Highly enantioselective hydrogenation of quinoline and pyridine derivatives with iridium-(P-Phos) catalyst

Article abstract of DOI:10.1002/adsc.200900870

The use of a chiral iridium catalyst gener-ated in situ from the (cyclooctadiene)iridium chlo-ride dimer, [Ir(COD)Cl]₂, the P-Phos ligand [4, 4'-bis(diphenylphosphino)-2, 2', 6, 6'-tetramethoxy-3, 3'-bi-pyridine] and iodine (I₂) for the asymmetric hydroge-nation of 2, 6-substituted quinolines and trisubstituted pyridines [2-substituted 7, 8-dihydroquinolin-5(6H)-one derivatives] is reported. The catalyst worked ef-ficiently to hydrogenate a series of quinoline deriva-tives to provide chiral 1, 2, 3, 4-tetrahydroquinolines in high yields and up to 96% ee. The hydrogenation was carried out at high S/C (substrate to catalyst) ratios of 2000-50000, reaching up to 4000 h^-1 TOF (turnover frequency) and up to 43000 TON (turn-over number). The catalytic activity is found to be additive-controlled. At low catalyst loadings, de-creasing the amount of additive I₂ was necessary to maintain the good conversion. The same catalyst system could also enantioselectively hydrogenate tri-substituted pyridines, affording the chiral hexahydro-quinolinone derivatives in nearly quantitative yields and up to 99% ee. Interestingly, increasing the amount of I₂ favored high reactivity and enantiose-lectivity in this case. The high efficacy and enantiose-lectivity enable the present catalyst system of high practical potential.

Full text of DOI:10.1002/adsc.200900870

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DOI: 10.1002/adsc.200900870
Highly Enantioselective Hydrogenation of Quinoline and Pyridine
Derivatives with Iridium-(P-Phos) Catalyst
Wei-Jun Tang,a,b Jing Tan,a Li-Jin Xu,a,* Kim-Hung Lam,b Qing-Hua Fan,c
and Albert S. C. Chanb
a
Department of Chemistry, Renmin University of China, Beijing 100872, Peopleꢀs Republic of China
Fax : (+86)-10-6251-6444; e-mail: xulj@chem.ruc.edu.cn
Department of Applied Biology & Chemical Technology and Open Laboratory of Chirotechnology of the Institute of
b
Molecular Technology for Drug Discovery & Synthesis, The Hong Kong Polytechnic University, Hong Kong, Peopleꢀs
Republic of China
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
c
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190. Peopleꢀs Republic of China
Received: December 17, 2009; Published online: April 7, 2010; Accepted: March 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900870.
Abstract: The use of a chiral iridium catalyst gener- additive-controlled. At low catalyst loadings, de-
ated in situ from the (cyclooctadiene)iridium chlo- creasing the amount of additive I2 was necessary to
ride dimer, [IrACHTUNGTRENNUNG(COD)Cl]2, the P-Phos ligand [4,4’- maintain the good conversion. The same catalyst
bis(diphenylphosphino)-2,2’,6,6’-tetramethoxy-3,3’-bi- system could also enantioselectively hydrogenate tri-
pyridine] and iodine (I2) for the asymmetric hydroge- substituted pyridines, affording the chiral hexahydro-
nation of 2,6-substituted quinolines and trisubstituted quinolinone derivatives in nearly quantitative yields
pyridines [2-substituted 7,8-dihydroquinolin-5(6H)- and up to 99% ee. Interestingly, increasing the
one derivatives] is reported. The catalyst worked ef- amount of I2 favored high reactivity and enantiose-
ficiently to hydrogenate a series of quinoline deriva- lectivity in this case. The high efficacy and enantiose-
tives to provide chiral 1,2,3,4-tetrahydroquinolines in lectivity enable the present catalyst system of high
high yields and up to 96% ee. The hydrogenation practical potential.
