Asymmetrie hydrogenation with water/silane as the hydrogen source

Article abstract of DOI:10.1002/chem.200902790

"Chamical Equation presentd" Water as a hydride source : A new pathway to form metal-hydride bonds has been developed through the reaction of easily available metal-silyl compounds with water. This method has been successfully applied to asymmetric hydrogenation of heteroaromatic compounds with up to 93 % ee under mild autoclave-free conditions (see scheme).

Full text of DOI:10.1002/chem.200902790

COMMUNICATION
DOI: 10.1002/chem.200902790
Asymmetric Hydrogenation with Water/Silane as the Hydrogen Source
Da-Wei Wang, Duo-Sheng Wang, Qing-An Chen, and Yong-Gui Zhou*[a]
Catalytic asymmetric hydrogenation of prochiral com-
pounds is one of most efficient methods to produce enantio-
pure compounds.[1] In recent decades, great success has been
achieved in the asymmetric hydrogenation of ketones,
imines, alkenes, and aromatic compounds[2] with excellent
enantioselectivity by using hydrogen gas,[3] iPrOH,[4]
HCOOH,[5] and Hantzsch esters[6] as the hydrogen source
[see Eq. (1)]. For asymmetric hydrogenation, the formation
only metal hydroxides are formed. It is relatively easy to
form metal–silyl bonds by the reaction of transition-metal
and commercially available silane compounds. Owing to the
high oxyphilicity of organic silicon compounds (silica gel is
easy to form and widely exists in nature), we envisioned
that metal–hydride bonds can be conveniently formed
through the reaction of readily available metal–silyl com-
pounds with water as shown in [Eq. (3)], and this method
can be applied to asymmetric hydrogenation under mild au-
toclave-free conditions.
À
and reactivity of metal–hydride bonds (M H) are the core
topic. In general, active metal–hydride bonds can be formed
by the reaction of transition-metal catalysts and the above-
mentioned hydrogen sources through homolytic or hetero-
lytic processes. However, reactivities and enantioselectivities
are generally substrate dependent. Because there is no om-
nipotent catalyst for every substrate, new strategies for the
formation of active metal–hydride bonds under mild condi-
tions, especially under autoclave-free conditions, are highly
desirable.
Water, the most abundant environmentally benign source
in nature, has been used in organic synthesis as a reaction
reagent and a reaction medium.[7] Despite advances in these
areas, water is far less explored as a reaction substrate in
asymmetric catalysis. To the best of our knowledge, there
are no reports of asymmetric hydrogenation occurring with
water as the hydrogen source. In general, it is very difficult
for water to donate hydride owing to the oxyphilicity of the
central metal as shown in [Eq. (2)], and as a result, usually
With this design in hand, triethylsilane and water were se-
lected as model substrates with iridium/bisphosphine as the
catalytic system (Scheme 1). No reaction occurred when
only triethylsilane was used in the presence of the iridium
[a] Dr. D.-W. Wang, D.-S. Wang, Q.-A. Chen, Prof. Y.-G. Zhou
State Key Laboratory of Catalysis
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (P.R. China)
Fax : (+86)411-84379220
E-mail: ygzhou@dicp.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902790.
Scheme 1. Initial experiments with water as the hydrogen source.
Chem. Eur. J. 2010, 16, 1133 – 1136
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1133

catalyst. Hydrogen gas was detected when triethylsilane and
water were used. To demonstrate the existence of hydrogen
gas, the gas generated from silane and water was transferred
to another reactor containing 4-methoxystyrene and Pd/C in
methanol; the result showed that full conversion was ob-
served. When D2O was used instead of water, analysis by
NMR spectroscopy showed that 35% of deuterium had
been incorporated at the a position and 63% at the b posi-
tion. A total of 98% (35+63%) deuterium incorporation
implied that one hydride was from silane and the other was
from water. The other product, (Et3Si)2O, was confirmed by
Next, the effect of solvent on reactivity and enantioselectivi-
ty was examined. The results showed that the reaction was
highly solvent dependent (Table 1, entries 1–5). The highest
enantioselectivity (87% ee) with good reactivity was ob-
tained in THF. Subsequently, a series of commercially avail-
able chiral bisphosphine ligands were screened for the asym-
metric hydrogenation reaction (Table 1, entries 5–9 and
Scheme 2), and it was found that (S)-SegPhos gave the best
result.
