Enantioselective synthesis of tunable chiral pyridine-aminophosphine ligands and their applications in asymmetric hydrogenation

Article abstract of DOI:10.1039/c9ob00770a

A small library of tunable chiral pyridine-aminophosphine ligands were enantioselectively synthesized based on chiral 2-(pyridin-2-yl)-substituted 1,2,3,4-tetrahydroquinoline scaffolds, which were obtained in high yields and with excellent enantioselectivities via ruthenium-catalyzed asymmetric hydrogenation of 2-(pyridin-2-yl)quinolines. The protocol features a wide substrate scope and mild reaction conditions, enabling scalable synthesis. These chiral P,N ligands were successfully applied in the Ir-catalyzed asymmetric hydrogenation of benchmark olefins and challenging seven-membered cyclic imines including benzazepines and benzodiazepines. Excellent enantio- and diastereoselectivity (up to 99% ee and >20:1 dr), and/or unprecedented chemoselectivity were obtained in the asymmetric hydrogenation of 2,4-diaryl-3H-benzo[b]azepines and 2,4-diaryl-3H-benzo[b][1,4]diazepines.

Full text of DOI:10.1039/c9ob00770a

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OrPgleanasice&dBoionmotoaledcjuulsatr mChaermgiinstsry
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DOI: 10.1039/C9OB00770A
ARTICLE
Enantioselective Synthesis of Tunable Chiral Pyridine–
Aminophosphine Ligands and Their Application in Asymmetric
Hydrogenation
Received 00th January 20xx,
Accepted 00th January 20xx
Youran Liu,a Fei Chen,a Yan-Mei He,a Chenghao Li,a and Qing-Hua Fan*a,b
DOI: 10.1039/x0xx00000x
A small library of tunable chiral pyridine–aminophosphine ligands were enantioselectively synthesized based on chiral 2-
(pyridin-2-yl)-substituted 1,2,3,4-tetrahydroquinoline scaffolds, which were obtained in high yields and excellent
enantioselectivities via ruthenium-catalyzed asymmetric hydrogenation of 2-(pyridin-2-yl)quinolines. The protocol features
wide substrate scope, mild reaction conditions and enabling scalable synthesis. These chiral P,N ligands were successfully
applied in the Ir-catalyzed asymmetric hydrogenation of benchmark olefins as well as challenging seven-membered cyclic
imines including benzazepines and benzodiazepines. Excellent enantio- and diastereoselectivity (up to 99% ee and >20:1 dr),
and/or unprecedented chemoselectivity were obtained in the asymmetric hydrogenation of 2,4-diaryl-3H-benzo[b]azepines
and 2,4-diaryl-3H- benzo[b][1,4]diazepines.
Introduction
number of chiral P,N ligands have been developed by combining
phosphorus units with oxazoline or other nitrogen-containing
heteroaromatic rings as the chelating moieties.1e,1f,5 Among
Advances in transition-metal catalyzed asymmetric catalysis are
closely related to the development of new chiral ligands, which
can lead to excellent enantioselective control in catalysis and
even enable previously impossible asymmetric transformations.
To date, a huge number of chiral ligands and their transition
metal complexes have been developed for different organic
them, only a few examples are the P,N ligands derived from
pyridine,5 more closely matching the Crabtree's catalyst. The
representative examples were chiral ligands
1 ~ 3 reported by
Pfaltz and co-workers (Figure 1a). All these ligands showed
excellent enantioselective control in the iridium-catalyzed
asymmetric hydrogenation. Particularly, the iridium complexes
transformations.1 However, only
a few of them have
of bicyclic P,N ligand
3 are highly efficient catalysts for the
demonstrated high generality for various asymmetric
reactions.1b,1c,1g The development of new tunable chiral ligands
is still one of the central themes in asymmetric catalysis. On the
other hand, preparation of chiral ligands relies heavily on optical
resolution of racemic backbones using resolving agents or the
use of the available pool of chiral building blocks. This classical
approach often suffers from a long synthetic route and/or
difficulty in tuning the electronic and steric effect of ligands. In
this context, alternative methodologies for efficient catalytic
enantioselective synthesis of chiral ligands remain rare1h,2 and
thus highly desirable.
asymmetric hydrogenation of challenging purely alkyl-
substituted olefins and furan derivatives.5c,5d Intrigued by the
excellent performance of these pyridine-containing P,N ligands,
we report herein a facile synthesis of a new type of tunable
chiral pyridine-aminophosphine ligands
4 derived from chiral
tetrahydroquinoline backbones (Figure 1b).
