Transfer hydrogenation of activated C=C bonds catalyzed by ruthenium amido complexes: Reaction scope, limitation, and enantioselectivity

Article abstract of DOI:10.1021/jo0478205

(Chemical Equation Presented) It was found that the chemoselectivity could be completely switched from C=O to C=C bonds in the transfer hydrogenation of activated α,β-unsaturated ketones catalyzed by diamine-ruthenium complex. Moreover, this addition via metal hydride had been applied to the reduction of various activated olefins. The electron-withdrawing ability of functional groups substituted on C=C bonds at the α- or β-position had strong influence on the reactivity. In addition, a wide variety of chiral diamine-Ru(II)-(arene) systems was investigated to explore the asymmetric transfer hydrogenation of prochiral α,α-dicyanoolefins. Two parameters had been systematically studied, (i) the structure of the N-sulfonylated chiral diamine ligands, in which several chiral diamines substituted on the benzene ring of DPEN were first reported, and (ii) the structure of the metal precursors, and high enantioselectivitiy (up to 89% ee) at the β-carbon was obtained.

Full text of DOI:10.1021/jo0478205

Transfer Hydrogenation of Activated CdC Bonds Catalyzed by
Ruthenium Amido Complexes: Reaction Scope, Limitation, and
Enantioselectivity
Dong Xue,†,‡ Ying-Chun Chen,§ Xin Cui,† Qi-Wei Wang,† Jin Zhu,† and Jin-Gen Deng*,†,‡
Key Laboratory of Asymmetric Synthesis & Chirotechnology of Sichuan Province and Union
Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy
of Sciences, Chengdu 610041, China, West China School of Pharmacy, Sichuan University,
Chengdu 610041, China, and Graduated School of Chinese Academy of Sciences, Beijing, China
jgdeng@cioc.ac.cn
Received December 13, 2004
It was found that the chemoselectivity could be completely switched from CdO to CdC bonds in
the transfer hydrogenation of activated R,â-unsaturated ketones catalyzed by diamine-ruthenium
complex. Moreover, this addition via metal hydride had been applied to the reduction of various
activated olefins. The electron-withdrawing ability of functional groups substituted on CdC bonds
at the R- or â-position had strong influence on the reactivity. In addition, a wide variety of chiral
diamine-Ru(II)-(arene) systems was investigated to explore the asymmetric transfer hydrogenation
of prochiral R,R-dicyanoolefins. Two parameters had been systematically studied, (i) the structure
of the N-sulfonylated chiral diamine ligands, in which several chiral diamines substituted on the
benzene ring of DPEN were first reported, and (ii) the structure of the metal precursors, and high
enantioselectivitiy (up to 89% ee) at the â-carbon was obtained.
Introduction
proven effective for transfer hydrogenation of CdC double
bonds.3 Recently, Noyori has achieved highly enantiose-
lective transfer hydrogenation of ketones and imines by
using chiral TsDPEN-Ru(II) catalysts4 and proposes a
concerted mechanism of hydrogen transfer involving
metal-to-ligand “bifunctional” hydrogen activation.5,6 Be-
sides this, another notable feature of these catalysts is that
the transfer hydrogenation reaction is highly chemose-
lective for the CdO function and tolerant of alkenes.4b,6
Excellent results have been obtained in the kinetic
The reduction of CdC double bonds is one of the most
fundamental synthetic transformations and plays a key
role in the manufacturing of a wide variety of bulk and
fine chemicals. Hydrogenation of olefins can be achieved
readily with molecular hydrogen in many cases, but
transfer hydrogenation methods using suitable donor
molecules such as formic acid or alcohols are receiving
increasing attention as possible synthetic alternatives as
they require no special equipment and avoid the handling
of potentially hazardous gaseous hydrogen.1 Highly ste-
reoselective methods have emerged from transfer hydro-
genation techniques based on the use of suitable chiral
transition metal complexes in homogeneous solution.2
Especially, chiral phosphine-rhodium complexes have
(3) (a) Brunner, H.; Leitner, W. Angew. Chem., Int. Ed. Engl. 1988,
27, 1180. (b) Brunner, H.; Graf, E.; Leitner, W.; Wutz, K. Synthesis
1989, 743. (c) Brunner, H.; Leitner, W. J. Organomet. Chem. 1990,
387, 209. (d) Sinou, D.; Safi, M.; Claver, C.; Masdeu, A. J. Mol. Catal.
1991, 68, L9.
(4) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1995, 117, 7562. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521.
(c) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 4916. (d) Murata, K.; Okano, K.; Miyagi,
M.; Iwane, H.; Noyori, R.; Ikariya, T. Org. Lett. 1999, 1, 1119.
(5) (a) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori,
R. Angew. Chem., Int. Ed. 1997, 36, 285. (b) Yamakawa, M.; Ito, H.;
Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466. (c) Yamakawa, M.;
Yamada, I.; Noyori, R. Angew. Chem., Int. Ed. 2001, 40, 2818. (d)
Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem. 2001, 66,
7931. (e) Pamies, O.; Backvall, J.-E. Chem. Eur. J. 2001, 7, 5052. (f)
Casey, C. P.; Johnson, J. B. J. Org. Chem. 2003, 68, 1998.
† Chengdu Institute of Organic Chemistry, Chinese Academy of
Sciences.
‡ Graduated School of Chinese Academy of Sciences.
§ Sichuan University.
(1) (a) Gladiali, S.; Mestroni, G. In Transition Metals for Organic
Synthesis; Beller, M., Bolm, C. Wiley-VCH: Weinheim, 1998; p 97. (b)
Johnston, R. B.; Wilby, A. H.; Entwistle, I. D. Chem. Rev. 1985, 85,
129.
(2) (a) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10,
2045. (b) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (c)
Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. Rev. 1992, 92, 1051.
