Asymmetric hydrogenation of quinolines catalyzed by iridium complexes of monodentate BINOL-derived phosphoramidites

Article abstract of DOI:10.1002/adsc.200800007

The monodentate BINOL-derived phosphoramidite PipPhos is used as ligand for the iridium-catalyzed asymmetric hydrogenation of 2- and 2,6-substituted quinolines. If tri-ortho-tolylphosphine and/or chloride salts are used as additives enantioselectivities are strongly enhanced up to 89%. NMR indicates that no mixed complexes are formed upon addition of tri-ortho-tolylphosphine.

Full text of DOI:10.1002/adsc.200800007

FULL PAPERS
DOI: 10.1002/adsc.200800007
Asymmetric Hydrogenation of Quinolines Catalyzed by Iridium
Complexes of Monodentate BINOL-Derived Phosphoramidites
a
b
b
a,
ˇ
ˇ ´
Natasa Mrsic, Laurent Lefort, Jeroen A. F. Boogers, Adriaan J. Minnaard, *
Ben L. Feringa,a,* and Johannes G. de Vriesa,b,*
Universityof Groningen , Stratingh Institute, Nijenborgh 4, 9747 AG Groningen, The Netherlands
a
E-mail: B.L.Feringa@rug.nl
b
DSM Pharmaceutical Products – Advanced Synthesis & Catalysis, P.O. Box 18, 6160 MD Geleen, The Netherlands
Fax : (+31)-46-476-7604; e-mail: Hans-JG.Vries-de@dsm.com
Received: January7, 2008; Published online: April 11, 2008
Dedicated to Prof. Dr. Andreas Pfaltz on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The monodentate BINOL-derived phos- indicates that no mixed complexes are formed upon
phoramidite PipPhos is used as ligand for the iridi- addition of tri-ortho-tolylphosphine.
um-catalyzed asymmetric hydrogenation of 2- and
2,6-substituted quinolines. If tri-ortho-tolylphosphine
and/or chloride salts are used as additives enantiose- Keywords: asymmetric hydrogenation; homogeneous
lectivities are stronglyenhanced up to 89%. NMR
catalysis; iridium; phosphoramidites; quinolines
Introduction
In 2007, Zhou et al. reported the use of (S)-Segphos
as chiral ligand in the iridium-catalyzed transfer hy-
Aymmetric hydrogenation of unsaturated prochiral drogenation of quinolines with Hantzsch esters (up to
compounds represents an attractive and versatile 91% ee).[10] The ee is stronglydetermined bythe ester
method for the preparation of enantiopure building groups of the Hantzsch ester.
blocks.[1,2] Although significant effort has been made
An asymmetric organocatalytic transfer hydrogena-
in the area of asymmetric hydrogenation of aromatic tion of heteroaromatic compound was reported by
and heteroaromatic compounds,[3] manychallenges Rueping in 2006.[11] The catalysts are bulky BINOL-
remain. Enantiopure tetrahydroquinolines represent derived phosphoric acids and Hantzsch esters were
important synthetic intermediates, as they are present used as stoichiometric hydrogen source (up to >99%
in numerous alkaloids and biologicallyactive com-
ee).
Bidentate chiral ligands were considered superior
pounds.[4] Transition metal-catalyzed asymmetric hy-
drogenation of quinolines is one of the best methods over monodentate ones in metal-catalyzed asymmet-
for their preparation, as manysubstituted quinolines
are commerciallyavailable.
ric hydrogenation for more than 30 years[1] as chela-
tion was believed to be necessaryto impart the rigidi-
In recent years, a number of examples of asymmet- tyto the metal complex for an efficient transfer of
ric hydrogenation of quinolines with high enantiose- chirality. Recently chiral monodentate phosphines,
lectivities were published.[5–9] In 2003 Zhou et al. re- phosphonites, phosphoramidites and phosphites were
ported the use of Ir complexes generated in situ from reported to lead to excellent results in the asymmetric
[Ir
C
results were described subsequentlybyChan et al.
using only0.1 mol% of a catalyst based on a diphos-
phosphoramidite ligands have the advantage of being
readilyaccessible, highlydiverse, air stable and inex-
phinite ligand.[9] In 2006 Reetz reported the use of a pensive compared to most bidentate ligands.[13] In ad-
[14]
combination of bis-phosphonites and monodentate dition, theyare amenable to parallel synthesis.
achiral phosphorus ligands (up to 96% ee).[7]
We have developed the use of monodentate phos-
phoramidites as ligands for asymmetric hydrogena-
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FULL PAPERS
tion,[15–17] conjugate addition[18], allylic alkylation,[19]
asymmetric arylation of aldehydes,[20] ketones[21,22] and
substituted imines.[23] Herein we report the first asym-
metric hydrogenation of quinolines catalyzed by iridi-
um complexes based on monodentate BINOL-derived
phosphoramidites.
Table 1. Solvent variation in the asymmetric hydrogenation
of quinaldine (1a).[a]
EntrySolvent
Conversion
[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
i-PrOH
MeOH
THF
Acetone
EtOAc
CH2Cl2
Toluene
91
47
97
97
96
96
96
9
11
21
18
28
18
36
Results and Discussion
Asymmetric hydrogenation of quinaldine (1a) was
chosen as a model reaction (Scheme 1). Initial hydro-
genation experiments were performed at 25 bar of hy-
drogen pressure and 608C, using 1 mol% of catalyst
with L*/Ir=2/1, prepared in situ. Using (S)-1-(3,5-
dioxa-4-phosphacyclohepta[2,1-a;3,4-a’]dinaphthalen-
4-yl)-piperidine (PipPhos) as ligand L* and [Ir-
[a]
Reaction conditions: 1-mmol scale, quinoline/[Ir-
(COD)Cl2]2/(S)-PipPhos=100/1/4, 4 mL of solvent, 608C
25 bar H2, 24 h.