Having established the optimal conditions, the scope of
the Ir-catalyzed asymmetric hydrogenation of quinolines
was explored (Table 2). A series of 2-substituted quinolines
1
GC–MS and H NMR spectroscopy. The above experiments
demonstrated that hydrogenation with water as the hydro-
gen source is feasible.
Table 2. Ir-catalyzed asymmetric hydrogenation of quinolines.[a]
Encouraged by these results, we extended this strategy to
the asymmetric hydrogenation of heteroaromatic com-
pounds.[2,8,9] Thus, 2-methylquinoline was selected as a
model substrate for condition optimization. First, the reac-
Entry R/R’
Time [h] Yield [%][b] ee [%][c]
tion was run by using the [IrACHTNUGRTNEUNG(COD)Cl]2/(S)-SynPhos/I2
system as the catalyst in toluene at room temperature
(Table 1, entry 1 and Scheme 2) from which 2a was obtained
in 24% yield and 70% ee in the presence of 2.0 equivalents
of water. The experiment showed that asymmetric hydro-
1
2
3
4
5
6
7
8
H/Me
H/Et
H/nPr
H/nBu
H/npentyl
H/phenethyl
F/Me
Me/Me
MeO/Me
H/Ph
24
24
24
24
24
24
24
48
72
72
48
24
48
48
92 (2a)
95 (2b)
93 (2c)
94 (2d)
96 (2e)
98 (2 f)
97 (2g)
90 (2h)
73 (2i)
83 (2j)
89 (2k)
84 (2l)
94 (2m)
84 (2n)
91 (S)
92 (S)
90 (S)
93 (S)
88 (S)
85 (S)
87 (S)
93 (S)
88 (S)
57 (R)
90 (R)
87 (R)
86 (S)
83 (S)
ACHTUNGTRENNUNGgenation could occur with water as the hydrogen source.
Table 1. Ir-catalyzed asymmetric hydrogenation of 1a.[a]
9
10
11
12
13
14
H/Bn
H/Me2C(OH)CH2
H/3,4-(OCH2O)C6H3ACTHNURGTENUNG(CH2)2
H/3,4-(MeO)2C6H
À
À
Yield [%][b]
ee [%][c]
À
3ACHTUGNRTEN(NUNG CH2)2
Entry
Solvent
Ligand
[a] Conditions:
1
(0.25 mmol), [Ir
G
1
2
3
4
5
6
7
8
9
toluene
CH2Cl2
EtOAc
acetone
THF
THF
THF
THF
THF
(S)-SynPhos
(S)-SynPhos
(S)-SynPhos
(S)-SynPhos
(S)-SynPhos
(S)-MeO-BiPhep
ACHTUNGTRENNUNG(R,R)-Me-DuPhos
(S)-BINAP
(S)-SegPhos
24
11
46
62
89
89
41
86
92
70
84
86
73
87
83
2
(2.2 mol%), I2 (10 mol%), Et3SiH (6.0 equiv), H2O (2.0 equiv), THF
(3 mL), RT. [b] Based on 1. [c] Determined by HPLC.
were smoothly hydrogenated to give the desired products in
excellent yields with 88–93% ee (Table 2, entries 1–5). 2-
Arenethyl-substituted quinolines were also hydrogenated
with good asymmetric induction (Table 2, entries 6, 13, and
14). For the substrate with an electron-donating group, only
moderate reactivity was obtained (Table 2, entry 9). Good
stereocontrol (87% ee) was achieved for the substrate that
had a free hydroxyl (Table 2, entry 12). For 2-benzylquino-
line, the reaction proceeded well to afford the desired prod-
uct with 90% ee. However, 2-phenylquinoline was hydro-
genated with only moderate yield and enantioselectivity
(57% ee, Table 2, entry 10).
