Efficient asymmetric transfer hydrogenation of activated olefins catalyzed by ruthenium amido complexes

Article abstract of DOI:10.1016/j.tetlet.2003.12.057

The asymmetric transfer hydrogenation of activated olefins with chiral ruthenium amido complexes (Noyori catalyst) using formic acid-triethylamine azeotrope as hydrogen source resulted in excellent yields and high enantioselectivities (up to 88.5%).

Full text of DOI:10.1016/j.tetlet.2003.12.057

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1555–1558
Efficient asymmetric transfer hydrogenation of activated olefins
catalyzed by ruthenium amido complexes
*
Ying-Chun Chen, Dong Xue, Jin-Gen Deng, Xin Cui, Jin Zhu and Yao-Zhong Jiang
Key Laboratory of Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis,
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
Received 7 August 2003; revised 11 November 2003; accepted 3 December 2003
Abstract—The asymmetric transfer hydrogenation of activated olefins with chiral ruthenium amido complexes (Noyori catalyst)
using formic acid–triethylamine azeotrope as hydrogen source resulted in excellent yields and high enantioselectivities (up to
8
8.5%).
Ó 2003 Elsevier Ltd. All rights reserved.
The asymmetric reduction of b,b-disubstituted a,b-
unsaturated carbonyl compounds is one of the most
important reactions to construct a chiral carbon center
formic acid–triethylamine azeotrope as hydrogen
source, and the transfer hydrogenation reaction is highly
chemoselective for C@O function and tolerant of alk-
1
7b;9
on the b-positions. Apart from asymmetric hydro-
genation catalyzed by chiral diphosphine–rhodium or
enes.
saturated monosulfonylated diamine–Ru(II) complexes
In our continuous study on these coordinately
2
10
ruthenium complexes, the conjugate reduction with
other reducing agents also plays a very important role in
this area. Although a number of metal catalysts have
catalyzed transfer hydrogenation reactions, we found
for the first time that the asymmetric reduction of the
highly activated a,a-dicyano alkenes proceeded with
quantitative yields and high enantioselectivities under
11
3
been employed for the conjugate reduction, there are
12
limited catalysts that can reduce C@C bonds to generate
a stereocenter with high enantioselectivity b to a car-
bonyl. PfaltzÕs chiral semicorrin cobalt system is a highly
efficient catalyst for the asymmetric conjugate reduction
mild transfer hydrogenation conditions.
In our initial studies, only moderate enantioselectivity
(49% ee, 94% yield) was obtained in the reduction of
1-phenylethylidenemalononitrile 2g (Fig. 2) with ruthe-
4
of a,b-unsaturated esters, amides and other compounds
using sodium borohydride as the stoichiometric reduc-
ing agent, but generally the reactions proceed rather
slowly. YamadaÕs chiral aldiminato cobalt complex is
nium amido catalyst, [RuCl
2 2
(cymeme)] -(R,R)-TsDPEN
(TsDPEN ¼ N-(p-toluenesulfonyl)-1,2-diphenylethylene-
13;14
diamine) (1a).
By using the cyclic 1,2,3,4-tetrahydro-
another example of asymmetric reduction catalysts for
5
1-naphthylidene malononitrile 2a gave higher enantio-
selectivity (60.6% ee, Table 1, entry 1), thus, we use 2a as
the model substrate to optimize the conditions. Solvents
were found to have mild effects on the enantioselectivity,
while the best results were obtained in THF (entries 1–
4). In order to improve the enantioselectivity, we deci-
ded to fine tune the substitution pattern of the
g-arene ligand and the structure of the TsDPEN ligand
4
a,b-unsaturated amides with premodified NaBH .
Recently, Buchwald reported that the chiral phosphine–
copper catalysts could catalyze the asymmetric conju-
gate reduction of a,b-unsaturated ester and cyclic
ketones with excellent enantioselectivity, employing
6
PMHS (polymethylhydro-siloxane) as the reductant.