Conversions were determined byGC.
Enantiomeric excess was determined byGC analsyis
with Chiralsil DEX CB column.
AHCTREUNG
[b]
[c]
ACHTREUNG
Surprisingly, it was observed that upon addition of
solvent screening showed that the enantioselectivity 10 mol% of piperidine hydrochloride to the standard
of the reaction is solvent-dependent. The best result hydrogenation reaction based on PipPhos and [Ir-
was obtained in the non-polar solvent toluene
(Table 1, entry7), whereas use of protic solvents such
ACHTREUNG
as MeOH and i-PrOH resulted in low enantioselectiv- broad range of chloride/metal ratios, from 2–100%.
ityand somewhat lower conversions (entries 1 and 2). We will discuss this finding in more detail further in
These results encouraged us to screen more phos- this paper. In most hydrogenations described here-
phoramidite ligands in toluene. High throughput ex- after we have used this additive.
perimentation (HTE)[14,24] is a methodologywhere a
large number of ligands are quicklysynthesized and
Both Reetz[25–27] and ourselves[28] have shown that
the use of mixtures of chiral monodentate ligands can
tested in parallel. It has the added advantage that in improve enantioselectivityand reactivit.y A mixed
addition to the chiral ligands, substrates, additives, sol- ligand approach has been employed in rhodi-
vents and reaction conditions can also be screened. um[17,25,28,29] and iridium-catalyzed[7] asymmetric hydro-
Although 48 different phosphoramidites and phos- genations and in rhodium-catalyzed additions of bor-
pites based on BINOL, 8H-BINOL, and 3,3’-dimeth- onic acids.[22] It is also possible to use mixed com-
yl-BINOL were tested, as well as two iridum precur- plexes based on a monodentate chiral ligand and a
sors ([Ir
N
N
able to reach higher enantioselectivities. Additional structure of monodentate ligands can be varied easily
monodentate and bidentate BINOL, TADDOL, bi- enables us to screen a verylarge number of different
phenol and catechol-based phosphoramidites and complexes in the asymmetric hydrogenation. Since
phosphites were also tested, to no avail.
the catalytically active species most likely contains
Scheme 1. Asymmetric hydrogenation of quinaldine (1a).
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Asymmetric Hydrogenation of Quinolines Catalyzed by Iridium Complexes
two monodentate ligands, two homo-complexes,
FULL PAPERS
Ir(L1)2 and Ir(L2)2, and the hetero-complex Ir(L1 L2)
G
will be formed simultaneously. The hetero-complex
represents a new catalyst, and if it is endowed with
higher activityand selectivitythan the two homo-
complexes, it will lead to better results.
We thus screened mixtures of (S)-PipPhos and achi-
ral phosphine ligands in the asymmetric hydrogena-
tion of quinaldine (1a). Reactions were performed
under 50 bar of H2 pressure in order to obtain full
conversions over 24 h. The results are shown in
Table 2. It was noticed that ortho-substituted phos-
phines, as well as tri-tert-butylphosphine lead to good
conversions and high enantioselectivities (Figure 1).
Surprisingly, the catalyst prepared from PipPhos and
triphenylphosphine leads to very low conversion
(entry1). The best result was obtained using PipPhos
and L1, giving full conversion and 83% ee (entry2).
High conversions were also obtained when L2 and L6
were used in combination with PipPhos (entries 3 and
7).
Figure 1. Achiral phosphines used in the mixed monoden-
tate ligand approach.
Since the [Ir(COD]Cl]2/tri-o-tolylphosphine/Pip-
G
Phos/piperidine hydrochloride catalytic system gave
the best result in the asymmetric hydrogenation of
quinaldine (1a) we further studied the effect of addi-
tion of different salts with this system (Table 3). We
observed that all tested chloride salts induced high
enantioselectivities. Cesium fluoride blocked the cata-
lyst activity completely (entry 5), whereas potassium
bromide and tetrafluoroborate (entries 6 and 8) led to
high conversions although the enantioselectivities
were somewhat lower. Addition of potassium iodide
also had a negative effect on the enantioselectivity
Table 3. Effect of the addition of salts on the enantioselec-
tivity of the asymmetric hydrogenation of quinaldine (1a).[a]
EntrySalt
Conversion
[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
-
100
100
100
98
0
100
98
63
83
83
81
-
69
30
77
Table 2. Asymmetric hydrogenation of quinaldine (1a) using
Piperidine·HCl
KCl
Et3N·HCl
CsF
KBr
KI
a mixture of monodentate ligands[a]
KBF4
98
[a]
[b] [%]
ee[c] [%]
Reaction conditions: 1-mmol scale, quinoline/[Ir-
(COD)Cl2]2/(S)-PipPhos/tri-o-tolylphosphine/salt=100/1/
4/2/10, 4 mL toluene, 608C, 50 bar H2, 24 h.
Conversions were determined byGC.
