Asymmetric transfer hydrogenation of prochiral ketones in aqueous media with new water-soluble chiral vicinal diamine as ligand

Article abstract of DOI:10.1021/ol0345125

(Matrix presented) An easily accessible water-soluble chiral o-sulfonated 1,2-diphenylethlenediamine 2 and its mono-N-tosylated derivative 3 were synthesized for the first time. The ruthenium-complex-catalyzed reduction of prochiral ketones in aqueous media has been examined by using 3 as ligand and sodium formate as the source of hydrogen. The asymmetric transfer hydrogenation of ω-bromo acetophenones was achieved, in which only formate displacement occurred when formic acid/triethylamine azeotrope was used as the hydrogen donor.

Full text of DOI:10.1021/ol0345125

ORGANIC
LETTERS
2003
Vol. 5, No. 12
2103-2106
Asymmetric Transfer Hydrogenation of
Prochiral Ketones in Aqueous Media
with New Water-Soluble Chiral Vicinal
Diamine as Ligand
Yaping Ma, Hui Liu, Li Chen, Xin Cui, Jin Zhu, and Jingen Deng*
Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry,
the Chinese Academy of Sciences, Chengdu 610041, China
jgdeng@cioc.ac.cn
Received March 24, 2003
ABSTRACT
An easily accessible water-soluble chiral o-sulfonated 1,2-diphenylethlenediamine 2 and its mono-N-tosylated derivative 3 were synthesized
for the first time. The ruthenium-complex-catalyzed reduction of prochiral ketones in aqueous media has been examined by using 3 as ligand
and sodium formate as the source of hydrogen. The asymmetric transfer hydrogenation of ω-bromo acetophenones was achieved, in which
only formate displacement occurred when formic acid/triethylamine azeotrope was used as the hydrogen donor.
As a consequence of the increasing demand for atom
economy and environmentally friendly methods, the water-
soluble ligands and their metal complexes are of great interest
in application to catalytic synthesis because of simpler
product separation and the possibility of recycling. It is not
necessary to use vigorous drying of solvents and substrates
in such reactions in aqueous media; unique reactivity and
selectivity are often observed in aqueous reactions.1 Chiral
vicinal diamine and its derivatives have been emerged as
medicinal agents, in particular in chemotherapy.2 Their use
in organic synthesis has also increased considerably recently,
especially in the field of catalytic asymmetric synthesis.3 The
related water-soluble diamine derivatives are of great interest
to us. Recently, Bujoli and co-workers developed a water-
soluble version of N,N-dimethyl-1,2-diphenylethane-1,2-
diamine by introduction of phosphonic acid moieties on the
para position of the aromatic rings via a multistep process.4
Here, we report an easily accessible water-soluble chiral
o-sulfonated 1,2-diphenylethlenediamine (DPEN) 2 by direct
sulfonation5 of the chiral DPEN, which is available in our
(1) For reviews on organic synthesis in aqueous media, see: (a) Cornils,
B. J. Mol. Cata. A: Chem. 1999, 143, 1-10. (b) Herrmann, W. A.;
Kohlpaintner, C. W. Angew. Chem., Int. Ed. Engl. 1993, 32, 1524-1544.
(c) Joo´, F. Acc. Chem. Res. 2002, 35, 738-745. (d) Dwars, T.; Oehme, G.
AdV. Synth. Catal. 2002, 344, 239-260. (e) Li, C.-J. Acc. Chem. Res. 2002,
35, 533-538. (f) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35,
209-217. (g) Lindstro¨m, U. M. Chem. ReV. 2002, 102, 2751-2772. (h)
Sinou, D. AdV. Synth. Catal. 2002, 344, 221-237.
(3) (a) Lucet, D.; Gall, T. L.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580-2627. For a recent example of catalytic asymmetric
synthesis, see: (b) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem.
Soc. 2002, 124, 5640-5641.
