Synthesis of tunable bisphosphine ligands and their application in asymmetric hydrogenation of quinolines

Article abstract of DOI:10.1021/jo800779r

(Chemical Equation Presented) A series of tunable axial chiral bisphosphine ligands have been synthesized from (S)-MeO-Biphep. The Ir complex of the MeO-PEG-supported ligand (S)-4k has been successfully applied in asymmetric hydrogenation of quinolines with up to 92% ee. The catalyst system is air-stable and recyclable.

Full text of DOI:10.1021/jo800779r

Synthesis of Tunable Bisphosphine Ligands and
Their Application in Asymmetric Hydrogenation
of Quinolines
SCHEME 1. Synthesis of Biphosphine Ligands (S)-4
Xiao-Bing Wang and Yong-Gui Zhou*
State Key Laboratory of Catalysis, Dalian Institute of
Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, People’s Republic of China
ygzhou@dicp.ac.cn
ReceiVed April 7, 2008
reactions. At present, varying the dihedral angle of the chiral
backbone, replacing P substitutes, and modification of the axial
chiral backbone are effective strategies for divergent synthesis
of biaryl bisphosphine ligands. Zhang and co-workers designed
modual TunePhos by connecting the two aryl moieties with
7
tunable chiral or achiral linkers. Zhang and co-workers
developed an effective method for the synthesis of bisphosphine
11b
ligands by changing the 5,6-substituents of every aryl moiety.
In this note, we have developed a new method for a divergent
synthesis of bisphosphine ligands by introduction of different
substituents at the 6,6′-positions of the biaryl backbone, and
these ligands have been successfully applied to asymmetric
hydrogenations of quinolines.
A series of tunable axial chiral bisphosphine ligands have
been synthesized from (S)-MeO-Biphep. The Ir complex of
the MeO-PEG-supported ligand (S)-4k has been successfully
applied in asymmetric hydrogenation of quinolines with up
to 92% ee. The catalyst system is air-stable and recyclable.
Optically active compounds are very important for the
synthesis of biologically active natural products and chiral
1
(
S)-MeO-Biphep was chosen as the starting material to make
drugs. Transition metal-catalyzed asymmetric reactions are most
2
the chiral bisphosphine ligands (Scheme 1). (S)-2 can be
conveniently synthesized through demethylating according to
often used for achieving high optical purity compounds. Design
and synthesis of chiral ligands are still a key issue for obtaining
high activity and selectivity. In the past 30 years, thousands of
chiral ligands have been synthesized and successfully applied
(4) (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi,
T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (b) Takaya, H.; Mashima,
K.; Koyano, K.; Yagi, M.; Kumobayashi, H.; Taketomi, T.; Akutagawa, S.;
Noyori, R. J. Org. Chem. 1986, 51, 629. (c) Noyori, R.; Takaya, H. Acc. Chem.
Res. 1990, 23, 345.
3
in academic research and industrial production. However,
reactivities and enantioselectivities are generally substrate-
dependent. There is no omnipotent ligand for every substrate,
so developing easily prepared, tunable ligands is still necessary.
Atropisomeric C2-symmetric biaryl bisphosphines such as
(5) Schmid, R.; Cereghetti, M.; Heiser, B.; Schonholzer, P.; Hansen, H.-J.
HelV. Chim. Acta 1988, 71, 897.
(6) (a) Schmid, R.; Foricher, J.; Cereghetti, M.; Schonholzer, P. HelV. Chim.
4
5
6
7
8
Acta 1991, 74, 370. (b) Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.;
Foricehr, J.; Lalonde, M.; Muller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U.
Pure Appl. Chem. 1996, 68, 131.
BINAP, BIPHEP, MeO-BIPHEP, TunePhos, P-Phos, Seg-
9
10
Phos, Diflurophos, and other important biaryl phosphine
1
1
(7) Zhang, Z.-G.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem. 2000,
ligands are very effective ligands for many asymmetric
6
5, 6223.
(8) (a) Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.; Chan, A. S. C.; Wong,
*
To whom correspondence should be addressed. Phone: +86-411-84379220.
Fax: +86-411-84379220.
1) For some recent books, see:(a) Ojima, I. Ed. Catalytic Asymmetric
W. T. J. Am. Chem. Soc. 2000, 122, 11513. (b) Wu, J.; Chen, H.; Kwok, W.-H.;
Guo, R.-W.; Zhou, Z.-Y.; Yeung, C.-H.; Chan, A. S. C. J. Org. Chem. 2002,
67, 7908. (c) Wu, J.; Chen, H.; Kwok, W-H.; Lam, K.-H.; Zhou, Z.-Y.; Yeung,
C.-H.; Chan, A. S. C. Tetrahedron Lett. 2002, 43, 1539.