10.1021/jo0478205 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/02/2005
3584
J. Org. Chem. 2005, 70, 3584-3591

Transfer Hydrogenation of Activated CdC Bonds
TABLE 1. Switched Chemoselectivity in Transfer
SCHEME 1
Hydrogenation of r,â-Unsaturated Ketonesa
[2a, TsDPEN ) N-(p-toluenesulfonyl)-1,2-diphenyleth-
ylenediamine] (Scheme 1), using the azeotrope of formic
acid and triethylamine (5:2) as hydrogen source under
established conditions.4,9 Like the kinetic resolution of
allylic alcohols reported early,7 for simple enones 3a-d
(Table 1, entries 1-5), the only detected reduction
products were the corresponding allylic alcohols 4a-d
with low to moderate enantioselectivities when chiral
ligand 2a was used (entries 2-5). When chalcone 3e was
employed (entry 6), however, saturated ketone 5e and
alcohol 6e were isolated.11 We inferred that the switched
chemoselectivity was due to the further activation of the
CdC bond by the benzene ring, so introduction of an
electron-withdrawing group at the R-position would
strengthen this effect.12 We were pleased to find that the
activated olefins 3f-h displayed much higher reactivity
toward the CdC bond in the presence of the diamine-
Ru(II) complex. The chemoselectivity was indeed com-
pletely switched from CdO to CdC bonds in the transfer
hydrogenation of these activated enones (entries 7-9),
and saturated ketones 5f-h were isolated in excellent
yield (%)b/
entry
substrate
ligand
T (h)
product
ee (%)
1
2
3
4
5
6
3a
3a
3b
3c
3d
3e
1
30
28
45
52
72
48
4a
4a
4b
4c
4d
5e
6e
5f
90
2a
2a
2a
2a
2a
89/39c
85/76c
98/38c
61/69c
75
23/93c
90
7
8
9
3f
3g
3h
1
1
1
5.5
9
2
5g
5h
94
91
a The ligand and Ru precursor were initially heated in methanol.
Reactions were conducted at 30 °C in 0.5 mL of CH2Cl2, S/C )
200. b Isolated yield. c Percent ee was determined by HPLC on a
chiral column.
1
yields in much shorter time. In the H and 13C NMR
resolution of allylic alcohols using acetone as hydrogen
acceptor.7 Moreover, R,â-acetylenic ketones were also
selectively reduced to give chiral propargylic alcohols in
excellent enantioselectivity.8 On the contrary, in our
continuous study on transfer hydrogenation reactions
catalyzed by these coordinately saturated monosulfony-
lated diamine-Ru(II) complexes,9 we found that the
chemoselectivity could be completely switched from
CdO to CdC bonds through further polarization of the
olefins.10
spectra (see Supporting Information), partial and com-
plete enolization of resulted ketones 5f and 5h was
observed, and the R-H of 5g could be partially deuterated
with D2O in the presence of triethylamine. Thus, asym-
metric transfer hydrogenation of 3g and 3h was not
further investigated.
While having discovered that diamine-Ru(II) com-
plexes had high catalytic activity in the transfer hydro-
genation of activated olefins, a series of activated R,â-
unsaturated substrates was employed to investigate the
reaction scope using achiral catalyst 1-Ru(II). The
results are summarized in Table 2, which showed that
this reaction could be successfully extended to a wide
range of activated olefins and CdC-bond-reduced prod-
ucts 8 were isolated in excellent yields, suggesting a
potential synthetic application of this catalyst system for
reduction of activated olefins under mild conditions.13 The
electron-withdrawing ability of functional groups substi-
tuted on CdC bonds had strong influence on the reactiv-
ity. 7a and 7b (entries 1 and 2) had different reactivity
owing to different electron-withdrawing power of COOMe
(Hammett substituent parameter σ ) 0.45) and NO2 (σ
) 0.78).14 For the substrates condensed from aromatic,
aliphatic aldehydes and ketones with various 1,3-
Results and Discussion
Table 1 shows the representative results for the
transfer hydrogenation of various R,â-unsaturated ke-
tones 3 catalyzed by ruthenium complexes [RuCl2-
(cymeme)]2-TsEN [1, TsEN ) N-(p-toluenesulfonyl)-1,2-
ethylenediamine] and [RuCl2(cymeme)]2-(R,R)-TsDPEN
(6) Hydrogenation catalysts Noyori’s Binap/1,2-diamine-Ru(II) and
hydroxycyclopentadienylruthenium hydride are also proposed to react
with a similar mechanism and show high chemoselectivity for carbonyl
over olefins, see: (a) Sandoval, C. A.; Ohkuma, T.; Mun˜iz, K.; Noyori,
R. J. Am. Chem. Soc. 2003, 125, 13490. (b) Abdur-Rashid, K.; Clapham,
S. E.; Hadzovic, A.; Harvey, J. N.; Lough, A. J.; Morris, R. H. J. Am.
Chem. Soc. 2002, 124, 15104 and references therein. (c) Casey, C. P.;
Singer, S. W.; Powell, D. R.; Hayashi, R. K.; Kavana, M. J. Am. Chem.
Soc. 2001, 123, 1090. (d) Noyori, R.; Ohkuma, T. Angew. Chem., Int.
Ed. 2001, 40, 40.
(7) Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.; Ikariya,
T.; Noyori, R. Angew. Chem., Int. Ed. 1997, 36, 288.
(8) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738.
(11) Recently Wills reported that chalcone was reduced with
TsDPEN-ruthenium complex to give saturated ketone in low yield,
see: Hannedouche, J.; Kenny, J. A.; Walsgrove, T.; Wills, M. Synlett
2002, 263.
(12) The theoretical calculation by Noyori predicts that the reactivity
of unsaturated compounds toward the Ru hydride depends on the
polarity of the double bonds and, by a concerted mechanism, ethylene
possesses much higher activation energy and also is entropically much
less favorable. See ref 5d.