was carried out at high S/C (substrate to catalyst)
ratios of 2000–50000, reaching up to 4000 hÀ1 TOF
(turnover frequency) and up to 43000 TON (turn- Keywords: asymmetric hydrogenation; iridium catal-
over number). The catalytic activity is found to be ysis; P-Phos; pyridines; quinolines
Introduction
series of heteroaryl compounds.[2–11] Zhou and co-
workers first reported the Ir-catalyzed asymmetric hy-
Optically active tetrahydroquinolines and decahydro- drogenation of 2,6-substituted quinolines with (R)-
quinolines are important structural units in a number MeO-BIPHEP [6,6’-dimethoxy-2,2’-bis(diphenylphos-
of natural and synthetic products with a wide variety phino)-1,1’-biphenyl] as the ligand to produce chiral
of biological activities.[1] Therefore, it is not surprising tetrahydroquinolines with up to 96% ee.[8a,b,e] Later
that the development of efficient methods to prepare the same group found that iridium catalyst generated
these enantiomerically enriched heterocycles has been from [Ir
an appealing goal in both academia and industry for chiral ferrocenyloxazoline P,N ligand or poly(ethylene
many years.[1a,b]
glycol)-supported ligand was capable of effectively
Asymmetric homogeneous hydrogenation of heter- catalyzing the asymmetric hydrogenation of quino-
oaromatic compounds to chiral heterocycles using in-
lines.[8c,d] Following this significant lead, a number of
ACHTUNGTRNEN(UNG COD)Cl]2 (COD=1,5-cyclooctadiene) and
AHCTUNGTRENNUNG
expensive molecular hydrogen and a small amount of catalyst systems have been developed to asymmetri-
chiral transition metal catalyst is perhaps the most cally hydrogenate the same class of substrates, and
straightforward, efficient and atom-economic method, good to excellent enantioselectivities have been ob-
and has been widely employed in the reduction of a served.[9] We have recently demonstrated that compa-
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Wei-Jun Tang et al.
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rable or better results could be achieved when em- for good performance of the catalyst. Herein we
ploying P-Phos [4,4’-bis(diphenylphosphino)-2,2’,6,6’- report a more extensive study into the Ir-catalyzed
tetramethoxy-3,3’-bipyridine],[10a,f] PQ-Phos {(6,8- enantioselective hydrogenation of quinolines with the
dimethyl-7,8-dihydro-6H-dibenzo
G
G
P-Phos ligand, and the reaction could be carried out
1,13-diyl)bis(diphenylphosphine)},[10c] dendrimer-sup- at high S/C ratios (up to 50000) with high TON (turn-
ported BINAP [2,2’-bis(diphenylphosphino)-1,1’-bi- over number) values (up to 43000) and excellent ee
naphthyl][10e] or chiral diphosphinite[10b,d] as the ligand values (up to 96%) under inert conditions. Interest-
in Ir-catalyzed hydrogenation of 2,6-substituted qui- ingly, this catalyst system was also successfully applied
nolines. We also described the excellent performance to the asymmetric hydrogenation of pyridine deriva-
of phosphine-free ruthenium[11a,c] and iridium[11b] com- tives, 2-substituted 7,8-dihydroquinolin-5(6H)-ones,
plexes to enantioselectively hydrogenate quinoline furnishing excellent yields and enantioselectivities (up
derivatives. Despite this significant progress, the cata- to 99% ee).
lyst efficiency is still far from being practical, as evi-
denced by the fact that good results could only be ob-
tained at a lower S/C (substrate to catalyst) ratio of Results and Discussion
100 in most cases.[8–11] From the viewpoints of both
scientific interest and practical applications, it is With P-Phos as the ligand and 2-methylquinoline (1a)
highly desirable to develop more efficient catalyst sys- as the model substrate, a systematic study was per-
tems for the enantioselective hydrogenation of quino- formed to establish the optimum hydrogenation con-
lines.