(
Synthesis; Wiley-VCH: New York, 2000. (b) Noyori, R. Ed. Asymmetric Catalysis
in Organic Synthesis; Wiley: New York, 1994. (c) Jacobsen, E. N.; Pfaltz, A.;
Yamamoto, H. Eds. ComprehensiVe Asymmetric Catalysis; Springer: Berlin,
Germany, 1999; Vols. 1-3.
(9) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.;
Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(10) Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Gen eˆ t, J.-
P.; Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004, 43, 320.
(11) (a) Wan, X.-B.; Sun, Y.-H.; Luo, Y.-F.; Li, D.; Zhang, Z.-G. J. Org.
Chem. 2005, 70, 1070. (b) Sun, Y.-H.; Wan, X.-B.; Guo, M.-J.; Wang, D.-H.;
Dong, X.-C.; Pan, Y.; Zhang, Z.-G. Tetrahedron: Asymmetry 2004, 15, 2185.
(c) Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Gen eˆ t, J.-P.;
Champion, N.; Deschaux, G.; Dellis, P. Org. Process Res. DeV. 2003, 7, 399.
(d) Lerouxa, F. R.; Mettler, H. AdV. Synth. Catal. 2007, 349, 323.
(
2) (a) Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998. (b) Noyori,
R. Angew. Chem., Int. Ed. 2002, 41, 2008. (c) Noyori, R.; Ohkuma, T. Angew.
Chem., Int. Ed. 2001, 40, 40. (d) Cui, X.; Burgess, K. Chem. ReV. 2005, 105,
3
272.
(
3) (a) Li, Y.-M.; Kwong, F.-Y.; Yu, W.-Y.; Chan, A. S. C. Coord. Chem.
ReV. 2007, 251, 2119. (b) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007,
0, 1278. (c) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
4
5
640 J. Org. Chem. 2008, 73, 5640–5642
10.1021/jo800779r CCC: $40.75  2008 American Chemical Society
Published on Web 06/25/2008

7
the reported procedure. Reaction of (S)-2 with halides or
TABLE 1. Condition Optimization for Ir-Catalyzed Asymmetric
a
Hydrogenation of 2-Methylquinoline
sulfonate esters in the presence of excess anhydrous K2CO3 in
acetone gave (S)-3 with 59-96% yields. (S)-4 was prepared
by the reaction of (S)-2 or (S)-3 with halides in the presence of
Cs2CO3 in DMF with 27-91% yields. Recently, separation and
recycling of the expensive chiral catalyst has been developed
by utilizing soluble PEG polymer supports. These catalysts have
catalytic activities and enanoselectivities similar to those of the
homogeneous parent systems. When the reaction is completed,
the catalyst can be separated by either extraction or precipita-
tion. MeO-PEG-based ligands were also prepared by the
reaction of MeO-PEG-OMs with (S)-2 or (S)-3 in the presence
of Cs2CO3 in DMF.
Asymmetric hydrogenation of easily accessible quinolines is
doubtless the most direct and convenient access toward chiral
tetrahydroquinoline derivatives, which are important synthetic
intermediates and structural units of natural products and
biologically active compounds. Recently, we discovered Ir
complexes bearing the bisphosphines or N,P ligands performed
effectively to give tetrahydroquinoline derivatives in the pres-
b
entry
ligand
R1
R2
ee (%)
1
2
3
4
5
6
7
8
9
(S)-4a
(S)-4b
(S)-4c
(S)-4d
(S)-4e
(S)-4f
(S)-4g
(S)-4h
(S)-4i
(S)-4j
(S)-4k
(S)-4l
(S)-4m
(S)-4n
(S)-4o
(S)-4p
(S)-4q
(S)-4k
(S)-4k
(S)-4k
n-C H -
1
6
33
n-C H -
n-C16H33-
Bn
Bn
16 33
93
89
87
91
92
83
86
90
80
81
91
89
85
87
74
90
89
87
86
89
n-C6H13-
n-C16H33-
n-C6H13-
n-C4H9-
Me
Et
1
2
Bn
MeO-PEG-(1600)
MeO-PEG-(1600)
MeO-PEG-(1600)
MeO-PEG-(1600)
MeO-PEG-(1600)
MeO-PEG-(1600)
MeO-PEG-(1600)
MeO-PEG-(1600)
MeO-PEG-(1600)
MeO-PEG-(1600)
MeO-PEG-(1100)
MeO-PEG-(5000)
MeO-PEG-(1600)
MeO-PEG-(1600)
MeO-PEG-(1600)
n-C4H9-
n-C6H13-
n-C8H17-
n-C12H25-
n-C16H33-
Bn
CH2dCHsCH2-
MeO-PEG-(1600)
n-C12H25-
n-C12H25-
n-C12H25-
n-C12H25-
n-C12H25-
10
11
12
13
14
15
16
17
18
13
ence of iodine with high enantioselectivity and excellent yield.