(4) Maillet, C.; Praveen, T.; Janvier, P.; Minguet, S.; Evain, M.; Saluzzo,
C.; Tommasino, M. L.; Bujoli, B. J. Org. Chem. 2002, 67, 8191-8196.
(5) For some examples of tris(m-sulfonatophenyl)phosphine associated
to rhodium for biphasic aqueous hydroformylation or hydrogenation, see:
(a) Kuntz, E. Rhoˆne-Poulenc Recherche FR Patent 2.314.910, 1975. Kuntz,
E. G. Chem. Technol. 1987, 570-575. (b) Grosselin, J. M.; Mercier, C.;
Grass, F. Organometallics 1991, 10, 2126-2133.
(2) For reviews on medicinal agents incorporating a vicinal diamine unit,
see: Michalson, E. T.; Szmuszkovicz, J. Prog. Drug. Res. 1989, 33, 135-
149.
10.1021/ol0345125 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/10/2003

laboratory on the kilogram scale. Preliminary experiments
were then run for the application of this water-soluble ligand
on the enantioselective transfer hydrogenation of prochiral
ketones by its mono-N-tosylated derivative 3. The enantio-
selective transfer hydrogenation of prochiral ketones has been
achieved using a range of catalysts.6 Among the best catalysts
for these reactions are ruthenium complexes using chiral
mono-N-tosylated vicinal diamine as ligand; developed by
Noyori7 and Knochel.8 We also studied dendritic Noyori
catalysts for asymmetric transfer hydrogenation of prochiral
ketones,9 which afforded good recyclable activity and
enantioselectivity.9a But there are still some environmental
problems existing in these homogeneous and heterogeneous
systems. The water-soluble chiral ruthenium-complex-
catalyzed reduction of prochiral ketones in aqueous media
may provide the green practice. Recently, Chung10a-c and
Ogo10d reported transfer hydrogenation of ketones with
HCO2Na as a hydrogen donor promoted by the chiral and
achiral water-soluble Ru(II) complexes, respectively. Also,
Williams11 reported the asymmetric transfer hydrogenation
of ketones in aqueous media with 2-propanol as a hydrogen
donor.
The water-soluble ruthenium catalyst was prepared by
reacting [RuCl2(p-cymene)]2 with (R,R)-3 at 40 °C for 1 h
in aqueous media in the concentration of 0.01 M, and a
purple Ru(II) complex was only observed in aqueous phase
after biphasic separation. (R)-Phenethyl alcohol with high
conversion and enantioselectivity (Table 1) was obtained in
Table 1. Asymmetric Transfer Hydrogenation of
Acetophenone in Aqueous Mediaa
metal
complexesb
HCO2Na
(equiv)
convnc
(%)
eec
entry
1
(%)
configd
[RuCl2 (p-Cy)]2
5
5
5
5
5
5
2
10
>99
>99
34
61
95
95
R
R
R
R
R
2e [RuCl2 (p-Cy)]2
93
89
94
93
ND
90
3f
[RuCl2 (p-Cy)]2
4g [RuCl2 (p-Cy)]2
5g,h [RuCl2 (p-Cy)]2
6i
7
8
9
[RuCl2 (p-Cy)]2
[RuCl2 (p-Cy)]2
[RuCl2 (p-Cy)]2
[RuCl2 (p-Cy)]2 HCO2NH4 (5)
[RuCl2 (p-Cy)]2 HCO2NH4 (10)
<1
47
R
R
R
R
R
R
R
R
The chiral water-soluble ligand (R,R)-2 was prepared by
>99 (75)j 94 (94)j
1
direct sulfonation as shown in Scheme 1. H NMR, 13C
3
5
17
66
10
92
7
29
94
71
58
84
10
11k [RuCl2 (p-Cy)]2
5
5
5
5
12
13
14
[RuCl2(PhH)]2
[Cp*IrCl2]2
[Cp*RhCl2]2
Scheme 1
a Unless otherwise noted, the reaction was carried out in organic solvent
free system at 40 °C for 24 h with 4 mol % SDS and S/C ) 100. b Cy )
cymene. c The conversion and ee were determined by GLC on a CP-
Cyclodex B-236 M column. d Configuration was determined by the sign
of rotation of the isolated product. e 15-Crown-5 was added as phase-transfer
catalyst. f The reaction was conducted without PTC or surfactant. g S/C )
200. h The reaction time is 48 h. i S/C ) 1000. j The data in parentheses
was obtained from the second recycling. k The reaction was carried out at
28 °C.