(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. (b) Chen, Y.-C.;
Deng, J.-G.; Wu, T.-F.; Cui, X.; Jiang, Y.-Z.; Choi, M. C. K.; Chan, A.
S. C. Chin. J. Chem. 2001, 19, 807. (c) Chen, Y.-C.; Wu, T.-F.; Deng,
J.-G.; Liu, H.; Xin, C.; Jiang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C. J.
Org. Chem. 2002, 67, 5301.
(13) For a recent example of reducing the activated olefins using
indium metal, see: Ranu, B. C.; Dutta, J.; Guchhait, S. K.Org. Lett.
2001, 3, 2603.
(10) For primary communication, see: Chen, Y.-C.; Xue, D.; Deng,
J.-G.; Cui, X.; Zhu, J.; Jiang, Y.-Z. Tetrahedron Lett. 2004, 45, 1555.
(14) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
J. Org. Chem, Vol. 70, No. 9, 2005 3585

Xue et al.
TABLE 2. Transfer Hydrogenation of Activated Olefins
TABLE 3. Asymmetric Transfer Hydrogenation of
Catalyzed by TsEN-Ru(II) Complexa
Prochiral Activated Olefins Catalyzed by
(R,R)-TsDPEN-Ru(II) Complexa
a The ligand and [RuCl2(cymene)]2 were initially heated in
methanol. Reaction was conducted in 0.5 M of DCM solution, S/C
) 100. b Isolated yield. c Percent ee was determined by HPLC on
chiral column.
T
yield
T
yield
(%)b
the highly active substrate 7k, simple [RuCl2(cymene)]2
without ligand could also catalyze the transfer hydroge-
nation but at a much lower rate.17 Nevertheless, an
experiment with 7k in 2-propanol catalyzed by TsEN-
Ru(II) revealed that 2-propanol cannot serve as a suc-
cessful hydrogen source.
entry substrate (h) (%)b entry substrate (h)
1
2
3
4
5
6
7
8
9
10
7a
7b
7c
7d
7e
7f
24
4
4.5 99
NRc
89
11
12
13
14
15
16
17
18
19
7k
7l
2
99
24 NRc,15
7m
7n
7o
7p
7q
7r
2
5
2
2
97
98
d
13
5
98
99
99
87
99
99
83
Since several types of R- and â-prochiral olefins could
be successfully reduced with diamine-Ru(II) complex as
catalyst, we investigated the potential application of this
methodology for the asymmetric reduction of prochiral
olefins. Complete racemic products were obtained for the
transfer hydrogenation of R-prochiral olefins 7c and 7d
(Table 3, entries 1 and 2) catalyzed by (R,R)-TsDPEN-
Ru(II) complex,18 which is a good catalyst for the asym-
metric transfer hydrogenation of ketones and imines.2a
Moreover, only low enantioselectivity was generated in
the reduction of R-phenylacrylic acid 7m and its ester
7n (entries 3 and 4). On the other hand, moderate enan-
tioselectivity (49% ee, entry 5) could be obtained in the
asymmetric reduction of â-prochiral 1-phenylethyliden-
emalononitrile 7r19 with the same catalyst. The cyclic
1,2,3,4-tetrahydro-1-naphthylidenemalononitrile 10a gave
higher enantioselectivity (54% ee, entry 6). Thus, the
olefin 10a was used as the model substrate for the
optimization of the asymmetric catalytic conditions.
2
d
7g
7h
7i
4
24 NRc,15
2
2
93
2
7s
24 NRc,15
7j
2
a The ligand and Ru precursor were initially heated in methanol.
Reactions were conducted at 30 °C in 0.5 mL of CH2Cl2, S/C )
200. b Isolated yield. c No reaction. d A complicate mixture was
obtained.
bifunctional compounds, the reactivity of the substrate
reflected the polarity of double bonds. R-(Acetylamino)
acrylate 7l15 (entry 12) was totally inactive under the
same conditions, probably due to the weak electron-
withdrawing effect of the acetylamino group (σ ) 0.00).14
Conjugate olefin 7o16 (entry 15) and heteroaromatic
substrate 7p (entry 16) gave complicate mixtures. The
substituent on the CdC bond at the â-position also had
subtle effects on the reactivity. R,â-Unsaturated carboxy-
lic acid 7m and its ester 7n, which are unsubstituted at
the â-position, had high reactivity (entries 13 and 14).
On the other hand, 7q and 7s, which are the â-methyl
analogue of 7e and 7f, respectively, were inactive even
at higher temperature, owing to the electron-donating
effect of CH3 (σ ) -0.17)14 (entry 17 vs 5 and 19 vs 6).
While 7r, the â-methyl analogue of 7k, was reduced
within 2 h due to the strong electron-withdrawing ability
of the di-CN substituents (σ ) 0.66),14 which made the
kinetic barrier to attack the double bond easier to
overcome (entry 18 vs 11). Interestingly, in the case of
Solvents were found to have mild effects on the
enantioselectivity, while the best results were obtained
in THF.10 Then, a wide variety of diamine(arene)-
Ru(II) systems was investigated to explore the effects on
(17) When [RuCl2(cymene)]2 alone was used as catalyst, 7% and 65%
conversions were obtained in 2 and 24 h, respectively, under the same
conditions.
(18) The R-H of 8f and 8k is highly active and could be completely
deuterated with D2O catalyzed by triethylamine, while no deuterium
incorporation was observed for 8c and 8d under same conditions, and
this implies that the racemic products were not produced from the
racemization of the R-carbon of 8c and 8d.
(15) No reaction was found in CH3OH, (CH3)2COH, or DMSO, and
no product was determined even in DMF at refluxing temperature.