ditions for the asymmetric hydrogenation of quino-
In contrast to the hydrogenation of quinolines, lines. Initial hydrogenation experiments were con-
rather few examples of transition metal-catalyzed ducted at 700 psi hydrogen pressure and room tem-
asymmetric hydrogenation of substituted pyridines perature, employing 1 mol% catalyst generated in situ
have been reported to date, and most of them focused from (R)-P-Phos, [IrACHTNUTRGNEUNG(COD)Cl]2 and I2. Since the ob-
on the reduction of mono- or disubstituted pyri- tained iridium catalyst was air-stable,[10a] the manipu-
dines.[4] In 2007, Rueping et al. found that BINOL lations prior to the charging of hydrogen were con-
(1,1’-binaphthyl-2,2’-diol)-derived chiral phosphoric ducted in air and solvents were used without pre-de-
acids could efficiently catalyze the asymmetric trans- gassing and drying. A series of organic solvents was
fer hydrogenation of trisubstituted pyridines by using firstly screened. It was clear that the choice of solvent
Hantzsch dihydropyridine as hydrogen source.[12] was critical in achieving good catalytic activity and
Enantioenriched hexahydroquinolinones (up to 92% enantioselectivity, and the most active and enantiose-
ee) were obtained, which could be easily transformed lective catalyst was observed in THF (tetrahydro-
into chiral decahydroquinolines. Shortly after, Zhou furan) (Table 1, entries 1–8). In contrast, with all the
and co-workers successfully accomplished Ir-catalyzed other solvents tested, a lower conversion and/or enan-
asymmetric hydrogenation of this class of challenging tioselectivity were obtained. With THF as the solvent,
substrates, affording the chiral hexahydroquinolinone lowering the reaction temperature only slightly im-
products with good to excellent enantioselectivities proved the enantioselectivity (Table 1, entry 9). A
(84–97% ee).[4f] However, this catalytic system suf- higher reaction temperature led to a decrease of both
fered from low reactivity (S/C ratio of 50). Therefore, conversion and enantioselectivity (Table 1, entry 10).
it is still a big challenge to realize the highly efficient The hydrogen pressure did not have much effect on
hydrogenation of pyridine derivatives.
enantioselectivity (Table 1, entry 11), but a lower
We have recently demonstrated the effectiveness of pressure decreased the conversion (entry 12). Further
chiral dipyridylphosphane ligands such as P-Phos in experimental studies demonstrated that changing the
many catalytic asymmetric hydrogenation reactions.[13] catalyst precursor to a cationic [Ir
ACHTUNGTRENNUNG
Among them, it is notable that the ruthenium com- [Ir
plexes, [Ru(C6H6)(P-Phos)Cl2] and [RuCl2A
ACHTUNGTRENNUNG
N
N
CHTUNGTRENNUNG
ACHTUNGTRENNUNG
display good air-stability even in solution, which is at- tries 13 and 14). In sharp contrast to Ir-(P-Phos), cata-
tributed to the dipyridyl structure of the ligand.[14] In- lyst Ir-(MeO-BIPHEP) gave the product with only
spired by these exciting findings, we extended the ap- 21% conversion and 28% enantioselectivity under
plication of this ligand in the asymmetric hydrogena- otherwise identical conditions (entry 15). This could
tion of heteroaryl compounds. Indeed, in our prelimi- be conceivably due to the high air-sensitivity of the Ir-
nary communication we found that the Ir-(P-Phos) (MeO-BIPHEP) catalyst.
catalyst was air-stable and recyclable for the asym-
Considering the remarkable impact of the additive
metric hydrogenation of quinolines, providing the on catalytic activity and enantioselectivity in the
products in high yields and excellent enantioselectivi- asymmetric hydrogenation of heteroaryl compounds,[2]
ties.[10a] However, a low S/C ratio of 100 was necessary we then examined the additive effect. It was notable
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Highly Enantioselective Hydrogenation of Quinoline and Pyridine Derivatives
Table 1. Asymmetric hydrogenation of 1a catalyzed by Ir-(P-Phos).[a]
Entry
Solvent
H2 [psi]
Temperature [8C]
Conversion [%][b]
ee [%][b,c]
1
2
toluene
benzene
CH2Cl2
DCE
700
700
700
700
700
700
700
700
700
700
1500
100
700
700
700
25
25
25
25
25
25
25
25
0
55
25
25
25
25
25
84
55
47
76
>99
33
83
60
92
85
>99
90
37
83
84 (R)
91 (R)
88 (R)
89 (R)
91 (R)
48 (R)
18 (R)
84 (R)
92 (R)
38 (R)
91 (R)
91 (R)
47 (S)
14 (S)
21 (R)
3
4[d]
5
THF
6
7
8
9
10
11
12
13[e]
14[f]
15[g]
MeOH
EtOH
i-PrOH
THF
THF
THF
THF
THF
THF
THF
28
[a]
Reaction conditions: 1 mmol 1a, [IrACTHUGNTREN(NUGN COD)Cl]2 (0.5 mol%), (R)-P-Phos (1.1 mol%), I2 (10 mol%), 2 mL undegassed sol-
vent, 20 h.
