Asymmetric Hydrogenation of Isoquinolines and Pyridines Using Hydrogen Halide Generated in Situ as Activator

Article abstract of DOI:10.1021/acs.orglett.7b02502

By employing halogenide trichloroisocyanuric acid as a traceless activation reagent, a general iridium-catalyzed asymmetric hydrogenation of isoquinolines and pyridines is developed with up to 99% ee. This method avoids tedious steps of installation and removal of the activating groups. The mechanism studies indicated that hydrogen halide generated in situ acted as an activator of isoquinolines and pyridines.

Full text of DOI:10.1021/acs.orglett.7b02502

Letter
pubs.acs.org/OrgLett
Asymmetric Hydrogenation of Isoquinolines and Pyridines Using
Hydrogen Halide Generated in Situ as Activator
Mu-Wang Chen,† Yue Ji,† Jie Wang,† Qing-An Chen,† Lei Shi,† and Yong-Gui Zhou*,†,‡
†State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: By employing halogenide trichloroisocyanuric acid as a
traceless activation reagent, a general iridium-catalyzed asymmetric
hydrogenation of isoquinolines and pyridines is developed with up to
99% ee. This method avoids tedious steps of installation and removal of
the activating groups. The mechanism studies indicated that hydrogen
halide generated in situ acted as an activator of isoquinolines and
pyridines.
Scheme 1. Enantioselective Hydrogenation of Isoquinolines
and Pyridines via Substrate Activation
hiral piperidines and tetrahydroisoquinolines are common
1
Cstructural motifs present in biologically active compounds,
and the development of efficient methods for their synthesis has
attracted increasing attention.2 One of the most straightforward
and atom-economic methods is direct asymmetric hydro-
genation of the corresponding pyridines3−7 and isoquinolines.8
However, the resonance stability and inhibiting effect of nitrogen
atom on chiral catalyst impeded efficient asymmetric hydro-
genation of these compounds.
In the past decades, chemists have made tireless efforts to
overcome these difficulties. A number of effective strategies,
including substrate activation and catalyst activation, have been
developed. In 2005, an elegant asymmetric hydrogenation of the
N-iminopyridinium ylides was reported by Charette’s group.4a
Next, the chloroformates, benzyl bromides, and Brønsted acids
were successfully used as substrate activators for asymmetric
hydrogenation of pyridines4−6 and isoquinolines8 (Scheme 1).
However, installation and removal of activating groups are the
major drawbacks for further synthetic applications. In addition,
some activating groups cannot be installed on the substrates due
to steric hindrance and electronic effects. Therefore, developing
an ideal activator for the direct asymmetric hydrogenation of
aromatic N-heterocycles is highly desirable. In this respect, an
ideal activator should possess the advantages of high efficiency,
simplified operation, and low cost. Furthermore, the crucial point
is the circumvention of tedious steps of installation and removal
without forming or breaking a covalent bond. An ideal activator
with these characters can be called a traceless activator. Herein,
we report a general enantioselective hydrogenation of isoquino-
lines and pyridines using trichloroisocyanuric acid (TCCA) as a
traceless activator with excellent enantioselectivity (Scheme 1),
and the salient features of this method are as follows: (1) simple
operation and (2) avoidance of tedious installation and removal
of activating groups.
Halogenides (such as NIS and TCCA) are commercially
available, stable, cheap, and low-toxic reagents, which have been
widely applied in organic synthesis.9 In 2007, a halogen-bonding
interaction involving the CN bond and NIS was reported by
the Vaquero group.10 The halogen bond, an important
noncovalent interaction between an electrophilic halogen
substituent X (X = Cl, Br, I) and a Lewis base, forms an
interaction angle close to 180°. Over the past decades, the
halogen bond has been applied to a variety of research disciplines
including crystal engineering and material sciences.11 Mean-
while, the application of the halogen bond in the field of organic
synthesis and catalysis also receives important attention but is
Received: August 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02502
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
still quite rare. For example, the reduction of quinolines with
Hantzsch ester using perfluorinated iodoalkanes or bis-
(iodoimidazolinium) compounds as halogen-bond activators
was reported by the groups of Bolm and Tan,12 respectively. In
addition, halogen-bond donors could also serve as activators in
the Morita−Baylis−Hillman reaction,13a Diels−Alder reac-
tion,13b,c and so on.13d−h Considering that the halogenides easily
form halogen-bond interactions with Lewis basic isoquinolines
and pyridines, the halogenides could act as the desirable traceless
activators. These activators might enhance the reactivity of
pyridines and isoquinolines and provide a new opportunity for
asymmetric hydrogenation of isoquinoline and pyridine
derivatives.