(16) Recently the selective reduction of the R,â-CdC double bond
by InCl3-NaBH4 was reported, see: Ranu, B. C.; Samanta, S. J. Org.
Chem. 2003, 68, 7130.
(19) For previous work on reduction of 7r with NADH model
compounds, see: (a) Ohno, A.; Ikeguchi, M.; Kimura, T.; Oka, S. J.
Am. Chem. Soc. 1979, 101, 7036. (b) Seki, M.; Baba, N.; Oda, J.; Inouye,
Y. J. Org. Chem. 1983, 48, 1370. (c) Zhang, B.-L.; Zhu, X.-Q.; Lu, J.-
Y.; He, J.-Q.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2003, 68, 3295.
3586 J. Org. Chem., Vol. 70, No. 9, 2005

Transfer Hydrogenation of Activated CdC Bonds
SCHEME 2
TABLE 4. Catalytic Effects of the N-Sulfonylated Chiral
SCHEME 3
Diamine Ligandsa
T
yield ee
T
yield ee
entry ligand (h) (%)b (%)c entry ligand (h) (%)b (%)c
1
2
3
4
5
6
7
8d
2a
2b
2c
2d
2e
2f
4
3
6
6
98
98
93
96
61
32
71
81
84
84
85
81
9
10
11
12
13
14
15
16
2i
3.5 97
52
47
60
75
58
53
66
85
2j
10
96
93
98
90
85
88
85
2k
2l
2m
2n
2o
2p
4
4
4
4
2
4
3.5 98
4
4
4
98
99
97
2g
2h
a The ligand and Ru precursor were initially heated in THF at
65 °C for 2 h, S/C ) 100. b Isolated yield. c Percent ee was
determined by HPLC on chiral OD column. d Ligand and Ru
precursor were previously heated in 2-propanol at 85 °C.
enantioselectivity and reactivity for the reduction of
activated olefins. When a NO2 group was introduced at
the ortho-position of phenyl groups of DPEN, it had little
effects on the enantioselectivity and activity (entry 11),
and moderate enantioselectivity (75%) was obtained
while bulky N-sulfonylated ligand 2l was used (entry 12).
The introduction of an amido group on the benzene rings
decreased the enantioselectivity (entries 13 and 14). It
was noted that the introduction of a methoxy group at
the para-position of the phenyl groups gave higher
enantioselectivity compared with TsDPEN 2a (entry 15
vs 1), while the bulky 2,4,6-triethylbenzene-sulfonylated
ligand 2p gave similar results compared with ligand 2g
(entry 16 vs 7).
Preliminary observation revealed that substituent on
the Ru-arene ring may also have a significant influence
on the performance of the catalyst system. This effect was
investigated by in situ combination of 2 equiv of N-
arylsulfonyl-DPEN and [RuCl2(arene)]2 precursor (Scheme
3). The Ru(II) dimers were easily prepared by reaction
of RuCl3‚3H2O with 1,4-dienes,21 which are available by
Birch reduction of the corresponding arenes. Table 5
the enantioselectivity and the catalytic activity. Two
parameters have been systematically studied: (i) the
structure of the N-sulfonylated chiral diamine ligands
and (ii) the structure of the metal precursors.
For the promotion of the enantioselectivity, we fine-
tuned the substitution on the N-sulfonylated chiral
diamine ligands (Scheme 2), and Table 4 shows the
representative results. While electron-withdrawing tri-
flate ligand 2c slightly increased the enantioselectivity
(entry 3, 71% ee), 1-Naphthysulfonyl-DPEN gave a much
better result (entry 4, 81% ee). When more bulky 2,4,6-
mesitylenesulfonyl-DPEN was used, the enantioselectiv-
ity was increased to 84% ee with high catalytic activity
(entry 5). Through fine-tuning of the substituents on the
benzene ring of N-sulfonyl group, the highest enantiose-
letivity (85% ee) was achieved while 2,4,6-triethylben-
zenesulfonyl-DPEN was used (entry 7). Monoalkylation
of the NH2 group on TsDPEN decreased both enantiose-
lectivity and activity (entries 9 and 10). On the other
hand, though 1,2-diphenylethylenediamine is an impor-
tant chiral ligand in asymmetric transfer hydrogenation,2a,b
up to now, there was scarce literature references20
reported the effect of substituents on the benzene ring
of DPEN on asymmetric transfer hydrogenation. Here,
we synthesized a series of phenyl-substituted chiral 1,2-
diphenylethylenediamines and studied the effect on the
(20) For the diamines substituted on the benzene ring of DPEN,
see: (a) Ma, Y.-P.; Liu, H.; Cui, X.; Zhu, J.; Deng, J.-G. Org. Lett. 2003,
5, 2013. (b) Itsuno, S.; Tsuji, A.; Takahashi, M. Tetrahedron Lett. 2003,
44, 3825. (c) Li, X.; Chen, W. P.; Hems, W.; King, F.; Xiao, J.
Tetrahedron Lett. 2004, 45, 951. (d) Li, X.; Wu, X.; Chen, W.; Hancock,
F. E.; King, F.; Xiao, J. Org. Lett. 2004, 6, 3321.
J. Org. Chem, Vol. 70, No. 9, 2005 3587

Xue et al.
TABLE 5. Catalytic Effect of Metal Precursora
SCHEME 4
metal
precursor
yield
(%)b
ee
entry
ligand
T (h)
(%)c
1
2
2g
2g
2g
2g
2a
2a
2f
2d
2a
2a
9a
9b
9c
9d
9e
9f
9b
9b
9g
9h
3
4
91
35
80
85
72
94
3
4
98
4
7
5
10
4
4
1
10
84
5
NRd
NRd
98
6
7
80
82
0
8
98
9
91
10
NRd
a The ligand and Ru precursor were initially heated in THF at
65 °C for 2 h, S/C ) 100. b Isolated yield. c Percent ee was
determined by HPLC on chiral column. d No reaction.