Enantiomeric excess was determined byGC analsyis
with Chiralsil DEX CB column.
EntryPhosphine
Conversion
AHCTREUNG
1
2
3
4
5
6
7
PPh3
L1
L2
L3
L4
L5
L6
2
nd
83
70
81
82
77
78
[b]
[c]
100
100
41
54
18
98
(entry7). Since with potassium chloride irreproduci-
ble results were obtained, piperidine hydrochloride
was chosen as the additive for further screenings.
To obtain more information on the relative effect
of the additional ligand and the salt we screened all
possible additive combinations in toluene and in di-
chloromethane in the asymmetric hydrogenation of
1a (Table 4). The use of 10 mol% of piperidine hydro-
[a]
Reaction conditions: 1-mmol scale, quinoline/[Ir-
(COD)Cl2]2/(S)-PipPhos/phosphine/piperidine hydrochlo-
ACHTREUNG
ride=100/1/4/2/10, 4 mL of toluene, 608C 50 bar H2,
24 h.
Conversions were determined byGC.
Enantiomeric excess was determined byGC analsyis
with Chiralsil DEX CB column.
[b]
[c]
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Table 4. Effect of the addition of piperidine hydrochloride on the ee in the asymmetric hydrogenation of 1a.[a]
EntrySolvent
L*
L
Additive
Conversion
100
[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
8
DCM
DCM
DCM
DCM
PipPhos
PipPhos
PipPhos
PipPhos
PipPhos
PipPhos
PipPhos
PipPhos
-
-
P
P
-
-
P
P
-
18
83
69
89
36
63
67
83
Piperidine·HCl
100
100
100
100
100
100
100
ACHTREUNG
A
Piperidine·HCl
Toluene
Toluene
Toluene
Toluene
-
Piperidine·HCl
-
G
G
Piperidine·HCl
[a]
Reaction conditions: 1-mmol scale, quinoline/[Ir(COD)Cl2]2/(S)-PipPhos/tri-o-tolylphosphine/piperidine hydrochloride=
A
100/1/4/2/10, 4 mL solvent, 608C, 50 bar H2, 24 h.
Conversions were determined byGC.
Enantiomeric excess was determined byGC analysis with Chiralsil DEX CB column.
[b]
[c]
Table 5. Asymmetric hydrogenation of quinaldine (1a).[a]
chloride as the sole additive in dichloromethane led
to an increase in enantioselectivityfrom 18 to 83%
(entries 1 and 2). In the mixed ligand system, the ad-
dition of chloride improved the enantioselectivity
from 69 to 89% (entries 3 and 4). A similar effect is
observed in toluene where using piperidine hydro-
chloride as the sole additive led to an increase in the
enantioselectivityfrom 36 to 63% (entries 5 and 6),
whereas adding the hydrochloride salt to the mixed
ligand system led to an increase in ee from 67 to 83%
(entries 7 and 8). It was even possible to hydrogenate
the hydrochloride salt of 1a in toluene without loss in
enantioselectivityalthough a longer reaction time
(48 h) was necessary, perhaps due to the lower solu-
bilityof the substrate.
EntrySolvent
H
[bar]
T
[8C]
Conv.[b]
[%]
ee[c]
[%]
2
1
2
3
4
5
6
7
8
Toluene
100
100
100
70
70
70
50
25
50
25
80
60
40
80
60
40
60
60
60
60
60
40
60
60
60
60
60
60
97
100
24
97
98
77
83
77
78
82
79
83
83
89
87
87
nd
88
87
87
87
80
65
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOAc
EtOAc
i-PrOAc
11
100
100
100
100
40
The effects of solvent, pressure and temperature on
the conversion and enantioselectivitywere also inves-
9
tigated using the [Ir(COD]Cl]2/PipPhos/phosphine/pi-
G
10
12
13
14
15
16
17
18
19
peridine hydrochloride catalytic system. The results
are summarized in Table 5. It was observed that the
rate of the reaction stronglydepends on the tempera-
ture. Conversions greater than 97% were achieved in
all aprotic solvents at 608C or higher. At lower tem-
peratures the reaction is much slower (entries 3, 6 and
13). The rate of the reaction depends on the hydrogen
pressure, but importantly, the enantioselectivity stays
the same for pressures above 10 bar, in keeping with
earlier findings in olefin hydrogenation.[16] The best
result (quantitative conversion and 89% ee) was ach-
ieved in dichloromethane at 50 bar of pressure and
608C.
10
50
50
50
7
100
100
100
100
100
91
50
ClCH2CH2Cl 50
Acetone
i-PrOH
50
50
[a]
Reaction conditions: 1-mmol scale, quinoline/[Ir-
(COD)Cl2]2/(S)-PipPhos/tri-o-tolylphosphine/piperidine
AHCTREUNG
hydrochloride=100/1/4/2/10, 4 mL solvent, 24 h.
Conversions were determined byGC.
Enantiomeric excess was determined byGC analsyis
with Chiralsil DEX CB column.
