Enantioselective hydrogenation of quinolines catalyzed by Ir(BINAP)-cored dendrimers: Dramatic enhancement of catalytic activity

Article abstract of DOI:10.1021/ol0631410

Figure presented The asymmetric hydrogenation of quinolines catalyzed by chiral dendritic catalysts derived from BINAP gave the corresponding products with high enantioselectivities (up to 93%), excellent catalytic activities (TOF up to 3450 h^-1), and productivities (TON up to 43 000). In addition, the third-generation catalyst could be recovered by precipitation and filtration and reused at least six times with similar enantioselectivity.

Full text of DOI:10.1021/ol0631410

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1243-1246
Enantioselective Hydrogenation of
Quinolines Catalyzed by Ir(BINAP)-Cored
Dendrimers: Dramatic Enhancement of
Catalytic Activity
Zhi-Jian Wang,†,‡ Guo-Jun Deng,† Yong Li,†,‡ Yan-Mei He,† Wei-Jun Tang,† and
Qing-Hua Fan*,†
Beijing National Laboratory for Molecular Sciences, Center for Chemical Biology,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China, and
Graduate School of the Chinese Academy of Sciences, Beijing 100080, China
fanqh@iccas.ac.cn
Received December 29, 2006
ABSTRACT
The asymmetric hydrogenation of quinolines catalyzed by chiral dendritic catalysts derived from BINAP gave the corresponding products with
-
high enantioselectivities (up to 93%), excellent catalytic activities (TOF up to 3450 h 1), and productivities (TON up to 43 000). In addition, the
third-generation catalyst could be recovered by precipitation and filtration and reused at least six times with similar enantioselectivity.
The use of metallodendrimers in homogeneous catalysis is
an important frontier of research in recent years.1 Because
of the well-defined molecular architecture of dendrimers, it
is possible to fine-tune their catalytic properties through the
systematic adjustment of their structure, size, shape, and
solubility. Thus, a number of organometallic dendrimers with
catalytic sites at either their core or their periphery have been
reported. Among them, however, only a few reported a strong
positive catalytic effect of dendrimers compared to that of
monomeric species.2,3 In the case of the core-functionalized
dendrimers, it is expected that the steric shielding or blocking
effect of the specific microenvironment created by the
branched shell could modulate the catalytic behavior of the
core. Recently, we reported a kind of BINAP-cored den-
drimer for asymmetric hydrogenation of prochiral olefins.3b
(2) For examples of achiral dendrimer catalysts with a positive dendrimer
effect, see: (a) Ropartz, L.; Morris, R. E.; Foster, D. F.; Cole-Hamilton,
D. J. Chem. Commun. 2001, 361. (b) Francavilla, C.; Drake, M. D.; Bright,
F. V.; Detty, M. R. J. Am. Chem. Soc. 2001, 123, 57. (c) Mizugaki, T.;
Murata, M.; Ooe, M.; Ebitani, K.; Kaneda, K. Chem. Commun. 2002, 52.
(d) Dahan, A.; Portnoy, M. Org. Lett. 2003, 5, 1197. (e) Mu¨ller, C.;
Ackerman, L. J.; Reek, J. M. H.; Kamer, P. C. J.; van Leeuwen, P. W. N.
M. J. Am. Chem. Soc. 2004, 126, 14960. (f) Ooe, M.; Murata, M.; Mizugaki,
T.; Ebitani, K.; Kaneda, K. J. Am. Chem. Soc. 2004, 126, 1604. (g) Fujihara,
T.; Obora, Y.; Tokunaga, M.; Sato, H.; Tsuji, Y. Chem. Commun. 2005,
4526. (h) Ouali, A.; Laurent, R.; Caminade, A.-M.; Majoral, J.-P.; Taillefer,
M. J. Am. Chem. Soc. 2006, 128, 15990.
† Institute of Chemistry, Chinese Academy of Sciences.
‡ Graduate School of the Chinese Academy of Sciences.
(1) For selected reviews on dendritic organometallic catalysts, see: (a)
Oosterom, G. E.; Reek, J. N. H.; Kamer, P. C. J.; van Leeuwen, P. W. N.
M. Angew. Chem., Int. Ed. 2001, 40, 1828. (b) Astruc, D.; Chardac, F.
Chem. ReV. 2001, 101, 2991. (c) van Heerbeek, R.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Reek, J. N. H. Chem. ReV. 2002, 102, 3717. (d)
Twyman, L. J.; King, A. S. H.; Martin, I. K. Chem. Soc. ReV. 2002, 31, 69.