TABLE 6. Asymmetric Transfer Hydrogenation of
Activated Olefins Catalyzed by (R,R)-2
g-[RuCl2(cymene)]2 Complexa
showed the representative results. When [RuCl2(benzene)]2
was used, low enantioselectivity was obtained (entry 1),
while the introduction of substitutes on the benzene ring
gave much higher enantioselectivities (entries 2-4). The
highest enantioselectivity was obtained when [RuCl2-
(cymene)]2-2g was used (entry 3). It was surprising that
the combination of [RuCl2(mesitylene)]2 or [RuCl2(HMB)]2
and 2a could not catalyze the reaction (entries 5 and 6)
owing to the different electronic properties of the arene
ligands. In addition, Rh-amido complex could catalyze
this reaction with high reactivity but no enantioselectiv-
ity (entry 9). However, the Ir-amido complex was inac-
tive in this reaction (entry 10).
yield
(%)b
ee (%)c
(rot. sign)
entry
substrate
T (h)
1
2
10a
10b
10c
10d
10e
10ee
10f
7r
10g
10h
10i
10j
4
98
85 (-)
3
37
58 (-)
3
3
96
93
88 (-)
4
3
83 (-)
5
3
95 (82)d
94
89 (99)d (-)
88 (-)
6
3
7
4
99
82 (+)
8
2.5
4
74
73 (-, S)f
43 (-)
9
82
10
11
12
4
84
15 (-)
3
85
59 (-)
According to above investigation, we found that the
best catalytic system was the combination of ligand 2g
and metal precursor [RuCl2(cymene)]2 (9c). The reaction
scope was assessed with various substrates 7r and 10a-j
as described in Scheme 4. As noted in Table 6, all
substrates were rapidly reduced within 5 h, and high
isolated yields were obtained. Activated olefins 10c-e
condensed from chromanones and malononitrile were
reduced with high enantioselectivity (entries 3-6). Un-
like the transfer hydrogenation of aromatic ketones, the
substituent on the arene ring had little effect on the
reactivity, and a slightly higher enantioselectivity was
obtained for 10e with an electron-donating substituent.
A similar result was seen in the reduction of 10e, when
the crowded ligand 2h-[RuCl2(cymeme)]2 complex was
used (entry 6). Moreover, it was noticeable that optically
pure compound 11e could be obtained via recrystalliza-
tion from EtOAc/petroleum ether with 82% overall yield
(entry 5). A thiochromanone derivative 10f was quanti-
tatively reduced with good enantioselectivity (entry 7).
Great improvement in enantioselectivity was also ob-
served with 2g as ligand in comparison to 2a (73% ee vs
49% ee, entry 8) in the reduction of 7r, and only low to
moderate enantioselectivities were obtained for 10g-i
derived from acyclic aromatic ketones and malononitrile
(entries 9-11). Substrate 10j derived from acyclic ali-
5
95
27 (-)
a 2g and Ru precursor were initially heated in 2-propanol at 85
°C for 2 h. b Isolated yield. c Percent ee was determined by HPLC
on chiral column. d After a single recrystallization from EtOAc-
petroleum ether (v/v, 1:8). e 2h as the chiral ligand. f The absolute
configuration was determined by the rotation comparison with
literature report.19a,b
phatic ketone gave low enantioselectivity (27% ee) but
high yield (entry 12).
In regard to the reaction mechanism, the transfer
hydrogenation of CdC bond catalyzed by chiral rhodium
phosphine complexes with formic acid as hydrogen source
has been studied in detail by Brunner and co-workers.22
But there were few reports on ruthenium-phosphine
complexes23 and ruthenium-nitrogen complexes. Re-
cently, Ikariya and co-workers reported mechanistic
aspects of the formation of chiral ruthenium hydride
complexes from 16-electron ruthenium-amido complexes
and formic acid.24 To give some useful information on the
mechanism of this reaction, we conducted a series of
(22) (a) Lange, S.; Leitner, W. J. Chem. Soc., Dalton Trans. 2002,
752. (b) Leitner, W.; Brown, J. M.; Brunner, H. J. Am. Chem. Soc. 1993,
115, 152.
(23) For asymmetric reduction of unsatutrated compounds catalyzed
by ruthenium-phosphine complexes, see: (a) Brown, J. M.; Brunner,
H.; Leitner, W.; Rose, M. Tetrahedron: Asymmetry 1991, 2, 331. (b)
Saburi, M.; Ohnuki, M.; Ogasawara, M.; Takahashi, T.; Uchida, Y.
Tetrahedron Lett. 1993, 33, 5783.
(21) Bennett, M. A.; Smith, A. K. J. Chem. Soc., Dalton Trans. 1974,
233.
(24) Koike, T.; Ikariya, T. Adv. Synth. Catal. 2004, 346, 37.
3588 J. Org. Chem., Vol. 70, No. 9, 2005

Transfer Hydrogenation of Activated CdC Bonds
SCHEME 5. Proposed Mechanism of the Reduction of CdC Bonds
TABLE 7. Transfer Hydrogenation of 7k with
Deuterium-Labeled Formic Acida
tion to the â-carbon of the CdC bond (asymmetry
generated step), the intermediate 15 might eliminate
from the metal complex and subsequently catches an-
other proton rapidly from the excess NEt3H+ in the
reaction mixture.27 Thus, no asymmetric induction could
be generated in the R-carbon center of 8c and 8d (Table
3, entries 1 and 2). In the reduction of 7m and 7n (Table
3, entries 3 and 4), we consider that a different protona-
tion step might be involved. After a conjugate hydride
transfer from the RuH to the â-carbon of the CdC bond,
the formation of a chiral ruthenium enolate intermediate
1628 may contribute to the generation of low enantiose-
lectivities. An asymmetric protonation of the R-carbon
in 16 may preferentially occur from the acidic NH group
of TsDPEN via a six-member transition state besides
catching a proton from the reaction mixture (Scheme 5).