[b]
1
The conversions were determined by H NMR and the enantioselectivities were determined by HPLC analysis with OJ-
H column.
[c]
[d]
[e]
[f]
The absolute configurations were determined by comparison with the literature data.
DCE: 1,2-dichloroethane.
[Ir
[Ir
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[g]
(R)-MeO-BIPHEP was used.
that in the absence of any additive, only 15% conver- composition did not obviously affect the reaction in
sion and 58% enantioselectivity were observed the case of high catalyst loading, but remarkably re-
(Table 2, entry 1). However, replacing I2 with other
additives, such as KI, NaI, BiI3, LiCl, or (n-Bu)4NI,
Table 2. Effect of additive on catalytic asymmetric hydroge-
only led to a slow reaction and decreased enantiose-
nation of 1a.[a]
lectivity (Table 2, entries 3–7). Obviously the use of I2
as the additive was the best choice.
Entry
Additive
Conversion [%][b]
ee [%][c]
The good performance of Ir-(P-Phos) prompted us
to further enhance the catalytic efficiency. When the
S/C ratio was increased to 1000, it was observed that
the conversion dropped to 86% in 20 h although with
unchanged enantioselectivity of 91% (Table 3,
entry 1). Further increasing the S/C ratio to 5000 led
to a much lower conversion (16%) and still high ee
(91%) (Table 3, entry 2). We envisioned that the ex-
perimental procedures in air and the use of unde-
gassed and undried solvent resulted in the presence of
oxygen in the reaction system, which would cause the
partial deactivation and/or decomposition of the cata-
lyst in the hydrogenation process, thereby deteriorat-
ing the catalyst activity. This deactivation and/or de-
1
2
3
4
5
6
7
none
I2
KI
NaI
BiI3
LiCl
15
>99
78
2
90
20
67
58
91
89
8
88
60
67
AHCTUNGTRENNUNG
[a]
Reaction
1 mmol
1a,
[IrACTHNGUTRENU(NG COD)Cl]2
(0.5 mol%), (R)-P-Phos (1.1 mol%), additive (10 mol%),
2 mL undegassed THF, room temperature, experimental
procedures in air, 20 h.
The conversions were determined by H NMR.
The enantioselectivities were determined by HPLC anal-
ysis with an OJ-H column.
[b]
[c]
1
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Table 3. Effect of S/C ratio on catalytic asymmetric hydroge-
nation of 1a.[a]
presence of 1.25 mol% I2, providing a high TON
value of 43000 (Table 3, entry 12). For comparison,
the performance of Ir-(MeO-BIPHEP), Ir-Synphos
[Synphos=6,6’-bis(diphenylphosphino)-2,2’,3,3’-tetra-
hydro-5,5’-bi-1,4-benzodioxin] and Ir-Spiropo {Spi-
ropo=7,7’-bis(diphenylphosphinooxy)-2,2’,3,3’-tetra-
Entry S/C
I2
Time
Conversion
[%][b]
ee
[mol%] [h]
[%][c]
1
1000 10
5000 10
5000 10
20
86
16
86
>99
63
>99
40
61
78
60
91 (R)
91 (R)
91 (R)
91 (R)
84 (R)
91 (R)
91 (R)
80 (R)
89 (R)
90 (R)
90 (R)
90 (R)
2
20
20
20
20
20
1
20
20
20
20
40
hydro-1,1’-spirobiACHTUNRGTNE[NUG indene]} catalyst systems was exam-
3[d]
4[d]
ined, and lower conversions and/or enantioselectivi-
ties were observed under otherwise identical condi-
tions (Table 3, entry 4 vs. entry 5; entries 8–10 vs.
entry 6).
