Unprecedented halide dependence on catalytic asymmetric hydrogenation of 2-aryl- and 2-alkyl-substituted quinolinium salts by using ir complexes with difluorphos and halide ligands

Article abstract of DOI:10.1002/chem.200901477

The first highly enantioselective hydrogenation of 2-arylquinolinium salts by using cationic dinuclear iridium (III) halide complexes with difluorphos and some atropisomeric chiral diphosphine ligands as catalyst precursors has been reported. Asymmetric h

Full text of DOI:10.1002/chem.200901477

DOI: 10.1002/chem.200901477
Unprecedented Halide Dependence on Catalytic Asymmetric Hydrogenation
of 2-Aryl- and 2-Alkyl-Substituted Quinolinium Salts by Using Ir Complexes
with Difluorphos and Halide Ligands
Hiroshi Tadaoka,[a] Damien Cartigny,[b] Takuto Nagano,[a] Tushar Gosavi,[b]
Tahar Ayad,[b] Jean-Pierre GenÞt,[b] Takashi Ohshima,*[a]
Virginie Ratovelomanana-Vidal,*[b] and Kazushi Mashima*[a]
Asymmetric hydrogenation by using chiral transition-
metal complexes represents one of the cleanest and most
environmentally benign processes available for producing
optically pure organic compounds.[1] Currently, a wide varie-
ty of chiral compounds with outstanding levels of enantiose-
lectivity has been synthesized by reduction of C=C,[1] C=
O,[2,3] C=N,[4–6] and, more recently, heteroaromatics com-
pounds.[7–18] Among heteroaromatics, 2-substituted quino-
lines have been targeted[9–18] because optically active 2-sub-
stituted-1,2,3,4-tetrahydroquinoline derivatives are key com-
ponents of many bioactive natural products and drugs.[19] In
contrast with the successful asymmetric hydrogenation of 2-
alkyl-substituted quinolines catalyzed by chiral iridium com-
plexes with an iodide source or iodine,[9–13] which dramatical-
ly enhances both catalytic activity and enantioselectivity,[5,9a]
only limited success has been achieved in the catalytic hy-
drogenation of 2-aryl-substituted quinolines. So far, the only
known examples used 2-phenylquinoline as a unique model
substrate. The first example of catalytic hydrogenation of 2-
phenylquinoline (72% ee (enantiomeric excess)), described
MeO-biphep/I2 (cod=1,5-cyclooctadiene; MeO-biphep=
6,6’-dimethoxy-2,2’-bis(diphenylphosphino)-1,1’-biphenyl)
catalytic system that was recently improved to 80% ee with
a moderate yield of 41% by using benzyl chloroformate as
an activating agent, although this required an additional de-
protection step on the resulting carbamate.[18] In recent
years, only a few examples of the catalytic hydrogenation of
2-phenylquinoline have been reported with ee values up to
88%.[14] We describe herein a highly enantioselective hydro-
genation of the HX salts (X=Cl, Br, and I) of various 2-
aryl-substituted quinolines by using cationic dinuclear iridi-
um complexes[6,17] with [(4,4’-bi-2,2-difluoro-1,3-benzodiox-
ole)-5,5’-diyl]bis(diphenylphosphine) (difluorphos),[20] which
demonstrates an unexpected halide effect in which iridium
complexes with chloro and bromo ligands serve as better
catalysts than an iodo–iridium complex. The present catalyst
was also effective for the hydrogenation of 2-alkyl-substitut-
ed quinolinium salts, which shows the high versatility of this
new catalyst system. Furthermore, this system was applied
to a formal asymmetric synthesis of selective estrogen recep-
tor modulator (SERM) 6-hydroxy-2-(4-hydroxyphenyl)-1-{4-
[2-(pyrrolidin-1-yl)ethoxy]-benzyl}-1,2,3,4-tetrahydroquino-
line (1)[21] by asymmetric hydrogenation of the HCl salt of
6-methoxy-2-(4-methoxyphenyl)quinoline (2·Cl) as a key
step.
