2,2-
trifluoroacetophenone, up to 42% ee was attained with
1a or Ts-DPEN after 24 h. By contrast, the reduction of
1,1,1-trifluoro-3-phenyl-2-propanone took place within
1 h and led to 98% ee using 1f.

ꢀ
D. Sterk et al. / Tetrahedron Letters 45 (2004) 535–537
537
O N
2
O N
2
O N
2
-SO
2
2
Ph
Ph
SO
2
NH
NO
2
Ph
Ph
NH
NH
R
2
2
(S,S)-DPEN
Cl
R
1
R
1
NH
2
R
2
1
2
R
H
R
3a
3b NO
NO
CF
2
3
2
Scheme 1. Synthesis of (1S,2S)-N-aryl-1,2-diphenylethylenediamine ligands.
10, 2045–2061; (d) Ohkuma, T.; Noyori, R. Hydrogena-
tion of Carbonyl Groups. In Comprehensive Asymmetric
Catalysis I; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer, 1999; p 199–246.
Attempting to prepare N-(2,4-dinitrophenylsulfonyl)-
DPEN ligand 2 following the standard procedure
resulted, during purification, in the formation of N-(2,4-
dinitrophenyl)-DPEN 3a (Scheme 1).13 No activity
was observed for the corresponding Ru-complex under
the standard conditions in the reduction of methyl
benzoylformate as well as using the complex derived
from N-(2,6-dinitro-4-trifluoromethylphenyl)-DPEN 3b,
which was prepared subsequently.
4. For NoyoriÕs Ts-DPEN ligand, see: (a) Hashiguchi, S.;
Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 7562–7563; (b) Fujii, A.; Hashi-
guchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 2521–2522.
5. For Ts-DPEN enclosed dendritic ligands, see: Chen,
Y.-C.; Wu, T.-F.; Deng, J.-G.; Liu, H.; Cui, X.; Zhu, J.;
Jiang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C. J. Org. Chem.
2002, 67, 5301–5306.
6. For polymer-supported Ts-DPEN ligand, see: Bayston, D.
J.; Travers, C. B.; Polywka, M. E. C. Tetrahedron:
Asymmetry 1998, 9, 2015–2018.
7. For 2,4,6-iPr3-C6H2SO2-DPEN ligand, see: Meuzelaar, G.
J.; van Vliet, M. C. A.; Maat, L.; Sheldon, R. A. Eur. J.
Org. Chem. 1999, 9, 2315–2321.
8. For water-soluble o- and p-HO3SC6H4SO2-DPEN ligands,
see: Bubert, C.; Blacker, J.; Brown, S. M.; Crosby, J.;
Fitzjohn, S.; Muxworthy, J. P.; Thorpe, T.; Williams, J.
M. J. Tetrahedron Lett. 2001, 42, 4037–4039.
9. (a) Mohar, B.; Valleix, A.; Desmurs, J.-R.; Felemez, M.;
Wagner, A.; Mioskowski, C. Chem. Commun. 2001, 2572–
2573; (b) Taran, F.; Gauchet, C.; Mohar, B.; Meunier, S.;
In addition, no reduction of methyl benzoylformate
occurred using the N-(o-aminophenylsulfonyl)-DPEN
ligand 1g prepared by hydrogenation of the corre-
sponding N-(o-nitrophenylsulfonyl)-DPEN ligand 1a.
In summary, novel chiral N-arenesulfonyl-1,2-diphenyl-
ethylenediamine ligands were prepared and excellent
enantioselectivities were obtained in the Ru(II)-cataly-
sed transfer hydrogenation of a-keto esters and a,a,a-
trifluoromethyl ketones. Enhanced enantioselectivity
was reached by switching the tosyl group of NoyoriÕs Ts-
DPEN ligand with other arenesulfonyl groups and,
in general, hindered ligands such as 1f performed better.
ꢁ
Valleix, A.; Renard, P. Y.; Cremion, C.; Grassi, J.;
Wagner, A.; Mioskowski, C. Angew. Chem. Int. Ed.
2002, 41, 124–127.
ꢀ
10. Sterk, D.; Stephan, M. S.; Mohar, B. Tetrahedron:
Acknowledgements
Asymmetry 2002, 13, 2605–2608.
11. Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc.
2000, 122, 1466–1478.
We thank the Ministry of Education, Science and
Technology of Slovenia for research grant Z1-3374-
0104.
12. a-Keto esters were prepared according to: (a) Nimitz, J. S.;
Mosher, H. S. J. Org. Chem. 1981, 46, 211–213; (b) Takao,
T. S.; Takashi, M. T.; Hisashi, T. O.; Hiromu, K. S. GB 1
533 491, 1978; Chem. Abstr. 1977, 86, 55465m; (c)
Domagala, J. M. Tetrahedron Lett. 1980, 21, 4997–5000.
13. Proven by 1H NMR spectroscopy before and after
purification and also by its independent preparation using
1-chloro-2,4-dinitrobenzene; (1S,2S)-N-(2,4-dinitrophenyl
sulfonyl)-1,2-diphenylethylenediamine (2): 1H NMR d 4.40
(d, 1H, CHNH2; J 3.2 Hz), 4.76 (d, 1H, CHNH; J 3.2 Hz),
6.98–7.42 (m, 10H, 2 · Ph), 7.64 (d, 1H, H-3; J 8.6 Hz),
8.08 (dd, 1H, H-5; J 8.6, 2.1 Hz), 8.45 (d, 1H, H-6;
J 2.1 Hz).
References and Notes
1. Sheldon, R. A. Chirotechnology; Marcel Dekker: New
York, 1993.
2. Use of 5 mol % Rh(cod)Cl2 and (1S,2S)-N,N0-dimethyl-
DPEN: Gamez, P.; Fache, F.; Lemaire, M. Tetrahedron:
Asymmetry 1995, 6, 705–718.
3. For reviews, see: (a) Zassinovich, G.; Mestroni, G.;
Gladiali, S. Chem. Rev. 1992, 92, 1051–1069; (b) Noyori,
R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97–102; (c)
Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999,