A series of 2-substituted and 2, 6-disubstituted
quinoline derivatives was then subjected to hydroge-
nation at a high S/C ratio, and the results are listed in
Table 4. The results demonstrated that 2-alkyl-substi-
tuted quinoline derivatives could undergo smooth hy-
drogenation at a high S/C ratio of 10000, giving high
isolated yields and good enantioselectivities (Table 4,
entries 1–6). The reaction was relatively insensitive to
the length of the side chain of 2-alkylated quinolines.
5000
5
5
5[d,e] 5000
6[d]
7[d]
10000 2.5
10000 2.5
8[d,e] 10000 2.5
9[d,f]
10000 2.5
10[d,g] 10000 2.5
11[d] 20000 2.5
12[d,h] 50000 1.25
>99
86
[a]
Reaction conditions: 2 mmol 1a, 700 psi H2, I2, 2 mL un-
degassed THF, room temperature, experimental proce-
dures in air, 20 h.
The conversions were determined by H NMR.
The enantioselectivities were determined by HPLC anal- Replacing the alkyl group at the 2-position with
ysis with OJ-H column.
Degassed THF was used with the experimental proce-
dures under N2 in a glove box.
(R)-MeO-BIPHEP was used.
(R)-Synphos was used.
(R)-Spiropo was used.
[b]
[c]
1
phenyl group still gave excellent catalytic activity but
lower enantioselectivity (Table 4, entry 7). The intro-
duction of either an electron-withdrawing or an elec-
tron-donating group on the 6-position had no signifi-
cant effect on enantioselectivity, but the presence of
an electron-donating group reduced the catalytic ac-
tivity (Table 4, entries 8–10). It was observed that a
low S/C ratio of 2000 was necessary for the hydroge-
[d]
[e]
[f]
[g]
[h]
12 mmol substrate in 12 mL degassed THF.
duced the catalytic activity at a high S/C ratio. In this nation of electron-donating group-containing sub-
context, the use of dried and degassed solvent in the strates 1i and 1j to high conversion; while the hydro-
absence of air might enhance the catalytic efficiency. genation of electron-withdrawing group-containing
As expected, under oxygen-free conditions the reac- substrate 1h could proceed smoothly at a high S/C
tion proceeded smoothly in dried THF at an S/C ratio ratio of 10000. The presence of a hydroxy group at
of 5000 to afford 86% conversion and unchanged the side chain enabled the hydrogenation to provide
enantioselectivity (Table 3, entry 3). Surprisingly, up to 96% ee (Table 4, entries 11–13), albeit at a low
when we decreased the amount of I2 from 10 mol% S/C ratio of 2000. It is noted that the asymmetric hy-
to 5 mol%, the reaction went to completion in 20 h drogenation of 3-methylquinoline proceeded smooth-
without compromising the enantioselectivity (Table 3, ly at an S/C ratio of 10000 with a full conversion in
entry 4). It was obvious that the amount of I2 had a 24 h, but only the racemic product was obtained.