by Zhou and co-workers,[9a] is based on an [Ir
ACTHNUTRGNEG(NU cod)Cl]2/
[a] H. Tadaoka, T. Nagano, Prof. Dr. T. Ohshima, Prof. Dr. K. Mashima
Department of Chemistry
Graduate School of Engineering Science, Osaka University
Toyonaka, Osaka 560-8631 (Japan)
Fax : (+81)6-6850-6245
E-mail: ohshima@chem.es.osaka-u.ac.jp
mashima@chem.es.osaka-u.ac.jp
We recently developed cationic dinuclear triply halogen-
bridged iridium complexes [{Ir[(S)-diphosphine](H)}2ACHTUNGTRENNUNG(m-
X)3]X (3–8; X=Cl, Br, and I) (Figure 1), which were con-
veniently prepared by adding excess aqueous HX to a mix-
ture of [{IrClACTHNUTRGNE(UNG coe)2}2] (coe=cyclooctene) and the required
[b] D. Cartigny, Dr. T. Gosavi, Dr. T. Ayad, Prof. Dr. J.-P. GenÞt,
Dr. V. Ratovelomanana-Vidal
Laboratoire Charles Friedel, UMR CNRS 7223
Ecole Nationale Supꢀrieure de Chimie de Paris
11 rue P. et M. Curie 75231 Paris cedex 05 (France)
Fax : (+33)144-071-062
chiral diphosphine ligand in toluene at room tempera-
ture.[6,22] Thus, we first examined the asymmetric hydrogena-
tion of 2-phenylquinolinium salts 9·X (X=Cl, Br, and I)
promoted by Ir–binap complex (S)-3·X. Each reaction was
conducted at 308C under hydrogen (30 bar) with 2 mol% of
Ir complex in THF followed by a basic workup (Table 1, en-
E-mail: virginie-vidal@enscp.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901477.
9990
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9990 – 9994

COMMUNICATION
ising 72% ee (Table 1, entry 1). A comparable result was ob-
tained when catalyst (S)-3·Br was used in combination with
HBr salt 9·Br (Table 1, entry 2; 95% conv., 71% ee), where-
as catalyst (S)-3·I showed poor catalytic activity in terms of
both conversion and selectivity with HI salt 9·I (Table 1,
entry 3; 76% conv., 14% ee). This surprising halogen de-
pendence is in striking contrast to the previously reported
finding that iodo–iridium complexes have superior catalytic
activity and enantioselectivity for the asymmetric hydroge-
nation of imines[5] and 2-alkylquinolines.[8a] At this stage, we
focused our attention on the effect of the solvent and the
ligand. Screening of toluene, dichloroACHTNUTRGNEUNGmethane, dioxane,
methanol, and a dioxane/methanol mixture as the hydroge-
nation solvent for the reaction of 9·Cl with (S)-3·Cl indicat-
ed that the dioxane/methanol (9:1) mixture provided the
best enantioselectivity and catalytic activity (Table 1,
entry 8; >95% conv., 73% ee), whereas the catalytic activi-
ties and enantioselectivities conducted in dioxane (Table 1,
entry 6; 67% conv., 68% ee) and methanol (Table 1,
entry 7; 44% conv., 39% ee) were not as good. Despite the
fact that reactions in THF and toluene produced (R)-10 in
the same enantioselectivity, we chose the dioxane/methanol
(9:1) mixture to increase the solubility of 9·Cl. For the chiral
ligand, chloro dinuclear iridium complexes (S)-4–8 (X=Cl)
with different chiral diphosphine ligands were tested as cata-
lysts for the hydrogenation of 9·Cl (Table 1, entries 9–13).
Among them, chloro complex (S)-8·Cl with the (S)-difluor-
phos ligand was the best in terms of enantioselectivity, pro-
ducing 2-phenyl-1,2,3,4-tetrahydroquinoline (R)-10 in 91%
ee with 38% conversion (Table 1, entry 13). Pleasingly, we
found that the corresponding bromo complex, (S)-8·Br, had
better catalytic activity and the same enantioselectivity for
HBr salt 9·Br (Table 1, entry 14; >95% conv., 91% ee).
Consistent with the results of binap catalysts, the asymmet-
ric hydrogenation of HI salt 9·I by using iodo complex (S)-
8·I resulted in a lower conversion and enantioselectivity
(Table 1, entry 15; 46% conv., 71% ee). Moreover, bromo
complex (S)-8·Br catalyzed the reaction of HCl salt 9·Cl
(Table 1, entry 16) with the same catalytic activity and enan-
tioselectivity as that of (S)-8·Br for 9·Br (Table 1, entry 14).
