Highly enantioselective iridium-Catalyzed hydrogenation of 2-Benzylquinolines and 2-Functionalized and 2,3-disubstituted quinolines

Article abstract of DOI:10.1021/jo900073z

The enantioselective hydrogenation of 2-benzylquinolines and 2-functionalized and 2,3-disubstituted quinohnes was developed by using the [Ir(COD)Cl]₂/bisphosphine/I₂ system with up to 96% ee. Moreover, mechanistic studies revealed the hydrogenation mechanism of quinoline involves a 1,4-hydride addition, isomerization, and 1,2-hydride addition, and the catalytic active species may be a Ir(III) complex with chloride and iodide.

Full text of DOI:10.1021/jo900073z

Highly Enantioselective Iridium-Catalyzed Hydrogenation of
2-Benzylquinolines and 2-Functionalized and 2,3-Disubstituted
Quinolines
Da-Wei Wang,† Xiao-Bing Wang,† Duo-Sheng Wang,† Sheng-Mei Lu,†
Yong-Gui Zhou,*,†,‡ and Yu-Xue Li*,‡
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
457 Zhongshan Road, Dalian 116023, China, and State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
ygzhou@dicp.ac.cn; liyuxue@mail.sioc.ac.cn
ReceiVed January 14, 2009
The enantioselective hydrogenation of 2-benzylquinolines and 2-functionalized and 2,3-disubstituted
quinolines was developed by using the [Ir(COD)Cl]2/bisphosphine/I2 system with up to 96% ee. Moreover,
mechanistic studies revealed the hydrogenation mechanism of quinoline involves a 1,4-hydride addition,
isomerization, and 1,2-hydride addition, and the catalytic active species may be a Ir(III) complex with
chloride and iodide.
Introduction
tion of quinoline derivatives using [Ir(COD)Cl]2/MeO-
BiPhep/I2 as catalyst with high enantioselectivity,7 and this
methodology has been successfully applied to the synthesis
of some tetrahydroquinoline alkaloids.8
Asymmetric hydrogenation of aromatic and heteroaromatic
compounds is a very useful reaction as it provides a
convenient access to numerous saturated or partially saturated
chiral cyclic compounds, whose synthesis by direct cycliza-
tion is often difficult.1 In the past decades, some successful
examples for the hydrogenation of heteroaromatic compounds
were achieved. Quinoxaline,2 pyridine,3 indole,4 pyrrole,5 and
furan6 have been hydrogenated with over 90% ee. Very
recently, we developed Ir-catalyzed asymmetric hydrogena-
(3) (a) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.; Lehmann, C. W.
Angew. Chem., Int. Ed. 2004, 43, 2850–2852. (b) Legault, C. Y.; Charette, A. B.
J. Am. Chem. Soc. 2005, 127, 8966–8967. (c) Lei, A.-W.; Chen, M; He, M.-S.;
Zhang, X.-M. Eur. J. Org. Chem. 2006, 434, 3–4347. (d) Studer, M.; Wedemeyer-
Exl, C.; Spindler, F.; Blaser, H.-U. Monatsh. Chem. 2000, 131, 1335–1343. (e)
Blaser, H.-U.; Hornig, H.; Studer, M.; Wedemeyer-Exl, C. J. Mol. Catal. A:
Chem. 1999, 139, 253–257. (f) Raynor, S. A.; Thomas, J. M.; Raja, R.; Johnson,
B. F. G.; Bell, R. G.; Mantle, M. D. Chem. Commun. 2000, 1925–1926. (g)
Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2007, 46, 4562–4565.
(h) Wang, X.-B.; Zeng, W.; Zhou, Y.-G. Tetrahedron Lett. 2008, 49, 4922–
4924. (i) Legault, C. Y.; Charette, A. B.; Cozzi, P. G. Hetereocycles 2008, 76,
1271–1283.
† State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences.
‡ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences.
(1) For some reviews and books on hydrogenation of aromatic compounds,
see: (a) Rylander, P. N. Catalytic Hydrogenation in Organic Synthesis; Academic
Press: New York, 1979; p 175. (b) Lu, S.-M.; Han, X,-W.; Zhou, Y.-G. Chin.
J. Org. Chem. 2005, 25, 634–640. (c) Glorius, F. Org. Biomol. Chem. 2005, 3,
4171–4175. (d) Dyson, P. J. Dalton Trans. 2003, 2964–2974. (e) de Vries, J. G.;
Elsevier, C. J., Eds. The Handbook of Homogeneous Hydrogenation; Wiley-
VCH: Weiheim, Germany, 2007. (f) Zhou, Y.-G. Acc. Chem. Res. 2007, 40,
1357–1366. (g) Kuwano, R. Hetereocycles 2008, 76, 909–922.
(2) (a) Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani, M.
Organometallics 1998, 17, 3308–3310. (b) Henschke, J. P.; Burk, M. J.; Malan,
C. G.; Herzberg, D.; Peterson, J. A.; Wildsmith, A. J.; Cobley, C. J.; Casy, G.
AdV. Synth. Catal. 2003, 345, 300–307.
(4) (a) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem.
Soc. 2000, 122, 7614–7615. (b) Kuwano, R.; Kaneda, K.; Ito, T.; Sato, K.;
Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6, 2213–2215. (c) Kuwano, R.;
Kashiwabara, M. Org. Lett. 2006, 8, 2653–2655. (d) Kuwano, R.; Kashiwabara,
M.; Sato, K.; Ito, T.; Kaneda, K.; Ito, Y. Tetrahedron: Asymmetry 2006, 17,
521–535.
(5) Kuwano, R.; Kashiwabara, M.; Ohsumi, M.; Kusano, H. J. Am. Chem.
Soc. 2007, 129, 808–809.
(6) (a) Ohta, T.; Miyake, T.; Seido, N.; Kumobayashi, H.; Takaya, H. J.
Org. Chem. 1995, 60, 357–363. (b) Kaiser, S.; Smidt, S. P.; Pfaltz, A. Angew.
Chem., Int. Ed. 2006, 45, 5194–5197. (c) Feiertag, P.; Albert, M.; Nettekoven,
U.; Spindler, F. Org. Lett. 2006, 8, 4133–4135.