the transfer hydrogenation of acetophenone without any
organic solvent after 24 h at 40 °C with this water-soluble
catalyst system, in which the best ratio of (R,R)-3 and [RuCl2-
(p-cymene)]2 is 2.2:1. Both SDS and 15-crown-5 as phase-
transfer catalysts (PTC) gave >99% conversion and good
enantioselectivity (95% and 93% ee, entries 1 and 2).
However, poor conversion and lower enantioselectivity were
observed without any PTC or surfactants (entry 3). Although
asymmetric reduction of acetophenone with S/C ) 200
proceeded to give chiral alcohol in 95% yield with 93% ee
by prolonging reaction time to 48 h (entries 4 and 5), an
increase in the ratio of S/C to 1000 caused a significant
NMR, and IR analyses showed that only o-sulfonated product
was provided.12 Subsequently, the mono-N-tosylated deriva-
tive (R,R)-3 was obtained by tosylation, and we initially
tested the ruthenium-catalyzed transfer hydrogenation of
acetophenone in aqueous media employing HCO2Na10 as the
source of hydrogen.
(6) For reviews on asymmetric transfer hydrogenation, see: (a) Palmer,
M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045-2061. (b) Noyori,
R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102. (c) Zassinovich, G.
Mestroni, G.; Gladiali. S. Chem. ReV. 1992, 92, 1051-1069.
(7) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521-2522. (b) Hashiguchi, S.; Fujii, A.;
Takehara, J.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562-
7563. (c) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Soc. Soc. 1997, 119, 8738-8739.
(8) Pu¨ntener, K.; Schwink, L.; Knochel, P. Tetrahedron Lett. 1996, 37,
8165-8168.
(9) (a) Chen, Y. C.; Wu, T. F.; Deng, J. G.; Liu, H.; Jiang, Y. Z.; Choi,
M. C. K.; Chan, A. S. C. Chem. Commun. 2001, 1488-1489. (b) 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.
(10) (a) Rhyoo, H. Y.; Yoon, Y. A.; Park, H. J.; Chung, Y. K.
Tetrahedron Lett. 2001, 42, 5045-5048. (b) Rhyoo, H. Y.; Park, H. J.;
Chung, Y. K. Chem. Commun. 2001, 2064-2065. (c) Rhyoo, H. Y.; Park,
H. J.; Suh, W. H.; Chung, Y. K. Tetrahedron Lett. 2002, 43, 269-272. (d)
Ogo, S.; Abura, T.; Watanabe, Y. Organometallics 2002, 21, 2964-2969.
(11) (a) 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. (b) Thorpe, T.; Blacker, J.; Brown, S. M.; Bubert, C.;
Crosby, J.; Fitzjohn, S.; Muxworthy, J. P.; Williams, J. M. J. Tetrahedron
Lett. 2001, 42, 4041-4043.
(12) See the Supporting Information.