71
91
[a] Conditions: 1a (0.25 mmol), [IrACHTNURGTNEUNG(COD)Cl]2 (1 mol%), ligand
(2.2 mol%), I2 (10 mol%), Et3SiH (6.0 equiv), H2O (2.0 equiv), solvent
(3 mL), 24 h, RT. [b] Based on 1a. [c] Determined by chiral HPLC analy-
sis.
Gratifyingly, the above asymmetric hydrogenation strat-
egy can also be extended to asymmetric hydrogenation of
the assorted quinoxaline derivatives. Alkyl- or aryl-substitut-
ed quinoxalines can be reduced smoothly with 58–78% ee
and full conversion under the above optimal conditions (see
products 4a–d in Scheme 3).
This methodology of Ir-catalyzed asymmetric hydrogena-
tion of quinolines with water/silane provides a convenient
route to synthesize optically active tetrahydroquinoline de-
rivatives from very cheap starting materials, quinolines. For
Scheme 2. The various chiral bisphosphine ligands used.
1134
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1133 – 1136

Asymmetric Hydrogenation
COMMUNICATION
Acknowledgements
We are grateful for financial support from National Natural Science
Foundation of China (20621063), National Basic Research Program of
China (2010CB833304) and Dalian Institute of Chemical Physics
(K2007F1).
Scheme 3. Ir-catalyzed hydrogenation of quinoxalines illustrating the ee
values and the yields of 4a–d.
Keywords: asymmetric catalysis · hydrogenation · iridium ·
quinolines · quinoxalines
example, the hydrogenation product of 6-fluoro-2-methyl-
quinoline (2g) is the key intermediate of the antibacterial
agent Flumequine.[10] Importantly, some naturally occurring
tetrahydroquinoline alkaloids such as angustrureine, galipi-
nine, and cuspareine were easily synthesized by N-methyla-
tion of hydrogenated products (2e, 2m, and 2n) with the
above-mentioned step (Scheme 4).[11,8e–f]
[1] a) H.-U. Blaser, B. Pugin, F. Spindler, Applied Homogeneous Cataly-
sis with Organometallic Compounds, 2nd ed. (Eds.: B. Cornils, W. A.
Herrmann), Wiley-VCH, Weinheim, 2000; Chapter 3.3.1; b) P. N.
Rylander, Catalytic Hydrogenation in Organic Synthesis, Academic
Press, New York, 1979, p. 175; c) The Handbook of Homogeneous
Hydrogenation (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH,
Weiheim, 2007.
[2] For some reviews on hydrogenation of aromatic compounds, see:
a) S.-M. Lu, X.-W. Han, Y.-G. Zhou, Chin. J. Org. Chem. 2005, 25,
634; b) F. Glorius, Org. Biomol. Chem. 2005, 3, 4171; c) P. J. Dyson,
Dalton Trans. 2003, 2964; d) Y.-G. Zhou, Acc. Chem. Res. 2007, 40,
1357; e) R. Kuwano, Heterocycles 2008, 76, 909.
[3] For selected reviews, see: a) R. Noyori, Angew. Chem. 2002, 114,
2108; Angew. Chem. Int. Ed. 2002, 41, 2008; b) S. Kobayashi, H. Ish-
itani, Chem. Rev. 1999, 99, 1069; c) J. M. Brunel, Recent Res. Dev.
Org. Chem. 2003, 7, 155; d) P. Liu, H.-F. Jiang, Chin. J. Org. Chem.
2004, 24, 1317; e) W. Tang, X. Zhang, Chem. Rev. 2003, 103, 3029;
f) R. Noyori, T. Ohkuma, Angew. Chem. 2001, 113, 40; Angew.
Chem. Int. Ed. 2001, 40, 40; g) W. S. Knowles, Angew. Chem. 2002,
114, 2096; Angew. Chem. Int. Ed. 2002, 41, 1998; h) K. Rossen,
Angew. Chem. 2001, 113, 4747; Angew. Chem. Int. Ed. 2001, 40,
4611; i) C. Jꢁkel, R. Paciello, Chem. Rev. 2006, 106, 2912.
Scheme 4. Some alkaloids and chiral drugs.
[4] For selected reviews, see: a) R. Noyori, S. Hashiguchi, Acc. Chem.