2780 J. Org. Chem. 2009, 74, 2780–2787
10.1021/jo900073z CCC: $40.75 2009 American Chemical Society
Published on Web 03/09/2009

EnantioselectiVe Hydrogenation of Quinolines
SCHEME 1. The Synthesis of 2-Benzylquinolines
After we reported our initial work on iridium-catalyzed
asymmetric hydrogenation of quinolines, several other groups
communicated their results in this area.9-15 Fan, Xu, and Chan
reported an air-stable catalyst system Ir/P-Phos/I2 for the
asymmetric hydrogenation of quinoline derivatives with 92%
ee.9a Similar results were subsequently described by their group
with chiral ligands based on H8-BINAPO and 1,1′-spirobiindane
backbone.9 Reetz found that chiral BINOL-derived diphospho-
nites further linked to an achiral diphenyl ether unit were also
effective for the asymmetric hydrogenation of quinolines.10 In
2006, Chan showed the usefulness of PQ-Phos as a chiral ligand
in this hydrogenation reaction.11 Fan and co-workers developed
enantioselective hydrogenation of quinolines by Ir(BINAP)-
cored dendrimers with dramatic enhancement of catalytic
activity, and the TON was up to 43 000.12a Later, the same group
reported ruthenium- and iridium-catalyzed asymmetric hydro-
genation of quinolines with up to 99% ee.12b,c Rueping
developed BINOL-derived chiral phosphoric acid-catalyzed
asymmetric transfer hydrogenation of 2-substituted and 3-sub-
stituted quinolines with up to 99% ee and 86% ee, respectively.13
Du explored double axially chiral phosphoric acid-catalyzed
asymmetric transfer hydrogenation of 2-substituted and 2,3-
disubstituted quinolines using Hantzsch esters as the hydrogen
source.14 Despite all the aforementioned excellent examples,
the substrate scope mainly focused on 2-alkyl, 2-aryl-substituted,
and 3-substituted quinoline derivatives. Highly enantioselective
hydrogenation of other quinoline substrates elaborately remains
a challenging task, particularly with 2-benzylquinolines and
2-functionalized and 2,3-disubstituted quinolines, since the
hydrogenation products are important organic synthetic inter-
mediates and structural units of alkaloids and biologically active
compounds. In this article, we present highly enantioselective
Ir-catalyzed asymmetric hydrogenation of 2-benzylquinolines
and 2-functionalized and 2,3-disubstituted quinolines with up
to 96% ee. Moreover, mechanistic studies revealed the hydro-
genation mechanism of quinolines involves a 1,4-hydride
addition, isomerization, and 1,2-hydride addition, and the
catalytic active species may be an Ir(III) complex with chloride
and iodide.
Results and Discussion
Asymmetric hydrogenation of 2-benzylquinolines is the most
convenient route to 2-benzyltetrahydroquinolin derivatives, but
no effective synthetic method of 2-benzylquinolines is provided.
In 2007, Oshima and co-workers reported a potent method for
the synthesis of 2-benzylpyridine derivatives from 2-(2-py-
ridyl)ethanol derivatives and aryl halides by Pd-catalyzed
chelation-assisted cleavage of unstrained Csp3-Csp3 bonds.16
To our delight, 2-benzylquinolines could also be conveniently
prepared according to the above procedure. Treatment of aryl
halides in the presence of cesium carbonate and a palladium
catalyst in refluxing xylene or toluene provided 2-benzylquino-
lines with moderate to good yields (Scheme 1).
The hydrogenation of these 2-benzyl-substituted quinolines
was studied after their synthesis. In our initial study, 2-ben-
zylquinoline was chosen as the model substrate for reaction
optimization. On the basis of our previous results,7 we first
examined the effect of solvents on the reactivity and enanti-
oselectivity using [Ir(COD)Cl]2/(S)-MeO-Biphep/I2 as the cata-
lyst. As shown in Table 1, the reaction was strongly solvent-
dependent. Low reactivity and moderate enantioselectivity were
obtained in CH2Cl2. Excellent reactivity and the highest enan-
tioselectivity were obtained in toluene (Table 1, entry 4).
Subsequently, some commercially available chiral bidentate
phosphine ligands were also tested (Table 1, entries 4-8), and
(S)-MeO-BiPhep gave the best results with 94% ee (Table 1,
entry 4). It should be noted that the hydrogenation could not
take place in the absence of iodine.
(7) (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am.
Chem. Soc. 2003, 125, 10536–10537. (b) Lu, S.-M.; Han, X.-W.; Zhou, Y.-G.
AdV. Synth. Catal. 2004, 346, 909–912. (c) Lu, S.-M.; Wang, Y.-Q.; Han, X.-
W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006, 45, 2260–2263. (d) Zhao, Y.-J.;
Wang, Y.-Q.; Zhou, Y.-G. Chin. J. Catal. 2005, 26, 737–739. (e) Wang, D.-W.;
Zeng, W.; Zhou, Y.-G. Tetrahedron: Asymmetry 2007, 18, 1103–1107. (f) Lu,
S.-M.; Han, X.-W.; Zhou, Y.-G. J. Organomet. Chem. 2007, 692, 3065–3069.
(g) Wang, X.-B.; Zhou, Y.-G. J. Org. Chem. 2008, 73, 5640–5642. (h) Wang,
D.-W.; Lu, S.-M.; Zhou, Y.-G Tetrahedron Lett. 2009, 50, 1282-1285. For the
personnel account, see the ref 1f.
(8) Yang, P.-Y.; Zhou, Y.-G. Tetrahedron: Asymmetry 2004, 15, 1145–1149.
(9) (a) Xu, L. J.; Lam, K. H.; Ji, J. X.; Fan, Q.-H.; Lo, W.-H.; Chan, A. S. C.
Chem. Commun. 2005, 1390–1392. (b) Lam, K. H.; Xu, L. J.; Feng, L. C.; Fan,
Q.-H.; Lam, F. L.; Lo, W.-H.; Chan, A. S. C. AdV. Synth. Catal. 2005, 347,
1755–1758. (c) Wu, J.; Chan, A. S. C. Acc. Chem. Res. 2006, 39, 711–720. (d)
Tang, W.-J.; Zhu, S.-F.; Xu, L.-J.; Zhou, Q.-L.; Fan, Q.-H.; Zhou, H.-F.; Lam,
K.; Chan, A. S. C. Chem. Commun. 2007, 613–615. (e) Chan, S.-H.; Lam, K.-
H.; Li, Y.-M.; Xu, L.-J.; Tang, W.-J.; Lam, F.-L.; Lo, W.-H.; Yu, W.-Y.; Fan,
Q.-H.; Chan, A. S. C. Tetrahedron: Asymmetry 2007, 18, 2625–2631.
(10) Reetz, M. T.; Li, X.-G. Chem. Commun. 2006, 2159–2160.
