Dual Stereocontrol for Enantioselective Hydrogenation of Dihydroisoquinolines Induced by Tuning the Amount of N-Bromosuccinimide

Article abstract of DOI:10.1002/cjoc.201700634

An efficient dual stereocontrol in iridium-catalyzed hydrogenation of 1-substituted 3,4-dihydroisoquinolines was realized by tuning the amount of N-bromosuccinimide using chiral ligand of single configuration, providing both enantiomers of 1-substituted 1,2,3,4-tetrahydroisoquinolines with up to 89% ee (S) and 98% ee (R), respectively. Dual activation role of N-bromosuccinimide is proposed to be responsible for the reversal of enantioselectivity under two hydrogenation conditions.

Full text of DOI:10.1002/cjoc.201700634

Dual Stereocontrol for Enantioselective Hydrogenation of
Dihydroisoquinolines Induced by Tuning the Amount of
N-Bromosuccinimide
Yue Ji,aJie Wang,aMu-Wang Chen,aLei Shi*a,band Yong-Gui Zhou*a
aState Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian
116023,P. R. China
bState Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, P. R. China
An efficient dual stereocontrolin iridium-catalyzed hydrogenation of 1-substituted 3,4-dihydroisoquinolines was
realized by tuning the amount of N-bromosuccinimide using chiral ligand of single configuration, providing both
enantiomers of 1-substituted 1,2,3,4-tetrahydroisoquinolineswith up to 89% ee (S) and 98% ee (R), respectively.
Dual activation role of N-bromosuccinimide is proposed to be responsible for the reversal of enantioselectivity
under two hydrogenation conditions.
Keywords: Reversal of enantioselectivity, hydrogenation, N-bromosuccinimide, 1,2,3,4-tetrahydroisoquinolines
Introduction
1,2,3,4-tetrahydroisoquinoline
were
traditionally
obtained by chemical resolution with two chiral
reagents or by asymmetric transformations with two
ligands of opposite configuration.15 In view of chiral
atom economy, dual enantioselective hydrogenation of
isoquinoline-type imine with single chiral catalyst is
undoubtedly highly preferred and desirable.
Since the tragedy of thalidomide event in 1950s, the
completely different pharmacological activities of both
enantiomers of chiral pharmaceuticals has drew
extensive attention from all around the world.1
According to regulations on Food and Drug Adminis-
tration in United States in 1992, all the listed racemic
medicines should be provided the details of two
enantiomers in biological activity and toxicity.2 The
complementary regulation in 1997 required that early
listed racemic medicines should be replaced by the
corresponding chiral enantiomer.3 Thus, the enantiose-
lective synthesis of both enantiomers of a chiral
pharmaceutical molecule is of great importance.
Normally, both enantiomers of a chiral molecule were
obtained by using two chiral reagents or ligands of
opposite configuration. To prepare two enantiomers of a
target compound from only one single-isomer of a chiral
catalyst is an intriguing subject in synthetic community.
The previous excellent researches suggested that
modifying achiral parameters of reaction,4 such as
metal,5 solvent,6 temperature,7 additives8 and others,9
would result in the reversal of enantioselectivity.
However, the lack of exact knowledge and general
regularity on switch in enantioselectivity make it
challenging for further application.
Scheme 1 The reversal of enantioselectivity induced by the
amount of NBS
For the past few years, our group has worked on
iridium-catalyzed asymmetric hydrogenation of hetero-
aromatics.11a-d It was found that oxidizing agents
containing halogen, such as N-iodosuccinimide (NIS),
N-bromosuccinimide (NBS), could significantly
improve the performance of the catalyst by elevating the
valence state of iridium (IrI to IrIII).16 Besides, halogen
source could also react with imines or amines as
oxidants.17 The dual activation of catalyst and substrate
with halogen source inspired us to conduct further
investigation of dual stereocontrol for asymmetric
hydrogenation of dihydroisoquinolines. Herein, we
describe an effective dual stereocontrol in
iridium-catalyzed asymmetric hydrogenation of
1-substituted3,4-dihydroisoquinoline derivatives solely
upon tuning the amount of NBS(Scheme 1).
A great progress has been made in iridium-catalyzed
asymmetric hydrogenationin the past decades.10
Iridium-catalyzed enantioselective hydrogenation of
isoquinoline,11isoquinoline-type imine12 and enamine13
can provide effective access to chiral 1,2,3,4-tetrahy-
droisoquinolines that represents one kind of privileged
scaffolds in pharmaceutical molecules and natural
alkoloids.14 Till now, despite of the achievements
mentioned above, both enantiomers of
a chiral
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may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1002/cjoc.201700634
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Experimental
(R)-BINAP as the chiral hydrogenation catalyst to
evaluate the hydrogenation parameters (Table 1). To our
delight, the desired product 1-phenyl-1,2,3,4-tetrahydro-
isoquinoline was obtained in the presence of 10 mol%
NBS in 1,2-dichloroethanewith full conversion and 82%
ee (Table 1, entry 1). Whereas further examinations
focused on solvents and chiral bisphosphine ligands
gave relatively lower enenatioselectivities (entries 2-7).