2104
Org. Lett., Vol. 5, No. 12, 2003

decrease in the reactivity (24 h, <1%, entry 6). Compared
with the results of different hydrogen sources of HCO2Na
and HCO2NH4, we found that HCO2Na worked effectively
(entries 1, 2, and 8 vs 9 and 10). When the amount of HCO2-
Na was reduced from 10 to 5 equiv (with respect to
acetophenone), the identical conversion and enantioselectivity
were obtained (entries 1 vs 8), but a remarkable decrease of
the conversion (47%) was observed with 2 equiv of HCO2-
Na (entry 7). As the temperature was lowered from 40 to 28
°C, the conversion decreased greatly but without loss of
enantioselectivity (entry 11). Other types of metal complexes
were tested as catalyst precursors and exhibited only moder-
ate enantioselectivities (entries 12-14). It is noticeable that
the ee value completely maintained with slight loss of activity
was observed in the reuse of the catalyst (entry 8).12 As
comparison, acetophenone was reduced with (R,R)-
TsDPEN-Ru(II) as a catalyst under these optimization con-
ditions,13a and we noticed a small decrease of enantioselec-
tivity (92% ee vs 95% ee, entry 1) but higher activity (TOF,
9.1 vs 5.0 h-1).13b
88%, and 83% ee for 5, 6, 7, and 8, respectively), but these
results were quite comparable to those in the homogeneous
transfer hydrogenation with TsDPEN as ligand.6 Good to
excellent enantioselectivities were observed in the reduction
of propiophenone 9, cyclic substrates 10 and 11, and 2′-
acetonaphthone 12 (80% to 98% ee), and the poor conversion
may be due to the poor solubility of these ketones in aqueous
media. In the reaction of heteroatom aromatic ketone 13,
chiral alcohol was obtained in high enantioselectivity (95%
ee) with moderate conversion (72%). The conversion can
be improved by liquid-liquid biphasic condition (DCM/H2O)
for the solid substrates 7, 8, and 12 but without loss of
enantiomeric purity.14b
To our surprise, the asymmetric transfer hydrogenation
of ω-bromoacetophenone 14a in aqueous media with sodium
formate as the source of hydrogen proceeded to give the
expected chiral 2-bromo-1-phenylethanol 15a (Table 2, entry
Table 2. Asymmetric Transfer Hydrogenation of ω-Bromo
Moreover, a variety of aromatic ketones (4-13) can be
converted to the corresponding chiral alcohols in organic
solvent free system under the optimization conditions as
shown in Figure 1.13a The ring-substituted acetophenones
Acetophenonesa
product
15
16
17
yieldb
(%)
eec
yieldb
(%)
eec
yieldb
(%)
(%)
(%)
1d
2f,g
3f
14a
14a
14a
14a
14a
14b
14c
57
46
87
e
75
58
47
92
93
94
trace
32
trace
e
ND
93
ND
e
4h,i
5f,h
6f
75
94
84
92k
trace
ND
7f,j
a Unless otherwise noted, the reaction was conducted with S/C ) 100
and (R,R)-3/[RuCl2(p-cymene)]2 ) 2.2 at 28 °C for 24 h. b Isolated yield.
c Ee was determined by GLC on CP-Cyclodex B-236 M column. d Organic
solvent free, at 40 °C. e No product was detected by 1H NMR analysis.
f Biphasic system, DCM/H2O (v/v ) 1:1). g At 40 °C. h (R,R)-TsDPEN -
[RuCl2(p-cymene)]2 as catalyst. i Neat HCO2H/NEt3 as hydrogen source.15
j 48 h. k Ee was determined by HPLC on OD column.
1), which is contrary to the result in homogeneous system
with formic acid/triethylamine azeotrope as the hydrogen
donor due to the formate displacement reaction (entry 4,
Scheme 2).15 When a biphasic system was employed, an
epoxide product in the same enantiomeric purity accompa-
nied 15a (entry 2). This epoxide can be controlled by
conducting the reaction at 28 °C with higher yields of 15a
(entry 3). In DCM/H2O biphasic conditions, 15a was
obtained as the major product without the formation of 17a
even with TsDPEN-Ru(II) as a catalyst, and this result
showed that the chemoselectivity can be changed by the
biphasic system (entry 5).15 The electron-withdrawing sub-
strate 14b and electron-donating substrate 14c were applied
to test the reaction scope, and the optically active 15b and
15c were obtained in moderate yields and good enantio-
selectivities (entries 6 and 7). However, only formate
Figure 1. Asymmetric transfer hydrogenation of the aromatic
ketones.