(11) Qiu, L.; Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan, S.; Yu, W.-Y.; Li,
Y.-M.; Guo, R.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2006, 128, 5955–
5965.
(12) (a) Wang, Z.-J.; Deng, G.-J.; Li, Y.; He, Y.-M.; Tang, W.-J.; Fan, Q.-
H. Org. Lett. 2007, 9, 1243–1246. (b) Li, Z.-W.; Wang, T.-L.; He, Y.-M.; Wang,
Z.-J.; Fan, Q.-H.; Pan, J.; Xu, L.-J. Org. Lett. 2008, 10, 5265–5268. (c) Zhou,
H.-F.; Li, Z.-W.; Wang, Z.-J.; Wang, T.-L.; Xu, L.-J.; He, Y.-M.; Fan, Q.-H.;
Pan, J.; Gu, L.-Q.; Chan, A. S. C. Angew. Chem., Int. Ed. 2008, 47, 8464–8467.
(13) (a) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem.,
Int. Ed. 2006, 45, 3683–3686. (b) Rueping, M.; Theissmann, T.; Antonchick,
A. P. Synlett 2006, 1071–1074. (c) Rueping, M.; Theissmann, T.; Raja, S.; Bats,
J. W. P. AdV. Synth. Catal. 2008, 350, 1001–1006.
Having established the optimal conditions, we explored the
scope of the Ir-catalyzed asymmetric hydrogenation of 2-benzyl-
substituted quinolines, and the results were summarized in Table
2. The reactions were carried out in toluene at room temperature
under 700 psi of hydrogen. In general, all the quinolines were
hydrogenated completely to give the corresponding 1,2,3,4-
tetrahydroquinolines. Excellent enantioselectivities and high
yields were obtained regardless of the electronic properties and
steric hindrance of substituent groups (Table 2, entries 1-9).
2-Benzyl-6-fluoroquinoline (3g) gave the highest enantioselec-
(14) Guo, Q.-S.; Du, D.-M.; Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759–
762.
(15) (a) Lu, S.-M.; Bolm, C. AdV. Synth. Catal. 2008, 350, 1101–1105. (b)
Mrsic, N.; Lefort, L.; Boogers, J. A. F.; Minnaard, A. J.; Feringa, B. L.; Vries,
J. G. AdV. Synth. Catal. 2008, 350, 1081–1089. (c) Yamagata, T.; Tadaoka, H.;
Nagata, M.; Hirao, T.; Kataoka, Y.; Ratovelomanana-Vidal, V.; Genet, J. P.;
Mashima, K. Organometallics 2006, 25, 2505–2513. (d) Jahjah, M.; Alame, M.;
Pellet-Rostaing, S.; Lemaire, M. Tetrahedron: Asymmetry 2007, 18, 2305–2312.
(e) Deport, C.; Buchotte, M.; Abecassis, K.; Tadaoka, H.; Ayad, T.; Ohshima,
T.; Genet, J.-P.; Mashima, K.; Ratovelomanana-Vidal, V. Synlett 2007, 2743–
2747. (f) Fache, F. Synlett 2004, 2827–2829. (g) Fujita, K.-I.; Kitatsuji, C.;
Furukawa, K.; Yamaguchi, R. Tetrahedron Lett. 2004, 45, 3215–3217. (h) You,
S.-L. Asian J. Chem. 2007, 2, 820–827.
(16) Niwa, T.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2007, 46,
2643–2645.
J. Org. Chem. Vol. 74, No. 7, 2009 2781

Wang et al.
TABLE 1. Ir-Catalyzed Asymmetric Hydrogenation of
2-Benzylquinolinea
TABLE 3. Ir-Catalyzed Hydrogenation of 2-Functionalized
Quinolinesa
entry
R1/R2
yieldb
eec (config)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
H/COPh
H/COMe
H/CO(n-Pr)
91 (6a)
93 (6b)
91 (6c)
84 (6d)
78 (6e)
89 (6f)
97 (6g)
97 (6h)
90 (6i)
89 (6j)
90 (6k)
82 (6l)
92 (6m)
95 (6n)
80 (6o)
88 (6p)
93 (6q)
98 (6r)
97 (6s)
90 (6t)
65 (6u)
96 (R)
90 (R)
84 (R)
83 (R)
95 (R)
95 (R)
96 (R)
95 (R)
95 (R)
95 (R)
87 (R)
94 (R)
96 (R)
94 (R)
95 (S)
82 (R)
92 (R)
80 (R)
90 (R)
94 (S)
89 (S)
H/CO(p-MeOPh)
H/CO(o-MeOPh)
H/CO(p-MePh)
H/CO(o-MePh)
H/CO(p-iPrPh)
H/CO(p-CF3Ph)
H/CO(1-naphthyl)
H/CO(CH2)2Ph
Me/COPh
F/COPh
H/CO(3,4-(MeO)2Ph)
H/p-MeOPhCH)CH
H/COOMe
H/COOEt
H/CONEt2
H/SO2Ph
H/(CH2)3OTBS
H/(CH2)4OTBS
e
a Conditions: 0.25 mmol of quinoline, [Ir(COD)Cl]2 (1 mol %), ligand
(2.2 mol %), I2 (10 mol%),
3
mL of benzene. b Based on 5.
c Determined by HPLC. d Determined by comparison of rotation sign
with the literature data or by analogue. e The double bond was also
hydrogenated.
Supporting Information). Under the optimized reaction condi-
tionssIr(COD)Cl]2/(S)-MeO-Biphep/I2, benzene as solvent, 800
psi of H2sa variety of 2-functionalized quinoline derivatives
could be successfully hydrogenated to afford their corresponding
derivatives (6). As illustrated in Table 3, full conversions were
achieved with all the functionalized quinolines. For the quinoline
substrates bearing alkyl ketones, the ee values were slightly
affected by the electronic properties and steric hindrance of
substituents, such as methyl ketone and propyl ketone, 90% ee
and 84% ee were obtained, respectively (Table 3, entries 2 and
3). With arylketone-substituted quinolines, the ee values of all
the products were excellent regardless of the electronic proper-
ties and steric hindrance (Table 3, entries 1, 4-10, and 12-14).