When reaction temperature decreased to 0 oC, an
enhancement of the enantioselectivity with 86% ee was
observed (entry 8).
General procedure for iridium-catalyzed dual enan-
tioselective hydrogenation of 3,4-dihydroisoquinoline
Condition A:A mixture of [Ir(COD)Cl]2 (4.0 mg,
0.006 mmol) and (R)-BINAP (8.2 mg, 0.0132 mmol) in
1,2-dichloroethane (DCE, 1.0 mL) was stirred at room
temperature in the glove box. After 10 min,
N-bromosuccinimde (NBS, 5.3 mg, 0.03 mmol) was
added to the mixture with another 10 min’s stirring. And
then the catalyst was transferred by a syringe to the
solution of 1-substituted 3,4-dihydroisoquinolines1(0.3
mmol) in 1,2-dichlorethane (2 mL). The hydrogenation
Table 1 Optimization of reaction conditionsa
o
was performed at 0 C and at a hydrogen pressure of
500 psi for 36 h. After carefully releasing the hydrogen
gas, the mixture was concentrated in vacuo and
purification wasperformed by a silica gel column eluted
with hexanes/ethyl acetate to give the enantiomerically
enriched products (S)-2.
NBS, Na2CO3
(mol %)
entry
solvent
(R)-L
ee (%)b
DCE
toluene
THF
10, 0
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-H8-BINAP
(R)-SynPhos
(R)-DifluroPhos
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
(R)-BINAP
82 (S)
79
1
2
Condition B: A mixture of [Ir(COD)Cl]2 (2.0 mg,
0.003 mmol) and (R)-BINAP (4.1 mg, 0.0066 mmol) in
1,2-dichloroethane (1.0 mL) was stirred at room
temperature for 10 min in the glove box. Then the
catalyst was transferred by a syringe to the mixture of
1-substituted 3,4-dihydroisoquinolines1(0.3 mmol),
N-bromosuccinimde (80.1 mg, 0.45 mmol), sodium
carbonate (23.9 mg, 0.225 mmol) and 1,2-dichlorethane
(3 mL) with 10 min’s stirring. Subsequently, the hydro-
10, 0
10, 0
71
3
4c
MeOH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
10, 0
68
5
10, 0
75
10, 0
63
6
7
10, 0
65
8d
9d
10
11
12
13
14
10, 0
86
o
10, 5
86
genation was performed at 30 C and at a hydrogen
50, 25
75, 38
90, 45
100, 50
120, 60
150, 75
55
pressure of 500 psi for 24 h. After carefully releasing
the hydrogen gas, the mixture was extracted with
diethyl ethertwice and the combined organic extracts
dried over sodium sulfate and then concentrated in
vacuum and purification was performed by a silica gel
column eluted with hexanes/ethyl acetate to give the
chiral products (R)-2.
13
-16
-53
-88
-91 (R)
15
a
Reaction conditions: 1a (0.2 mmol), [Ir(COD)Cl]2 (1.0
mol%), (R)-L (2.2 mol%), NBS, Na2CO3, solvents (3 mL), 24 h,
30 oC, H2 (500 psi); Conversions are over 95% determined by 1H
(S)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline (2a):
Condition A: 57 mg, 92% yield, 86% ee, pale yellow
solid, [α]25 = +15.17 (c1.14, CHCl3), Rf = 0.45
D
b
NMR, unless mentioned; Determined by HPLC for the corre-
(hexanes/ethyl acetate 2:1); 1H NMR (400 MHz, CDCl3)
δ 7.34-7.25 (m, 5H), 7.14 (d, J = 4.1 Hz, 2H), 7.03 (dt, J
= 8.1, 4.2 Hz, 1H), 6.75 (d, J = 7.7 Hz, 1H), 5.10 (s, 1H),
3.30-3.24 (m, 1H), 3.13-3.01 (m, 2H), 2.87-2.79 (m,
1H), 1.90 (brs, 1H);13C NMR (100 MHz, CDCl3) δ
144.9, 138.3, 135.5, 129.1, 129.0, 128.5, 128.1, 127.4,
126.3, 125.7, 62.1, 42.3, 29.8; Enantiomeric excess was
determined by HPLC for the corresponding benzamide
(AD-H column, hexane/ iPrOH 70/30, 0.80 mL/min, 230
nm): t1 = 12.9 min(major), t2 = 15.6 min.
sponding benzamidederivatives;c91% conversion; d 0 oC, 36 h.