the above results, some other halogenides were tested (entries
10−12). TCCA gave the most favorable 96% ee, albeit with
slightly low reactivity. Fortunately, the reactivity increased
obviously using THF instead of dioxane with the identical
enantioselectivity (entry 13). To our delight, no loss in
conversion and enantioselectivity was observed with the
decreased loadings of catalyst and TCCA (entry 15). Therefore,
the optimal reaction conditions were established as [Ir(COD)-
Cl]2/(R)-SegPhos/TCCA/THF.
After establishing the optimal conditions, we examined the
substrate scope, and the results are summarized in Scheme 2. A
a−c
Scheme 2. Substrate Scope of Isoquinolines
With this hypothesis in mind, 1-phenylisoquinoline (1a) was
chosen as a model substrate. We tested asymmetric hydro-
gennation of 1a with NIS as substrate activator and [Ir(COD)-
Cl]2/ (R)-SegPhos as catalyst in THF under hydrogen gas (1200
psi) at 80 °C (Table 1). Gratifyingly, the reaction proceeded
a
Table 1. Optimization of Reaction Conditions
b
c
entry
solvent
ligand
halogenide
conv (%)
ee (%)
1
2
3
4
5
6
7
8
THF
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
L1
NIS
95
40
91
63
90
94
85
94
89
73
71
95
94
96
95
95
95
CH2Cl2
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
NIS
NIS
78
NIS
>95
75
NIS
NIS
>95
91
NIS
NIS
81
d
9
NIS
17
a
b
2c−g: [Ir(COD)Cl]2 (2.0 mol %), (R)-SegPhos (4.4 mol %). 2h−
10
11
12
13
NBS
NCS
TCCA
TCCA
TCCA
TCCA
>95
>95
66
c
o: TCCA (1.0 equiv). 2p−q: dioxane/iPrOH (v/v = 5:1, 3.0 mL), H2
(600 psi), TCCA (1.0 equiv), 20 h, 30 °C.
>95
>95
>95
e
14
THF
series of 1-aryl-substituted isoquinolines could be smoothly
hydrogenated, giving the corresponding tetrahydroisoquinolines
with excellent yields and enantioslectivities (2a−d) regardless of
the electronic properties of 1-aryl substituents. Moreover, the
position of substituents on 1-aryl had a marginal effect on the
reactivity and enantioselectivity (2d, 2e). When the aryl
substituent on C1 was replaced with an alkyl substituent, good
enantioselectivity and reactivity were obtained (2f). Introducing
an electron-donating methoxy substituent on the isoquinoline
core (2g) resulted in slightly lower enantioselectivity. Then,
more challenging 1,3-disubstituted isoquinolines were tackled to
deliver two stereocenters in one step. To our delight, 1,3-diaryl-
(1h−m), 1-aryl-3-alkyl- (1n), and 1-alkyl-3-aryl-disubstituted
isoquinolines (1o) can be hydrogenated with high enantiose-
lectivities and diasteroselectivities. For example, the hydro-
genation of 1,3-diphenylisoquinoline furnished the desired
product 2h in 99% yield and 98% ee. To further explore the
scope of substrates, the hydrogenation of fluorinated 3,4-
disubstituted isoquinolines was evaluated, providing the
corresponding hydrogenation products with 92−93% ee, and
no defluorination products were detected. To demonstrate the
practicality of this method, the asymmetric hydrogenation of 1a
was performed on gram scale under the standard conditions with
94% yield and 94% ee without loss of reactivity and
enantioselectivity.
e,f
15
THF
a
Conditions: 1a (0.125 mmol), [Ir(COD)Cl]2 (2.0 mol %), ligand
(4.4 mol %), H2 (1200 psi), solvent (3.0 mL), halogenide (1.0 equiv),
b
c
48 h, 80 °C. Determined by 1H NMR spectroscopy. Determined by
d
HPLC analysis of the corresponding N-benzoyl derivatives. NIS (5.0
e
f
mol %). TCCA (0.36 equiv). 1a (0.25 mmol), [Ir(COD)Cl]2 (1.0
mol %), (R)-SegPhos (2.2 mol %). NIS = N-iodosuccinimide, NBS =
N-bromosuc-cinimide, NCS = N-chlorosuccinimide, TCCA =
trichloroisocyanuric acid.