Moreover, Noyori has recently disclosed that ruthenium
amido complexes are highly efficient catalysts for the
(Fig. 1). Since the bulky complex TsDPEN–
7;8
7b;d
1
,2-reduction of C@O and C@N bonds, using the
[RuCl (HMB)] (HMB ¼ hexamethylbenzene)
failed
2
2
to catalyze the reaction probably due to the steric rea-
son, we turned to modify the structure of the TsDPEN
ligand. However, monoalkylation of the –NH group of
Keywords: Activated olefins; Asymmetric transfer hydrogenation;
2
TsDPEN resulted in reducing both catalytic activity and
enantioselectivity (entries 5 and 6). Fortunately, when
N-2,4,6-mesitylenesulfonyl-DPEN (1d) was used (entry
Ruthenium amido complexes.
*
Corresponding author. Tel.: +86-28-85229250; fax: +86-28-852239-
8; e-mail: jgdeng@cioc.ac.cn
7c
7
0
040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.057

1556
Y.-C. Chen et al. / Tetrahedron Letters 45 (2004) 1555–1558
a
Table 1. Optimization of the catalytic conditions for asymmetric transfer hydrogenation of activated olefin 2a
NC
CN
NC
CN
*
L*-[RuCl (cymene)]
2
2
o
Solvent, TEAF, 30 C
2a
3b
b
c
Entry
Ligand
Solvent
THF
T (h)
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1c
1d
1e
1f
2
2
98
98
98
97
97
96
98
98
99
95
97
96
97
99
95
60.6
52.3
53.7
59.2
52.1
46.8
84.1
84.3
85.1
57.9
81.3
81.1
64.8
85.9
62.5
CH
CH
3
2
CN
Cl
2
2
Toluene
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
2.5
3.5
10
3.5
4
4
10
11
12
13
14
15
1g
1g
1h
1f
20
4
d
d
e
f
6
15
4
1f
g
1f
1.5
a
b
c
d
e
f
The ligand and Ru precursor were initially heated in THF at 65 °C for 2 h, S/C ¼ 100.
Isolated yield.
Ee was determined by HPLC on chiral OD column.
1g, 1h and Ru precursor were previously heated in 2-propanol at 85 °C for 2 h.
S/C ¼ 500.
S/C ¼ 50.
g
For the reaction at 40 °C.
Ph
Ph
increase the reaction temperature to 40 °C resulted in
shorter reaction time with low enantioselectivity (62.5%
ee) and high yield (95%) (entry 15). At 0 °C, the reaction
proceeded very slowly. These results indicated that the
reaction activity depends on the temperature.
1
1
1
a: R = H
O
S
O
b: R = CH
3
5
R
NH HN
Me
c: R = C H
2
1
1
1
1
1
d: Ar = 2,4,6-(CH ) C H
3 3 6 2
Ph
Ph
e: Ar = 2,3,5,6-(CH ) C H
3
4 6
O
S
O
f: Ar = 2,4,6-(C H ) C H
2
5 3 6 2
H N HN
Ar
Having established the optimal catalytic system and
13
2
g: Ar = 2,4,6-(2-C H ) C H
h: Ar = 1-naphthyl
3
7 3
6
2
conditions, reaction scopes were assessed with the
various substrates 2a–i described in Figure 2. As noted
Figure 1. Chiral monosulfonylated DPEN ligands.
in Table 2, all substrates were rapidly reduced within
5
h, and in general, high isolated yields were obtained.
Activated olefins 2c–e condensed from chromanones
and malononitrile were reduced with high enantio-
selectivity (entries 3–6). Unlike the transfer hydrogena-
7
8
), the enantioselectivity was dramatically increased to
4.1% ee without much effect on the reactivity. More-
7b;10c
over, through fine tuning the substituents on the benz-
ene ring, the enantioselectivity could be marginally
improved and the highest enantioselectivity (85.1%) was
tion of aromatic ketones,
the substituents on the
achieved
ethylbenzenesulfonyl-DPEN (1f) and [RuCl
entry 9). It should be noted that further increase of the
steric effect on arene ring will decrease both the reac-
tivity and enantioselectivity (entry 10), and pre-activa-
tion in higher temperature (refluxing in 2-propanol) was
very crucial to obtain high catalytic efficiency for the
steric hindered ligand 1g (entries 10 vs 11). 1-Naph-
thylsulfonyl-DPEN (1h) also gave high enantioselectiv-
ity (81.1% ee, entry 12). An increase in the S/C ratio to
with
the
complex
of
N-2,4,6-tri-
NC
CN
n
NC
CN
NC
CN
2
(cymene)]
2
R1
R2
(
O
2
S
1
2
2
2
c: R = H, R = H
d: R = Br, R = H
2a: n=1
1
2
2f
2
b: n=0
1
2
e: R = CH , R = CH
3
3
CN
CN
CN
CN
CN
CN
5
(
00 caused a significant decrease in the enantioselectivity
64.8% ee vs 85.1% ee) but high yield (entry 13). How-
2
g
2h
2i
ever, a slight increase of the enantioselectivity (85.9% ee)
was observed with 50 of S/C ratio (entry 14). An
Figure 2. Activated olefins for asymmetric transfer hydrogenation.