[b]
[c]
Kinetics
slow formation of the catalytically active species
during the first hour (10% of conversion). This is also
confirmed bythe induction time that is observed in
the hydrogenation (Figure 2b). We tried to overcome
In order to examine the stabilityof the catalsyt
during the reaction, the enantioselectivitywas moni-
tored over time (Figure 2a). An increase of the enan- this drawback bypre-stirring the iridium complex in
tioselectivityover 24 h was observed. The low ee at the presence of the ligand under the reaction condi-
the beginning of the reaction maybe explained bythe
tions during 1 h, followed bythe addition of the sub-
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Asymmetric Hydrogenation of Quinolines Catalyzed by Iridium Complexes
FULL PAPERS
Figure 2. Kinetics of the asymmetric hydrogenation of quinaldine (1a). Reaction conditions: 1-mmol scale, quinoline/[Ir-
(COD)Cl2]2/(S)-PipPhos/tri-o-tolylphosphine/piperidine hydrochloride=100/1/4/2/10, 4 mL solvent, 24 h. Conversion was de-
ACHTREUNG
termined byGC and enantiomeric excess was determined byGC analysis with Chiralsil DEX CB column.
strate. Unfortunately, this did not improve the enan- were obtained with methyl- and i-Pr-substituted quin-
tioselectivityof the reaction.
oline (89% ee, entries 1 and 3), while the lowest enan-
Under the optimized conditions, a varietyof substi-
tioselectivitywas obtained with benzly-substituted
tuted quinolines was hydrogenated using the [Ir- quinoline (76% ee, entry7). Introduction of electron-
(COD]Cl]2/PipPhos/phosphine/piperidine hydrochlo- donating or withdrawing substituents in 6-position did
ride catalytic system in toluene or dichloromethane. not affect the enantioselectivitysignificantly(en-
The best results are summarized in Table 6. tries 5–7), whilst introduction of longer alkyl chains
ACHTREUNG
All quinolines studied were hydrogenated with high resulted in a small drop of ee. (entries 8 and 9).
conversions and enantioselectivities. The best results
Table 6. Asymmetric hydrogenation of 2,6-substituted quinolines using (S)-PipPhos and achiral ligands L1–L6.[a]
Solvent
R1/R2
Ligand
Conversion[b] [%]
ee[c] [%]
Configuration[d]
1
2
3
4
5
6
7
8
DCM
DCM
Toluene
Toluene
DCM
DCM
DCM
DCM
DCM
Me/H (2a)
Et/H (2b)
i-Pr/H (2c)
L1
L1
L1
L1
L1
L1
L5
L1
L1
L1
L6
100
100
100
98
100
73
100
100
100
100
88
89
88
89
86
85
82
88
83
78
76
88
(S)
(S)
(R)
nd
(S)
(S)
(S)
(S)
nd
i-Bu/H (2d)
Me/Me (2e)
Me/MeO (2f)
Me/F (2g)
n-Pentyl/H (2h)
n-Hexyl/H (2i)
Benzyl/H (2j)
Ph/H (2k)
9
10
11
DCM
Toluene
nd
(S)
[a]
Reaction conditions: 1-mmol scale, quinoline/[Ir
10, 4 mL solvent, 608C, 50 bar H2, 24 h.
Conversions were determined by H NMR.
Enantiomeric excess was determined byGC and HPLC.
Absolute configuration of the product is assigned bycomparison with literature data.
A
[b]
[c]
[d]
1
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Scheme 2. Preparation of quaternized ligand 2s.
Mechanistic Discussion
of the added phosphine ligand is even more obscure.
It mayjust serve as a scavenger of traces of oxygen. It
In order to gain understanding of the mechanism of is also possible that mixed ligand species are formed
the reaction, high pressure 31P NMR experiments in one or more intermediates of the catalytic cycle
were performed on the asymmetric hydrogenation of but not in the resting state, thus making them unob-
1a using a mixture of PipPhos and achiral phosphine servable.
(2:1) as ligands at 608C and 25 bar of H2 pressure. To
Mass spectral studies into the nature of the catalyst
our surprise, no mixed ligand iridium species were ob- were hampered bythe fact that these catalsyts are
served when tri-o-tolylphosphine was used as achiral neutral species and thus lead to feeble signals in ES-
phosphine. A large tri-ortho-tolylphosphine peak was MS. To solve this problem we decided to develop an
visible in the NMR prior to and throughout the hy- analogous catalyst which carries a positive charge in
drogenation reaction. In the case of triphenylphos- the ligand. This approach has been used with great
phine and PipPhos, mixed ligand species were ob- success byChen in his MS studyof metathesis cata-
served, however, this catalyst gave only 2% conver- lysts.[31]
sion in the hydrogenation of 1a. It should be added
Thus, we prepared quaternized ligand 2s
that addition of other unhindered ligands such as tri- (Scheme 2). The synthesis starts with Boc-protection
phenyl phosphite (not shown in Table 2) also led to of 1-methylpiperazine (2m), followed bymethylation
almost no conversion. These results suggests that o- with methyl triflate in dichloromethane at room tem-
substituted achiral phosphines are perhaps sterically perature, and deprotection with triflic acid. The pre-
too demanding for coordination to the iridium togeth- pared quaternized amine 2o was isolated in 76%
er with PipPhos, making it impossible to form a yield. (S)-BINOL was refluxed in neat PCl3 in order
mixed ligand species. In addition, no difference was to obtain chlorophosphite 2r. This was stirred with 2n
observed between the 31P NMR spectra of the reac- in the presence of triethylamine in THF to give the
tions with and without added piperidine hydrochlo- quaternized phosphoramidite 2s in overall 27% yield.