critical effect on the hydrogenation, and decreasing
With 7,8-dihydro-2-methylquinolin-5(6H)-one (1n)
the amount of I2 facilitated the reaction at a high S/C as a model substrate, we next evaluated the perfor-
ratio. Similar observations were made in the Ir-cata- mance of the Ir-(P-Phos) catalyst system in the asym-
lyzed asymmetric hydrogenation of quinolines with metric hydrogenation of trisubstituted pyridines
dendrimer-supported BINAP ligand.[10e] As a result, a under oxygen-free conditions. Considering the impor-
small amount of 2.5 mol% I2 was well suited to give tance of the solvent effect, a series of organic solvents
full conversion and high enantioselectivity at a high was tested with the catalyst generated in situ from
S/C ratio of 10000 (Table 3, entry 6). Notably a high (S)-P-Phos and [IrACHTUNTRGNEUNG(COD)Cl]2 and I2. As can be seen
TOF (turnover frequency) of 4000 hÀ1 was observed, in Table 5, the hydrogenation was sensitive to the
and to the best of our knowledge, this was the highest choice of reaction medium, and the best enantioselec-
TOF obtained so far for the asymmetric hydrogena- tivity of 89% was obtained in dichloromethane albeit
tion of quinolines (Table 3, entry 7). Further study in- at a lower conversion (Table 5, entry 1). In contrast,
dicated that the catalyst maintained its activity and other aprotic solvents such as toluene, benzene,
enantioselectivity well even at a high S/C ratio of PEGDME (polyethylene glycol dimethyl ether, MW~
20000 (Table 3, entry 11). When the S/C ratio was in- 500), DCE (1,2-dichloroethane) and THF gave either
creased to 50000, the catalytic system still gave 86% lower conversions and/or lower enantioselectivities
conversion with retained enantioselectivity in the (Table 5, entries 2–6). Complete conversion was ob-
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Highly Enantioselective Hydrogenation of Quinoline and Pyridine Derivatives
Table 4. Asymmetric hydrogenation of 2,6-substituted quinoline derivatives catalyzed by Ir-(P-Phos).[a]
Entry
Substrate
S/C
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
10000
10000
10000
10000
10000
10000
10000
10000
2000
2000
2000
2000
2000
99 (2a)
98 (2b)
98 (2c)
99 (2d)
99 (2e)
99 (2f)
98 (2g)
99 (2h)
99 (2i)
89 (2j)
98 (2k)
97 (2l)
97 (2m)
91 (R)
92 (R)
91 (R)
90 (R)
92 (R)
90 (R)
60 (S)
88 (R)
88 (R)
90 (R)
92 (S)
96 (S)
87 (S)
9
10
11
12
13
1j
1k
1l
1m
[a]
Reaction conditions: 0.3 mmol substrate, I2 (2.5 mol% for 1a–1h; 5 mol% for 1i–1m), 0.6 mL degassed THF, room temper-
ature, 24 h.
Isolated yield.
[b]
[c]
The enantioselectivities were determined by HPLC analysis with OJ-H (2a–2e, 2g, 2i–2j), OD-H (2h, 2k and 2m), AS-H
(2f) and OJ (2l) columns.
The absolute configurations were determined by comparison with the literature data.
[d]
served in methanol, but a lower ee of 66% was ob- hydrogen was carried out in air and the solvent was
tained (Table 5, entry 7). With dichloromethane as the used without drying and degassing. Disappointingly,
reaction medium, we then turned our attention to the only 87% conversion and 88% enantioselectivity were
additive effect. The observation of the critical effect observed (Table 5, entry 15). Next the catalytic perfor-
of I2 in the asymmetric hydrogenation of quinolines mance of Ir-(P-Phos) at different S/C ratios was inves-
prompted us to investigate whether the catalytic per- tigated. It was found that increasing the S/C ratio
formance could be improved by varying the amount from 200 to 1000 had no significant effect on the reac-
of I2 (Table 5, entries 8–11). In the absence of any ad- tivity, but the enantioselectivities decreased gradually
ditive, no reaction was observed. Increasing the (95% vs. 88%) (Table 5, entries 16–18). Switching the
amount of I2 to 10 mol% led to 87% conversion and ligand to MeO-BIPHEP, Synphos or Spiropo at an
91% enantioselectivity. Adding 20 mol% I2 gave a S/C ratio of 100 resulted in a similar conversion, but
complete conversion and a better ee of 95%. When the enantioselectivity was reduced (Table 5, en-
more I2 was added to the reaction mixture, full con- tries 19–21).
version and slightly lower enantioselectivity were ob-
Based on the optimal conditions, the asymmetric
tained (Table 5, entry 11). Lowering the reaction tem- hydrogenation of a series of trisubstituted pyridine
perature to 08C had no obvious effect on either reac- derivatives was conducted, and the results are listed
tivity or enantioselectivity, but higher reaction tem- in Table 6. Generally, nearly quantitative yields were
perature reduced the enantioselectivity (Table 5, en- obtained for all the substrates along with high enan-
tries 12 and 13). Decreasing the hydrogen pressure tioselectivities. Excellent ee values were obtained in
resulted in unchanged reactivity but lower enantiose- the hydrogenation of 2-alkyl-substituted substrates,
lectivity (Table 5, entry 14). To test the effect of air and the length of the alkyl group affected the enantio-
on the reaction, the operation prior to the charging of selectivity slightly (Table 6, entries 1–7). For example,
Adv. Synth. Catal. 2010, 352, 1055 – 1062
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Wei-Jun Tang et al.