In the case of 2-vinyl-substituted quinoline, both the double bond
and the pyridine ring of quinoline can be hydrogenated with
95% ee (Table 3, entry 15). Interestingly, the system could
tolerate the esters, amide, and benzenesulfonyl groups and all
these substrates were transformed to the corresponding tetrahy-
droquinoline derivatives with 80-92% ee values (Table 3,
entries 16-19). It is noted that substrates with hydroxyl by TBS
protected could also be hydrogenated smoothly with high
enantioselectivities (Table 3, entries 20-21), which could be
converted to the key intermediate of the alkaloid of gephyrotoxin
conveniently by two steps with high yields (Scheme 2).17
Mechanism Study. The Function of Iodine. In the past
decades, the additives have been elegantly used by chemists in
asymmetric catalysis. The addition of suitable achiral additives,
which could support the chiral catalyst system and enhance the
yield, especially, in some cases also enhance the enantioselec-
tivity efficiently and the success of this strategy can be
a Conditions: 0.25 mmol of quinoline, [Ir(COD)Cl]2 (1 mol %), ligand
(2.2 mol %), I2 (10 mol%),
3
mL of solvent. b Based on 3a.
d
c Determined by HPLC. Determined by H NMR analysis.
1
TABLE 2. Ir-Catalyzed Asymmetric Hydrogenation of
2-Benzylquinolinesa
d
entry
R/Ar
H/C6H5
H/2-MeC6H4
H/1-C10H7
H/2-CF3C6H4
H/4-CF3C6H4
H/4-FC6H4
F/C6H5
yield (%)b
ee (%)c
config
1
2
3
4
5
6
7
8
9
95 (4a)
88 (4b)
93 (4c)
92 (4d)
89 (4e)
93 (4f)
97 (4g)
93 (4h)
93 (4i)
94
95
95
88
93
94
96
95
94
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
Me/C6H5
H/3,4-(MeO)2C6H3
a Conditions: 0.25 mmol of quinoline, [Ir(COD)Cl]2 (1 mol %), ligand
(2.2 mol %), I2 (10 mol%), 3 mL of toluene. b Based on 3. c Determined
by HPLC. d Determined by comparison of rotation sign with the
literature data or by analogue.
tivity with 96% ee (Table 2, entry 7). A slightly lower enantio-
selectivity (88% ee) was obtained when the aryl substituent was
2-trifluoromethylphenyl (Table 2, entry 4).
Asymmetric Hydrogenation of 2-Functionalized Quino-
lines. Next, we challenged the hydrogenation of 2-functionalized
quinolines, which were prepared from their corresponding
2-methylquinolines according to the known procedures (see the
(17) Pearson, W. H.; Fang, W. J. Org. Chem. 2000, 65, 7158–7174.
2782 J. Org. Chem. Vol. 74, No. 7, 2009

EnantioselectiVe Hydrogenation of Quinolines
TABLE 4. Effect of Additives on Activity and Enantioselectivity
SCHEME 2. The Synthesis of the Key Intermediate of
Gephyrotoxin
recognized by a comparison of the results obtained with and
without the additives.18 Recently, molecular iodine and iodides
were also found to be effective additives in asymmetric
hydrogenation.19 In 1990, an interesting additive effect was
observed by the Osborn group, when investigating the iridium-
catalyzed asymmetric hydrogenation of imines using KI as
additive.19a Later, Togni also showed the usefulness of this
strategy to asymmetric hydrogenation of MEA-imine in the
Syngenta Metolachlor process using iodine as additive.19b Xumu
Zhang and co-workers reported the iridium-catalyzed asym-
metric hydrogenation of arylimines also using I2 as an
additive.19d They suggested that the active catalyst was the Ir(III)
hydrido chloro iodo species generated by oxidative addition of
I2 to the Ir(I) precursor in the presence of hydrogen with
hydrogen iodide elimination, but no strong evidence was
provided. This strategy was also applied to the Ir-catalyzed
enantioselective reductive amination of aryl ketones by the same
group.19e Bolm studied the iridium-catalyzed asymmetric hy-
drogenation of imines in the presence of iodine.19f Charette and
Legault developed an efficient iodine-activated hydrogenation
of N-iminopyridinium ylides.3b Zhou’s group introduced rhodium-
catalyzed asymmetric hydrogenation of enamines using mono-
dente spiro phosphonite ligands in the presence of iodine.19g
Zhang and co-workers explored ruthenium-catalyzed asymmetric
hydrogenation of sulfonyl ketones with excellent reactivity and
enantioselectivity also in the presence of iodine, and mechanism
study revealed that in situ generated anhydrous hydrogen iodide
might be the operating additive.19h Dorta, Togni, and co-workers
explored the mechanism of Ir-catalyzed asymmetric hydrogena-
tion of MEA-imine in the Syngenta Metolachlor process in the
presence of iodine, and successfully isolated the adduct of
iridium with iodine and catalyst-substrate adduct;19i the adduct
of iridium complex with iodine, which was formed by oxidative
addition of iodine, was structurally characterized by single-
a Conditions: 1 mmol of quinoline, [Ir(COD)Cl]2 (0.5 mol %), ligand
(1.1 mol %), additive (10 mol%), 3 mL of toluene. b Determined by 1H
NMR analysis. c Determined by HPLC. d NBS: N-bromosuccinimide.
NIS: N-iodosuccininide.
crystal X-ray diffraction as iodo-bridged dinuclear species and
tested as a single catalyst precursor for the asymmetric
hydrogenation. Their mechanism study indicated that both
chloride and iodide are crucial for the activity and enantiose-
lectivity.
Recently, we developed Ir-catalyzed asymmetric hydrogena-
tion of quinolines with excellent enantioselectivities using I2 as
an additive.7 The hydrogenation reaction cannot take place in
the absence of iodine. In our initial studies, besides iodine, we
also tested the impact of other additives such as NBS, TCIA,
IBr, n-Bu4NBH4, MeI, etc. Full conversion and good enanti-
oselectivities were obtained with TCIA, IBr, ICl, BCDMH, and
DCDMH as the additives (Table 4). Almost full conversion and
good enantioselectivities were obtained with NBS, NIS, and
DBDMH. Interestingly, MeI could also give 40% of conversion
with moderate enantioselectivity (Table 4, entry 12). The best
result was obtained by using iodine as the additive.
In the above results, it appeared that the additive was
necessary for the asymmetric hydrogenation of quinolines. Two
kinds of functions of iodine were suggested: one is the substrate
activation by formation of a complex of iodine and quinolinesthe
iridium catalyst can hydrogenate the complex of iodine and
quinoline; the other is catalyst activationsa new and highly
active catalyst is formed by the oxidative addition. To dif-
ferentiate the two activation strategies, 2-methylquinoline was
allowed to react with iodine in toluene for 24 h according to
the known literature.20 A yellow complex was obtained and
subjected to asymmetric hydrogenation with use of [Ir(COD)Cl]2/
(S)-MeO-Biphep as catalyst in the absence of iodine; surpris-
(18) (a) Cornils, B.; Hermann, W. A., Eds. In Applied Homogeneous Catalysis
with Organometallic Compounds; VCH: Weinheim, Germany, 1996; Vol. 2, pp
74 and-351. For reviews see: (b) Vogl, E. M.; Groger, H.; Shibasaki, M. Angew.