Several groups reported the asymmetric hydrogenation of
quinolines using other chiral phosphine ligands. Asymmetric
transfer hydrogenation of quinolines with organocatalysis has
c
d
e
1
4
19
2
0
1
5
also been reported.
a
All reactions were performed on a 0.5-mmol scale: [Ir(COD)Cl]2 0.5
With these chiral bisphosphine ligands in hand, Ir-catalyzed
asymmetric hydrogenation of 2-methylquioline as a model
substrate was performed under the standard reaction (toluene
as solvent, I2 as additive, 600 psi of H2, rt). We first screened
the effects that different ligands with alkyl and Bn group
substitution had on the asymmetric hydrogenation of quinolines
mol %, ligand 1.1 mol %, I2 5 mol%, H2 600 psi, toluene 2 mL, 16 h,
b
room temperature, >95% conversion. Determined by HPLC analysis
c
d
e
with OJ-H column. CH2Cl2 as solvent. THF as solvent. The reaction
was carried out in air.
substitutents. MeO-PEG-(1600)-based chiral ligands bearing
different alkyl substituents gave 80-91% ee. The different
enantioselectives may be due to the varying of the dihedral angle
of the chiral backbone. The introduction of the different
molecular weight of MeO-PEG- on the ligands had no
significant effect on the ee values (entries 11, 16, and 17).
The best enantioselectivity was achieved by using ligand (S)-
4k (entry 11). The effect of solvents on the reactivity and
enantioslectivity was also studied with (S)-4k as ligand. Full
conversions were achieved in CH2Cl2 and THF with slightly
lower enantioselectivies (entries 18 and 19). It is coming to
light that the existence of trace air in the reaction can lead
to deactivation of the catalyst and irreproducible results
because the transition metal catalyst is air sensitive. Hence
it is highly desirable to develop a catalyst with high activity
and good air-stability. It is notable that our catalyst displayed
the same activity with slightly lower enantioselectivity when
it was prepared in air (entry 20).
(
entries 1-5, Table 1). The enantioselectivities varied from 87%
to 93% ee. MeO-PEG-based ligands were also screened (entries
-17), showing moderate enantioselectivity (74% ee, entry 15)
when using (S)-4o with the same two MeO-PEG-(1600)
6
(
12) For PEG-supported chiral catalysts for asymmetric hydrogenation
reactions, see: (a) Li, X.; Chen, W.; Hems, W.; King, F.; Xiao, J. Org. Lett.
003, 5, 4559. (b) Saluzzo, C.; Lamouille, T.; Herault, D.; Lemaire, M. Bioorg.
2
Med. Chem. Lett. 2002, 12, 1841. (c) Fan, Q.; Deng, G.; Lin, C.; Chan, A. S. C.
Tetrahedron: Asymmetry 2001, 12, 1241. (d) Fan, Q.; Deng, G.; Chen, X.; Xie,
W.; Jiang. D.; Liu, D.; Chan, A. S. C. J. Mol. Catal. A: Chem. 2000, 159, 37.
(
e) Chai, L.; Chen, H.; Li, Z.; Wang, Q.; Tao, F. Synlett 2006, 15, 2395. (f) Hu,
X.-P.; Huang, J.-D.; Zeng, Q.-H.; Zheng, Z. Chem. Commun. 2006, 293.
13) For our recent work on asymmetric hydrogenation of quinolines and
(
isoquinolines, see: (a) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357. (b) Wang,
W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc.
2
2
003, 125, 10536. (c) Lu, S.-M.; Han, X.-W.; Zhou, Y.-G. AdV. Synth. Catal.
004, 346, 909. (d) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew.
Chem., Int. Ed. 2006, 45, 2260. (e) Zhao, Y.-J.; Wang, Y.-Q.; Zhou, Y.-G. Chin.
J. Catal. 2005, 26, 737. (f) Wang, D.-W.; Zeng, W.; Zhou, Y.-G. Tetrahedron:
Asymmetry 2007, 18, 1103.
