Iridium-catalyzed asymmetric hydrogenation of quinoline derivatives with C3*-tunephos

Article abstract of DOI:10.1002/adsc.201000485

A series of C₃-TunePhos chiral diphosphine ligands has been successfully applied in the iridium-catalyzed enantioselective hydrogenation of quinolines, and this methodology provided an efficient access to a variety of optically active tetrahydroquinolines with up to 93% ee. Furthermore, attempts on the asymmetric hydrogenation of quinoline N-oxide are also discussed.

Full text of DOI:10.1002/adsc.201000485

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DOI: 10.1002/adsc.201000485
Iridium-Catalyzed Asymmetric Hydrogenation of Quinoline
Derivatives with C3*-TunePhos
Fa-Rong Gou,a,b Wei Li,a,c Xumu Zhang,a,* and Yong-Min Liangb,*
a
Department of Medicinal Chemistry, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway,
NJ 08854, USA
Fax : (+1)-732-445-6312; e-mail: xumu@rci.rutgers.edu
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
b
Fax : (+86)-931-891-2582; e-mail: liangym@lzu.edu.cn
Department of Chemistry, The Pennsylvania State University, 104 Chemistry Building, University Park, PA 16802, USA
c
Received: June 22, 2010; Published online: October 12, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000485.
Abstract: A series of C3*-TunePhos chiral diphos-
phine ligands has been successfully applied in the
iridium-catalyzed enantioselective hydrogenation of
quinolines, and this methodology provided an effi-
cient access to a variety of optically active tetrahy-
droquinolines with up to 93% ee. Furthermore, at-
tempts on the asymmetric hydrogenation of quino-
line N-oxide are also discussed.
Keywords: asymmetric catalysis; enantioselectivity;
hydrogenation; iridium; quinolines
Scheme 1. C3-TunePhos and C3*-TunePhos.
The direct catalytic asymmetric hydrogenation of qui- lylphthalimides,[7g] b-keto esters[7h] and unfunctional-
nolines constitutes the most convenient route to enan- ized ketones.[7i] Chan et al. demonstrated the catalytic
tiomerically pure tetrahydroquinolines,[1] which are capability of (S),
ACTHUNTGRENNG(U S,S)-1b for the iridium-catalyzed re-
not only useful synthetic intermediates[2] but also duction of some heteroaromatic compounds,[7j] how-
structural moieties in alkaloids which are natural ever, hard modifications on P-aryl groups restrict
products and biologically active compounds.[3] The their potential applications, since for atropisomeric
first example of asymmetric hydrogenation of quino- biaryldiphosphines, a small variation of the dihedral
lines was reported by Zhou[4a] and co-workers, and angle of the ligands can have a significant impact on
some progresses has been achieved thereafter.[4–6] the reactivity and selectivity of the reaction. Thus, to
However, the challenges of developing easily accessi- screen the catalytic performance of C3*-TunePhos
ble, air-stable, chiral ligands and their application in families and illustrate their potential utilities, we sum-
the direct asymmetric hydrogenation of highly substi- marized our efforts in the iridium-catalyzed asymmet-
tuted quinolines still remain.
ric hydrogenation of highly substituted quinoline de-
In previous communications, we have developed a rivatives.
practical and convenient synthetic route to prepare a
Our initial study began with hydrogenation of 2-
series of air-stable, modular, biaryl chiral diphosphine methylquinoline 1a as the model substrate and a brief
ligands C3*-TunePhos (Scheme 1).[7] These ligands screening of the performance of different catalysts.
were designed to achieve superior enantioselectivities Key results are shown in Table 1. First, different iridi-
for asymmetric hydrogenations utilizing the highly um precursors were screened using C3-TunePhos as
modular nature of their unique steric and electronic the ligand. It was shown that the neutral precursor
properties and they have been demonstrated to be [Ir
ACHTUNGTRENNUNG
highly effective in the hydrogenation N-substituted al- cies with BF4 and BARF {tetrakisAHCTUNGTRENNUNG
Adv. Synth. Catal. 2010, 352, 2441 – 2444
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Fa-Rong Gou et al.
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Table 1. Catalytic asymmetric hydrogenation of 1a.[a]
Despite the recent progresses in the asymmetric hy-
drogenation of quinolines, highly enantioselective hy-
drogenation of various functionalized quinolines still
remains as a challenging task. However, reactivity
and enantioselectivity are often substrate-dependent:
subtle variations of steric and electronic properties of
the substituents could lead to significant changes in
reactivity and enantioselectivity. Nevertheless, previ-
ous reports on the hydrogenation of quinolines have
mainly focused on 2- or 6-substituted analogues, and
a systematic examination of the substrate scope of
substituted quinolines is rare. Thus, under the opti-
mized conditions, the generality of the iridium-C3*-
TunePhos catalyst was further investigated, and the
results are summarized in Table 2. Slightly decreased
conversion and ee values were observed in the hydro-
genation of substrate 1b which bears a more bulky
alkyl group (Table 2, entry 2). However, changing the
alkyl group at the 2-position to a phenyl group result-
ed in significant erosion of the enantioselectivity
(entry 3). On the other hand, this hydrogenation
could tolerate various substituents at the 6- or 7-posi-
tion, including fluoro, chloro, bromo, methyl and me-
thoxy groups (entries 4–11). However, a nitro-substi-
tuted substrate afforded lower enantioselectivity
(75% ee; entry 9), possibly due to the strong electron-
ic property of the nitro group. When switching to 8-
Entry Metal
precursor
Ligand
L*
Solvent Conv. ee
[%][b] [%][c]
1
[Ir
N
(S),
N
84
70
62
90
91
88
93
91
64
82
86
84
93
91
2
3
4
5
6
7
8
9
Ir(COD)2BARF (S),
Ir(COD)2BF4 (S),(S,S)-1a toluene 99
(COD)Cl]2 (S),(S,S)-1b toluene 99
(COD)Cl]2 (S),(S,S)-1c toluene 98
(COD)Cl]2 (S),(S,S)-1d toluene 98
(COD)Cl]2 (S),(S,S)-1e toluene 97
(COD)Cl]2 (S),(S,S)-1f toluene 98
(COD)Cl]2 (S),(S,S)-1e THF 92
(COD)Cl]2 (S),(S,S)-1e CH2Cl2 96
(COD)Cl]2 (S),(S,S)-1e AcOEt 95
(COD)Cl]2 (S),(S,S)-1e i-PrOH 95
(COD)Cl]2 (S),(S,S)-1e toluene 98
(COD)Cl]2 (S),(S,S)-1e toluene 99
N
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
R
E
E
R
R
E
10
11
12
G
R
E
T
13[d] [Ir
14[e]
A
ACHTUNGTRENNUNG
[a]
All reactions were performed on a 0.5-mmol scale: iridi-
um/ligand/I2 =0.5/1.05/5, 1 mol% iridium catalyst, 2.5 mL
solvent, 50 atm H2 pressure, room temperature, 24 h.
Determined by GC analysis.
The ee was determined by chiral GC analysis or chiral
HPLC analysis (see the Supporting Information). The
absolute configuration of product is assigned by compari-
son of optical rotation with literature data.
20 atm H2 pressure.
[b]
[c]
Table 2. Catalytic asymmetric hydrogenation of quinoline
derivatives.[a]
[d]
[e]
10 atm H2 pressure.
thyl)phenyl]borate} counterions, and afforded 96%
conversion and 84% ee (Table 1, entries 1–3). Further
studies showed that the reactions proceeded smoothly
with high conversions and ee values when switching to
the C3*-TunePhos ligand family with various aryl sub-
stituents on the phosphine moiety (entries 4–8). To
our delight, the highest enantioselectivity of 93% ee
was achieved by applying the di-t-Bu-phenyl-substitut-
Entry
R1/R2 of 1
Product
Conv.
[%][b]
ee [%]
AHCTUNGTRENNUNG
(config.)[c]
1
2
3
4
5
6
7
8
H/Me (1a)
H/Et (1b)
H/Ph (1c)
2a
2b
2c
2d
2e
2f
2g
2h
2i
98
94
98
97
99
99
95
84
98
99
99
99
93 (S)
88 (S)
73 (S)
91 (S)
90 (À)
90 (À)
92 (S)
89 (S)
75 (À)
92 (À)
90 (À)
56 (À)
6-F/Me (1d)
6-Cl/Me (1e)
6-Br/Me (1f)
6-Me/Me (1g)
6-MeO/Me (1h)
6-NO2/Me (1i)
7-F/Me (1j)
7-Cl/Me (1k)
8-Cl/Me (1l)
ed ligand (S),ACHTUNGTRENNUNG(S,S)-1e (entry 7). Greater than 90%
conversions were achieved in all solvents examined,
either protic or aprotic solvents (entries 9–12). But
the use of THF as solvent resulted in low enantiose-
lectivity and somewhat a slightly lower conversion
(entry 9). Compared with other solvents, toluene was
more effective. The best result was obtained under
20 atm H2 and the ee value remained the same under
the milder conditions (entries 13 and 14). Considering
the crucial influence of additives on reactivity,[8] we
further evaluated a number of additives including KI,
NaI, LiI, tetrabutylammonium iodide and some or-
ganic and inorganic acids, such as CF3SO3H,
CF3COOH, CH3COOH, HCl and H2SO4, etc., I2 was
found to be essential and the most effective additive.
9
10
11
12
2j
2k
2l
[a]
All reactions were performed on a 0.5-mmol scale:
[Ir(COD)Cl]2 0.5 mol%, (S),(S,S)-1e 1.05 mol%, I2
U
ACHTUNGTRENNUNG
5 mol%, H2 20 atm, toluene 2.5 mL, room temperature,
24 h.
[b]
[c]
Determined by GC analysis.
The ee was determined by chiral GC analysis or chiral
HPLC analysis (see the Supporting Information). The
absolute configuration of product is assigned by compari-
son of rotation sign with literature data.
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Adv. Synth. Catal. 2010, 352, 2441 – 2444