The iridium complexes of chiral P,N ligands have been
recognized as powerful catalysts in the asymmetric
hydrogenation of unfunctionalized olefins and imines3 since the
pioneering work of Pfaltz and co-workers,1e who developed
chiral PHOX ligands to mimic Crabtree’s catalyst.4 To date, a
Figure 1. Representative chiral pyridine-containing P,N ligands
(a) and designed synthetic route to new pyridine-
aminophosphine ligands (b).
a.
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences (CAS), and University of Chinese Academy of Sciences, Beijing 100190, P.
R. China; E-mail: fanqh@iccas.ac.cn
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin
300072, P. R. China.
a
4
Recently, we have demonstrated that the ruthenium
complexes of chiral monosulfonated diamines6 are excellent
catalysts for the asymmetric hydrogenation of quinolines and
b.
†
Electronic Supplementary Information (ESI) available: experimental procedures
and characterization for all of the compounds. See DOI: 10.1039/x0xx00000x
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Journal Name
Table 1. Optimization of Reaction Conditions a
other heteroaromatics.7,8 In particular, this catalytic system was
also very effective in the hydrogenation of polycyclic
heteroarenes such as 1,10-phenanthrolines, naphthyridines
and bisquinolines with excellent enantioselectivity.8 Intrigued
by these results, we envision that these ruthenium complexes
could catalyze the asymmetric hydrogenation of challenging 2-
(pyridin-2-yl)quinoline derivatives, thus providing a chiral
tetrahydroquinoline backbone for the facile synthesis of chiral
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DOI: 10.1039/C9OB00770A
P,N ligands 4 (Figure 1b). The notable features of these new P,N
ligands are their tunability by variation of the substituents on
both the pyridyl ring (R1) and the tetrahydroquinoline backbone
(R2), which would have a great impact on the efficiency and
stereoselectivity of their iridium catalysts in the asymmetric
hydrogenation of olefins and cyclic imines.
Results and Discussion
Asymmetric
Derivatives.
Hydrogenation
of
2-(Pyridin-2-yl)quinoline
The substrates containing a pyridyl group are difficult to be
hydrogenated, because the pyridyl group has strong coordination to
the metal center and may thus deactivate the catalyst.9 As far as we
know, the asymmetric hydrogenation of pyridine-substituted
quinoline derivatives have not been reported so far, and only a few
hydrogenations with achiral catalyst have been reported.10 In our
initial experiment, 2-(pyridin-2-yl)quinoline 6a was chosen to be
hydrogenated with (R,R)-5a in iPrOH under 50 atm H2. However, the
reduced product 2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline was
not detected. Similarly, hydrogenation of 2-(pyridin-3-yl)quinoline
6b and 2-(pyridin-4-yl)quinoline 6c could neither take place. Notably,
reaction of 2-(6-methylpyridin-2-yl)quinoline 6d was hydrogenated
smoothly, and full conversation with 90% ee was observed under the
same conditions. This was probably due to the steric effect of the
ortho-substituted methyl group which could reduce the coordinating
ability of nitrogen atom.9c,11 In addition, the introduction of a
substituent at the ortho position of pyridine ring not only improves
the catalytic reactivity, but also enables further tuning of the steric
effect of ligand.
aReaction conditions：substrate 6 (0.1 mmol), iPrOH (1 mL), Ru-catalyst 5 (2.0 mol
%), H2 (50 atm), stirred at rt for 4 h. The conversions were determined by 1H NMR
spectroscopy of the crude reaction mixture. The ee values were determined by
chiral OB-H column.