In the next experiment investigation on the effect of
NBS, it were found that increasing the amount of NBS
resulted in a lower reactivity and the hydrogenation
would be completely dead with 150 mol % NBS as
additive. Fortunately, the hydrogenation was carried out
smoothly in full conversion when with the addition of
sodium carbonate. However, as the amount of NBS
increased to 50 mol%, the ee value was decreased
dramatically (entry 10). Further research turned out that
the ee value of product then sharply jumped up to 91%
with 150 mol% NBS to afford a product with the
reversed enantioselectivity after meeting with an almost
racemate (entries 9-15). These results showed that the
enantioselectivity almost has a linear dependence
relation with the amount of NBS (Figure 1) and the
reversed enantioselectivity may be attributed to two
completely different reaction modes. Thus, the amount
(R)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline (2a):
Condition B: 59 mg, 94% yield, 92% ee, [α]25D = -15.33
(c0.30, CHCl3).
Results and Discussion
Initially, 1-phenyl-3,4-dihydroisoquinoline1a was
chosen as the model substrate using [Ir(COD)Cl]2/
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of NBS was vital to establish the final systems (entries 8
and 15) on the dual enantioselective hydrogenation of
1-substituted 3,4-dihydroisoquinolines 1.
8
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
85
95
91
95
88
93
85
96
94
95
93
98
92
93
90
92
78
90 (+)
89 (+)
89 (-)
84 (+)
83 (-)
84 (+)
66 (-)
86 (+)
95 (-)
86 (+)
94 (-)
85 (+)
93 (-)
85 (+)
91 (-)
75 (-)
60 (+)
9
1e
1f
H/H/3-MeC6H4
H/H/4-MeC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1g H/H/4-MeOC6H4
1h
1i
H/H/4-FC6H4
H/H/4-ClC6H4
H/H/4-BrC6H4
1j
1k H/H/2-Naphthyl
Figure 1The effect of amount of NBS on enantioselectivity.
1l
aConditionA:
H/H/iPr
With the optimized conditions established, we then
set out to demonstrate the generality of
iridium-catalyzed dual enantioselective hydrogenation
of 3,4-dihydroisoquinoline derivatives and the results
are summarized in Table 2. Generally, the reactions
were performed smoothly, giving the desired products
with two isomers in good to excellent yields and
enantioselectivities. For 1-aryl substituted substrate,
high enantioselectivities were achieved regardless of the
electronic properties of the substrates under condition A.
On the contrary, the electronic properties of R group
played an important role in the enantioselectivity of the
reaction under condition B. It showed that an upward
tendency of ee values was achieved as the enhanced
electron-deficiency of the aryl group. And higher ees
were obtained with electronically deficient substituent
groups (Table 2, entries 16, 18, 20). However,
electron-donating groups on the C-1 aryl ring made
negative effects on enantioselectivity (entries 10, 12, 14).
Significantly, with a methoxy group on 1-aryl of the
substrate, a dramatic decrease in enatioselectivity with
66% ee was observed (entry 14). The isopropyl
substituted substrate could also be hydrogenated
smoothly but only in moderate enantioselectivity under
both conditions (entries 23, 24).
1
(0.3 mmol), [Ir(COD)Cl]2 (2 mol%),
(R)-BINAP (4.4 mol%), NBS (10 mol%), DCE(3 mL), 36 h, 0 oC,
H2 (500 psi); ConditionB:1 (0.3 mmol), [Ir(COD)Cl]2 (1 mol%),
(R)-BINAP (2.2 mol%), NBS (150 mol%), Na2CO3 (75 mol%),
DCE(4 mL), 24 h, 30 oC, H2 (500 psi); Isolated yields.
Determined by HPLC for the corresponding benzamide
derivatives.