Chem., Int. Ed. 1999, 38, 1570–1577. (c) Berrisford, D. J.; Bolm, C.; Sharpless,
K. B. Angew. Chem., Int. Ed. 1995, 34, 1059–1070. (d) Fagnou, K.; Lautens,
M. Angew. Chem., Int. Ed. 2002, 41, 26–47. (e) Maitlis, P. M.; Haynes, A.;
James, B. R.; Catellani, M.; Chiusoli, G. P. Dalton Trans. 2004, 3409–3419. (f)
Wang, C.-Y.; Xi, Z.-F Chem. Soc. ReV. 2007, 36, 1395–1406. See also: (g) Jiang,
Q.-Z.; Jiang, Y.-T.; Xiao, D.-M.; Cao, P.; Zhang, X.-M. Angew. Chem., Int. Ed.
1998, 37, 1100–1103. (h) Buriak, J. M.; Klein, J. C.; Herrington, D. G.; Osborn,
J. A. Chem. Eur. J. 2000, 6, 139–150.
(19) (a) Chan, Y. N. C.; Osborn, J. A. J. Am. Chem. Soc. 1990, 112, 9400–
9401. (b) Togni, A. Angew. Chem., Int. Ed. 1996, 35, 1475–1477. (c) Spindler,
F.; Blaser, H.-U. Enantiomer 1999, 4, 557–568. (d) Xiao, D.-M.; Zhang, X.-M.
Angew. Chem., Int. Ed. 2001, 40, 3425–3428. (e) Chi, Y.-X.; Zhou, Y.-G.; Zhang,
X.-M. J. Org. Chem. 2003, 68, 4120–4122. (f) Moessner, C.; Bolm, C. Angew.
Chem., Int. Ed. 2005, 44, 7564–7567. (g) Hou, G.-H.; Xie, J.-H.; Wang, L.-X.;
Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 11774–11775. (h) Wan, X.-B.; Meng,
Q.-H.; Zhang, H.-W.; Sun, Y.-H.; Fan, W.-Z.; Zhang, Z.-G. Org. Lett. 2007, 9,
5613–5616. (i) Dorta, R.; Broggini, D.; Stoop, R.; Ruegger, H.; Spindler, F.;
Togni, A. Chem. Eur. J. 2004, 10, 267–278.
J. Org. Chem. Vol. 74, No. 7, 2009 2783

Wang et al.
SCHEME 3. The Possible Hydrogenation Pathway of
ingly, no product was detected (eq 1), which suggested that the
substrate activation may not be possible.
Quinolines
Next, the function of catalyst activation was investigated:
iodine was added to a mixture of the complex [Ir(COD)Cl]2/
(S)-SegPhos, which was obtained in CH2Cl2 by stirring for 30
min at room temperature, and then stirred for 12 h. After the
solvent was removed under reduced pressure, a brown solid Cat
A was afforded (eq 2). However, Cat A was a very complex
mixture according to the 31P NMR spectrum due to the
coexistence of chloride and iodide. It is very exciting that the
desired product with 93% ee was achieved for the hydrogenation
of 2-methylquinoline by using the brown solid Cat A as a
catalyst. To obtain relatively pure catalyst, chloride should
be exchanged for iodide. So, the complex [Ir(COD)Cl]2/
(S)-SegPhos was treated with 1 equiv of KI in acetone to afford
[Ir(COD)(SegPhos)I], then the complex was treated with an
equimolar amount of iodine in toluene and a new species Cat
B was formed according to Dorta’s method (eq 3).19i Surpris-
ingly, this dinuclear Ir precatalyst Cat B gave 88% conversion
and 81% enantioselectivity, which is lower than Cat A in
reactivity and enantioselectivity. It is shown that chloride and
iodide are crucial for the reactivity and enantioselectivity. The
above experimental results and the work of Osborn and Dorta
reveal that the iodine activates the catalyst in the hydrogenation
of quinolines.
SCHEME 4. The Synthesis and Hydrogenation of
Intermediate Enamine 10
SCHEME 5. Computed Thermodynamic Values for
Hydride Addition of 2-Methylquinoline
(S)-MeO-Biphep/I2 as catalyst in the absence of hydrogen in 5
min (eq 4). Unfortunately, this experiment could not solve the
above problem. Next, we sought the synthesis of the intermedi-
ate of 1,4-hydride addition.
The Hydrogenation Process Study. By analysis of the
iridium-catalyzed hydrogenation sequence of CdC and CdN
bonds of quinolines, we envisioned that there might be two
possible pathways for the hydrogenation of quinoline derivatives
(Scheme 3). The first pathway is 1,2-hydride addition, then 3,4-
hydride addition; the second one is 1,4-hydride addition,
isomerization, and then 1,2-hydride addition.
To demonstrate which pathway is possible, the synthesis of
reaction intermediate is very important and sometimes could
provide direct proof to support the mechanism. The intermediate
of 1,2-hydride addition can be synthesized conveniently by the
reaction of quinoline with methyl lithium. However, the
intermediate is easy to dehydrogenate to form the aromatic
2-methylquinoline at room temperature by using [Ir(COD)Cl]2/
The intermediates of 1,4-hydride addition are somewhat not
stable at room temperature,21 and difficult to separate. To obtain
the stable intermediate of this reaction, compound 5a bearing a
functional group was chosen as the starting material (Scheme
4). To our pleasure, when 5a was treated by using Pd/C with
hydrogen in MeOH, the steady intermediate 10 was achieved
after isomerization from the intermediate 9. Subsequently, the
hydrogenation of enamine 10 was carried out, and the desired
product was obtained with 96% ee, which was the same
enantioselectivity as direct hydrogenation of compound 5a. We
can also detect the existence of intermediate 10 in the direct
hydrogenation of compound 5a with a low pressure of hydrogen
and in a shorter reaction time. The above experiments demon-
(20) (a) Boraei, A. A.-A. A.; Alla, E. M. A.; Mahmoud, M. R. Bull. Chem.
Soc. Jpn. 1994, 67, 603–606. (b) Reid, C.; Mulliken, R. S. J. Am. Chem. Soc.
1954, 76, 3869–3874. (c) Krishna, V. G.; Bhowmik, B. B. J. Am. Chem. Soc.