ride. Despite the significant improvement of the selec-
Unfortunately, the results in the iridium-catalyzed
tivity, the role of the achiral phosphine and chloride hydrogenation of 1a with ligand 2s were dramatically
salt has not been elucidated until now. However, it is different from the results obtained with PipPhos
known that iridium catalysts tend to decompose to in- (Table 7). Thus, this ligand cannot be assumed to be a
active hydride-bridged clusters in the absence of sub- good model compound for PipPhos. In spite of this
strate.[12,30] If the substrate is a weak ligand, this de- we did an ES-MS analysis of the hydrogenation reac-
composition can be competitive with hydrogenation. tions of Table 7. In all MS veryminor peaks of iridi-
It is conceivable that the chloride salt prevents the um complexes were observable, none of which could
formation of poorlyactive iridium clusters. The role
be associated with 2s. In addition, the spectra showed
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Asymmetric Hydrogenation of Quinolines Catalyzed by Iridium Complexes
FULL PAPERS
Table 7. Asymmetric hydrogenation of quinaldine (1a) using
quaternized ligand 2s.[a]
2,2-Dimethylpropionic Acid 4-methyl-piperazin-1-yl
Ester (2m)
Entry 2s/PipPhos/P
(o-tol)3/ClÀ/ Conversion[b]
A
ee[c]
[%]
To a solution of 1-methylpiperazine (5 g, 50 mmol) in diox-
ane (100 mL) di-tert-butyl dicarbonate (11.98 g, 55 mmol)
and potassium carbonate (7.59 g, 55 mmol) were added and
reaction mixture was stirred over night at room tempera-
ture. The resulting mixture was washed with water (100 mL)
and water layer was extracted with ethyl acetate (100 mL).
The combined organic layers were dried on anhydrous mag-
nesium sulfate and filtered. The solvent was removed under
vacuum, and 2m was isolated as a yellow oil; yield: 9.1 g
(92%).
Ir
[%]
1
2
3
4
5
6
7
1/1/0/0/1
1/1/1/0/1
1/1/1/5/1
1/1/0/5/1
2/0/0/0/1
2/0/1/0/1
2/0/1/5/1
31
0
4
19
41
6
3
-
44
12
6
7
18
2
[a]
Reaction conditions: 1-mmol scale, 4 mL of dichlorome-
thane, 608C, 25 bar H2, 2 h.
Conversions were determined byGC.
Enantiomeric excess was determined byGC analsyis
with Chiralsil DEX CB column
1,1-Dimethylpiperazinium Trifluoromethanesulfonate
(2o)
[b]
[c]
To a solution of 4-methyl-piperazine-1-carboxylic acid tert-
butyl ester (7.1 g, 35.4 mmol) in dry dichloromethane
(50 mL), methyl triflate was added dropwise (4 mL,
35.4 mmol). The reaction was stirred at room temperature
over 1 h, followed byaddition of triflic acid (4.97 mL,
56.2 mmol). After 1 h, the solvent was decanted and 50 mL
of methanol were added. After stirring for 15 min the pre-
cipitated white solid was filtered off and dried to afford the
quaternized amine 2o; yield: 7.63 g (82%).
onlyverysmall peaks of the molecular ion of 2s. We
have not yet arrived at a satisfactory explanation for
these results. One possibilityis that the majorityof
the iridium is present in the form of nanoparticles,
stabilized by 2s.
Although low enantioselectivities were obtained in
the asymmetric hydrogenation of quinaldine (1a)
using quaternized ligand 2s, it was observed that using
2 equivalents of 2s per iridium atom, hydrogenation is
much faster than with PipPhos, giving 41% conversion
within 2 h (entry5). Moreover, using mixture of 2s
and PipPhos (1:1) reaction is still significantlyfaster
(entry1).
(S)-4-(3,5-Dioxa-4-phosphacyclohepta[2,1-a;3,4-a’]di-
naphthalen-4-yl)-1,1-dimethylpiperazinium Trifluoro-
methanesulfonate (2s)
In a Schlenk tube (S)-BINOL (1.5 g, 5.24 mmol) was re-
fluxed in neat phosphorus trichloride (5 mL) over night.
After cooling the reaction mixture, the excess of phosphorus
trichloride was distilled off and the resulting phosphorus
chloride (2r) was washed with drytoluene (3”5 mL), and
dissolved in dryTHF (5 mL). In another Schlenk tube qua-
Conclusions
ternized amine 2o (1.38 g, 5.24 mmol) and tri
(726 mL, 5.24 mmol) were dissolved in 5 mL of THF. The so-
ylphosphine/piperidine·HCl is a good catalyst for the lution of 2r was then added to the solution of 2o and trie-
ethylamine
The combination [Ir(COD)Cl]2/PipPhos/tri-ortho-tol-
G
thylamine at 08C. After 10 min, the reaction mixture was
warmed to room temperature and stirred overnight. The
precipitated crystals were filtered off and ether was added
(10 mL). The newlyformed white precipitate was filtered
off and washed with dichloromethane to afford pure phos-
phoramidite 2s; yield: 1.09 g (36%).
enantioselective hydrogenation of 2- and 2,6-substitut-
ed quinolines. Full conversions and enantioselectivi-
ties up to 89% were obtained.
