Highly enantioselective iridium-catalyzed hydrogenation of heteroaromatic compounds, quinolines

Article abstract of DOI:10.1021/ja0353762

The highly enantioselective hydrogenation of quinoline derivatives is developed using [Ir(COD)Cl]₂/(R)-MeO-Biphep/I₂ system, and this methodology has been applied to the asymmetric synthesis of three naturally occurring alkaloids angustureine, galipinine, and cuspareine. This method provided an efficient access to a variety of optically active tetrahydroquinolines with up to 96% ee. Copyright

Full text of DOI:10.1021/ja0353762

Published on Web 08/09/2003
Highly Enantioselective Iridium-Catalyzed Hydrogenation of Heteroaromatic
Compounds, Quinolines
Wen-Bo Wang, Sheng-Mei Lu, Peng-Yu Yang, Xiu-Wen Han, and Yong-Gui Zhou*
Dalian Institute of Chemical Physics, the Chinese Academy of Sciences, Dalian 116023, P. R. China
Received March 30, 2003; E-mail: ygzhou@dicp.ac.cn
Catalytic asymmetric hydrogenations of prochiral unsaturated
compounds, such as olefin, ketone, and imine, have been intensively
studied and are considered as a versatile method of creating a chiral
Scheme 1
1
carbon center. However, asymmetric hydrogenation of hetero-
aromatic compounds is less explored, resonance stability of
heteroaromatic compounds might impede the enantioselective
hydrogenation.2 To date, only a few papers on homogeneous
asymmetric hydrogenation of heteroaromatic compounds have been
reported. Kuwano and co-workers reported a highly effective
Table 1. Catalytic Asymmetric Hydrogenation of 1aa
entry
H
2
(psi); T (
°C)
solvent
convnb (%)
eec (%)
hydrogenation of N-Boc- or Ac-substituted indoles by application
3
1
2
3
4
5
6
7
8
9
10
700; 25
700; 25
700; 25
700; 25
700; 25
700; 25
700; 25
1500; 25
100; 25
700; 55
CH2Cl2
(ClCH2)2
MeOH
i-PrOH
THF
toluene
benzene
toluene
toluene
toluene
>99
>99
85
>99
>99
>99
>99
>99
68
85
85
9
84
85
94
94
91
94
90
of Rh/Ph-TRAP/Cs
2
CO
3
catalyst, and up to 95% ee was obtained.
Bianchini developed an orthometalated dihydride iridium complex
4
for hydrogenation of 2-methylquinoxaline with 90% ee. Studer
2 4
and co-workers employed Rh(NBD) BF /DIOP as the catalyst for
hydrogenation of monosubstituted pyridine and furans with only
a
2
4-27% ee.5 Rh(DIOP)H was used as the catalyst for hydrogena-
5b
tion of 2-methylquinoxaline with only 3% ee. The search for a
new catalytic system for asymmetric hydrogenation of hetero-
aromatic compounds is still a challenge.
>99
a
Reaction conditions: 1 mmol quinoline, [Ir(COD)Cl]2 (0.5%), chiral
Direct hydrogenation of easily available quinoline derivatives
is the most convenient route to synthesize tetrahydroquinoline
derivatives, which are important organic synthetic intermediates6
and structural units of alkaloids and biologically active compounds.7
Although many efforts have been made toward development of
b
1
ligand (1.1%), I2 (10%), 5 mL solvent. Determined by H NMR analysis
of the crude products. c Determined by HPLC analysis with Chiralpak OJ-H
column, the absolute configuration of product is assigned by comparison
of rotation sign with literature data.
could proceed well to give 2-methyl-1,2,3,4-tetrahydrohydroquino-
line (2a) in excellent conversion in 18 h with high to excellent
enantioselectivities. In contrast to alcoholic solvents (entries 3, 4),
aprotic solvents (entries 1-2, 5-7) gave better enantioselectivities.
In all cases, there were no 2-methyl-5,6,7,8-tetrahydroquinoline and
8
9
hydrogenation of quinolines using homogeneous achiral Rh or Ru
catalysis, to the best of our knowledge, no report on homogeneous
asymmetric hydrogenation of quinolines has appeared in the
literature. Therefore, we decided to focus on this reaction. In this
communication, we report our preliminary results and describe the
first example of highly enantioselective iridium-catalyzed hydro-
genation of quinolines.
1
2-methyl-1,2,3,4,5,6,7,8-octahydro-quinoline detected by H NMR
analysis of the reaction mixture. A change in hydrogen pressure
had no clear effect on enantioselectivity (entries 7-9), but
conversion was decreased under lower pressure (entry 9). A slightly