b
c
Scheme 2Dual enantioselective synthesis of AMPA receptor
antagonist
MeO
1. Condition A
NAc
2. AcCl, Et3N, DCM
MeO
97% yield, 81% ee
3
(S)-
MeO
MeO
N
Cl
1m
MeO
MeO
1. Condition B
2. AcCl, Et3N, DCM
NAc
Cl
98% yield, 91% ee
3
(R)-
AMPA Receptor Antagonist
Cl
Furthermore, both enantiomers of a biologically
active compound 3 were conveniently prepared through
dual enantioselective hydrogenation under the above
standard conditions and acylation in 81% ee (S) and 91%
ee (R), respectively (Scheme 2). Notably, (R)-3 is a
potent noncompetitive AMPA receptor antagonist.18
Table2Iridium-catalyzed dual enantioselective hydrogenation of
3,4-dihydroisoquinolines 1a
R2
R1
R2
R1
[Ir(COD)Cl]2/(R)-BINAP
N
NH
∗
A
B
Condition or
R
R
1
2
Scheme 3Control experiments
yield
(%)b
92
O
O
entry
1
R1/R2/R
condition
ee (%)c
[Ir(COD)Cl]2/(R)-BINAP
N
Br
N
H
+
HBr
1
2
3
4
5
6
7
A
B
A
B
A
B
A
86 (S)
92(R)
89 (-)
98 (+)
89 (-)
95 (+)
88 (-)
DCE, 500 psi H2, 30 oC, 18 h
1a
1b
1c
H/H/C6H5
O
O
94
92
88
93
85
89
>95% conv.
Me/H/C6H5
[Ir(COD)Cl]2/(R)-BINAP
N•HBr
NH
Ph
NBS (10 mol%), Na2CO3 (0.5 eq.)
DCE, 500 psi H2, 30 oC, 24 h
Ph
MeO/H/C6H5
4
2a
(R)-
96% ee (> 95% conv.)
1d MeO/MeO/C6H5
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To gain more information on the role of NBS in
reaction, some control experiments were conducted in
the presence of iridium catalyst and hydrogen. The
hydrogenolysis of NBS performed smoothly using the
above chiral iridium complex as catalyst,11h giving the
succinimide and hydrogen bromide in full conversion
(Scheme 3). Next, 1-phenyl-3,4-dihydroiso-quinoline
hydrobromide4 was synthesized and subjected to the
iridium-catalyzed enantioselective hydrogenation under
the above standard condition B, providing the desired
product 2a in identical 96% ee with (R)-configuration,
which is accordant with the result of condition B.
Therefore, the hydrogenation with 150 mol% NBS
could be probably illustrated as the enantioselective
hydrogenation of 1-phenyl-3,4-dihydroisoquinoline
hydrobromide, which is considered to be formed in situ
with substrate and hydrogen bromide. As to the role of
sodium carbonate, so far it is hard to explain exactly
how it works. Neutralizing a part of excess acid to keep
a subtle pH condition may be very crucial for reactivity
and enantioselectivity of this process.
mechanism and application of this catalysis system with
dual stereo- control are ongoing in our group.
Acknowledgement
We are grateful for the financial support from Na-
tional Natural Science Foundation of China (21472188,
21690074), State Key Laboratory of Fine Chemicals
(KF1503) and Youth Innovation Promotion Association
of Chinese Academy of Sciences (2014167).
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Figure 2The two probable transition state of hydrogenation.
Combining with these results and the related
mechanistic research,16,19 a proposal on the stereo-
control mode for dual enantioselective hydrogenation of
dihydroisoquinolines is illustrated as follows. In the
presence of 10 mol% NBS, the hydrogenation proceeds
mainly through a four-membered cyclic transition state
TS1. In the presence of 150 mol% NBS, the
hydrogenation proceeds via a six-membered cyclic
transition state TS2 due tothe formation of salts
betweensubstrate and the hydrogen bromide in situ
generated from the hydrogenolysis of NBS (Figure 2).
Consequently,NBS was not only used to improve the
performance of catalyst by elevating the valence state of
the center metal, but also to activate the imine
substratethrough hydrogen bromide.
Conclusions
In summary, we have successfully developed an
effective dual stereocontrol in iridium-catalyzed asym-
metric hydrogenation of 1-substituted 3,4-dihydroiso-
quinolines. It provides a simple and convenient route to
two enantiomers of 1-substituted tetrahydroisoquino-
lines with up to 89% ee (S) and 98% ee (R) only using
(R)-BINAP, respectively. Dual activation role of
N-bromosuccinimideis proposed to be responsible for
the reversal of enantioselectivity under two different
hydrogenation conditions. Further investigations on
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Entry for the Table of Contents
Page No.
Dual Stereocontrol for Enantioselective
Hydrogenation of Dihydroisoquinolines
Induced by Tuning the Amount of N-Bro-
mosuccinimide
An efficient dual stereocontrolin iridium-catalyzed hydrogenation of 1-substituted
3,4-dihydroisoquinolines was realized by tuning the amount of N-bromosuccinimide
using chiral ligand of single configuration.The dual activation role of N-bromo-
succinimideis proposed to be responsible for the reversal of enantioselectivity under two
hydrogenation conditions.
Yue Ji, Jie Wang, Mu-Wang Chen,Lei
Shi*andYong-Gui Zhou*
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