Interestingly, the opposite combination, chloro complex (S)-
8·Cl and HBr salt 9·Br (Table 1, entry 17) gave comparable
results in terms of conversion to those obtained with (S)-
8·Cl and HCl salt 9·Cl (Table 1, entry 13). These results sug-
gests that original halogen ligand X of iridium complex 9·X
remains in a catalytically active IrIII·X complex and almost
no halogen ligand exchange takes place even in the presence
of excess amounts of a different halogen anion, which
makes it possible to use less expensive and more readily ac-
cessible HCl salts as the substrate even for the reaction of
(S)-8·Br. In contrast to the asymmetric hydrogenation of
quinolinium salts, the asymmetric hydrogenation of 2-phe-
nylquinoline by using the difluorphos catalysts (S)-8·X (X=
Cl, Br, and I) gave (R)-10 with lower enantioselectivities
(83, 82, and 70% ee, respectively),[23] which indicates that
the formation of quinolinium salts prior to the reduction of
quinoline derivatives has synthetic merit in that it increases
Figure 1. Cationic dinuclear IrIII complexes [{Ir[(S)-diphosphine](H)}
2ACTHNUTRGENUG(N m-
X)3]X (3–8) and chiral diphosphine ligands used as catalysts for asymmet-
ric hydrogenation; binap=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl,
segphos=[(4,4’-bi-1,3-benzodioxole)-5,5’-diyl]bis(diphenylphosphine)
synphos=[2,2’,3,3’-tetrahydro(5,5’-bi-1,4-benzodioxin)-6,6’-diyl]bis(diphe-
nylphosphine).
Table 1. Optimization of the hydrogenation conditions with 2-phenylqui-
nolinium salts 9·X.[a]
Entry
Catalyst
X
Solvent
Conv.[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
(S)-3·Cl
(S)-3·Br
(S)-3·I
Cl
Br
I
THF
THF
THF
toluene
CH2Cl2
dioxane
MeOH
>95
95
76
66
64
67
44
>95
43
62
>95
52
38
>95
46
>95
30
72
71
14
72
69
68
39
73
68
78
79
24
91
91
71
91
84
(S)-3·Cl
(S)-3·Cl
(S)-3·Cl
(S)-3·Cl
(S)-3·Cl
(S)-4·Cl
(S)-5·Cl
(S)-6·Cl
(S)-7·Cl
(S)-8·Cl
(S)-8·Br
(S)-8·I
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
I
dioxane/MeOH[d]
dioxane/MeOH[d]
dioxane/MeOH[d]
dioxane/MeOH[d]
dioxane/MeOH[d]
dioxane/MeOH[d]
dioxane/MeOH[d]
dioxane/MeOH[d]
dioxane/MeOH[d]
dioxane/MeOH[d]
9
10
11
12
13
14
15
16
17
(S)-8·Br
(S)-8·Cl
Cl
Br
[a] Reaction conditions: quinolinium salt (0.22 mmol), Ir complex
(4.4 mmol), H2 (30 bar), solvent (3 mL) at 308C for 16 h. [b] Conversion
of 9·X was determined by 1H NMR analysis. [c] The ee of 10 was deter-
mined by HPLC analysis. The absolute configuration of 10 was (R).[23]
[d] The ratio of dioxane and MeOH was 9:1 (v/v).
tries 1–3). This preliminary catalyst screening demonstrated
that hydrogenation of HCl salt 9·Cl catalyzed by (S)-3·Cl
gave compound (R)-10 in excellent conversion with a prom-
Chem. Eur. J. 2009, 15, 9990 – 9994
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9991

T. Ohshima, K. Mashima, V. Ratovelomanana-Vidal et al.
enantioselectivity. DFT calculations with the B3LYP hybrid
density functional theory of Ir–diphosphine complexes re-
vealed dihedral angles (q) of Ir–difluorphos (69.18)<Ir–seg-
phos (71.18)<Ir–synphos (72.68)<Ir–binap (73.68).[23] As
previously observed in ruthenium-promoted asymmetric hy-
drogenation by our group[20] and others,[24] ligands with nar-
rower dihedral angles tend to provide higher enantioselec-
tivities because the narrower q should cause a higher
ligand–substrate interaction and provide a better chiral dis-
crimination of the catalyst.