FULL PAPERS
Table 5. Asymmetric hydrogenation of 1n catalyzed by
Table 6. Asymmetric hydrogenation of 2-substituted 7,8-di-
hydroquinolin-5(6H)-one derivatives catalyzed by Ir-(P-
Phos).[a]
Ir-(P-Phos).[a]
Entry Solvent
I2
Temperature Conversion ee
[%] [oC]
[%][b]
[%][b,c]
1
2
3
4
5
6
7
8
CH2Cl2
benzene
toluene
DCE
THF
PEGDME 2
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
2
2
2
2
25
25
25
25
25
25
25
25
25
25
25
0
40
25
25
25
25
25
25
25
25
41
43
29
42
79
45
89 (S)
74 (S)
71 (S)
85 (S)
59 (S)
52 (S)
66 (S)
Nd
91 (S)
95 (S)
94 (S)
94 (S)
90 (S)
91 (S)
88 (S)
91 (S)
89 (S)
88 (S)
89 (R)
88 (R)
89 (R)
Entry
Substrate
Yield [%][b]
ee [%][c,d]
1
2
3
4
5
6
7
8
9
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
98
96
97
97
96
98
98
99
98
99
95 (S)
94 (S)
95 (S)
97 (S)
93 (S)
97 (S)
99 (S)
81 (R)
92 (R)
96 (S)
2
0
>99
<1
87
>99
>99
>99
>99
>99
87
>99
>99
95
>99
>99
>99
9
10
20
25
20
20
20
20
20
20
20
20
20
20
10
11
12
13
10
14[d] CH2Cl2
15[e] CH2Cl2
[a]
Reaction conditions: 0.15 mmol substrate, [IrACTHNUGTRENUNG(COD)Cl]2
16[f]
CH2Cl2
(0.5 mol%), (S)-P-Phos (1.1 mol%), I2 (20 mol%),
0.6 mL degassed CH2Cl2, room temperature, 20 h.
Isolated yield.
The enantioselectivities were determined by HPLC anal-
ysis with OD-H (2n–2t, 2v, 2w) and AS-H (2u) columns.
The absolute configurations were determined by compar-
ison with the literature data.
17[g] CH2Cl2
[b]
[c]
18[h] CH2Cl2
19[i]
20[j]
CH2Cl2
CH2Cl2
[d]
21[k] CH2Cl2
[a]
Reaction conditions: 0.15 mmol 1n, [IrACTHNURTGNENG(U COD)Cl]2
(0.5 mol%), (S)-P-Phos (1.1 mol%), I2, 0.7 mL degassed
solvent, room temperature, 20 h.
The conversions were determined by H NMR and the
ed 7,8-dihydroquinolin-5(6H)-ones underwent smooth
hydrogenation to afford 92% and 96% ee, respective-
ly (Table 6, entries 9 and 10). We also tried the hydro-
genation of other trisubstituted pyridines that are not
fused to a cyclohexanone, such as 1x and 1y, but no
reaction was observed.
[b]
[c]
1
enantioselectivities were determined by HPLC analysis
with OD-H column.
The absolute configurations were determined by compar-
ison with the literature data.
With 100 psi H2.
The catalyst was prepared in undegassed CH2Cl2 without
use of glove box.
S/C=200.
S/C=500.
S/C=1000.
(R)-MeO-BIPHEP was used.
(R)-Synphos was used.
(R)-Spiropo was used.