Experimental Section
General Experimental Procedure for Hydrogenation
Acknowledgements
A mixture of [Ir(COD)Cl]2 (6.72 mg, 0.01 mmol), (S)-1-(3,5-
A
dioxa-4-phosphacyclohepta[2,1-a;3,4-a’]dinaphthalen-4-yl)-
piperidine [(S)-PipPhos] (15.98 mg, 0.04 mmol), achiral
phosphine (0.02 mmol), substrate (1 mmol) and piperidine
hydrochloride (12.16 mg, 0.1 mmol) were dissolved in 4 mL
of solvent, in a glass vial. The vial was placed in a stainless
steel autoclave. Hydrogenation was performed at 608C
We thank Dr. I. Toth (DSM, Geleen) for performing the high
pressure NMR experiments, and A. Kiewiet (MS) for techni-
cal support (Stratingh Institute, University of Groningen).
under 50 bar of hydrogen pressure for 24 h. After cooling References
the autoclave, hydrogen pressure was carefully released. The
reaction mixture was flushed over a short silica column. Sol-
vent was removed under vacuum and conversion was deter-
mined byGC or NMR. Crude product was purified bychro-
matography(silica gel, heptane/EtOAc =4/1).
[1] a) R. Noyori, Angew. Chem. 2002, 114, 2108; Angew.
Chem. Int. Ed. 2002, 41, 2008; b) T. Ohkuma, M. Kita-
mura, R. Noyori, Catalytic Asymmetric Synthesis,
Wiley-VCH, Weinheim, 2000, p 1; c) H.-U. Blaser, C.
Adv. Synth. Catal. 2008, 350, 1081 – 1089
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1087

ˇ
ˇ ´
Natasa Mrsic et al.
FULL PAPERS
Malan, B. Pugin, F. Spindler, H. Steiner, M. Studer,
Adv. Synth. Catal. 2003, 345, 103; d) W. S. Knowles,
Angew. Chem. 2002, 114, 2096; Angew. Chem. Int. Ed.
2002, 41, 1998; e) The Handbook of Homogeneous Hy-
drogenation, (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-
VCH, Weinheim, 2007, Chapters 23–37.
[8] S.-M. Lu, X.-W. Han, Y.-G. Zhou, Adv. Synth. Catal.
2004, 346, 909.
[9] K. H. Lam, L. Xu, L. Feng, Q.-H. Fan, F. L. Lam, W.-
H. Lo, A. S. C. Chan, Adv. Synth. Catal. 2005, 347,
1755.
[10] D.-W. Wang, W. Zeng, Y.-G. Zhou, Tetrahedron: Asym-
metry 2007, 18, 1103.
[11] M. Rueping, A. P. Antonchick, T. Theissmann, Angew.
Chem. 2006, 118, 3765; Angew. Chem. Int. Ed. 2006, 45,
3683.
[2] Comprehensive Asymmetric Catalysis, (Eds.: E. N. Ja-
cobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin,
1999.
[3] a) F. Glorius, Org. Biomol. Chem. 2005, 3, 4171; b) Y.-
G. Zhou, Acc. Chem. Res. 2007, 40, 1357; c) W. Tang,
X. Zhang, Chem. Rev. 2003, 103, 3029; d) Principles
and Applications of Asymmetric Synthesis, Wiley-Inter-
science, New York, 2001; e) R. Kuwano, K. Sato, T.
Kurokawa, D. Karube, Y. Ito, J. Am. Chem. Soc. 2000,
122, 7614; f) C. Bianchini, P. Barbaro, G. Scapacci, J.
Organomet. Chem. 2001, 621, 26; g) M. Studer, C. We-
demeyer-Exl, F. Spindler, H.-U. Blaser, Monatsh.
Chem. 2000, 131, 1335; h) S. Murata, T. Sugimoto, S.
Matsuura, Heterocycles 1987, 26, 763; i) J. P. Henschke,
M. J. Burk, C. G. Malan, D. Herzberg, J. A. Peterson,
A. J. Wildsmith, C. J. Cobley, G. Casy, Adv. Synth.
Catal. 2003, 345, 300; j) R. Kuwano, K. Kaneda, T. Ito,
K. Sato, T. Kurokawa, Y. Ito, Org. Lett. 2004, 6, 2213;
k) C. Bianchini, P. Barbaro, G. Scapacci, E. Farnetti, M.
Graziani, Organometallics 1998, 17, 3308; l) C. J.
Cobley, J. P. Henschke, Adv. Synth. Catal. 2003, 345,
195; m) S. A. Raynor, J. M. Thomas, R. Raja, B. F. G.
Johnson, R. G. Bell, M. D. Mantle, Chem. Commun.
2000, 1925; n) H.-U. Blaser, H. Hornig, M. Studer, C.
Wedemeyer-Exl, J. Mol. Catal. A 1999, 139, 253; o) F.
Glorius, N. Spielkamp, S. Holle, R. Goddard, C. W.
Lehmann, Angew. Chem. 2004, 116, 2910; Angew.
Chem. Int. Ed. 2004, 43, 2850; p) B. Scheiper, F. Glo-
rius, A. Leitner, A. Furstner, Proc. Natl. Acad. Sci.
USA 2004, 101, 11960; q) C. Y. Legault, A. B. Charette,
J. Am. Chem. Soc. 2005, 127, 8966.
[12] a) T. Jerphagnon, J.-L. Renaud, C. Bruneau, Tetrahe-
dron: Asymmetry 2004, 15, 2101; b) J. G. de Vries, in:
Handbook of Chiral Chemicals, 2nd edn., (Ed.: D. J.