Having established the optimal reaction condition, we then
The hydrogenation of 2-(6-methylpyridin-2-yl)quinoline (6d) explored the substrate scope of the hydrogenation reactions
was chosen as the model substrate for the optimization of reaction (Scheme 1). Generally, all 2-(pyridin-2-yl)quinoline derivatives
conditions. Firstly, all catalysts described in Table 1 were tested. studied were hydrogenated smoothly in full conversions with good
Generally, the catalytic performance was significantly affected by to excellent enantioselectivities (77%-98% ee). Excellent
both the substituents of the η6-arene ligand and the N-sulfonate enantioselectivities were achieved with the substrates 6d-6i bearing
substituents. Introducing alkyl substituents into the η6-arene of the either an alkyl or aryl substituents at the 2-position of pyridine ring.
Ru catalysts led to significant increase in enantioselectivity, and the Notably, the hydrogenation of substrate 6j bearing a Br substituent
catalyst bearing a hexamethylbenzene ligand (R,R)-5h offered 97% on the pyridine proceeded smoothly with 5.0 mol% catalyst, and 97%
ee and full conversion. In addition, the influence of solvent was ee was observed. Introducing substituents at the 6-position or 8-
studied and iPrOH was selected as the solvent of choice in terms of position of quinoline backbone resulted in lower reactivity, and 5.0
both reactivity and enantioselectivity (entries 1-7 in Table S1, mol% catalyst was needed to achieve full conversion (6k-6p).
Supporting Information). The influences of temperature and Meanwhile, a lower enantioselectivity was obtained when an
hydrogen pressure were also studied. Reducing the hydrogen electron-withdrawing CF3 group was located at the 6-position of
pressure or increasing the reaction temperature resulted in a slightly quinoline backbone (6l). In the cases of 8-substituted 2-(pyridin-2-
decrease in enantioselectivity (entries 8-10 in Table S1).
yl)quinolines, the ee value dropped sharply as the steric hindrance of
the alkyl side chain increased (6m-6o). The hydrogenation of 8-
phenyl substituted substrate 6p proceeded smoothly but giving only
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80% ee. In addition, the absolute configuration of 7g’ was
determined to be S based on single-crystal X-ray analysis.
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DOI: 10.1039/C9OB00770A
Scheme 1. Asymmetric Hydrogenation of 2-(Pyridin-2-yl)quinoline
(2) Synthesis of chiral P,N-ligands 4
Derivativesa
(3) Synthesis of chiral Ir-complexes 8
The synthesized iridium complexes 8d-g and 8m were
characterized by NMR and ESI-MS. Luckily, the single crystals of the
complexes (S)-8f, (S)-8g and (S)-8m were obtained.14 As shown in
Figure 2, in all cases, the Ir-complex adopts a boatlike conformation
and the two P-phenyl groups adopt the normal axial-equatorial
orientations with respect to the coordination plane defined by the P-
Ir-N core. The structure of (S)-8f and (S)-8g is very similar. The
substituents on the pyridine ring in both complexes extend towards
the coordination sphere and, therefore, are expected to interact with
alkene substrate bounded at the adjacent coordination site. In the
case of (S)-8m bearing another methyl substituent at the 8-position
of tetrahydroquinoline backbone, its structure is somewhat different
and the tetrahydroquinoline motif extends towards the coordination
sphere. This difference in structure may has a great impact on their
catalytic performance.
aReaction conditions: substrates 6d-i (0.2 mmol), iPrOH (2 mL), 2.0 mol % of (R,R)-
5h, H2 (50 atm), stirred at 25 oC for 12 h; substrates 6j-p with 5.0 mol % of (R,R)-
5h. The conversions were determined by 1H NMR spectroscopy of the crude
reaction mixtures. The enantiomeric excesses were determined by HPLC with a
chiral HPLC column. The absolute configuration of 7g’ was determined to be S on
the basis of single-crystal X-ray analysis.12
The Synthesis of P,N-Ligands 4 and Their Ir-Complexes 8.