smoothly, and excellent conversion as well as enantioselectivity
was obtained (entry 1). Subsequently, the solvent effects were
examined (entries 1−4). It was found that solvents played a
crucial role, and dioxane was more suitable than the others (entry
4). Some commercially available chiral bisphosphine ligands
were also evaluated, and the best result was achieved with (R)-
SegPhos L1 and (R)-DifluorPhos L3 (94% ee; entries 4 and 8).
Notably, poor reactivity was observed without stoichiometric
halogenide activator, and this result showed the halogen-bond
interaction might improve reactivity (entry 9). Encouraged by
B
DOI: 10.1021/acs.orglett.7b02502
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
The success of asymmetric hydrogenation of isoquinolines
encouraged us to apply this strategy to more challenging
substrate, pyridines. Initially, we investigated the feasibility of this
approach by evaluating asymmetric hydrogenation of 6-methyl-
2-phenylpyridine (3a) under conditions of [Ir(COD)Cl]2/(R)-
SegPhos/TCCA (0.36 equiv) in THF at 80 °C. The desirable
hydrogenation product 4a could be obtained with 68%
conversion, moderate 76% enantioselectivity, and excellent
diastereoselectivity (>20:1). Fortunately, the 86% ee value and
full conversion were obtained by adjusting the amount of
activator TCCA from 0.36 to 1.0 equiv.
Scheme 3. Control Experiments
Having identified the optimal reaction conditions, we
commenced the extension of substrate scope (Table 2). A series
a
Table 2. Substrate Scope of Pyridines
our studies on the basis of the hypothesis that the asymmetric
hydrogenation of isoquinolines and pyridines was activated by
halogenide through halogen-bond interactions. Fortunately, the
stable 1:1 halogen-bond complex was formed by mixing 1-
phenylisoquinoline 1a and NIS in CH2Cl2, and the structure was
confirmed by single-crystal X-ray crystallography (eq 1). The
angle of N(2)−I(1)−N(1) is 175.86 (9)°, almost linear
disposition, and the bond length of I(1)−N(1) is 2.502(3) Å
and I(1)−N(2) is 2.086(3) Å. However, the partially hidden
Brønsted acid activation could not be completely ruled out in the
application of halogen bond in the field of organic synthesis and
catalysis.13b,14 Furthermore, the desired product 2a was obtained
by direct asymmetric hydrogenation of 1a·NIS complex (eq 2)
under the standard conditions with identical results (Table 1,
entry 4). In addition, the hydrogenolysis of NIS was conducted
under the standard conditions (eq 3), giving the succinimide and
hydrogen iodide with full conversion. Surprisingly, hydro-
genation of 2-phenylisoquinolinium chloride 5 was conducted
(eq 4), and identical reactivity and enantioselectivity were
obtained under the standard conditions. The above experimental
results support the asymmetric hydrogenation of isoquinolines
and pyridines using hydrogen halide generated in situ as
activator.
In summary, a general and highly enantioselective iridium-
catalyzed asymmetric hydrogenation of isoquinolines and
pyridines has been successfully developed with up to 99% ee.
This work features a traceless activation strategy and circumvents
the tedious steps of installation and removal of the activating
reagents. This hydrogenation reaction can be easily scalable and
is valuable for the preparation of chiral tetrahydroisoquinolines
and piperidines with multiple stereocenters. The mechanism
studies indicated that hydrogen halide generated in situ acted as
the activator of isoquinolines and pyridines. Further investigation
on the application of the related traceless activation strategy to
other substrates and detailed mechanistic studies are currently
ongoing in our laboratory.