Y.-C. Chen et al. / Tetrahedron Letters 45 (2004) 1555–1558
1557
a
Table 2. Asymmetric transfer hydrogenation of activated olefins catalyzed by 1f–[RuCl
2
(cymene)]
2
complex
b
c
Entry
Substrate
T (h)
Yield (%)
Ee (%) (Rotation sign)
1
2
3
4
5
2a
2b
2c
2d
2e
2e
2f
4
98
37
96
93
84.9 ())
58.2 ())
87.5 ())
82.5 ())
88.5 (99) ())
88.4 ())
82.4 (+)
3
3
3
d
d
3
95 (82)
e
6
3
94
99
74
85
95
7
8
9
4
f
2g
2h
2i
2.5
3
72.7 (), S)
59.2 ())
27.2 ())
10
5
a
b
c
d
e
f
1
f and Ru precursor was initially heated in 2-propanol at 85 °C for 2 h, S/C ¼ 100.
Isolated yield.
Ee was determined by HPLC on chiral OD column.
After a single recrystallization from EtOAc–petroleum ether (v/v, 1:8).
1g as the chiral ligand.
The absolute configuration was determined by the rotation comparison to that of the literature, see Ref. 17.
arene ring had little effects on the reactivity and a
slightly higher enantioselectivity was obtained for 2e
with electron-donating substituents. The similar result
was received in the reduction of 2e, while the steric
Concd. HCl
CN
CN
COOH
Reflux, 4h, 99%
3
g (73% ee)
5 (73% ee)
2 2
hindered ligand 1g-[RuCl (cymeme)] complex was used
as catalyst (entry 6). It is noticeable that optical pure
product 3e could be obtained through a single recrys-
tallization from EtOAc/petroleum ether with 82%
overall yield (entry 5). A thiochromanone derivative 2f
was quantitatively reduced with good enantioselectivity
Scheme 2.
16
same isomers were obtained (Scheme 1). Moreover,
5% of c-CH of reduction product 3b was deuterated
6
2
2
using HCO D-triethylamine as hydrogen source, which
(
entry 7). On the other hand, moderate enantioselectiv-
proved that H–D exchange occurred at the allylic CH
before the reduction of the olefin.
2
ities were obtained for 2g and 2h derived from acyclic
aromatic ketones and malononitrile (entries 8 and 9).
Great improvement in enantioselectivity of 2g was also
observed if using 1f as ligand in comparison to 1a (73%
ee vs 49% ee). Substrate 2i derived from acyclic aliphatic
ketone gave lower enantioselectivity (27.2% ee) but high
yield (entry 10).
The product 3g was hydrolyzed in concd HCl to give the
b-chiral acids 5 quantitatively without any racemization
(
Scheme 2). Thus, based on the rotation of known
17
compound 5, the absolute configuration of 3g can be
assigned as (S)-form. This implies that other chiral b,b-
disubstituted acids could be easily obtained from those
chiral malononitriles 3.