On the basis of the hydrogenation results, the reduced products 7d-
7g and 7m which have excellent ee values were chosen for the
further synthesis of chiral P,N ligands. As illustrated in Scheme 2, the
synthesis of enantiopure P,N-ligands and catalysts are quite simple
and straightforward. First, the hydrogenation of 2-(pyridin-2-yl)
quinolines 6 on gram-scale with (R,R)-5h under the optimal reaction
conditions gave chiral products 7 with excellent yields (89-95%) and
well maintained enantioselectivities (94-98%). Then, the resulting
chiral 1,2,3,4-tetrahydroquinolines 7 were readily converted into
P,N-ligands 4 by treatment with PPh2Cl in the presence of
triethylamine or n-BuLi. Moderate isolated yields and unchanged
enantioselectivities were obtained. After recrystallization from
methanol, all ligands 4 with 99% ee could be obtained. Finally, the
iridium complexes 8 were prepared in very good yields (75-85%) by
mixing ligand 4 with [Ir(COD)Cl]2 in CH2Cl2 followed by anion
(S)-8f
(S)-8g
(S)-8m
Figure 2. Crystal structures of (S)-8f, (S)-8g and (S)-8m; the anion
BArF- and hydrogen atoms are omitted for clarity. Seleted bond
lengths [Å] and angles [o], (S)-8f: Ir-N 2.142(13), Ir-P 2.303(4); N–Ir–P
83.8(4). (S)-8g: Ir-N 2.140(8), Ir-P 2.290(2); N–Ir–P 84.3(2). (S)-8m: Ir-
N 2.114(3), Ir-P 2.264(8); N–Ir–P 82.3(8).
exchange
in
the
presence
of
sodium
tetrakis-3,5-
bis(trifluoromethyl)phenylborate.13
Scheme 2. Synthesis of P,N-Ligands 4 and Their Ir-Complexes 8
Applications in Asymmetric Hydrogenation of Olefins and Cyclic
Imines
(1) Gram-scale asymmetric hydrogenation
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The trans-beta-methylcinnamate 9a and E-1,2-diphenylpropene 9b
Journal Name
a
challenge to precisely control the chemoselectivity,
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were chosen as the model substrates to test the performance of enantioselectivity and diastereoselectivity.4
catalysts 8. The reactions were performed in CH2Cl2 under 50 atm
DOI: 10.1039/C9OB00770A
hydrogen pressure at 25 oC. As shown in Table 2, in the
Table 3. Optimization of Reaction Conditions for the Hydrogenation
of 2,4-Diaryl-3H-benzo[b]azepines a
hydrogenation of 9a, catalyst (S)-8d, 8e and 8f bearing an alkyl group
on the pyridine ring gave similar enantioselectivity around 88-92% ee
(entries 1-3). Much lower conversion and ee value were observed by
using catalyst 8g bearing a aryl group on the pyridine ring (entry 4).
Notably, catalyst (S)-8m bearing another methyl group at the 8-
position of tetrahydroquinoline backbone, led to remarkable
increase in enantioselectivity (90% ee vs 99% ee) but with high
catalyst loading (entry 1 vs 5). For substrate 9b, similar results were
obtained with these iridium catalysts (entries 6-10), and excellent
enantioselecivity (99% ee) was achieved with catalyst (S)-8m (entry
10). Theses results indicate that the new Ir-P,N-ligand complexes 8
are efficient catalysts for the hydrogenation of trisubstituted olefins.
Entry
Cat. (mol%)
Conv.