(e) Helms, B.; Fre´chet, J. M. J. AdV. Synth. Catal. 2006, 348, 1125. (f)
Kassube, J. K.; Gade, L. H. Top. Organomet. Chem. 2006, 20, 61.
(3) For examples of chiral dendrimer catalysts with a positive dendrimer
effect, see: (a) Breinbauer, R.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2000, 39, 3604. (b) Fan, Q. H.; Chen, Y. M.; Chen, X. M.; Jiang, D. Z.;
Xi, F.; Chan, A. S. C. Chem. Commun. 2000, 789. (c) Hu, Q. S.; Pugh, V.;
Sabat, M.; Pu, L. J. Org. Chem. 1999, 64, 7528. (d) Ribourdouille, Y.;
Engel, G. D.; Richard-Plouet, M; Gade, L. H. Chem. Commun. 2003, 1228.
(e) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8,
4417.
10.1021/ol0631410 CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/01/2007

It was found that the rate of the reaction increased using the
higher-generation dendritic catalysts. In contrast, dendritic
catalysts with a chiral diphosphine pyrphos located at the
focal point showed a dramatic decrease in catalytic activity
on going from generation 3 to generation 4.4 This negative
effect might be due to the steric shielding effect of the
dendritic shell. Here, we wish to report a strong positive
dendrimer effect in the Ir-catalyzed asymmetric hydrogena-
tion of quinolines by using our BINAP-cored dendrimers.
Asymmetric hydrogenation of quinolines constitutes the
most convenient route to enantiomerically pure 1,2,3,4-
tetrahydroquinolines, compounds which not only are useful
synthetic intermediates but also are the structural units in
naturally occurring alkaloids.5 Although a variety of chiral
Rh, Ru, and Ir complexes have been demonstrated to be
highly efficient and enantioselective in the hydrogenation
of prochiral olefins, ketones, and imines,6 most of these
catalysts failed to give satisfactory results in the asymmetric
hydrogenation of heteroaromatic compounds.7-9 Successful
examples in the asymmetric hydrogenation of quinolines are
rare.8,9 Recently, Zhou and co-workers found that the iridium
complex generated in situ from [Ir(COD)Cl]2 and (R)-MeO-
BIPHEP or the ferrocenyloxazoline-derived P,N-ligand is
effective in the hydrogenation of 2-substituted quinolines
with high enantioselectivities and reaction yields.8a,c Similar
results were subsequently described by Fan and Chan et al.
with the air-stable and recyclable Ir-P-Phos catalyst system.9a
More recently, Fan and Chan et al. further reported that the
iridium complexes prepared from the easily available chiral
phosphinite H8-BINAPO or spiro diphosphinite were able
to catalyze the enantioselective hydrogenation of quinolines
with high enantioselectivities and very good yields.9b,c Reetz
and co-workers also demonstrated BINOL-derived diphos-
phonites with achiral P-ligands as additives to be highly
efficient for the same reactions.9d However, almost all these
catalytic systems suffered from low catalyst efficiency as
evidenced by the fact that good results could only be obtained
at a low substrate-catalyst ratio of 100. Although the
mechanism of this reaction is not clear at this
moment, it is believed that the high catalyst loading may be
due to the catalyst deactivation during the reaction. Recently,
it was reported that the Ir complexes were effective in the
asymmetric hydrogenation of imines.10 However, the forma-
tion of an irreversible iridium dimer could retard the reaction,
as it was a pathway for catalyst deactivation.11 Therefore,
we anticipated that the encapsulation of such an iridium
complex into a dendrimer framework would reduce dimer-
ization and therefore enhance the productivity of the catalyst.
Fre´chet-type polyaryl ether dendrons were chosen for this
study owing to their chemical inertness and inability to
coordinate iridium.12 The synthesis and structures of the
dendritic ligands were outlined in Scheme 1. According to
Scheme 1. Synthesis and Structures of Dendritic
GnDenBINAP Ligands
(4) Yi, B.; Fan, Q. H.; Deng, G. J.; Li, Y. M.; Qiu, L. Q.; Chan, A. S.
C. Org. Lett. 2004, 6, 1361.
(5) For a review on 1,2,3,4-tetrahydroquinolines, see: Katritzky, A. R.;
Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031.