(
14) For other group’s work on asymmetric hydrogenation of quinolines,
see: (a) Xu, L.-J.; Lam, K.-H.; Ji, J.-X.; Wu, J.; Fan, Q.-H.; Lo, W.-H.; Chan,
A. S. C. Chem. Commun. 2005, 1390. (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,
On the basis of the optimized reaction conditions, asymmetric
hydrogenation of a variety of 2-substituted quinoline derivatives
were also carried out. The results are summarized in Table 2.
Good to excellent enantioselectivities were achieved in the
hydrogenation of 2-alkyl-substituted quinolines. The length of
the alkyl chain has no significant effect on the ee values (entries
1-4). When the alkyl group at the 2-position was replaced by
the phenyl group, a lower enantioselectivity was observed (entry
8). However, 2-phenylethyl-substituted quinolines can afford
excellent enantioseletivity (92% ee). With 6-substituted quino-
lines, the strong electro-donating methoxy group afforded lower
enantioselectivity (78% ee, entry 13). The hydrogenation of
quinolines with hydroxyl groups also proceeded smoothly,
affording excellent enantioselectivities (entries 9 and 10).
3
47, 1755. (c) Yamagata, T.; Tadaoka, H.; Nagata, M.; Hirao, T.; Kataoka, Y.;
Ratovelomanana-Vidal, V.; Genet, J. P.; Mashima, K. Organometallics 2006,
2
5, 2505. (d) Reetz, M. T.; Li, X. Chem. Commun. 2006, 2159. (e) Wu, J.;
Chan, A. S. C. Acc. Chem. Res. 2006, 39, 711. (f) Tang, W.-J.; Zhu, S.-F.; Xu,
L.-J.; Zhou, Q.-L.; Fan, Q.-H.; Zhou, H.-F.; Lam, K.-H.; Chan, A. S. C. Chem.
Commun 2007, 613. (g) Qiu, L.-Q.; Kwong, F.-Y.; Wu, J.; Lam, W.-H.; Chan,
S.-S.; Yu, W.-Y.; Li, Y.-M.; Guo, R.-W.; Zhou, Z.-Y.; Chan, A. S. C. J. Am.
Chem. Soc. 2006, 128, 5955. (h) Wang, Z.-J.; Deng, G.-J.; Li, Y.; He, Y.-M.;
Tang, W.-J.; Fan, Q.-H. Org. Lett. 2007, 9, 1243. (i) 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. (j) Jahjah, M.;
Alame, M.; Pellet-Rostaing, S.; Lemaire, M. Tetrahedron: Asymmetry 2007, 18,
2
305.
(
15) Asymmetric transfer hydrogenation of quinolines with organocatalysis,
see: (a) Rueping, M.; Antonchick, A. P.; Theissmann, T. Angew. Chem., Int.
Ed. 2006, 45, 3683. (b) Guo, Q.-S.; Du, D.-M.; Xu, J.-X. Angew. Chem., Int.
Ed. 2008, 47, 759.
J. Org. Chem. Vol. 73, No. 14, 2008 5641

TABLE 2. Ir-Catalyzed Asymmetric Hydrogenation of
TABLE 3. Recyclability of the Ir Complex in Asymmetric
a
a
Quinolines
Hydrogenation of Quinolines
1
2
b
cycle
run 1
run 2
run 3
run 4
run 5
entry
R /R
yield (%)
ee (%)
b
conv (%)
>95
91
>95
90
>95
88
>95
85
95
84
1
2
3
4
5
6
7
8
9
H/Me (5a)
H/Et (5b)
H/n-Bu (5c)
H/n-pentyl (5d)
91 (6a)
93 (6b)
91 (6c)
93 (6d)
92 (6e)
92 (6f)
90 (6g)
96 (6h)
85 (6i)
97 (6j)
98 (6k)
91 (6l)
91(6m)
91(S)
91(S)
89(S)
91(S)
92(S)
92(S)
92(S)
72(R)
91(R)
91(R)
90(S)
91(S)
78(S)
c
ee (%)
a
Reaction conditions: 1 mmol of 5a in toluene/CH2Cl2 (3/1) 4 mL,
Ir(COD)Cl]2 0.5 mol %, (S)-4k 1.1 mol %, I2 5 mol %, 600 psi H2,
room temperature, 16 h. Conversions were determined by H NMR
analysis of the crude products. Determined by HPLC analysis with an
OJ-H column.