Ager), CRC Press, Boca Raton, 2005, p 269; c) M.
van den Berg, B. L. Feringa, A. J. Minnaard, in: The
Handbook of Homogeneous Hydrogenation, (Eds.:
J. G. de Vries, C. J. Elsevier), Wiley-VCH, Weinheim,
2007, p 995.
[13] A. J. Minnaard, B. L. Feringa, L. Lefort, J. G. de Vries,
Acc. Chem. Res. 2007, 40, 1267.
[14] L. Lefort, J. A. F. Boogers, A. H. M. de Vries, J. G.
de Vries, Org. Lett. 2004, 6, 1733.
[15] a) D. PeÇa, A. J. Minnaard, J. G. de Vries, B. L. Feringa,
J. Am. Chem. Soc. 2002, 124, 14552; b) D. PeÇa, A. J.
Minnaard, A. H. M. de Vries, J. G. de Vries, B. L. Ferin-
ga, Org. Lett. 2003, 5, 475; c) R. Hoen, M. van den
Berg, H. Bernsmann, A. J. Minnaard, J. G. de Vries,
B. L. Feringa, Org. Lett. 2004, 6, 1433; d) H. Bern-
smann, M. van den Berg, R. Hoen, A. J. Minnaard, G.
Mehler, M. T. Reetz, J. G. de Vries, B. L. Feringa, J.
Org. Chem. 2005, 70, 943; e) L. Panella, B. L. Feringa,
J. G. de Vries, A. J. Minnaard, Org. Lett. 2005, 7, 4177;
f) L. Panella, A. M. Aleixandre, G. J. Kruidhof, J. Rob-
ertus, B. L. Feringa, J. G. de Vries, A. J. Minnaard, J.
Org. Chem. 2006, 71, 2026.
[16] M. van den Berg, A. J. Minnaard, R. M. Haak, R.
Leeman, E. P. Schudde, A. Meetsma, B. L. Feringa,
A. H. M. de Vries, C. E. P. Maljaars, C. E. Willans, D.
Hyett, J. A. F. Boogers, H. J. W. Henderickx, J. G. de V-
ries, Adv. Synth. Catal. 2003, 345, 308.
[17] R. Hoen, J. A. F. Boogers, H. Bernsmann, A. J. Min-
naard, A. Meetsma, T. D. Tiemersma-Wegman,
A. H. M. de Vries, J. G. de Vries, B. L. Feringa, Angew.
Chem. 2005, 117, 4281; Angew. Chem. Int. Ed. 2005, 44,
4209.
[18] B. L. Feringa, R. Naasz, R. Imbos, L. A. Arnold,
Modern Organocopper Chemistry, VCH, Weinheim,
2002, p 224.
[19] a) A. W. van Zijl, L. A. Arnold, A. J. Minnaard, B. L.
Feringa, Adv. Synth. Catal. 2004, 346, 413; b) H. Malda,
A. W. van Zijl, L. A. Arnold, B. L. Feringa, Org. Lett.
2001, 3, 1169.
[20] R. B. C. Jagt, P. Y. Toullec, J. G. de Vries, B. L. Feringa,
A. J. Minnaard, Org. Biomol. Chem. 2006, 4, 773.
[21] a) J.-G. Boiteau, R. Imbos, A. J. Minnaard, B. L. Ferin-
ga, Org. Lett. 2003, 5, 681; b) J.-G. Boiteau, R. Imbos,
A. J. Minnaard, B. L. Feringa, Org. Lett. 2003, 5, 1385;
c) S. L. X. Martina, R. B. C. Jagt, J. G. de Vries, B. L.
Feringa, A. J. Minnaard, Chem. Commun. 2006, 4093.
[22] a) A. Duursma, J.-G. Boiteau, L. Lefort, J. A. F. Boo-
gers, A. H. M. de Vries, J. G. de Vries, A. J. Minnaard,
B. L. Feringa, J. Org. Chem. 2004, 69, 8045; b) A.
[4] a) J. G. Keay, Comprehensive Organic Synthesis, Perga-
mon, Oxford, 1991, Vol. 8, p 579; b) A. R. Katritzky, S.
Rachwal, B. Rachwal, Tetrahedron 1996, 52, 15031;
c) D. H. Barton, K. Nakanishi, O. Meth-Cohn, Compre-
hensive Natural Products Chemistry, Elsevier, Oxford,
1999, Vol. 1–9.
[5] a) P.-Y. Yang, Y.-G. Zhou, Tetrahedron: Asymmetry
2004, 15, 1145; b) L. Xu, K. H. Lam, J. Ji, J. Wu, Q.-H.
Fan, W.-H. Lo, A. S. C. Chan, Chem. Commun. 2005,
11, 1390; c) S. H. Chan, K. H. Lam, Y.-M. Li, L. Xu, W.
Tang, F. L. Lam, W. H. Lo, W. Y. Yu, Q. Fan, A. S. C.
Chan, Tetrahedron: Asymmetry 2007, 18, 2625; d) C.
Deport, M. Buchotte, K. Abecassis, H. Tadaoka, T.
Ayad, T. Ohshima, J.-P. Genet, K. Mashima, V. Ratove-
lomanana-Vidal, Synlett 2007, 17, 2743; e) Z. J. Wang,
G. J. Deng, Y. Li, Y. M. He, W. J. Tang, Q. H. Fan, Org.
Lett. 2007, 9, 1243; f) W.-J. Tang, S.-F. Zhu, L.-J. Xu,
Q.-L. Zhou, Q.-H. Fan, H.-F. Zhou, K. Lam, A. S. C.