4-8 were reduced with more than 99% conversion except
4′-nitroacetophenone 7 (88%).14a The electron-withdrawing
groups, especially on the meta or ortho position in the
acetophenones decrease the enantiomeric purities (92%, 87%,
(13) (a) Optimization conditions: (R,R)-3 and [RuCl2(p-cymene)]2 (2.2:
1) were incubated at 40 °C for 1 h before the substrate (S/C ) 100/1), 4
mol % SDS, and 5 equiv of HCO2Na were added and the reaction was
carried out under vigorously stirring in organic solvent free system at 40
°C for 24 h. (b) Average turnover frequency calculated over the 11 h reaction
time.
(14) (a) The data in parentheses are the isolated yields. (b) The data
were obtained in DCM/H2O biphasic system.
(15) Cross, D. J.; Kenny, J. A.; Houson, I.; Campbell, L.; Walsgrove,
T.; Wills, M. Tetrahedron: Asymmetry 2001, 12, 1801-1086.
Org. Lett., Vol. 5, No. 12, 2003
2105

Scheme 2
source of hydrogen in aqueous media, and high reactivity
displacement products 17b and 17c formed with the formic
acid/triethylamine azeotrope as the hydrogen donor in
homogeneous system (Scheme 2).
Because optically active styrene oxides are the key
intermediates for the synthesis of various â-adrenergic
receptor agonists.16,17 The resulting 2-bromo-1-phenyl etha-
nols 15a,b were transformed to the corresponding epoxides
16a,b in good yields without any loss of enantiomeric purity
under basic conditions (Scheme 2).17,18
In summary, we have developed a novel water-soluble
chiral vicinal diamine 2 and synthesized its mono-N-tosylated
derivative 3 for the first time. The ruthenium complex of 3
was examined for the catalytic asymmetric transfer hydro-
genation of prochiral ketones with sodium formate as the
and enantioselectivity were achieved for most of prochiral
aromatic ketones in organic solvent free system. It is
noticeable that the asymmetric transfer hydrogenation of
ω-bromo acetophenones was achieved, in which the formate
displacement reaction occurred while employing formic acid/
triethylamine azeotrope as the hydrogen donor in a homo-
geneous system. This will provide an alternative way for
the synthesis of â-adrenergic receptor agonists.16-18 The
further application of this new water-soluble chiral vicinal
diamine 3 on a variety of asymmetric reactions and the
recyclability of the chiral catalysts in aqueous media are
under investigation.
Acknowledgment. We are grateful for the financial
support of the National Natural Science Foundation of China.
(16) Wilkinson, H. S.; Tanoury, G. J.; Wald, S. A.; Senanayake, C. H.
Org. Process Res. DeV. 2002, 6, 146-148.
(17) For the transformation of 2-bromo-1-(4′-benzyloxyphenyl)ethanol
15c into its corresponding oxetanes 16c, see: Goswami, J.; Bezbaruah, R.
L.; Goswami, A.; Borthakur, N. Tetrahedron: Asymmetry 2001, 12, 3343-
3348.
(18) Very recently Izawa and Ikariya reported a practical method for
the synthesis of optically active styrene oxides from the asymmetric transfer
hydrogenation of ω-chloro acetophenones with HCO2H/Et3N containing
Cp*RhCl[(R,R)-Tsdpen] and the sequential treatment with NaOH in one
pot procedure, see: Hamada, T.; Torii, T.; Izawa, K.; Noyori, R.; Ikariya,
T. Org. Lett. 2002, 4, 4373-4376.
Supporting Information Available: Experimental pro-
cedure for the synthesis and characterization of (R,R)-2 and
(R,R)-3 and the analytical data for chiral aromatic alcohols.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0345125
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Org. Lett., Vol. 5, No. 12, 2003