Res. 1997, 30, 97; b) M. J. Palmer, M. Wills, Tetrahedron: Asymmetry
1999, 10, 2045; c) G. Zassinovich, G. Mestroni, S. Gladiali, Chem.
Rev. 1992, 92, 1051.
[5] For selected reviews, see: a) S. Gladiali, E. Alberico, Chem. Soc.
Rev. 2006, 35, 226; b) T. Ikariya, K. Murata, R. Noyori, Org.
Biomol. Chem. 2006, 4, 393; c) J. S. M. Samec, J.-E. Bꢁckvall, P. G.
Andersson, P. Brandt, Chem. Soc. Rev. 2006, 35, 237.
In summary, we have developed the first asymmetric hy-
drogenation with water/silane as the hydrogen source under
mild autoclave-free reaction conditions with up to 93% ee.
For this hydrogenation reaction two hydrides are from si-
lanes and the other two are from water. This methodolgy
has been successfully applied to the asymmetric synthesis of
some alkaloids and chiral drugs. Further studies on using
water as the sole hydride source are in progress.
[6] For selected reviews, see: a) S.-L. You, Chem. Asian J. 2007, 2, 820;
b) C. Wang, X. Wu, J. Xiao, Chem. Asian J. 2008, 3, 1750; c) S. J.
Connon, Org. Biomol. Chem. 2007, 5, 3407.
[7] For recent examples, see: a) M. Tokunaga, J. F. Larrow, F. Kakiuchi,
E. N. Jacobsen, Science 1997, 277, 936; b) J. M. Ready, E. N. Jacob-
sen, J. Am. Chem. Soc. 2001, 123, 2687; c) G. J. ten Brink, I. W. C. E.
Arends, R. A. Sheldon, Science 2000, 287, 1636; d) S. Narayan, J.
Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb, K. B. Sharpless,
Angew. Chem. 2005, 117, 3339; Angew. Chem. Int. Ed. 2005, 44,
3275; e) Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushi-
ma, M. Shoji, Angew. Chem. 2006, 118, 972; Angew. Chem. Int. Ed.
2006, 45, 958.
[8] For recent examples of the asymmetric hydrogenation of quinolines,
see: a) M. Rueping, T. Theissmann, S. Raja, J. W. P. Bats, Adv.
Synth. Catal. 2008, 350, 1001; b) H.-F. Zhou, Z.-W. Li, Z.-J. Wang,
T.-L. Wang, L.-J. Xu, Y.-M. He, Q.-H. Fan, J. Pan, L.-Q. Gu, A. S. C.
Chan, Angew. Chem. 2008, 120, 8592; Angew. Chem. Int. Ed. 2008,
47, 8464; c) D.-W. Wang, X.-B. Wang, D.-S. Wang, S.-M. Lu, Y.-G.
Zhou, J. Org. Chem. 2009, 74, 2780; d) Q.-S. Guo, D.-M. Du, J. Xu,
Angew. Chem. 2008, 120, 771; Angew. Chem. Int. Ed. 2008, 47, 759;
e) M. Rueping, A. P. Antonchick, T. Theissmann, Angew. Chem.
2006, 118, 3765; Angew. Chem. Int. Ed. 2006, 45, 3683; f) S.-M. Lu,
Y.-Q. Wang, X.-W. Han, Y.-G. Zhou, Angew. Chem. 2006, 118, 2318;
Angew. Chem. Int. Ed. 2006, 45, 2260; g) W.-B. Wang, S.-M. Lu, P.-
Y. Yang, X.-W. Han, Y.-G. Zhou, J. Am. Chem. Soc. 2003, 125,
10536; h) X.-B. Wang, Y.-G. Zhou, J. Org. Chem. 2008, 73, 5640;
Experimental Section
Typical procedure for asymmetric hydrosilylation of quinolines: A mix-
ture of [IrACHTUNGTRENNUNG(COD)Cl]2 (1.7 mg, 0.0025 mmol) and (S)-SegPhos (3.4 mg,
0.0055 mmol) in THF (1 mL) was stirred at room temperature for 10 min
in a Schlenk tube, then I2 (6.4 mg, 0.025 mmol) was added and stirred for
another 10 min. The substrate (0.25 mmol) and Et3SiH (174 mg,
1.50 mmol) were added, followed by THF (2 mL) with H2O (9 mg,
0.50 mmol). The resulting mixture was allowed to stir at RT for 24–72 h
and monitored by TLC analysis. The reaction mixture was purified by
using a silica-gel column and was eluted with ethyl acetate/petroleum
ether to give the pure product. The enantiomeric excesses were deter-
mined by chiral HPLC analysis.