In conclusion, we demonstrate that the chemoselectiv-
ity can be completely switched from CdO to CdC bonds
in the transfer hydrogenation of activated R,â-unsatur-
ated ketones catalyzed by the amido-ruthenium hydride
complexes. This reaction has been applied to CdC bond
reduction of extensively activated R,â-unsaturated com-
pounds, and high enantioselectivity (up to 89% ee) was
obtained in the asymmetric transfer hydrogenation of
prochiral R,R-dicyanoolefins by screening a variety of
ruthenium complexes of arenes and chiral diamines.
Moreover, a stepwise conjugate reduction mechanism was
hydrogen source
HCOOD
DCOOH
DCOOD
relative deuterium
distributionb
R
â
0
0
0
99
0
99
a 30 °C, 1 M DCM solution, S/C ) 100. b Determined by 1H NMR
using mesitylene as internal standard.
deuterium label experiments25 for the reduction of R,R-
dicyanoolefin 7k with labeled formic acid. The relative
deuterium incorporation of substrate was summarized
in Table 7.
When formyl-D acid was used, 99% deuterium was
labeled on the â-carbon, which provided strong evidence
that the hydrogen from the formyl position of formic acid
was directly transferred to ruthenium24 and subsequently
the ruthenium hydride attacked the electron-deficient
â-carbon of CdC bond. However, no deuterium labeling
was observed in the R-position for all formic acids. We
speculated that the rapid H-D exchange on the acidic
R-H of 8k in the presence of a base during the workup
would account for the phenomena. In fact, it was verified
that the R-H of 8k is highly active and could be com-
pletely deuterated with D2O catalyzed by triethylamine,
while no deuterium incorporation could occur in the
absence of a base.18 Therefore, considering the charac-
teristics of activated olefins and the hydridic amido-
ruthenium complex (RuH), which is a coordinately satu-
rated complex,5,24 the reduction of the polarized R,â-
unsaturated compounds is proposed to proceed in a
stepwise conjugate reduction procedures (Scheme 5),26
rather than in a concerted mechanism in the transfer
hydrogenation of ketones.5 After a RuH conjugate addi-
(26) For selected reports on other metallic hydride mediated asym-
metric conjugate reductions, see: (a) Misun, M.; Pfaltz Helv. Chim.
Acta 1996, 79, 961 and references therein. (b) Yamada, T.; Ohtsuka,
Y.; Ikeno, T. Chem. Lett. 1998, 1129. (c) Chiu, P.; Szeto, C.-P.; Geng,
Z.; Cheng, K.-F. Org. Lett. 2001, 3, 1901. (d) Kamenecha, T. M.;
Overman, L. E.; Ly Sakata, S. K. Org. Lett. 2002, 4, 79. (e) Zhao, C.-
X.; Duffey, M. O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001, 3, 1829
and references therein. (f) Jurkauskas V.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 2892 and references therein. (g) Lipshutz, B.
H.; Servesko, J. M. Angew. Chem., Int. Ed. 2003, 42, 4789 and
references therein. (h) Czekelius, C.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2003, 42, 4793.
(27) For hydride transfer as the key step in the hydrogenation of
iminium ion catalyzed by a P-P* ruthenium hydride complex, see:
(a) Magee, M. P.; Norton, J. R. J. Am. Chem. Soc. 2001, 123, 1778. (b)
Rossen, K. Angew. Chem., Int. Ed. 2001, 40, 4611.
(25) For deuterium labeling experiments on transfer hydrogenation
using labeled formic acid as deuterium source, see: (a) Wu, X. F.; Li,
X. G.; Hems, W.; King, F.; Xiao, J. L. Org. Biomol. Chem. 2004, 1818.
(b) Yu, J.; Spencer, J. B. Chem. Commun. 1998, 1935. (c) Yu, J.;
Spencer, J. B. Chem. Eur. J. 1999, 5, 2237. (d) Tanchoux, N.; de
Bellefon, C. Eur. J. Inorg. Chem. 2000, 1495. Also see ref 22.
(28) Ruthenium enolates were also proposed as intermediates in the
reports, see: (a) Alvarez, S. G.; Hasegawa, S.; Hirano, M.; Komiya, S.
Tetrahedron Lett. 1998, 39, 5209. (b) Chang, S.; Na, Y.; Choi, E.; Kim,
S. Org. Lett. 2001, 3, 2089. (c) Watanabe, M.; Ikagawa, A.; Wang, H.;
Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2004, 126, 11148 and
references therein.
J. Org. Chem, Vol. 70, No. 9, 2005 3589

Xue et al.
75 MHz) δ 170.3, 142.8, 138.6, 138.5, 128.9, 128.5, 128.1, 126.7,
123.2, 122.9, 119.2, 118.9, 118.4, 64.2, 60.3, 22.5, 20.1 ppm;
IR (KBr) 3361, 2925, 1672, 1612, 1556, 1492, 1444, 1373, 1321,
1202, 1158, 1092 cm-1; HRMS (ESI) calcd for C25H28N4O4S +
H 481.1904, obsd 481.1900.
proposed following a deuterium labeled experiment and
the results of the asymmetric reductions. It is noticeable
that the novel chiral diamines substituted on the benzene
ring of DPEN were synthesized and first used in asym-
metric transfer hydrogenation.20 Future work to apply
this methodology to other asymmetric reductions of
activated olefins is actively in progress.