lower ee was obtained under higher temperature (entry 10).
Therefore, the optimal condition for hydrogenation of 1a was shown
in entry 6. Under these experimental conditions, other commercially
available chiral bidentate phosphine ligands were also tested for
hydrogenation of 1a, and it was found that enantioselectivities
decreased whenever Ir-BINAP (87% ee), Ir-DIOP (53% ee), or Ir-
Me-DuPhos (51% ee) was used instead of Ir-MeO-Biphep (entry
Considering that iridium has been successfully applied to
asymmetric hydrogenation of imines and unfunctionalized olefins
1
recently, we first examined the [Ir(COD)Cl]
2
/MeO-Biphep/DCM
system for hydrogenation of 2-methylquinoline (1a) (Scheme 1).
Unfortunately, it was found that the catalytic activity is very low,
and only a trace amount of product with low ee was obtained when
the reaction was carried out in methylene chloride at room
temperature under 700 psi of hydrogen for 18 h. A number of
literature reports have appeared documenting the dramatic impact
6, 94% ee). Thus, the optimized conditions are: [Ir(COD)Cl] /MeO-
2
10
of additives on catalytic turnover and enantioselectivity. Accord-
Biphep/I /toluene/H 700 psi/25 °C.
2
2
1
1
12,13
ingly, we evaluated a number of additives, such as I
2
n-Bu
4
NI,
Under optimized condition, a variety of substituted quinoline
derivatives were hydrogenated using Ir/MeO-Biphep/I catalyst.
13
14
15
3
BiI ,
phthalimide, benzylamine, etc., in an attempt to promote
2
reaction turnover. Gratifyingly, iodine proved to be the most
efficient additive in this reaction. Chiral iridium complex prepared
in situ from [Ir(COD)Cl] and chiral bisphosphine (R)-MeO-Biphep
2
were employed as catalysts, and the reactions were carried out at
room temperature under 700 psi of hydrogen with a substrate:[Ir]:
Several 2-alkyl substituted quinolines were hydrogenated with high
enantioselctivities (>92% ee) regardless of the length of side chain
(entries 1-6 in Table 2). Branched substituent (i-Pr) in the 2
position also gave good enantioselectivity (entry 18). 2-Arenethyl-
substituted quinolines also gave excellent asymmetric induction
(entries 7-9). With 2-aryl-substituted quinolines (entry 13), slightly
lower enantioselectivity was obtained. It is noted that this catalytic
system can tolerate hydroxyl and ester groups (entries 14-17, 19),
ligand:I
reaction was strongly solvent-dependent. As shown in Table 1, the
reactions in THF, benzene, toluene, DCM, ClCH CH Cl, i-PrOH
2
ratio of 100:0.5:1.1:10. Further studies showed that this
2
2
10536
9
J. AM. CHEM. SOC. 2003, 125, 10536-10537
10.1021/ja0353762 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Iridium-Catalyzed Asymmetric Hydrogenation of 1a
through our synthesis (for the detailed procedure, see Supporting
Information). 2j is the key intermediate in the synthesis of anti-
bacterial agent of flumequine,16 which was obtained through the
resolution method.
In conclusion, we developed the first example of highly enan-
tioselectiVe hydrogenation of quinoline deriVatiVes using an Ir/
phosphine/I system and applied it to the asymmetric synthesis of
2
three naturally occurring alkaloids angustureine, galipinine, and
cuspareine. This method provides an efficient access to a variety
of optically active tetrahydroquinolines with up to 96% ee. Since
tetrahydroquinoline derivatives are important synthetic intermediates
and biologically active compounds, the current method has a high
potential for practical use in organic synthesis. Further work will
be directed toward detailed study of the reaction mechanism and
the development of the hydrogenation of a broader range of
substrates and other heteroaromatic systems.
Acknowledgment. We are grateful for the financial support
from Talent Scientist Program, the Chinese Academy of Sciences.
Supporting Information Available: Characterization data for all
compounds and experimental procedures (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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f
(
Scheme 2
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7
b
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