With the optimized reaction conditions and Ir–difluorphos
complexes (S)-8·Cl and (S)-8·Br in hand, a range of 2-aryl-
quinolinium salts was reduced to the corresponding tetrahy-
droquinolines in high chemical yield and good-to-excellent
enantiomeric excess. The HCl and/or HBr salts of various
para-, meta-, and ortho-substituted phenyl derivatives of qui-
nolinium salts 11–18 were used as substrates, and represen-
tative results are given in Table 2.[23] para-Substituted quino-
linium salts 11–14 were consistently hydrogenated to give
the corresponding tetrahydroquinolines (R)-19–22 with 95–
88% ee. In a similar way, the hydrogenation of meta-substi-
tuted derivatives 15 and 16 gave (R)-23 (90% ee) and (R)-
24 (82% ee), respectively. ortho-Substituted derivatives (R)-
17 and (R)-18 resulted in lower enantioselectivities (Table 2,
entries 7 and 8) compared with the corresponding meta- and
para-substituted derivatives. Bulkiness due to the ortho-Me
and ortho-OMe substituents reduced their enantioselectivi-
ties. This experimental evidence for a nonchelating mecha-
nism, as opposed to chelation of the substrates to the metal
center in most of the successful asymmetric hydrogenations
or hydrogen-transfer reactions of the functionalized ketones
and related substrates,[2a,f,g,3,24,25] suggests that coordinatively
unsaturated species with the empirical formula of Ir(chelate
diphosphine)(H)X2, derived from the dinuclear complexes,
are pentacoordinated and the iminium moiety of the sub-
strates coordinates in a h2 fashion to the vacant site, as ob-
served for the iridium–binap–P–N system that catalyzed a
highly enantioselective asymmetric hydrogenation of simple
ketones.[26] To our delight, the present catalyst system was
also highly effective for the reaction of 2-alkyl-substituted
quinolinium salts 27–29 (Table 2, entries 9–11). The reaction
of the HBr salt of 2-methylquinoline, 27·Br, proceeded with
higher enantioselectivity (Table 2, entry 9, 94% ee) than our
original
conditions
(2-methylquinoline,
[Ir{(S)-
difluorophos}(H)AHCTUNGTRENNUNG
(O2CMe)]/HBr, 90% ee),[17] which again
shows advantage of using the quinolinium salt. Substrates
with ethyl (Table 2, entry 10) and isopropyl (Table 2,
entry 11) substituents were also hydrogenated with the same
efficiency to (S)-31 and (R)-32 with ee values up to 95%.
These results prompted us to reduce substrate 2·Cl using
Ir-difluorphos (S)-8·Br as a key step for synthesizing optical-
ly active 1 (Scheme 1).[21] The catalytic hydrogenation of the
Table 2. Asymmetric hydrogenation of 2-arylquinolinium salts 11–18 and
2-alkylquinolinium salts 27-29 catalyzed by Ir-difluorphos complexes (S)-
8·Cl or (S)-8·Br.[a]
Entry
Substrate
Catalyst
Product[b]
ee[c] [%],
abs. config.
1
2
3
4
5
6
7
8
11·Br
12·Cl
13·Cl
14·Cl
15·Cl
16·Cl
17·Cl
18·Br
27·Br
28·Cl
29·Cl
(S)-8·Br
(S)-8·Cl
(S)-8·Cl
(S)-8·Cl
(S)-8·Cl
(S)-8·Cl
(S)-8·Cl
(S)-8·Br
(S)-8·Br
(S)-8·Cl
(S)-8·Cl
19[d]
20
21
22
23
95, (R)
90, (R)
89, (R)
88, (R)
90, (R)
82, (R)
62, (R)
86, (R)
94, (S)
93, (S)
95, (R)
Scheme 1. Formal asymmetric synthesis of bioactive compound 1. Re-
agents and conditions: a) (S)-8·Br (2 mol%), dioxane/MeOH (7:3 v/v),
408C, H2 (30 bar), 30 h, then basic workup; b) 1-(benzyloxy)-4-(chlorome-
thyl)benzene, BuLi, THF, À788C, 18 h.