b
c
entry
R, R′
Ar
C6H5
yield (%)
ee (%)
1
2
3
4
5
Me, H
81 (4a)
90 (4b)
64 (4c)
75 (4d)
86 (4e)
98 (4f)
97 (4g)
96 (4h)
85 (4i)
91 (4j)
98 (4k)
91 (4l)
82 (4m)
96 (4n)
86
85
85
85
73
90
90
89
90
87
88
89
89
85
Me, H
4-CF3C6H4
3-MeC6H4
3,5-F2C6H3
1-naphthyl
C6H5
Me, H
Me, H
Me, H
d
6
Me, CF3
Me, CF3
Me, CF3
Me, CF3
Me, CF3
Me, CF3
Me, CF3
Et, CF3
nBu, CF3
d
7
4-MeC6H4
3-MeC6H4
4-MeOC6H4
4-CF3C6H4
4-C6H5C6H4
2-naphthyl
C6H5
d
8
d
9
d
10
d
11
d
12
d
13
d
14
C6H5
a
Conditions: 3 (0.25 mmol), [Ir(COD)Cl]2 (2.0 mol %), (R)-
SegPhos (4.4 mol %), H2 (1200 psi), THF (3.0 mL), TCCA (1.0
b
c
equiv), 48 h, 80 °C. Isolated yield. Determined by HPLC analysis of
d
the corresponding N-benzoyl derivatives. [Ir(COD)Cl]2 (2.5 mol %),
(R)-DifluorPhos (5.5 mol %), H2 (800 psi), DCM:iPrOH (v:v = 3:1,
3.0 mL), TCCA (1.0 equiv), 36 h, rt.
of 2,6-disubstituted pyridines were successfully converted to the
chiral piperidines with good to excellent enantioselectivities. The
electronic properties and steric effects on the 6-arylpyridines had
a marginal effect on the yields and ee values (entries 1−5).
Notably, this method can provide higher enantioselectivities
compared to previous method using pyridium chloride as
substrates (for example, 3a: 86% ee vs 78% ee6b). Furthermore,
to demonstrate the versatility of this method, we turned our
attention to the asymmetric hydrogenation of trifluoromethyl-
substituted pyridines. After a condition reoptimization, a range of
2,3,6-trisubstituted pyridines bearing a trifluoromethyl group
could be well hydrogenated with high enantioselectivities
(entries 6−14). The steric and electronic nature of the aryl
substituents had little influence on the outcome of the reaction,
giving the corresponding products with 85−90% ees (entries 6−
12). To our delight, pyridines bearing longer alkyl chain groups
instead of a methyl group at the 6-position were also good
partners with 85−89% ees (entries 13−14). In the previous
method,6b we could not obtain the target product 4n because the
3n·HCl could not be prepared.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02502.
Experimental procedures, characterization data, and NMR
spectra (PDF)
X-ray data for 1a·NIS (CIF)
To gain more insight into the reaction mechanism, the
following investigations were performed (Scheme 3). We began
C
DOI: 10.1021/acs.orglett.7b02502
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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and hydrochlorides, see: (a) Kita, Y.; Iimuro, A.; Hida, S.; Mashima, K.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ygzhou@dicp.ac.cn.
ORCID
(8) For asymmetric hydrogenation of isoquinolines, see: (a) Lu, S.-M.;
Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006, 45,
2260. (b) Shi, L.; Ye, Z.-S.; Cao, L.-L.; Guo, R.-N.; Hu, Y.; Zhou, Y.-G.
Angew. Chem., Int. Ed. 2012, 51, 8286. (c) Ye, Z.-S.; Guo, R.-N.; Cai, X.-
F.; Chen, M.-W.; Shi, L.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2013, 52,
3685. (d) Guo, R.-N.; Cai, X.-F.; Shi, L.; Ye, Z.-S.; Chen, M.-W.; Zhou,
Y.-G. Chem. Commun. 2013, 49, 8537. (e) Iimuro, A.; Yamaji, K.;
Kandula, S.; Nagano, T.; Kita, Y.; Mashima, K. Angew. Chem., Int. Ed.
2013, 52, 2046. (f) Ding, Z.-Y.; Wang, T.; He, Y.-M.; Chen, F.; Zhou, H.-
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Mashima, K. Chem. - Eur. J. 2015, 21, 1915. (h) Wen, J.; Tan, R.; Liu, S.;
Zhao, Q.; Zhang, X. Chem. Sci. 2016, 7, 3047.
Mu-Wang Chen: 0000-0001-6493-1363
Yue Ji: 0000-0002-0303-7971
Qing-An Chen: 0000-0002-9129-2656
Yong-Gui Zhou: 0000-0002-3321-5521
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science Foundation
of China (21532006, 21690074) and the Strategic Priority
Program of Chinese Academy of Sciences (XDB17020300) is
acknowledged.
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