[d]
[e]
[f]
[g]
[h]
[i]
[j]
[k]
Conclusions
substrate 1t underwent exceedingly efficient hydroge- In conclusion, the results presented in this paper indi-
nation to give 98% yield and 99% enantioselectivity cated that the iridium complex generated in situ from
(Table 6, entry 7). It was notable that asymmetric hy- [IrACHTNUTRGNEUGN(COD)Cl]2, P-Phos and I2 was an excellent catalyst
drogenation of pyridine 1n led to 98% yield and 95% for the asymmetric hydrogenation of a wide range of
ee (Table 6, entry 1). When Ir-(MeO-BIPHEP) was 2,6-substituted quinolines and trisubstituted pyridines
used for this reaction, the yield and enantioselectivity [2-substituted 7,8-dihydroquinolin-5(6H)-one deriva-
were reported to be 80% and 86%, respectively.[4f] tives], affording high yields and enantioselectivities.
Replacing the alkyl group at 2-position with the In the asymmetric hydrogenation of quinolines, the
phenyl group eroded the enantioselectivity (Table 6, catalyst performed efficiently at high S/C ratios of
entry 8), but the 2-benzyl- and 2-phenethyl-substitut- 2000–50000 to produce chiral 1,2,3,4-tetrahydroquino-
1060
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1055 – 1062

Highly Enantioselective Hydrogenation of Quinoline and Pyridine Derivatives
which I2 (15.2 mg, 0.06 mmol) and substrate (0.3 mmol)
lines in excellent yields and up to 96% ee. Notably up
to 4000 hÀ1 TOF and 43000 TON values were
achieved. The amount of additive I2 had a critical
effect on the catalytic reactivity, and decreasing I2
amount favored the hydrogenation at lower catalyst
loadings. The effectiveness of this catalyst system was
further demonstrated by the excellent yields and
enantioselectivies observed in the hydrogenation of
trisubstituted pyridines [2-substituted 7,8-dihydroqui-
nolin-5(6H)-one derivatives]. In contrast to the hy-
drogenation of quinolines, increasing the amount of I2
facilitated the reaction in the case of hydrogenation
of pyridines. Owing to the extraordinary performance
of this catalyst system, there is good potential for its
practical applications in large-scale settings.
were placed before hand. The hydrogenation was performed
at room temperature under H2 (700 psi) for 20 h. After care-
fully releasing the hydrogen gas, the reaction mixture was
diluted with dichloromethane (5 mL) followed by the addi-
tion of saturated sodium carbonate aqueous solution
(2.0 mL). After stirring for 15 min, the aqueous layer was
extracted with CH2Cl2 (1ꢂ3 mL). The combined organic
layers were dried with sodium sulfate and concentrated
under vacuum to give the crude product. Purification on an
Al2O3 column gave the pure product. The enantiomeric
excess was determined by HPLC with a chiral column (OD-
H, or AS-H). For details, see Supporting Information
Acknowledgements
Financial supports from National Natural Science Founda-
tion of China (20873179 and 20973178), the Ministry of Sci-
ence and Technology under grant Nos. 2007CB935904 and
2010CB833305, Renmin University of China, the Hong Kong
Research Grants Council (PolyU 5001/07P), the Hong Kong
UGC AoE Scheme (AoE P/10-01) and the Hong Kong Poly-
technic University Areas of Strategic Development Fund, are
gratefully acknowledged.
Experimental Section
General Methods
Unless otherwise noted, all experiments were carried out
under an atmosphere of nitrogen using standard Schlenk
techniques or in a nitrogen-filled glovebox. 1H NMR and
13C NMR spectra were recorded on a Bruker Model Avance
DMX 400 Spectrometer (1H 400 MHz and 13C 106 MHz, re-
spectively). Chemical shifts (d) are given in ppm and are
referenced to residual solvent peaks. Optical rotations were
measured with PerkinElmer 341 polarimeter. All organic
solvents were dried using standard, published methods and
were distilled before use. All other chemicals were used as
received from Aldrich or Acros without further purification.
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2,6-Substituted Quinolines
A mixture of [IrACHTUNGTRENNUNG(COD)Cl]2 (1.0 mg, 0.0015 mmol) and the
ligand (R)-P-Phos (2.0 mg, 0.003 mmol) in THF (2.0 mL)
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Adv. Synth. Catal. 2010, 352, 1055 – 1062
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1061

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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1055 – 1062