24
25
26
9
10
11
30[d]
31[d]
32[d]
HCl salt 2·Cl and following basic workup gave 6-methoxy-2-
(4-methoxyphenyl)-1,2,3,4-tetrahydroquinolinium salt (R)-33
(>95% conv., 84% ee). Alkylation of the nitrogen atom by
the reaction of BuLi and 1-(benzyloxy)-4-(chloromethyl)-
benzene in THF gave (R)-34 without loss of enantiomeric
purity (90% yield, 84% ee). The synthetic route from (R)-
34 to (R)-1 was reported by Wallace et al.[21] Thus, the
[a] Reaction conditions: substrate (0.22 mmol), Ir complex (4.4 mmol), H2
(30 bar), 1,4-dioxane/MeOH (3 mL; 9:1 v/v) at 308C for 16 h. [b] Conver-
sions of substrates 12–18 were determined by 1H NMR analysis (over
95%). [c] The ee values of the products were determined by HPLC anal-
ysis.[23] [d] Conversions of 11·Br, 27·Br, 28·Br, and 29·Br were 65, 81, 81,
and 84%, respectively.
9992
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9990 – 9994

2-Aryl- and 2-Alkyl-Substituted Quinolinium Salts
COMMUNICATION
Noyori, H. Takaya, Acc. Chem. Res. 1990, 23, 345–350; e) R.
Noyori, T. Ohkuma, Angew. Chem. 2001, 113, 40–75; Angew. Chem.
Int. Ed. 2001, 40, 40–73; f) R. Noyori, Angew. Chem. 2002, 114,
2108–2123; Angew. Chem. Int. Ed. 2002, 41, 2008–2022; g) J.-P.
Genet, Acc. Chem. Res. 2003, 36, 908–918.
formal asymmetric synthesis of bioactive compound (R)-1
was accomplished.
In conclusion, we have developed the first highly enantio-
selective hydrogenation of 2-arylquinolinium salts by using
cationic dinuclear iridiumACHTNUTRGNE(UNG III) halide complexes with di-
[2] a) R. Noyori, T. Ohkuma, M. Kitamura, H. Takaya, N. Sayo, H. Ku-
mobayashi, S. Akutagawa, J. Am. Chem. Soc. 1987, 109, 5856–5858;
b) T. Ohkuma, H. Ooka, S. Hashiguchi, T. Ikariya, R. Noyori, J.
Am. Chem. Soc. 1995, 117, 2675–2676; c) H. Doucet, T. Ohkuma,
K. Murata, T. Yokozawa, M. Kozawa, E. Katayama, A. F. England,
T. Ikariya, R. Noyori, Angew. Chem. 1998, 110, 1792–1796; Angew.
Chem. Int. Ed. 1998, 37, 1703–1707; d) K. Makino, T. Goto, Y.
Hiroki, Y. Hamada, Angew. Chem. 2004, 116, 900–902; Angew.
Chem. Int. Ed. 2004, 43, 882–884; e) T. Ohkuma, C. A. Sandoval, R.
Srinivasan, Q. Lin, Y. Wei, K. Muniz, R. Noyori, J. Am. Chem. Soc.
2005, 127, 8288–8289; f) T. Ohkuma, K. Tsutsumi, N. Utsumi, N.
Arai, R. Noyori, K. Murata, Org. Lett. 2007, 9, 255–257; g) T.
Ohkuma, N. Utsumi, M. Watanabe, K. Tsutsumi, N. Arai, K.
Murata, Org. Lett. 2007, 9, 2565–2567.
[3] a) V. Ratovelomanana-Vidal, J.-P. Genet, Can. J. Chem. 2000, 78,
846–851; b) J.-P. Genet, Pure Appl. Chem. 2002, 74, 77–83; c) C.
Mordant, P. Dꢂnkelmann, V. Ratovelomanana-Vidal, J.-P. Genet,
Chem. Commun. 2004, 1296–1297; d) C. Mordant, S. Reymond, H.
Tone, D. Lavergne, R. Touati, B. Ben Hassine, V. Ratovelomanana-
Vidal, J.-P. Genet, Tetrahedron 2007, 63, 6115–6123.
fluorphos and some atropisomeric chiral diphosphine li-
gands as catalyst precursors. The resulting ee values of up to
95% are much better than those of the reduction of the cor-
responding 2-arylquinolines.[23,27] Moreover, this new catalyst
system also successfully converted 2-alkylquinolinium salts
to the corresponding tetrahydroquinolines with excellent
enantioselectivities (up to 95% ee). A notable feature of
this catalysis is the unexpected superiority of chloro– and
bromo–iridium catalysts over the corresponding iodo–iridi-
um catalyst, which is opposite to the halide effect. As an ap-
plication of our new catalyst system, we demonstrated an ef-
ficient access to the optically active 6-hydroxy-2-(4-hydroxy-
phenyl)-1-(4-(2-(pyrrolidin-1-yl)ethoxy)-benzyl)-1,2,3,4-tet-
rahydroquinoline (1).