(6) For reviews, see: (a) Noyori, R. Asymmetric Catalysis in Organic
Synthesis; Wiley: New York, 1994. (b) Ojima, I. Catalytic Asymmetric
Synthesis, 2nd ed.; Wiley: New York, 2000. (c) ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
1999; Vol. 2. (d) Lin, G. Q.; Li, Y. M.; Chan, A. S. C. Principles and
Applications of Asymmetric Synthesis; Wiley-Interscience: New York, 2001.
(7) (a) For a recent review, see: Glorius, F. Org. Biomol. Chem. 2005,
3, 4171. (b) Legault, C.; Charette, A. J. Am. Chem. Soc. 2005, 127, 8966.
(c) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653. (d) Lu, S.;
Wang, Y.; Han, X.; Zhou, Y. Angew. Chem., Int. Ed. 2006, 45, 2260.
(8) (a) Wang, W.; Lu, S.; Yang, P.; Han, X.; Zhou, Y. J. Am. Chem.
Soc. 2003, 125, 10536. (b) Yang, P.; Zhou, Y. Tetrahedron: Asymmetry
2004, 15, 1145. (c) Lu, S.; Han, X.; Zhou, Y. AdV. Synth. Catal. 2004,
346, 909.
(9) (a) Xu, L.; Lam, K.; Ji, J.; Wu, J.; Fan, Q.; Lo, W.; Chan, A. S. C.
Chem. Commun. 2005, 1390. (b) Lam, K.; Xu, L.; Feng, L.; Fan, Q.; Lam,
F.; Lo, W.; Chan, A. S. C. AdV. Synth. Catal. 2005, 347, 1755. (c) 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. (d) Reetz, M.; Li, X. Chem.
Commun. 2006, 2159. (e) Yamagata, T.; Tadaoka, H.; Nagata, M.; Hirao,
T.; Kataoka, Y.; Ratovelomanana-Vidal, V.; Geneˆt, J.; Mashima, K.
Organometallics 2006, 25, 2505.
our previous study,3b the chiral dendrimer ligands GnDen-
BINAP were synthesized by condensation of the dendritic
wedges Gn-COOH with (S)-5,5′-diamino BINAP (S)-1 in the
presence of triphenylphosphite, pyridine, and calcium chlo-
ride in N-methyl-2-pyrrolidone (NMP) at 120 °C overnight
in more than 80% reaction yield, respectively. These ligands
1
were fully characterized by H, 13C, and 31P NMR spectros-
copy, MALDI-TOF mass spectrometry, and elemental analy-
sis. All results are in full agreement with the compounds
synthesized.
(10) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(11) Blaser, H.-U.; Pugin, B.; Spindler, F.; Togni, A. C. R. Chim. 2002,
5, 379.
(12) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
1244
Org. Lett., Vol. 9, No. 7, 2007

With these dendritic ligands in hand, we initially focused
on the examination of reaction parameters. The effects of
the solvents, temperature, hydrogen pressure, and additive
on the activity and enantioselectivity were investigated by
using the second-generation dendrimer catalyst, which was
generated in situ from G2DenBINAP and [Ir(COD)Cl]2
(Table 1).
Table 2. Minimum Amount of Dendritic Ir(G2DenBINAP)
Catalystsa
entry sub./cat. time (h)
TON
conversion (%)b ee (%)c
1
2
3
4
5
6
7d
400
1000
2000
1.5
5
5
5
5
400
1000
2000
4550
7450
>95
>95
>95
91
75
>95
86
89
89
89
88
88
88
88
5000
10000
10000
50000
20
48
10000
43000
Table 1. Asymmetric Hydrogenation of Quinaldine (2a)
Catalyzed by Dendritic Ir(G2DenBINAP) Catalysta
a
Reaction conditions: 0.2∼0.5 mmol of quinaldine (2a) in THF,
b
1
1.25∼5.0 mol % of I2, 45 atm H2, 15∼20 °C. Determined by H NMR
analysis of the crude product. c Determined by HPLC analysis. d Substrate
) 17.875 g, 1.25 mol % of I2, 60 mL of THF, 45 atm H2, 15∼20 °C.
entry
solvent
toluene
CH2Cl2
1,4-dioxane
THF
THF/MeOH (4:1)
THF
THF
THF
THF
THF
THF
time (h) conversion (%)b ee (%)c
1
2
3
4
5
20
20
20
20
20
>95
>95
>95
>95
70
81
85
88
89
88
89
88
90
86
85
89
86
nd
time, giving 88% ee and more than 95% conversion (entry
6). It was worthy to note that the reaction performed well
under rather low catalyst loading on a large scale, giving a
TON of 43 000, which is the highest TON reported to date.