Quite different from the six-member analogue 2a, much
lower yield and enantioselectivity were observed in the
reduction of 1-indanylidenemalononitrile (2b) (Table 2,
entry 2) and a byproduct 4 was isolated in higher yield,
but no enantioselectivity determined by chiral HPLC
analysis (Scheme 1). This showed that the c-allylic C–H
demonstrated unusually high acidity owing to the strong
In conclusion, we demonstrated for the first time that
chiral ruthenium amido complexes (Noyori catalyst)
were efficient asymmetric catalysts for the transfer
hydrogenation of activated olefins, using the formic
18;19
15
acid–triethylamine azeotrope as hydrogen source.
Now, future work to extend the reaction scope and
improve the enantioselectivity is in progress.
electron-withdrawing ability of malononitrile residue.
In fact, 1,4-addition product 4 readily formed in the
presence of the catalytic amount of triethylamine (TEA)
even at ambient temperature with 75% yield and the
Acknowledgements
NC
CN
1
NC
CN
NC
CN
*
We are grateful for the financial support of the National
Science Fund for Distinguished Young Scholars of
China (no 20025205).
mol% Ru catalyst
*
*
+
o
TEAF, THF, 30 C
NC
4
3b
4
CN
2
b
9%, 0% ee
3
7%
only two enantiomers
5
8.2% ee
References and notes
5
mol% TEA, r.t., 5h, 75%
1
. For a recent reviews on asymmetric conjugate addition to
generate a stereocenter b to a carbonyl. see: (a) Krause, N.;
Scheme 1.

1558
Y.-C. Chen et al. / Tetrahedron Letters 45 (2004) 1555–1558
Hoffmann-R o€ der, A. Synthesis 2001, 171–196; (b) Sibi, M.
P.; Manyem, S. Tetrahedron 2000, 56, 8033–8061.
. (a) Takaya, H.; Ohta, T.; Noyori, R. In Catalytic
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2
12. For examples of transfer hydrogenation of a,b-unsatu-
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3
. For reports on metal-catalyzed conjugate reduction. See:
(
a) Ikeno, T.; Kimura, T.; Ohtsuka, Y.; Yamada, T.
Synlett 1999, 96–98; (b) Sakaguchi, S.; Yamaga, T.; Ishii,
Y. J. Org. Chem. 2001, 66, 4710–4712; (c) Hays, D. S.;
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(
2
d) Saito, S.; Yamamoto, H. J. Org. Chem. 1996, 61, 2928–
929; (e) Chiu, P.; Szeto, C.-P.; Geng, Z.; Cheng, K.-F.
Org. Lett. 2001, 3, 1901–1903; (f) Kamenecha, T. M.;
Overman, L. E.; Ly Sakata, S. K. Org. Lett. 2002, 4, 79–
13. General procedures for the transfer hydrogenation of
olefins: Monosulfonylated chiral DPEN ligand
82; (g) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am.
2 2
(0.0044 mmol), [RuCl (cymene)] (0.002 mmol) and trieth-
Chem. Soc. 2000, 122, 4528–4529; (h) Zhao, C.-X.; Duffey,
M. O.; Taylor, S. J.; Morken, J. P. Org. Lett. 2001, 3,
ylamine (0.008 mmol) were heated in 2-propanol (0.5 mL)
for 2 h. Then, 2-propanol was removed in vacuo. A
solution of olefin substrate (0.4 mmol) in THF (0.4 mL)
and the formic acid–triethylamine azeotrope (0.25 mL)
were added in turn, and the mixture was stirred at 30 °C.
After completion, the mixture was diluted with EtOAc,
and the organic phase was washed with water, dried over
1829–1831; (i) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian,
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4
. (a) Leutenegger, U.; Madin, A.; Pfaltz, A. Angew. Chem.,
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Pfaltz, A. Helv. Chim. Acta 1996, 79, 961–972.
2 4
Na SO , and the pure products were obtained by flash
chromatography on silica gel.
14. Chalcone was reduced with TsDPEN–ruthenium complex
to give saturated ketone and alcohol in quantitive yield
5
. Yamada, T.; Ohtsuka, Y.; Ikeno, T. Chem. Lett. 1998,
1
3
1129–1130.
under our condition (Deng, J.; et al. unpublished
results), but only saturated ketone was obtained in low
yield under organic solvent-free condition. See: Hanne-
douche, J.; Kenny, J. A.; Walsgrove, T.; Wills, M. Synlett
2002, 263–266.