1968, 90, 1700–1705.
(21) (a) Coates, R. M.; Johnson, E. F. J. Am. Chem. Soc. 1971, 93, 4016–
4027. (b) Bubting, J. W.; Meathrel, W. G. Tetrahedron Lett. 1971, 12, 133–
136. (c) Birch, J.; Lehman, P. G. J. Chem. Soc., Perkin Trans. 1 1973, 2754–
2759.
2784 J. Org. Chem. Vol. 74, No. 7, 2009

EnantioselectiVe Hydrogenation of Quinolines
SCHEME 6. The Proposed Possible Mechanism for Ir-Catalyzed Asymmetric Hydrogenation of Quinolines
strated the second pathway might be possible and reasonable.
To further understand hydrogenation sequence of CdC and
CdN bonds of quinolines, a computational study was performed
to rationalize the experimental observations. 2-Methylquinoline
was selected as the model substrate and the reaction sequence
was examined. Thermodynamic values for hydride addition to
2-methylquinoline were calculated at the DFT/B3LYP level by
using the 6-311++G(d,p) basis set. As shown in Scheme 5,
the computational result suggested that the first step, 1,4-hydride
addition, was more favorable than 1,2-hydride addition.22a
Therefore, the computational result offered another proof to
support the above experimental phenomena.
aromatization of 1,2,3,4-tetrahydroquinolines, and hydrogen gas
was released. The dehydrogenation reaction was carried out in
xylene at reflux temperature for 48 h and the desired product
was obtained with 92% yield (eq 5), which provides a potential
catalytic system for reversible hydrogenation and dehydroge-
nation reactions of nitrogen heterocycles22 toward recyclable
hydrogen storage.23
By analysis of the above hydrogenation phenomena of
quinolines and the suggestions of the groups Zhang19d and
Rueping,13c we envisioned that the catalytic process with I2 as
an additive might be a cascade reaction involving a 1,4-hydride
addition, isomerization, and 1,2-hydride addition (Scheme 6).
We proposed that the oxidative addition of I2 to Ir(I) to generate
the Ir(III) species is also possible in iridium-catalyzed asym-
metric hydrogenation of quinolines in the presence of iodine,
and the active catalytic species might be the Ir(III) hydrido
chloro iodo complex. Therefore, a plausible mechanism was
proposed as follows: The oxidative addition of I2 to the Ir(I)
species precursor A generates the Ir(III) species, and subsequent
heterolytic cleavage of H2 can occur to form the Ir(III)-H species
B with hydrogen iodide elimination. The quinoline substrate
could coordinate with Ir(III) species B (the I and Cl were omited
for clearness), and then 1,4-hydride transfer affords the inter-
mediate D. Subsequently the heterolytic cleavage of H2 with
the intermediate D gives an enamine F and regenerates the
Ir(III)-H species B. The enamine F isomerizes to yield imine
G, which might be catalyzed by the generated HI acting as a
strong Brønsted acid, which was also explained by Rueping.13c
Imine intermediate G could coordinate with Ir(III)-H species B
to form the intermediate H, followed by insertion and σ-bond
metathesis to release the product 1,2,3,4-tetrahydroquinolines
P to complete the catalytic cycle.
Asymmetric Hydrogenation of 2,3-Disubstituted Quino-
lines. Considering that iridium has been successfully applied
to asymmetric hydrogenation of 2-substituted quinolines. Then
we examined the [Ir(COD)Cl]2/MeO-BiPhep/toluene/I2 system
for the hydrogenation of 2,3-dimethylquinoline. Unfortunately,
it was found that almost racemic product was obtained when
the reaction was carried out in toluene at room temperature under
700 psi of hydrogen for 12 h.
On the basis of the above mechanism and observations, we
thought that the hydrogenation mechanism of 2,3-disubstituted
quinolines was somewhat different from that of 2-substituted
quinolines (Scheme 7). For the hydrogenation of 2-substituted
quinoline, the hydrogenation of the CdN bond is the enantio-
selectivity-controlled step (Scheme 6, H to I), while the
enantioselectivity-controlled step of 2,3-disubstituted quinolines
is the isomerization of enamine to imine and the hydrogenation
of the CdN bond, which is in fact a dynamic kinetic resolution
process. To obtain high enantioselectivity, it should meet the
(22) For some examples for dehydrogenation of nitrogen heterocycles, see:
(a) Moores, A.; Poyatos, M.; Luo, Y.; Crabtree, R. H. New J. Chem. 2006, 30,
1675–1678. (b) Pez, G. P.; Scott, A. R.; Cooper, A. C.; Cheng, H. EP Pat. Appl.
2004, 1475349. (c) Schwarz, D. E.; Cameron, T. M.; Hay, P. J.; Scott, B. L.;
Tumas, W.; Thorn, D. L. Chem. Commun. 2005, 5919–5921. (d) Cui, Y.; Kwok,
S.; Bucholtz, A.; Davis, B.; Whitney, R. A.; Jessop, P. G. New J. Chem. 2008,
32, 1027–1037. (e) Clot, E.; Eisenstein, O.; Crabtree, R. H. Chem. Commun.
2007, 2231–2233.
Interestingly, the hydrogenation catalyst [Ir(COD)Cl]2/bis-
phosphine/I2 was found to also catalyze the dehydrogenation
(23) For a review, see: van den Berg, A. W. C.; Area´n, C. O. Chem. Commun.
2008, 668–681, and references cited therein.
J. Org. Chem. Vol. 74, No. 7, 2009 2785

Wang et al.
TABLE 6. Iridium-Catalyzed Asymmetric Hydrogenation of
SCHEME 7. The Possible Mechanism of Ir-Catalyzed
Asymmetric Hydrogenation of 2,3-Disubstituted Quinolines
2,3-Disubstituted Quinolinesa
TABLE 5. Ir-Catalyzed Asymmetric Hydrogenation of
2,3-Dimethylquinolinea
T
P
yield syn/ ee of
entry
ligand
solvent (°C) (psi) (%)b antic sync
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(S)-MeO-BiPhep
(S)-MeO-BiPhep
(S)-MeO-BiPhep
(S)-MeO-BiPhep
(S)-MeO-BiPhep
(S)-MeO-BiPhep
(S)-MeO-BiPhep
(S)-MeO-BiPhep
(S)-MeO-BiPhep
(S)-MeO-BiPhep
(S)-SegPhos
THF
THF
THF
THF
THF
THF
toluene
25
25
25
60
60
70
70
700
200
80
80
40
40
40
40
40
40
40
40
40
40
93
83
20:1
20:1
5
21
41
66
72
73
55
50
67
40
72
70
1
88d 20:1
85
88d 20:1
95 20:1
57d 20:1
20:1
a Conditions: 0.25 mmol of quinoline, [Ir(COD)Cl]2 (1 mol %), ligand
(2.2 mol %), I2 (10 mol%), 3 mL of toluene. b Based on 7. c Determined
by HPLC. d The product was 8d.
dioxane 70
85
93
4:1
20:1
EtOAc
TBME
THF
70
70
70
70
70
70
8d 10:1
95
20:1
20:1
5:1
(S)-SynPhos
(R,R)-Me-DuPhos THF
(S)-BINAP THF
THF
93
27d
95
(73% ee). Therefore, the optimized reaction condition is the
following: [Ir(COD)Cl]2/(S)-MeO-Biphep/I2/THF/70 °C/H2 (40
psi).