Next, we investigated the effect of dendrimer generation
on the catalyst performance (Table 3). It was found that the
6
1.5
1.5
6
1.5
1.5
1.5
1.5
>95
>95
>95
71
7d
8e
9f
10g
11h
12i
13j
50
Table 3. Effect of Dendrimer Generationa
>95
>95
< 5
THF
THF
b
entry
ligand
TOF (h-1
)
conversion (%)c ee (%)d
20
1
2
3
4
5f
6f,g
7f,h
G1DenBINAP
G2DenBINAP
G3DenBINAP
G4DenBINAP
BINAP
1000
1500
1580
>1900
430
50
75
79
>95
43
23
89 (90)e
89 (89)e
88 (90)e
87 (89)e
71 (75)e
87
a
Reaction conditions: 0.25 mmol of quinaldine (2a) in 1.25 mL of
solvent, 0.5 mol % of [Ir(COD)Cl]2, 1.1 mol % of (S)-G2DenBINAP, I2/
catalyst ) 10 (mol/mol), 45 atm H2, 15∼20 °C. b Determined by 1H NMR
c
analysis of the crude product. Determined by HPLC analysis with a
Chirapak OJ-H column. The predominated product was in the S-configu-
d
e
f
ration. Reaction temperature ) 50 °C. Reaction temperature ) 0 °C.
G3DenBINAP
BINAP
3450
625
g
h
i
H2 ) 100 atm. H2 ) 10 atm. I2/catalyst ) 5 (mol/mol). I2/catalyst )
25
71
j
1 (mol/mol). I2 ) 0 mol %.
a
Reaction conditions: 2.5 mmol of quinaldine (2a) in 5 mL of THF,
sub./cat. ) 10 000 (mol ratio), 1.25 mol % of I2, 45 atm H2, 15∼20 °C, 5
h. b Average TOF over the reaction time. c Determined by 1H NMR analysis
of the crude product. Determined by HPLC analysis. Data in brackets
were obtained with 1 mol % of catalyst, and complete conversion was
observed. f Sub./cat. ) 5000. g Reaction time ) 20 min. h Reaction time )
2 h.
d
e
It is interesting to find that the dendritic catalyst is effective
in the asymmetric hydrogenation of 2a with I2 as an additive.
A series of organic solvents were tested, and THF was found
to be the best choice in terms of both conversion and
enantioselectivity (entries 1-5). The use of alcoholic solvent
such as methanol resulted in much lower catalytic activity
(entry 5 vs 6). The enantioselectivity of the reaction was
slightly increased at low temperature, but the reaction could
be completed at prolonged time (entry 8). Notably, low
conversion and enantioselectivity were observed under both
higher and lower hydrogen pressure (entries 9 and 10). The
reaction could not proceed without iodine as an additive
(entry 13).
catalytic activity gradually increased with increasing den-
drimer generation. Under low catalyst loading, the high-
generation catalysts gave only slightly lower enantioselec-
tivities. The maximum initial TOF thus reached 3450 (entry
6) which, to our knowledge, is the highest TOF obtained so
far for the asymmetric hydrogenation of quinolines. In
contrast, BINAP-Ir catalyst gave much lower enantioselec-
tivity and catalytic activity (entries 5 and 7). The rate
enhancement of the dendritic catalysts was further demon-
strated by the results of the time-conversion curves (Figure
1). Although the nature of the observed strong dendrimer
effect is not clear, the isolation effect of the steric dendritic
shell might be responsible for this rate enhancement.