(%)b
>99
>99
>99
>99
>99
>99
>99
>99
Ratio
(12b:13b)
>99 : nd
>99 : nd
>99 : nd
87 : 13
Ee (%)c
(12b/13b)
58/--
Dr
(13b)d
--
1
2
(S)-8d (1.0)
(S)-8e (1.0)
(S)-8f (2.0)
(S)-8g (4.0)
(S)-8m (2.0)
(S)-8e (3.0)
(S)-8e (3.0)
Ir-PHOX (4.0)
90/--
--
3
54/--
--
Table 2. Asymmetric hydrogenation of Ethyl trans-beta-
Methylcinnamate and E-Methysibenea
4
16/--
--
5
>99 : nd
nd : > 99
nd : >99
>99 : nd
20/--
--
6
--/84
3:1
12:1
--
7e
8f
--/90
69/--
aReaction conditions: substrate 11b (0.05 mmol) in CH2Cl2 (0.5 mL), Ir-catalyst 8, H2
(50 atm), stirred at rt for 12 h. bThe conversions were determined by 1H NMR
spectroscopy of the crude reaction mixtures. cThe enantiomeric excesses were
determined by HPLC with a chiral OD-H column. dThe dr was determined by 1H
NMR spectroscopy. eTwo-step one-pot process: 11b was hydrogenated with 1.0%
mol (S)-8e for 12 h, and then released the hydrogen gas and added another 2.0%
mol (S)-8e followed by hydrogenation for another 12 h. f With 1.0 mol% Ir-PHOX,
92% conversion with the same chemo- and enantioselectivity.
Entry
Substrate
Catalyst
Sub/Cat
Conv. (%)b
Ee (%)c
1
2
9a
9a
9a
9a
9a
9b
9b
9b
9b
9b
(S)-8d
(S)-8e
(S)-8f
100
100
100
100
50
>99
>99
>99
39
90
88
3
92
4
(S)-8g
(S)-8m
(S)-8d
(S)-8e
(S)-8f
54
5
>99
>99
>99
>99
32
>99
94
In our previous study,16b,16g the asymmetric hydrogenation of
2,4-diaryl-3H-benzo[b]azepines with chiral Ru- and Ir-catalyst only
gave the partially hydrogenated products 2,4-diaryl-2,3-dihydro-1H-
benzo[b]azepines, in which the C=C bond cound not be reduced. We
firstly examined the asymmetric hydrogenation of 2,4-di-p-tolyl-3H-
benzo[b]azepine (11b) catalyzed by 1.0 mol % of (S)-8d in CH2Cl2
under 50 atm H2 pressure at 25 oC for 12 h. The reaction proceeded
smoothly, and only the partially hydrogenated product 12b was
observed in full conversion with 58% ee (entry 1 in Table 3).
Encouraged by this result, we subsequently screened other iridium
catalysts (entries 2-5). It was found that the catalytic performance
was significantly affected by both the substituents on the pyridine
ring and tetrahydroquinoline backbone. Among these iridium
catalysts, (S)-8e bearing an isopropyl substitution on the pyridine ring
exhibited the best enantioselectivity (90% ee, entry 2). In contrast,
the best catalyst (S)-8m in the hydrogenation of olefins gave much
lower enantioselectivity (entry 5). It was noted that the fully reduced
product 13b was observed when 4.0 mol% (S)-8g was used (entry 4).
We thus increased the catalyst loading of (S)-8e from1.0 to 3.0 mol%,
and 13b was obtained as the sole product with 84% ee and 3:1 dr
(entry 6). Interestingly, when this reaction was carried out through a
two-step one-pot process (entry 7), obviously higher enantio- and
diastereoselectivity was obtained (90% ee and 12:1 dr). In
comparison, when 4.0 mol% Ir-PHOX was used as the catalyst under
6
100
50
7
87
8
50
82
9
(S)-8g
(S)-8m
25
42
10
25
>99
>99
aReaction conditions: substrate 9 (0.1 mmol) in CH2Cl2 (1.0 mL), Ir-catalyst, H2 (50
atm), stirred at rt for 12 h. bThe conversions were determined by 1H NMR
spectroscopy of the crude reaction mixtures. cThe enantiomeric excesses were
determined by HPLC with a chiral column, and the absolute configuration was
determined by comparison of optical rotation with literature data.
Having established these complexes as effective catalyts in the
reduction of olefins, we then turned our attention to the asymmetric
hydrogenation of some challenging seven-membered cyclic imines.