20:1
60
a Conditions: 0.25 mmol of quinoline, [Ir(COD)Cl]2 (1 mol %), ligand
(2.2 mol %), I2 (10 mol %), 3 mL of solvent, 12-16 h, b Based on 7a.
c Determined by HPLC. d The convn was determined by 1H NMR
analysis.
Under the optimized condition, a variety of 2,3-disubstituted
quinoline derivatives were investigated. To our pleasure, 2-ethyl-
3-methylquinoline was hydrogenated with a higher ee (85% ee)
than 2,3-dimethylquinoline (Table 6, entry 2), which was
probably attributable to the steric effect. Several 2,3-alkyl-
disubstituted quinolines were hydrogenated smoothly to give
the corresponding 1,2,3,4-tetrahydroquinolines with full conver-
sions and in 73-86% ee (Table 6, entries 1-11). The CdC
double bond in the side chain of substrate 7f (Table 6, entry 6)
could be hydrogenated under the standard conditions. For 2,3,6-
trisubstituted quinolines, the reactions proceeded well, and
excellent reactivities with good enantioselectivities were ob-
tained (Table 6, entries 9-11). Interestingly, for the cyclic
compounds 8l and 8n, excellent reactivities and diastereose-
lectivities (up to >20:1, major in the cis isomer) were obtained
(Table 6, entries 12 and 14), which was complementary for the
trans configuration reported by Du using chiral phosphoric acid
as catalyst.14 For 2-phenyl-substituted quinoline compound 8m,
only moderate 38% ee was obtained, and the reason for this is
not clear. It is noteworthy that the successful hydrogenation of
2,3-disubstituted quinolines provides new evidence for the
hydrogenation mechanism proposed by us.
requirement that Kiso . Khy. A high temperature could accelerate
the rate of isomerization (Kiso) of (S)-G and (R)-G, and a low
pressure of hydrogen gas can decrease the rate of hydrogenation
(Khy). Therefore, the asymmetric hydrogenation reactions should
be performed in high reaction temperature and low hydrogen
pressure.
Next, the effect of pressure and temperature on reactivity and
enatioselectivity was studied. When hydrogen gas pressure
decreases from 700 to 200 psi, a higher enantioselectivity was
obtained (Table 5, 21% vs. 5% ee). When the reaction was
performed under 80 psi of hydrogen 41% ee and 88% conver-
sion were obtained. The reaction temperature has a significant
effect on the enantioselectivity: 66% ee with full conversion
was obtained when the reaction temperature was increased from
25 to 60 °C. The best combination of reaction temperature and
pressure of hydrogenation was 70 °C and 40 psi of hydrogen
pressure (Table 5, entry 6). Then, the solvent effect was studied
again; the reaction proceeded well in THF, dioxane, and ethyl
acetate, and low activity was observed in toluene and TBME.
The highest enatioselectivity was obtained in THF. Subse-
quently, some commercially available chiral bisphosphine
ligands were tested for the asymmetric hydrogenation of 2,3-
dimethylquinoline, and (S)-MeO-BiPhep gave the best result
Conclusions
In summary, we developed a highly enantioselective hydro-
genation of 2-benzylquinolines and 2-functionalized and 2,3-
disubstituted quinolines with the [Ir(COD)Cl]2/bisphosphine/I2
2786 J. Org. Chem. Vol. 74, No. 7, 2009

EnantioselectiVe Hydrogenation of Quinolines
and (S)-MeO-BiPhep (3.2 mg, 0.0055 mmol) in THF (1 mL) was
stirred at room temperature for 10 min in a glovebox, then I2 (6.4
mg, 0.025 mmol) and substrate 7a (39 mg, 0.25 mmol) together
with 2 mL THF were added and the solution was stirred for another
10 min. The hydrogenation was performed at 70 °C under H2 (40
psi) for 12-16 h. After the hydrogen was carefully released, the
reaction mixture was purified by a silica gel column eluted with
ethyl acetate/petroleum to give pure product. The enantiomeric
excesses were determined by chiral HPLC with chiral columns (OD-
H, OJ-H, AS-H, and AD-H).
system under mild reaction conditions, and up to 96% ee value
was obtained, which provides an efficient and convenient route
to synthesize tetrahydroquinolines and their derivatives. More-
over, mechanistic studies revealed the hydrogenation of quino-
lines involves a 1,4-hydride addition, isomerization, and 1,2-
hydride addition. The function of iodine is to activate the Ir(I)
to form highly active Ir(III) species. Further investigation on
the range of substrates and other heteroaromatic systems is in
progress.
cis-2,3-Dimethyl-1,2,3,4-tetrahydroquinoline (8a): colorless oil,
92% yield, 73% ee, [R]RTD -19.25 (c 0.90, CHCl3); 1H NMR (400
MHz, CDCl3) δ 0.92 (d, J ) 7.2 Hz, 3H), 1.10 (d, J ) 6.8 Hz,
3H), 2.00-2.05 (m, 1H), 2.49 (dd, J ) 16.0, 6.0 Hz, 1H), 2.90
(dd, J ) 16.4, 5.2 Hz, 1H), 3.42-3.47 (m, 1H), 3.66 (br, 1H),
6.46 (d, J ) 7.6 Hz, 1H), 6.60 (t, J ) 7.4 Hz, 1H), 6.95 (t, J ) 7.6
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 14.6, 18.3, 30.7, 34.0,
50.1, 114.0, 117.1, 120.2, 126.8, 130.0, 144.1; HPLC (OJ-H; elute:
hexanes/i-PrOH ) 95/5; detector: 254 nm; flow rate: 0.8 mL/min),
minor isomer t1 ) 12.7 min, major isomer t2 ) 16.6 min.