[4] a) A. Trifonova, J. S. Diesen, C. J. Chapman, P. G. Andersson, Org.
Lett. 2004, 6, 3825–3827; b) C. Moessner, C. Bolm, Angew. Chem.
2005, 117, 7736–7739; Angew. Chem. Int. Ed. 2005, 44, 7564–7567;
c) Q. Yang, G. Shang, W. Gao, J. Deng, X. Zhang, Angew. Chem.
2006, 118, 3916–3919; Angew. Chem. Int. Ed. 2006, 45, 3832–3835;
d) C. Li, J. Xiao, J. Am. Chem. Soc. 2008, 130, 13208–13209; e) S.
Shirai, H. Nara, Y. Kayaki, T. Ikariya, Organometallics 2009, 28,
802–809.
[5] For the effects of iodide sources or iodine on Ir-catalyzed hydroge-
nation of imines, see: a) F. Spindler, B. Pugin, H.-U. Blaser, Angew.
Chem. 1990, 102, 561–562; Angew. Chem. Int. Ed. Engl. 1990, 29,
558–559; b) F. Spindler, B. Pugin, H.-P. Jalett, H.-P. Buser, U. Pittel-
kow, H.-U. Blaser, Chem. Ind. 1996, 68, 153–166; c) K. Satoh, M. In-
enaga, K. Kanai, Tetrahedron: Asymmetry 1998, 9, 2657; d) H.-U.
Blaser, H.-P. Buser, K. Coers, R. Hanreich, H.-P. Jalett, E. Jelsch, B.
Pugin, H.-D. Schneider, F. Spindler, A. Wegmann, Chimia 1999, 53,
275–280; e) D. Xiao, X. Zhang, Angew. Chem. 2001, 113, 3533–
3536; Angew. Chem. Int. Ed. 2001, 40, 3425–3428; f) R. Dorta, D.
Broggini, R Stoop, H. Ruegger, F. Spindler, A. Togni, Chem. Eur. J.
2004, 10, 267–278.
Experimental Section
General procedure for the Ir-catalyzed asymmetric hydrogenation of 2-
arylquinolinium salts: 2-phenylquinolinium HBr salt 9·Br (63.4 mg,
0.22 mmol) and Ir–difluorphos complex (S)-8·Br (9.2 mg, 4.4 mmol,
2 mol%) were placed in a glass tube and 1,4-dioxane/MeOH (9:1 v/v,
3 mL) was added under argon. The reaction mixture was then stirred
under 30 bar of H2 at 308C for 16 h. After removal of H2 and treatment
with aqueous NaOH (2m), the reaction mixture was extracted with ether
and the organic layer was concentrated. The conversions were deter-
mined by 1H NMR spectroscopic analysis of the crude product. The en-
antiomeric excesses of the products were determined by HPLC analysis
of the crude product (Chiralcel OD-H, eluent: hexane/iPrOH (90:10),
detector: 254 nm, flow rate: 1 mLminÀ1, (S)-(À) tR =9.5 min, (R)-(+) tR =
11.0 min). The crude product was purified by using silica gel column
chromatography with hexane/EtOAc (9:1) as the eluent to quantitatively
give (R)-2-phenyl-1,2,3,4-tetrahydroquinoline (R)-10 (91% ee) as a color-
less oil.
[6] T. Yamagata, H. Tadaoka, M. Nagata, T. Hirao, Y. Kataoka, V. Ra-
tovelomanana-Vidal, J.-P. GenÞt, K. Mashima, Organometallics
2006, 25, 2505–2513.
[7] For recent reviews on hydrogenation of heteroaromatic compounds,
see a) F. Glorius, Org. Biomol. Chem. 2005, 3, 4171–4175; b) R.
Kuwano, Heterocycles 2008, 76, 909–922.
Acknowledgements
This work was financially supported by the JSPS-CNRS joint program
(2007 and 2008). H.T. thanks the Global COE program “Global Educa-
tion and Research Center for Bio-Environmental Chemistry” of Osaka
University.
[8] For recent examples of asymmetric hydrogenation of heteroaromatic
compounds other than quinolines, see a) R. Kuwano, K. Sato, T.