[
H/phenethyl (5e)
b
1
H/3,4-methylenedioxy-phenethyl (5f)
H/3,4-(MeO)2C6H3(CH2)2- (5g)
H/Ph (5h)
H/c-C6H10(OH)CH2- (5i)
H/Ph2CH(OH)CH2- (5j)
Me/Me (5k)
c
10
11
12
13
was added Cs
(S)-2 or 1.0 equiv for (S)-3). The mixture was heated at 65 °C for
16 h. After removal of Cs CO , the residue was evaporated and
dissolved in CH Cl (2 mL). Hexane (25 mL) was added slowly to
2 3
CO (4 equiv) and MeO-PEG-OMs (2.0 equiv for
F/Me (5l)
MeO/Me (5m)
2
3
2
2
a
the solution with vigorous stirring at -20 °C. The precipitate formed
Reaction conditions: 0.5 mmol quinolines, [Ir(COD)Cl]2 (0.5 mol
was isolated by filtration and then dried in vacuo to give the MeO-
%
1
), (S)-4k (1.1 mol %), I2 (5 mol %), 2 mL of toluene, 600 psi H2, rt,
6 h. Determined by HPLC analysis with OJ-H, OD-H, and AS-H
columns.
b
25
PEG derivatives (S)-4f-q. (S)-4k: [R]
D
3
-5.1 (c 2.00, CHCl );
1
73%; H NMR (400 MHz, CDCl
3
) δ 0.77 (t, J ) 6.4 Hz, 3H),
.93-122 (m, 20H), 3.10-3.16 (m, 1H), 3.42-3.48 (m, 1H),
.19-3.81 (polyethylene glycol peaks), 6.59-7.08 (m, 4H),
0
3
7
We then examined recyclability of the Ir complex of the
MeO-PEG-(1600)-supported ligand (S)-4k in asymmetric hy-
drogenation of quinolines. After the first run of the reaction,
hexane was added to the reaction mixture, precipitating out the
catalyst, which was then filtered off and washed with hexane
three times. Because the recovered catalyst cannot be entirely
redissolved in toluene, we chose CH2Cl2/toluene (1/3) as solvent
to test the recyclability of the catalyst. The recovered catalyst
could be recycled with only a slight loss in the activity and
enantioselectivity for asymmetric hydrogenation of quinolines
from 91% ee in the first run to 84% ee in the fifth run, Table
). These results demonstrate further advantages of the type of
ligands, which can be reused in asymmetric hydrogenation of
quinolines.
In conclusion, a series of tunable chiral bisphosphine ligands
were conveniently synthesized and successfully applied in
asymmetric hydrogenation of quinolines. [Ir(CODCl)2/(S)-4k/
I2 catalyst has the advantage of air-stability and easy reutiliza-
tion. Future work on the application of these ligands will focus
on extension of other transition metal-catalyzed enantioselective
reactions.
31
.08-7.19 (m, 22H); P NMR (162 MHz, CDCl
Procedure for Asymmetric Hydrogenation of Quinoline
Derivatives. A mixture of [Ir(COD)Cl] (1.7 mg, 0.0025 mmol)
3
) δ -13.91.
2
and (S)-4k (14.4 mg, 0.0055 mmol) in toluene (2 mL) was stirred
at room temperature for 10 min in a glovebox, then the mixture
was transferred by syringe to an autoclave in which I
.025 mmol) and substrate (0.5 mmol) were placed beforehand.
The hydrogenation was performed at room temperature under H
600 psi) for 16 h. After the hydrogen was carefully released, the
2
(6.4 mg,
0
2
(
reaction mixture was concentrated to afford the crude product.
Purification was performed by a silica gel column eluted with
hexane/EtOAc to give pure product. (S)-2-Methyl-1,2,3,4-tetrahy-
droquinoline (6a): Yield 91%, [R] -78.3 (c 0.76, CHCl ); H
NMR (400 MHz, CDCl
(
3
2
5
1
D
3
3
) δ 1.24 (t, J ) 6.5 Hz, 3H), 1.62 (m,
1H), 1.96 (m, 1H), 2.81 (m, 2H), 3.42 (m, 1H), 3.50 (br, 1H), 6.49
(
d, J ) 8.2 Hz, 1H), 6.63 (m 1H), 6.98 (m, 2H).
Acknowledgment. We are grateful to the financial support
from the National Science Foundation of China (20532050 and
2
0621063) and the Chinese Academy of Sciences.
Supporting Information Available: Spectroscopic date,
Experimental Section
HPLC spectra, and experimental details. This material is
available free of charge via the Internet at http://pubs.acs.org.
General Procedure for the Synthesis of (S)-4f-q. A solution
of (S)-2 or (S)-3 in DMF was bubbled with N
2
. To this solution
JO800779R
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642 J. Org. Chem. Vol. 73, No. 14, 2008