Compound 2n: yield 83.6%; mp 115-116 °C; [R]28D -21.7°
1
(c 0.24, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.49-7.25 (m,
8H), 7.14-6.88 (m, 6H), 4.35 (d, J ) 4.6 Hz, 1H), 4.14 (d, J )
4.7 Hz, 1H), 2.30 (s, 3H), 1.30 (s, 18H) ppm; 13C NMR (CDCl3,
75 MHz) δ 176.9, 176.7, 142.6, 142.0, 140.4, 138.2, 138.1, 129.1,
128.9, 126.8, 122.9, 122.3, 119.5, 119.3, 118.7, 118.3, 62.8, 60.0,
39.6, 27.6, 21.4 ppm; IR (KBr) 3377, 2965, 1662, 1609. 1586,
1537, 1489, 1435, 1316, 1158, 1092 cm-1; HRMS (ESI) calcd
for C31H40N4O4S + H 565.2843, obsd 565.2838.
Experimental Section
General Methods. Melting points were determined in open
capillaries and were uncorrected. NMR spectra were recorded
with tetramethylsilane as the internal standard. Chiral 1,2-
diphenylethylenediamine was produced in our laboratory,
Compound 2o: yield 92%; white solid; mp 188-190 °C;
[R]22D +121.81° (c 0.67, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.30 (d, J ) 8.2 Hz, 2H), 7.20 (d, J ) 8.2 Hz, 2H), 6.84 (dd, J
) 8.2, 1.7 Hz, 4H), 6.59 (d, J ) 8.6 Hz, 2H), 6.33 (d, J ) 8.6
Hz, 2H), 4.84 (d, J ) 10.1 Hz, 1H), 4.77 (d, J ) 10.1 Hz, 1H),
3.59 (s, 3H), 3.58 (s, 3H), 2.22 (s, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 159.4, 158.6, 142.1, 137.4, 129.7, 129.0, 128.7, 128.4,
127.1, 113.8, 113.2, 61.7, 59.1, 54.9, 21.3 ppm; IR (KBr) 3411,
3037, 2909, 2863, 1613, 1516, 1252, 1159 cm-1; HRMS (ESI)
calcd for C23H26N2O4S + H 427.1692, obsd 427.1686.
[R]20 ) +106.7 (c 1.0, methanol, R,R-isomer). All other
D
reagents were used without purification as commercially
available.
General Procedure for Monosulfonylation of Chiral
Ligands. To a stirred solution of (R,R)-diamine (1.0 mmol)
and DIPEA (0.19 mL, 1.1 mmol) in DCM (10 mL) was added
a solution of arylsulfonyl chloride (1.1 mmol) in DCM (5 mL)
dropwise at 0 °C. The solution was stirred overnight at room
temperature. After washed with water, the solution was dried
and concentrated, and flash chromatography (DCM/methanol)
gave the monosulfonylated ligand.29
Compound 2p: yield 87%; solid; mp 108-109 °C; [R]28
D
1
+33.1° (c 0.36, CHCl3); H NMR (CDCl3, 300 MHz) δ 6.93 (d,
J ) 8.6 Hz, 2H), 6.79(d, J ) 8.6 Hz, 2H), 6.76 (s, 2H,), 6.66 (d,
J ) 8.7 Hz, 2H), 6.52 (d, J ) 8.7 Hz, 2H), 4.27 (d, J ) 6.4 Hz,
1H), 3.91 (d, J ) 6.8 Hz,1H), 3.74 (s, 3H), 3.68 (s, 3H), 2.78
(m, 4H), 2.54 (q, J ) 7.61 Hz, 2H), 1.18 (m, 9H) ppm; 13C NMR
(CDCl3, 75 MHz) δ 158.8, 158.6, 147.8, 145.1, 133.9, 133.6,
130.8, 128.6, 128.3, 127.5, 113.6, 113.2, 62.9, 60.2, 55.2, 55.1,
28.4, 28.3, 16.6, 15.1 ppm; IR (KBr) ν 3408, 2965, 2874, 1612,
1515, 1461, 1314, 1250, 1154, 1033, 911, 834, 663, 568; HRMS
(ESI) calcd for C28H36N2O4S + H 497.2474, obsd 497.2469.
Procedure for the Transfer Hydrogenation of R,â-
Unsaturated Ketones and Olefins. Diamine ligand (0.0028
mmol), [RuCl2(cymene)]2 (0.76 mg, 0.00125 mmol), and tri-
ethylamine (0.69 µL, 0.005 mmol) were heated in methanol
(0.5 mL) for 0.5 h. Methanol was then removed under vacuum.
Olefin substrate (0.5 mmol) in DCM (0.5 mL) and the azeotrope
of formic acid and triethylamine (0.2 mL) were added in turn.
The mixture was stirred at 30 °C. After completion, the
solution was diluted with EtOAc, washed with water, and
dried. Flash chromatography gave the pure products.30
General Procedure for Asymmetric Transfer Hydro-
genation of Olefins. Monosulfonylated chiral ligand (0.0044
mmol), [RuCl2(cymene)]2 (1.2 mg, 0.002 mmol), and triethyl-
amine (1.1 µL, 0.008 mmol) were heated in 2-propanol (0.5 mL)
for 2 h. Then 2-propanol was removed under vacuum. Olefin
substrate (0.4 mmol) in THF (0.4 mL) and the azeotrope of
formic acid and triethylamine (0.25 mL) were added in turn.
The mixture was stirred at 30 °C. After completion, the
solution was diluted with EtOAc, washed with water, and
dried. Flash chromatography on silica gel gave the pure
products.30
Compound 2f: yield 75%; mp 140-142 °C; [R]28 +22.2°
D
1
(c 0.36, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.11-6.87 (m,
11H), 4.41 (d, J ) 7.4 Hz, 1H), 4.18 (d, J ) 6.9 Hz, 1H), 2.32
(s, 6H), 2.10 (s, 6H) ppm; 13C NMR (CDCl3, 75 MHz) δ 141.4,
138.3, 138.1, 135.3, 135.1, 134.6, 128.1, 127.6, 127.3, 127.1,
127.0, 126.6, 63.8, 60.3, 20.8, 17.1 ppm; IR (KBr) 3366, 3307,
3201, 1583, 1451, 1317, 1142, 1009 cm-1; HRMS (ESI) calcd
for C24H28N2O2S + H 409.1949, obsd 409.1942.