Kurokawa, D. Karube, Y. Ito, J. Am. Chem. Soc. 2000, 122, 7614–
7615; b) C. Y. Legault, A. B. Charette, J. Am. Chem. Soc. 2005, 127,
8966–8967; c) S. Kaiser, S. P. Smidt, A. Pfaltz, Angew. Chem. 2006,
118, 5318–5321; Angew. Chem. Int. Ed. 2006, 45, 5194–5197; d) M.
Rueping, A. P. Antonchick, Angew. Chem. 2007, 119, 4646–4649;
Angew. Chem. Int. Ed. 2007, 46, 4562–4565; e) R. Kuwano, M. Ka-
shiwabara, M. Ohsumi, H. Kusano, J. Am. Chem. Soc. 2008, 130,
808–809.
Keywords: asymmetric synthesis
hydrogenation · iridium · quinolines
·
enantioselectivity
·
[9] a) W.-B. Wang, S.-M. Lu, P.-Y. Yang, X.-W. Han, Y.-G. Zhou, J. Am.
Chem. Soc. 2003, 125, 10536–10537; b) S.-M. Lu, X.-W. Han, Y.-G.
Zhou, Adv. Synth. Catal. 2004, 346, 909–912; c) Y.-G. Zhou, Acc.
Chem. Res. 2007, 40, 1357–1366; d) X.-B. Wang, Y.-G. Zhou, J. Org.
Chem. 2008, 73, 5640–5642; e) X.-B. Wang, W. Zeng, Y.-G. Zhou,
Tetrahedron Lett. 2008, 49, 4922–4924; f) D.-W. Wang, X.-B. Wang,
D.-S. Wang, S.-M. Lu, Y.-G. Zhou, Y.-X. Li, J. Org. Chem. 2009, 74,
2780–2787.
[1] For comprehensive reviews on asymmetric catalysis, see: a) R.
Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley, New
York, 1994, Chapter 2, pp. 16–94; b) J. M. Brown, R. L. Halterman,
T. Ohkuma, R. Noyori, H.-U. Blaser, F. Spindler in Comprehensive
Asymmetric Catalysis, Vol. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Ya-
mamoto), Springer, Berlin, 1999, pp. 122–266; c) T. Ohkuma, M. Ki-
tamura, R. Noyori in Catalytic Asymmetric Synthesis, 2nd ed. (Ed.:
I. Ojima), Wiley-VCH, Weinheim, 2000, Chapter 1, pp. 1–110; d) R.
Chem. Eur. J. 2009, 15, 9990 – 9994
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9993

T. Ohshima, K. Mashima, V. Ratovelomanana-Vidal et al.
[10] a) L. Xu, K. H. Lam, J. Ji, J. Wu, Q.-H. Fan, W.-H. Lo, A. S. C.
Chan, Chem. Commun. 2005, 1390–1392; b) K. H. Lam, L. Xu, L.
Feng, Q.-H. Fan, F. L. Lam, W. Lo, A. S. C. Chan, Adv. Synth. Catal.
2005, 347, 1755–1758; c) 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, 613–615; d) S. H. Chan, K. H. Lam, Y.-M. Li, L. Xu, W. Tang,
F. L. Lam, W. H. Lo, W. Y. Yu, Q. Fan, A. S. C. Chan, Tetrahedron:
Asymmetry 2007, 18, 2625–2631; e) H. Zhou, Z. Li, Z. Wang, T.
Wang, L. Xu, Y. He, Q.-H. Fan, J. Pan, L. Gu, A. S. C. Chan, Angew.
Chem. 2008, 120, 8592–8595; Angew. Chem. Int. Ed. 2008, 47, 8464–
8467.
[11] M. T. Reetz, X. Li, Chem. Commun. 2006, 2159–2160.
[12] M. Jahjah, M. Alame, S. Pellet-Rostaing, M. Lemaire, Tetrahedron:
Asymmetry 2007, 18, 2305–2312.
[13] Z.-J. Wang, G.-J. Deng, Y. Li, Y.-M. He, W.-J. Tang, Q.-H. Fan, Org.
Lett. 2007, 9, 1243–1246.
[14] N. Mrsic, L. Lefort, J. A. F. Boogers, A. J. Minnaard, B. L. Feringa,
J. G. de Vriesa, Adv. Synth. Catal. 2008, 350, 1081–1089.
[15] S.-M. Lua, C. Bolm, Adv. Synth. Catal. 2008, 350, 1101–1105.