6
. (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E.
M.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9473–
9474; (b) Moritani, Y.; Appella, D. H.; Jurkauskas, V.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 6797–6798;
(
(
2
c) Yun, J.; Buchwald, S. L. Org. Lett. 2001, 3, 1129–1131;
d) Jurkauskas, V.; Buchwald, S. L. J. Am. Chem. Soc.
002, 124, 2892–2893.
15. For a review on acidities of active compounds, see:
Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
1
16. Characterization of 4: H NMR (CDCl
3
, 300 MHz), d 7.98
7
. (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562–7563; (b)
Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.;
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Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.;
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Murata, K.; Okano, K.; Miyagi, M.; Iwane, H.; Noyori,
R.; Ikariya, T. Org. Lett. 1999, 1, 1119–1121.
(d, J ¼ 7:5 Hz, 1H, ArH), 7.43–7.38 (m, 5H, ArH), 7.32–
7.27 (m, 2H, ArH), 5.52 (br s, 2H, CH, CH ), 3.43–3.38
(m, 2H, CH ), 3.35 (s, 1H, CH), 3.18–3.08 (m, 1H, CH ),
2.87–2.78 (m, 1H, CH
NMR (CDCl , 75 MHz), d 148.3, 148.2, 144.6, 143.5,
2
2
2
1
3
2
), 2.65–2.54 (m, 1H, CH
2
);
C
3
140.4, 140.0, 134.7, 130.2, 129.4, 127.8, 127.0, 125.9, 124.6,
124.5, 119.3, 117.0, 112.8, 112.6, 72.5, 58.8, 48.3, 36.7,
34.5, 30.8; IR (KBr), m 3415, 3305, 3189, 2219, 1650, 1570,
À1
À
8
9
. For reviews, see: (a) Noyori, R.; Hashiguchi, S. Acc.
Chem. Res. 1997, 30, 97–102; (b) Palmer, M. J.; Wills, M.
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K.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1997,
1467, 764, 663 cm . ESI MS 359.2 [M)H] (100). Only
two peaks with the same area were resolved by HPLC on
chiral OD column, 20% 2-propanol/hexane, 1.0 mL/min,
UV 254 nm, t
1
¼ 7:46 min, t ¼ 8:51min.
2
17. 3g was heated in concd HCl for 4 h. After a base and acid
extraction procedure, the corresponding (S)-3-phenyl-
36, 288–290; (b) Matsumura, K.; Hashiguchi, S.; Ikariya,
T.; Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738–8739.
2
D
8
butyric acid 5 was obtained as an oil. ½aꢀ +40.9° (c
2
5
1
0. (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.
0.74, benzene) [lit. ½aꢀ )48.32° (c 2.69, benzene), 83% ee
D
(R)]. See: Ref. 2b.
2
001, 1488–1489; (b) Chen, Y.-C.; Deng, J.-G.; Wu, T.-F.;
18. The theoretical calculation by Noyori predicts that the
reactivity of unsaturated compounds toward the Ru
hydride depends on the polarity of the double bonds by
a concerted mechanism. Ethylene possesses much higher
activation energy and also is entropically much less
favorable. See: Noyori, R.; Yamakawa, M.; Hashiguchi,
S. J. Org. Chem. 2001, 66, 7931–7944.
Cui, X.; Jiang, Y.-Z.; Choi, M. C. K.; Chan, A. S. C. Chin.
J. Chem. 2001, 19, 807–810; (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, 5301–5306; (d)
Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.; Deng, J. Org.
Lett. 2003, 5, 2103–2106.
1
1. Other b-disubstituted prochiral activated olefins, even
dimethyl 1-phenylidenemalonate, are inactive in this cata-
lytic system. For a recent example of reducing these
activated olefins using indium metal. See: (a) Ranu, B. C.;
Dutta, J.; Guchhait, S. K. Org. Lett. 2001, 3, 2603–2605;
19. Enantioselective Michael reaction catalyzed by TsDPEN–
metal complexes, see: (a) Suzuki, T.; Torii, T. Tetrahedron:
Asymmetry 2001, 12, 1077–1081; (b) Watanabe, M.;
Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2003, 125,
7508–7509.