Compound 2g: yield 78%; mp 128-130 °C; [R]28 +21.3°
D
1
(c 0.40, CHCl3); H NMR (CDCl3, 300 MHz) δ 7.14-6.89 (m,
10H), 6.74 (s, 2H), 4.37 (d, J ) 6.7 Hz, 1H), 4.0 (d, J ) 6.7 Hz,
1H), 2.91-2.71 (m, 4H), 2.54 (q, J ) 7.5 Hz, 2H), 1.22-1.16
(m, 9H) ppm; 13C NMR (CDCl3, 75 MHz) δ 143.1, 140.3, 136.9,
133.9, 128.7, 123.9, 123.4, 123.0, 122.8, 122.7, 122.5, 122.3,
121.9, 121.8, 58.8, 55.9, 23.6, 23.5, 11.8, 10.3 ppm; IR (KBr)
3369, 1967, 1600, 1451, 1340, 1155 cm-1; HRMS (ESI) calcd
for C26H32N2O2S + H 437.2262, obsd 437.2257.
Compound 2k: yield 44%; mp 183-185 °C; [R]28 +32.9°
D
(c 0.98, CH3OH); 1H NMR (CDCl3, 300 MHz) δ 8.06-7.98 (m,
4H), 7.59-7.30(m, 6H), 6.97 (d, J ) 8.4 Hz, 2H), 6.22 (br.s,
NH), 4.53 (d, J ) 4.7 Hz, 1H), 4.33 (d, J ) 4.7 Hz, 1H), 2.30
(s, 3H) ppm; 13C NMR (CDCl3, 75 MHz) δ 148.2, 143.5, 142.8,
141.1, 136.6, 133.2, 132.60, 129.6, 129.6, 129.4, 127.9, 127.3,
126.6, 123.8, 122.8, 121.8, 121.4, 62.2, 59.6, 21.3 ppm; IR (KBr)
3278, 3088, 1597, 1526, 1347, 1157, 1091 cm-1; HRMS (ESI)
calcd for C21H20N4O6S + H 457.1176, obsd 457.1164.
Compound 2l: yield 74.5%; mp 174-176 °C; [R]25D +32.7°
1
(c 0.31, CHCl3); H NMR (CDCl3, 300 MHz) δ 8.00-7.80 (m,
4H), 7.47-7.21 (m, 4H), 6.67 (s, 2H), 4.64 (d, J ) 7.1 Hz, 1H),
4.30 (d, J ) 7.1 Hz, 1H), 2.91-2.71 (m, 4H), 2.46 (q, J ) 7.6
Hz, 2H), 1.15 (m, 9H) ppm; 13C NMR (CDCl3, 75 MHz) δ 148.5,
148.1, 147.8, 144.9, 143.2, 133.7, 133.5, 133.0, 132.6, 129.9,
129.6, 128.9, 122.9, 122.7, 121.9, 121.4, 62.6, 60.3, 28.5, 28.1,
16.7, 16.1, 14.9, 14.6 ppm; IR (KBr) ν 3450, 3386, 2895, 2933,
2873, 1599, 1529, 1456, 1349, 1154, 904, 877, 807, 742, 692;
HRMS (ESI) calcd for C26H30N4O6S + H 527.1964, obsd
527.1957.
General Procedure for Deuterium Labeling Experi-
ments. TsDPEN-RuCl(cymene)5a (2.6 mg, 0.004 mmol) was
dissolved in 0.5 mL of DCM. Activated olefin 7k (62 mg, 0.4
mmol), triethylamine (112 µL, 0.8 mmol), and deuterium
labeled formic acid (78 µL, 2.0 mmol) were added in turn. Then
the solution was stirred at 30 °C. After completion, the mixture
was concentrated, and flash chromatography directly on silica
gel gave the reduced product.30
Compound 2m: yield 62.5%; mp 213-215 °C; [R]20D +80.5°
(c 0.32, CH3OH); 1H NMR (CD3OD, 300 MHz) δ 7.38-7.31 (m,
4H), 7.13-6.99 (m, 6H), 6.89-6.84 (m, 2H), 6.56 (d, J ) 7.8
Hz, 2H,), 4.38 (d, J ) 9.1 Hz, 1H), 4.09 (d, J ) 9.1 Hz, 1H),
2.26 (s, 3H), 2.07 (s, 3H), 2.06 (s, 3H) ppm; 13C NMR (CD3OD,
Acknowledgment. This work was financially sup-
ported by the National Natural Science Foundation of
China (No. 203900507, 20025205) and Y.-C.C. is grate-
ful for the financial support of Sichuan University.
(29) For the details of the synthesis of the chiral ligands and the
physical and spectroscopic data of 2c,d,h, see the Supporting Informa-
tion.
(30) For the physical and spectroscopic data of the products, see the
Supporting Information.
3590 J. Org. Chem., Vol. 70, No. 9, 2005

Transfer Hydrogenation of Activated CdC Bonds
Supporting Information Available: Experimental pro-
cedures of the synthesis of the ligands and olefins 7r and
10a-i and the transfer hydrogenation; characterization
data for 2c-d,h, 4a-d, 5e-h, 6e, 8b-k,m,n,r, 11a-j;
copies of NMR and MS spectra of ligands 2f,g,k-p and
reduced products 5f,h, 8d,e,g,k,r, and 11a-j. This ma-
terial is available free of charge via the Internet at
http://pubs.acs.org.
JO0478205
J. Org. Chem, Vol. 70, No. 9, 2005 3591