The resulting chiral nitrogen hetercycles such as benzoazepines and
benzodiazepines are versatile pharmacophores in medicinal
chemistry.15 In sharp contrast to simple olefins and acyclic imines,
asymmetric hydrogenation of such benzo-fused cyclic imines
remains less explored.16 We first studied the asymmetric
hydrogenation of benzoazepine derivatives containing both C=C and
C=N bonds. Considering the facts that iridium complexes of P,N-
ligands are effective catalysts for both C=C and C=N bonds, it is thus
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otherwise the same conditions, only 12b were observed with regardless of either the electronic effect or the position of
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moderate enantioselectivity (entry 8).
substituents at the phenyl ring. Notably,DOthI:e10h.1y0d3r9o/gCe9nOaBt0io0n770oAf
substrate 14f bearing a CH3 substituent gave a much lower enantio-
and diastereoselectivity (entry 6). In comparison, when Ir-PHOX
complex was used as the catalyst for substrate 14a, much lower
enantioselectivity and diastereoselectivity were obtained (entry 1 vs
7)
Table 4. Asymmetric Hydrogenation of Benzazepines Catalyzed by
(S)-8ea
Table 5. Asymmetric Hydrogenation of Benzodiazepines Catalyzed by
(S)-8ea
Entry
R2/R1
Conv.
(%)b
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
Ratio
Ee (%)c
Drd
(substrate)
(12:13)
>99:nd
>99:nd
>99:nd
>99:nd
>99:nd
70:30
1
2
H/Ph (11a)
86 (-)
90 (-)
-
-
H/p-tolyl (11b)
H/4-MeO-Ph (11c)
H/4-Cl-Ph (11d)
H/4-Br-Ph (11e)
MeO/Ph (11f)
H/Ph (11a)
Entry
R2/R1 (substrate)
H/Ph (14a)
Conv. (%)b
>99
Ee (%)c
Drd
16:1
10:1
>20:1
20:1
>20:1
1:2
3
95 (S)
92 (-)
-
1
2
99 (2S,4S)
97 (2S,4S)
99 (2S,4S)
99 (2S,4S)
99 (2S,4S)
10 (2R,4R)
84 (2R,4R)
4
-
H/4-Cl-Ph (14b)
H/4-Br-Ph (14c)
MeO/Ph (14d)
Cl/Ph (14e)
>99
5
88 (-)
-
3
>99
6e
7f
90 (-)
-
4
>99
nd:>99
nd:>99
nd:>99
nd:>99
nd:>99
nd:>99
90 (+)
88 (+)
99(2S,4S)
94 (+)
90 (+)
88 (+)
12:1
8:1
16:1
20:1
5:1
11:1
5
>99
11f
9f,g
10f
11f
12f
H/p-tolyl (11b)
H/4-MeO-Ph (11c)
H/4-Cl-Ph (11d)
H/4-Br-Ph (11e)
MeO/Ph (11f)
6
H/Me (14f)
>99
7e
H/Ph (14a)
>99
4:1
aReaction conditions: substrate 14 (0.2 mmol) in CH2Cl2 (2 mL), 4.0 mol% (S)-8e, H2
(50 atm), stirred at rt for 12 h. bThe conversions were determined by 1H NMR
spectroscopy of the crude reaction mixtures. cThe enantiomeric excesses were
determined by HPLC with a chiral OD-H column; and the absolute configuration
was determined by comparison of optical rotation with literature data. dThe dr
were determined by 1H NMR. eWith 4.0 mol% (S)-PHOX-Ir catalyst under otherwise
the same conditions.
aReaction conditions: substrate 11 (0.2 mmol) in CH2Cl2 (2.0 mL), 1.0 mol % (S)-8e,
H2 (50 atm), stirred at rt for 12 h. bThe conversions were determined by 1H NMR
spectroscopy of the crude reaction mixtures. cThe enantiomeric excesses were
determined by HPLC with a chiral OD-H column. The absolute configuration of 12c
was determined to be S based on single-crystal X-ray analysis,17 and the absolute
configuration of 13c was determined to be (2S,4S) based on the absolute
configuration of 12c and 2D-NOESY spectrum. dThe dr were determined by 1H
f
Conclusions
NMR. eWith 0.5 mol% (S)-8e and H2 (20 atm). Hydrogenation through two-step
one-pot process (entry 7 in Table 3). gIn the second step, 3 mol % (S)-8e was added
and stirred for 18 h.