Chan, Chem. Commun. 2007, 6, 613; g) S. M. Lu, Y. Q.
Wang, X. W. Han, Y. G. Zhou, Angew. Chem. 2006,
118, 2318; Angew. Chem. Int. Ed. 2006, 45, 2260.
[6] W.-B. Wang, S.-M. Lu, P.-Y. Yang, X.-W. Han, Y.-G.
Zhou, J. Am. Chem. Soc. 2003, 125, 10536.
[7] M. T. Reetz, X. Li, Chem. Commun. 2006, 20, 2159.
1088
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 1081 – 1089

Asymmetric Hydrogenation of Quinolines Catalyzed by Iridium Complexes
FULL PAPERS
Duursma, R. Hoen, J. Schuppan, R. Hulst, A. J. Min-
naard, B. L. Feringa, Org. Lett. 2003, 5, 3111.
[23] R. B. C. Jagt, P. Y. Toullec, D. Geerdink, J. G. de Vries,
B. L. Feringa, A. J. Minnaard, Angew. Chem. 2006, 118,
2855; Angew. Chem. Int. Ed. 2006, 45, 2789.
[27] a) M. T. Reetz, X. Li, Angew. Chem. 2005, 117, 3019;
b) M. T. Reetz, T. Sell, A. Meiswinkel, G. Mehler,
Angew. Chem. 2003, 115, 814.
[28] a) A. Duursma, D. PeÇa, A. J. Minnaard, B. L. Feringa,
Tetrahedron: Asymmetry 2005, 16, 1901; b) D. PeÇa,
A. J. Minnaard, J. A. F. Boogers, A. H. M. de Vries,
J. G. de Vries, B. L. Feringa, Org. Biomol. Chem. 2003,
1, 1087.
[29] a) M. T. Reetz, Y. Fu, A. Meiswinkel, Angew. Chem.
2006, 118, 1440; Angew. Chem. Int. Ed. 2006, 45, 1412;
b) M. T. Reetz, M. Surowiec, Heterocycles 2006, 67,
567; c) M. T. Reetz, H. Guo, Beilstein J. Org. Chem.
2005, 1, 3; d) M. T. Reetz, Chim. Oggi 2003, 21, 5; e) C.
Monti, C. Gennari, U. Piarulli, J. G. de Vries, A. H. M.
de Vries, L. Lefort, Chem. Eur. J. 2005, 11, 6701; f) C.
Monti, C. Gennari, U. Piarulli, Tetrahedron Lett. 2004,
45, 6859.
[30] a) J. Halpern, D. P. Riley, A. S. C. Chan, J. J. Pluth, J.
Am. Chem. Soc. 1977, 99, 8055; b) J. Halpern, D. P.
Riley, A. S. C. Chan, J. J. Pluth, Adv. Chem. Ser. 1979,
173, 16; c) A. S. C. Chan, J. Halpern, J. Am. Chem. Soc.
1980, 102, 838.
[24] a) J. G. de Vries, A. H. M. de Vries, Eur. J. Org. Chem.
2003, 799; b) A. Hagemeyer, B. Jandeleit, Y. Liu, D. M.
Poojary, H. W. Turner, A. F. Volpe, W. H. Weinberg,
Appl. Catal. A 2001, 221, 23; c) M. T. Reetz, Angew.
Chem. 2001, 113, 292; d) M. T. Reetz, Angew. Chem.
2001, 113, 292; Angew. Chem. Int. Ed. 2001, 40, 284;
e) S. Dahmen, S. Brꢁse, Synthesis 2001, 1431; f) A.
Hoveyda, Handbook of Combinatorial Chemistry,
Wiley-VCH, Weinheim, 2002, Vol. 2, p 991; g) K. Ding,
H. Du, Y. Yuan, J. Long, Chem. Eur. J. 2004, 10, 2872;
h) J. G. de Vries, L. Lefort, Chem. Eur. J. 2006, 12,
4722; i) R. Hoen, T. D. Tiemersma-Wegman, B. Procu-
ranti, L. Lefort, J. G. De Vries, A. J. Minnaard, B. L.
Feringa, Org. Biomol. Chem. 2007, 5, 267.
[25] a) M. T. Reetz, X. Li, Tetrahedron 2004, 60, 9709;
b) M. T. Reetz, G. Mehler, A. Meiswinkel, Tetrahedron:
Asymmetry 2004, 15, 2165; c) M. T. Reetz, T. Sell, A.
Meiswinkel, G. Mehler, Angew. Chem. 2003, 115, 814;
Angew. Chem. Int. Ed. 2003, 42, 790.
[26] a) M. T. Reetz, X. Li, Angew. Chem. 2005, 117, 3022;
Angew. Chem. Int. Ed. 2005, 44, 2962; b) M. T. Reetz,
X. Li, Angew. Chem. 2005, 117, 3022; c) M. T. Reetz,
G. Mehler, Tetrahedron Lett. 2003, 44, 4593.
[31] C. Adlhart, C. Hinderling, H. Baumann, P. Chen, J.
Am. Chem. Soc. 2000, 122, 8204.
[32] L. A. Arnold, R. Imbos, A. Mandoli, A. H. M. de Vries,
R. Naasz, B. L. Feringa, Tetrahedron 2000, 56, 2865.
Adv. Synth. Catal. 2008, 350, 1081 – 1089
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1089