Chem. Eur. J. 2010, 16, 1133 – 1136
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1135

Y.-G. Zhou et al.
i) Z.-W. Li, T.-L. Wang, Y.-M. He, Z.-J. Wang, Q.-H. Fan, J. Pan, L.-
J. Xu, Org. Lett. 2008, 10, 5265; j) S.-M. Lu, C. Bolm, Adv. Synth.
Catal. 2008, 350, 1101; k) M. T. Reetz, X.-G. Li, Chem. Commun.
2006, 2159; l) Z.-J. Wang, G.-J. Deng, Y. Li, Y.-M. He, W.-J. Tang,
Q.-H. Fan, Org. Lett. 2007, 9, 1243; m) W.-J. Tang, S.-F. Zhu, L.-J.
Xu, Q.-L. Zhou, Q.-H. Fan, H.-F. Zhou, K. Lam, A. S. C. Chan,
Chem. Commun. 2007, 613; n) L. J. Xu, K. H. Lam, J. X. Ji, Q.-H.
Fan, W.-H. Lo, A. S. C. Chan, Chem. Commun. 2005, 1390; o) C.
Wang, C. Q. Li, X. F. Wu, A. Pettman, J. L. Xiao, Angew. Chem.
2009, 121, 6646; Angew. Chem. Int. Ed. 2009, 48, 6524; p) H. Tadao-
ka, D. Cartigny, T. Nagano, T. Gosavi, T. Ayad, J.-P. Genet, T. Oh-
shima, V. Ratovelomanana-Vidal, K. Mashima, Chem. Eur. J. 2009,
15, 9990; q) Z.-J. Wang, H.-F. Zhou, T.-L. Wang, Y.-M. He, Q.-H.
Fan, Green Chem. 2009, 11, 767.
Charette, J. Am. Chem. Soc. 2005, 127, 8966; c) R. Kuwano, K. Sato,
T. Kurokawa, D. Karube, Y. Ito, J. Am. Chem. Soc. 2000, 122, 7614;
d) P. Feiertag, M. Albert, U. Nettekoven, F. Spindler, Org. Lett.
2006, 8, 4133; e) R. Kuwano, M. Kashiwabara, Org. Lett. 2006, 8,
2653; f) R. Kuwano, K. Kaneda, T. Ito, K. Sato, T. Kurokawa, Y. Ito,
Org. Lett. 2004, 6, 2213; g) M. Rueping, A. P. Antonchick, Angew.
Chem. 2007, 119, 4646; Angew. Chem. Int. Ed. 2007, 46, 4562.
[10] J. Bꢂlint, G. Egri, E. Fogassy, Z. Bçcskei, K. Simon, A. Gajꢂry, A.
Friesz, Tetrahedron: Asymmetry 1999, 10, 1079.
[11] a) I. Jacquemond-Collet, S. Hannedouche, N. Fabre, I. Fourastꢃ, C.
Moulis, Phytochemistry 1999, 51, 1167; b) J. H. Rakotoson, N. Fabre,
I. Jacquemond-Collet, S. Hannedouche, N. Fabre, I. Fourastꢃ, C.
Moulis, Planta Med. 1998, 64, 762; c) P. J. Houghton, T. Z. Wolde-
mariam, Y. Watanabe, M. Yates, Planta Med. 1999, 65, 250.
[9] For selected examples of asymmetric hydrogenation of other aro-
matic compounds, see: a) R. Kuwano, M. Kashiwabara, M. Ohsumi,
H. Kusano, J. Am. Chem. Soc. 2007, 129, 808; b) C. Y. Legault, A. B.
Received: October 29, 2009
Published online: December 9, 2009
1136
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 1133 – 1136