Iridium-Catalyzed Asymmetric Hydrogenation of Quinoline Derivatives
Experimental Section
General Procedure for Asymmetric Hydrogenation of
Quinolines
A mixture of [Ir
ACHTUNGTNER(NUNG COD)Cl]2 (1.7 mg, 0.0025 mmol) and
(S),(S,S)-1e (5.6 mg, 0.00525 mmol) in toluene (1 mL) was
AHCTUNGTRENNUNG
Scheme 2. Catalytic asymmetric hydrogenation of quinoline
N-oxide.
stirred at room temperature for 10 min in a glovebox, then
I2 (6.4 mg, 0.025 mmol) and substrate (0.5 mmol) together
with 1.5 mL of toluene were added and the solution was
stirred for another 10 min. The hydrogenation was per-
formed under 20 atm H2 at room temperature for 24 h.
After the hydrogen had been carefully released, the reaction
solution was purified on a silica gel column to give the prod-
uct, which was then analyzed by chiral GC to determine the
conversions and enantiomeric excesses.
substituted substrate 1l, a dramatic drop of ee was ob-
served (entry 12), In this case, the lower enantioselec-
tivity may be attributed to the steric hindrance of the
substituent. Additional attempts to examine 3- or 4-
substituted quinolines exhibited no effect, and the
result is consistent with Zhouꢀs finding with the iridi-
um-MeOBIPHEP catalyst system.[4a]
(À)-7-Chloro-2-methyl-1,2,3,4-tetrahydroquinoline (2k):
1
99% conversion; 90% ee; H NMR (CDCl3, 400 MHz): d=
The above results encouraged us to extend our in-
vestigation of asymmetric hydrogenation to other re-
lated substrates by applying the iridium-C3*-TunePhos
catalyst. We envisioned that our approach could be
applied to enantioselectively reduce quinoline N-
oxide derivatives. Utilizing substrate 3a as a model
substrate, the reaction conditions were optimized to
achieve this goal (Scheme 2). The best result was ach-
ieved in THF under 50 atm H2. The reaction pro-
duced a 9:1 ratio of (R)-2-methyl-1,2,3,4-tetrahydro-
quinoline 4a with 41% ee and 2-methylquinoline
(>99% conversion). We envisioned one pathway of
this transformation might have proceeded in two se-
quential steps, involving an iridium-catalyzed reduc-
tion of quinoline N-oxide step which afforded the key
6.76 (d, J=4.0 Hz, 1H), 6.47–6.44 (m, 1H), 6.34 (s, 1H),
3.62 (s, 1H), 3.32–3.27 (m, 1H), 2.67–2.60 (m, 2H), 1.85–
1.80 (m, 1H), 1.49–1.43 (m, 1H), 1.11 (d, J=8.0 Hz, 3H);
13C NMR (CDCl3, 100 MHz): d=145.7, 131.9, 130.2, 119.4,
116.6, 113.3, 47.0, 29.8, 26.1, 22.5; IR (neat): n=1602, 1494,
1330, 1296, 1139, 1081, 933, 820, 756 cmÀ1; chiral GC
(Gamma Dex 225, 30 mꢂ0.25 mm, column temperature:
1308C, carrier gas: He, 1.0 mLminÀ1): t1 =81.12 min, t2 =
83.83 min; HR-MS: m/z=182.0741, calcd. for C10H13ClN
[M+H]+: 182.0737; [a]D20: À68.5 (c 0.5, CHCl3).
Acknowledgements
We thank the National Institutes of Health (GM58832) and
intermediate 1a, followed by an asymmetric hydroge- Merck & Co., Inc., for the financial support.
nation step to form the final product 4a with the op-
posite configuration. We also believe that there exist
other hydrogenation pathways because of the only
moderate enantioselectivity and more importantly the
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Adv. Synth. Catal. 2010, 352, 2441 – 2444