Encouraged by these excellent results, we decided to
further investigate the applications of the dendritic catalyst
in the asymmetric hydrogenation of other 2-substituted
quinoline derivatives using G2DenBINAP as the ligand
On the basis of the optimized reaction conditions, the
asymmetric hydrogenation of 2a was also used to assess the
minimum amount of the dendritic catalysts. In sharp contrast
to the small diphosphine ligands,8,9 the dendritic catalyst was
found to be highly effective even at extremely high substrate/
catalyst ratio (Table 2). Most importantly, the enantioselec-
tivity did not decrease under low catalyst loading. For
example, in the presence of 0.01 mol % of G2DenBINAP-
Ir, the reaction proceeded smoothly upon prolonged reaction
Org. Lett., Vol. 9, No. 7, 2007
1245

The reaction is relatively insensitive to the length of the
2-alkylated side chain of quinolines, and high enantioselec-
tivities and good yields have been consistently obtained
(entries 1-3). 2-Arenethyl-substituted quinolines gave slightly
low enantioselectivity (entries 4 and 5). The asymmetric
hydrogenation of quinolines bearing hydroxyl groups pro-
ceeded smoothly, affording good to high enantioselectivities
(entries 6-8). With 6-substituted quinolines (entries 9-11),
slightly low enantioselectivities and conversions were ob-
served. Notably, under low catalyst loading, the reactions
performed well, affording similar enantioselectivities, albeit
low catalytic activities (entries 1-7).
Having established the efficacy of the dendritic cata-
lysts, we then investigated their recyclability (Table 5).
Table 5. Recovery and Recycling of Ir(G3DenBINAP)
Catalysta
Figure 1. Time course curves of the hydrogenation of 2a for Ir-
(G3DenBINAP) and Ir(BINAP) catalysts (reaction conditions: 0.25
mmol of 2a in THF, sub./cat. ) 5000, 5.0 mol % of I2, 45 atm H2,
25 °C).
cycle
run 1 run 2 run 3 run 4 run 5 run 6
conversion (%)b
ee (%)c
>95
87
>95
85
>95
86
>95
85
80
85
80
85
a
Reaction conditions: 2.5 mmol of quinaldine (1a) in 1.25 mL of THF,
sub./cat. ) 1000 (mol ratio), 0.5 mol % of I2, 45 atm H2, 25∼30 °C, 8 h
(Table 4). In general, all substituted quinolines studied were
hydrogenated with good enantioselectivities and conversions.
b
for runs 1∼3, 16 h for runs 4 and 5, and 32 h for run 6. Determined by
c
1H NMR analysis of the crude product. Determined by HPLC analysis.
G3DenBINAP-Ir-catalyzed asymmetric hydrogenation of 2a
was chosen as the standard reaction. Upon the completion
of the reaction, the catalyst was quantitatively precipitated
by the addition of hexane and reused at least six times with
similar enantioselectivities but at the expense of relatively
low catalytic activities. The leaching of iridium was measured
by ICP-XRF at the second cycle and found to be no more
than 0.024 ppm.
Table 4. Catalytic Asymmetric Hydrogenation of Quinoline
Derivativesa
In conclusion, we have demonstrated for the first time the
importance of the dendritic wedges on the catalytic activity
in the Ir-catalyzed asymmetric hydrogenation of quinolines.
Good to high enantioselectivities with significantly high
catalytic activities (TOF up to 3450 h-1) and productivities
(TON up to 43 000) have been obtained in this challenging
reaction. Such dendritic enhancement is very rare in the field
of dendrimer chemistry. Current work is aiming at detailed
insight of the nature of the strong dendrimer effect and the
exploration of these dendritic catalysts in other asymmetric
hydrogenations of heteroaromatic compounds.
Acknowledgment. Financial support from the National
Natural Science Foundation of China, the Major State Basic
Research Development Program of China (Grant No.
2005CCA06600), and the Chinese Academy of Sciences is
greatly acknowledged.
a
Reaction conditions: 0.25 mmol of substrate in 1.25 mL of THF, 0.25
b
mol % of Ir(G2DenBINAP) catalyst, 5 mol % of I2, 20∼25 °C, 1.5 h.
Supporting Information Available: General experimen-
tal methods, preparation and characterization data for den-
dritic ligands GnDenBINAP, and 1H and 13C NMR spectral
data for the reduced products. This material is available free
of charge via the Internet at http://pubs.acs.org.
Determined by 1H NMR analysis of the crude product. Determined by
c
HPLC analysis with Chirapak OJ-H (2a∼2c, 2i, and 2j), AS-H (2d and
d
2e), and OD-H (2f∼2h and 2k) columns. The absolute configuration is
assigned by comparison of the HPLC retention time with those reported in
the literature data. e Data in brackets were obtained by using 0.01% catalyst
under the following conditions: 2.5 mmol of substrate in 5 mL of THF,
f
1.25 mol % of I2, 20∼25 °C, 24 h. Reaction time ) 36 h.
OL0631410
1246
Org. Lett., Vol. 9, No. 7, 2007