[16] Z.-W. Li, T.-L. Wang, Y.-M. He, Z.-J. Wang, Q.-H. Fan, J. Pan, L.-J.
Xu, Org. Lett. 2008, 10, 5265–5268.
[17] C. Deport, M. Buchotte, K. Abecassis, H. Tadaoka, T. Ayad, T. Oh-
shima, J.-P. GenÞt, K. Mashima, V. Ratovelomanana-Vidal, Synlett
2007, 2743–2747.
[18] S.-M. Lu, Y.-Q. Wang, X.-W. Han, Y.-G. Zhou, Angew. Chem. 2006,
118, 2318–2321; Angew. Chem. Int. Ed. 2006, 45, 2260–2263.
[19] a) P. D. Leeson, R. W. Carling, K. W. Moore, A M. Moseley, J D.
Smith, G. Stevenson, T. Chan, R. Baker, A. C. Foster, Med. Chem.
1992, 35, 1954–1968; b) Y. Yoneda, T. Suzuki, K. Ogita, D. Han, J.
Neurochem. 1993, 60, 634–645; c) P. P. Mager, Drug Des. Discovery
1994, 11, 185–196; d) P. Y. Yang, Y. G. Zhou, Tetrahedron: Asymme-
try 2004, 15, 1145–1149.
[20] a) S. Jeulin, S. Duprat de Paule, V. Ratovelomanana-Vidal, J.-P.
GenÞt, N. Champion, Angew. Chem. 2004, 116, 324–329; Angew.
Chem. Int. Ed. 2004, 43, 320–325; b) S. Jeulin, S. Duprat de Paule,
V. Ratovelomanana-Vidal, J.-P. GenÞt, N. Champion, Proc. Natl.
Acad. Sci. USA 2004, 101, 5799–5804.
[21] The biological activity of a racemic form of 1 as a SERM have been
examined, see:O. B. Wallace, K. S. Lauwers, S. A. Jones, J. A.
Dodge, Bioorg. Med. Chem. Lett. 2003, 13, 1907–1910.
[22] Preparation of dinuclear iridium complexes according to ref. [6]: A
mixture of [IrClACTHNUTRGNE(UNG coe)2]2 (50 mmol) and chiral diphosphine ligand
(2.05 equiv) in CH2Cl2 (5 mL) was stirred for 3 h at RT. Upon addi-
tion of HX (10 equiv; X=Cl, Br, or I), the color of the solution im-
mediately turned yellow. After stirring for an additional 30 min, all
volatiles were removed under reduced pressure. The residue was
washed three times with hexane to remove excess diphosphine
ligand and cyclooctene. The obtained air-stable pale yellow complex
was used for the hydrogenation without further purification.
[23] See the Supporting Information for details.
[24] a) X. Zhang, K. Mashima, K. Koyano, N. Sayo, H. Kumobayashi, S.
Akutagawa, H. Takaya, J. Chem. Soc. Perkin Trans. 1 1994, 2309–
2322; b) T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T.
Miura, H. Kumobayashi, Adv. Synth. Catal. 2001, 343, 264–267; c) S.
Subongkoj, S. Lange, W. Chen, J. Xiao, J. Mol. Catal. A 2003, 196,
125–129.
[25] For references regarding the asymmetric transfer hydrogenation of
ketones, see: a) R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30,
97–102; b) T. Ikariya, A. J. Blacker, Acc. Chem. Res. 2007, 40,
1300–1308; c) M. Kitamura, M. Yoshimura, N. Kanda, R. Noyori,
Tetrahedron 1999, 55, 8769–8785; d) R. Noyori, M. Kitamura, T.
Ohkuma, Proc. Natl. Acad. Sci. USA 2004, 101, 5356–5362.
[26] X. Zhang, T. Taketomi, T. Yoshizumi, H. Kumobayashi, S. Akutaga-
wa, K. Mashima, H. Takaya, J. Am. Chem. Soc. 1993, 115, 3318–
3319.
[27] During the review process of our manuscript, W. Leitner et al. re-
ported the asymmetric hydrogenation of 2-phenylquinoline using a
phosphine–phosphoramidite with ee up to 95% and 72% conversion,
see M. Eggenstein, A. Thomas, J. Theuerkauf, G. Franciꢃ, W. Leit-
ner, Adv. Synth. Catal. 2009, 351, 725–732.
Received: June 2, 2009
Published online: August 26, 2009
9994
www.chemeurj.org
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 9990 – 9994