In summary, the first asymmetric hydrogenation of 2-(pyridin-
2-yl)quinoline derivatives was developed with up to 98% ee by
With the optimizing conditions in hand (entries 2 and 7 in Table
3), we further explored the scope of the Ir-catalyzed asymmetric
hydrogenation of benzazepines (Table 4). In the presence of 1.0 mol%
(S)-8e, full conversions and excellent enantioselectivities were
observed in all cases (entries 1-6). Notably, hydrogenation of 11f
bearing a methoxy substituent at the 7-position gave a mixture of
both products 12f and 13f even under low hydrogen pressure and
catalyst loading (entry 6). In addition, the fully reduced products
could be obtained through a two-step one-pot process with excellent
enantioselectivities (up to 99% ee) and moderate to high
diastereoselectivities (entries 7-12).
using chiral cationic Ru(
Ⅱ) diamine catalysts. Based on these
chiral 2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline scaffolds, a
small library of tunable chiral pyridine–aminophosphine ligands
(S)-
4
and their iridium complexes (S)-
8
4
were readily synthesized.
could be fine-tuned by
The steric properties of the ligands
simply changing the substituents on the chiral
tetrahydroquinoline backbone and/or the pyridine ring, thereby
providing a facile approach for catalysts optimization. These
iridium catalysts were found to be efficient in the asymmetric
hydrogenation of benchmark alkene substrates as well as
challenging seven-membered cyclic imines including
benzazepines and benzodiazepines. Excellent enantio- and
diastereoselectivity (up to 99% ee and >20:1 dr), and/or
unprecedented chemoselectivity were obtained in the
asymmetric hydrogenation of 2,4-diaryl-3H-benzo[b]azepines
and 2,4-diaryl-3H-benzo[b][1,4]diazepines. Further applications
of these new ligands in other asymmetric catalysis are currently
underway in our laboratory.
Encouraged by the above excellent results, we then extended
this catalytic system to the asymmetric hydrogenation of
benzodiazepines (Table 5). To our delight, the optimal reaction
conditions selected for the hydrogenation of benzazepines could also
work well for benzodiazepines. Several 2,4-diaryl-substituted
benzodiazepines (14) were hydrogenated smoothly (entries 1–5),
affording the reduced products in very good yields with excellent
enantio- and diastereoselectivities (up to 99% ee and >20:1 dr),
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10536; (e) H. Zhou, Z. Li, Z. Wang, T. Wang, L. Xu, Y. He, Q.-H.
Conflicts of interest
There are no conflicts to declare.
View Article Online
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Acknowledgements
We thank the National Natural Science Foundation of China
(NSFC, 21790332, 21521002 and 21672218) and CAS
(QYZDJSSWSLH023) for financial support.
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6 | J. Name., 2012, 00, 1-3
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free of charge from The Cambridge Crystallographic Data
Centre.
View Article Online
DOI: 10.1039/C9OB00770A
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB00770A
TOC
1) Ph2PCl
Ru-diamine/H2
R1
N
N
R1
N
N
N
H
2) Ir(COD)Cl2/NaBArF
up to 98% ee
N
R2
BArF
R2
Ph2P
R2
Ir
R1
13 examples
R1
R1
R1
H
H
N
R2
R2
R2
R
N
H
N
N
H
R1
R1
6 examples, up to 99% ee, >20:1 dr
R1
H
R = CO2Et, >99% ee
R = Ph, 99% ee
6 examples, up to 95% ee
6 examples, up to 99% ee, >20:1 dr
A small library of tunable chiral pyridine–aminophosphine ligands were synthesized
based on chiral tetrahydroquinoline scaffolds, which were obtained via Ru-catalyzed
asymmetric hydrogenation. The ligands were successfully applied in the Ir-catalyzed
asymmetric hydrogenation of olefins and cyclic imines.