Typical Procedure for Hydrogenation of Exocyclic
Enamines 10. A mixture of [Ir(COD)Cl]2 (1.7 mg, 0.0025 mmol)
and (S)-MeO-BiPhep (3.2 mg, 0.0055 mmol) in benzene (1 mL)
was stirred at room temperature for 10 min in a glovebox, then I2
(6.4 mg, 0.025 mmol) and substrate 10 (62 mg, 0.25 mmol) together
with 2 mL of benzene were added and the solution was stirred for
another 10 min. The hydrogenation was performed at room
temperature under H2 (800 psi) for 12-16 h. After the hydrogen
was carefully released, the reaction mixture was purified by a silica
gel column eluted with ethyl acetate/petroleum to give pure product
6a. The enantiomeric excesses were determined by chiral HPLC
with chiral columns (OJ-H).
Experimental Section
Typical Procedure for Hydrogenation of 2-Benzylquinoline
3a. A mixture of [Ir(COD)Cl]2 (1.7 mg, 0.0025 mmol) and (S)-
MeO-BiPhep (3.2 mg, 0.0055 mmol) in toluene (1 mL) was stirred
at room temperature for 10 min in a glovebox, then I2 (6.4 mg,
0.025 mmol) and substrate 3a (55 mg, 0.25 mmol) together with 2
mL of toluene were added and the solution was stirred for another
10 min. The hydrogenation was performed at room temperature
under H2 (700 psi) for 12-16 h. After the hydrogen was carefully
released, the reaction mixture was purified with a silica gel column
eluted with ethyl acetate/petroleum to give pure product. The
enantiomeric excesses were determined by chiral HPLC with chiral
columns (OD-H, OJ-H, AS-H, and AD-H).
(R)-2-Benzyl-1,2,3,4-tetrahydroquinoline (4a): colorless oil,
95% yield, 94% ee, [R]RTD -104.5 (c 0.70, CHCl3); 1H NMR (400
MHz, CDCl3) δ 1.72 (m, 1H), 1.99-2.03 (m, 1H), 2.67-2.87 (m,
4H), 3.49-3.51 (m, 1H), 3.73 (br, 1H), 6.37 (d, J ) 7.9 Hz, 1H),
6.59 (t, J ) 7.4 Hz, 1H), 6.95 (m, 2H), 7.22-7.31 (m, 3H), 7.35
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 26.4, 28.4, 43.2, 52.8,
114.4, 117.4, 121.5, 126.7, 126.9, 128.8, 129.5, 138.7, 144.5; HPLC
(OJ-H; elute: hexanes/i-PrOH ) 95/5; detector: 254 nm; flow rate:
0.8 mL/min), (S) t1 ) 15.9 min, (R) t2 ) 17.6 min.
Typical Procedure for Dehydrogenation of 2-Methyl-
1,2,3,4-tetrahydroquinoline. A mixture of [Ir(COD)Cl]2 (1.7 mg,
0.0025 mmol) and (S)-SynPhos (3.6 mg, 0.0055 mmol) in xylene
(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 the solution
was stirred for another 10 min, then 2-methyl-1,2,3,4-tetrahydro-
quinoline (0.074, 0.50 mmol) together with 2 mL of xylene were
added. The resulting mixture was allowed to stir at reflux temper-
ature for 48 h. The reaction mixture was purified by a silica gel
column eluted with ethyl acetate/petroleum to give pure product
Typical Procedure for Hydrogenation of 2-Functionalized
Quinoline 5a. A mixture of [Ir(COD)Cl]2 (1.7 mg, 0.0025 mmol)
and (S)-MeO-BiPhep (3.2 mg, 0.0055 mmol) in benzene (1 mL)
was stirred at room temperature for 10 min in a glovebox, then I2
(6.4 mg, 0.025 mmol) and substrate 5a (62 mg, 0.25 mmol) together
with 2 mL of benzene were added and the solution was stirred for
another 10 min. The hydrogenation was performed at room
temperature under H2 (800 psi) for 12-16 h. After the hydrogen
was carefully released, the reaction mixture was purified with a
silica gel column eluted with ethyl acetate/petroleum to give pure
product. The enantiomeric excesses were determined by chiral
HPLC with chiral columns (OD-H, OJ-H, AS-H, and AD-H).
(R)-2-(1,2,3,4-Tetrahydroquinolin-2-yl)-1-phenylethanone
1
2-methylquinoline (1a): colorless oil, 92% yield; H NMR (400
MHz, CDCl3) δ 2.74 (s, 3H), 7.27 (m, 1H), 7.47 (t, J ) 7.3 Hz,
1H), 7.67 (dt, J ) 8.2, 1.2 Hz, 1H), 7.74 (d, J ) 8.1 Hz, 1H), 8.01
(d, J ) 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 25.6, 122.1,
125.8, 126.6, 127.6, 128.8, 129.6, 136.3, 148.1, 159.1.
(6a): pale yellow oil, 91% yield, 96% ee, [R]25 -96.6 (c 0.54,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.80-1.84 (m, 1H),
2.00-2.05 (m, 1H), 2.74-2.80 (m, 1H), 2.85-2.89 (m, 1H),
3.16-3.18 (m, 2H), 3.92-3.96 (m, 1H), 4.58 (br, 1H), 6.48 (d, J
) 8.2 Hz, 1H), 6.62 (t, J ) 7.3 Hz, 1H), 6.96 (t, J ) 7.1 Hz, 2H),
7.47 (t, J ) 7.5 Hz, 2H), 7.58 (t, J ) 7.0 Hz, 1H), 7.96 (d, J ) 7.8
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 25.9, 28.4, 45.2, 47.4,
114.9, 117.5, 121.1, 127.1, 128.2, 128.9, 129.4, 133.6, 137.0, 144.5,
199.7; HRMS calcd for C17H17NONa [M + Na]+ 274.1208, found
274.1204; HPLC (OD-H column; hexanes/i-PrOH ) 80/20; flow
rate ) 0.8 mL/min) t1) 8.5 min, t2 ) 10.2 min.
Acknowledgement.. The authors acknowledge financial
support from the National Natural Science Foundation of China
(20621063 and 20532050) and the Chinese Academy of
Sciences.
Supporting Information Available: Experimental proce-
dures and characterization data for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
Typical Procedure for Hydrogenation of 2,3-Disubstituted
Quinoline 7a. A mixture of [Ir(COD)Cl]2 (1.7 mg, 0.0025 mmol)
JO900073Z
J. Org. Chem. Vol. 74, No. 7, 2009 2787