Enantioselective iridium-catalyzed hydrogenation of 3,4-disubstituted isoquinolines

Article abstract of DOI:10.1002/anie.201203647

Reining in the outliers: An efficient approach for enantioselective hydrogenation of 3,4-disubstituted isoquinolines was successfully developed. When isoquinolines are treated with [Ir(cod)Cl]₂/(R)-synphos in the presence of 1-bromo-3-chloro-5,

Full text of DOI:10.1002/anie.201203647

Angewandte
Chemie
DOI: 10.1002/anie.201203647
Asymmetric Hydrogenation
Enantioselective Iridium-Catalyzed Hydrogenation of 3,4-
Disubstituted Isoquinolines**
Lei Shi, Zhi-Shi Ye, Liang-Liang Cao, Ran-Ning Guo, Yue Hu, and Yong-Gui Zhou*
The past decade has witnessed rapid progress in the field of
asymmetric hydrogenation of aromatic compounds, a trans-
formation, which is regarded as one of the most straightfor-
ward means for accessing enantiopure cyclic compounds.[1]
Extensive research has significantly expanded the substrate
scope of this reaction, and substrates such as quinolines,[2]
quinoxalines,[3] indoles,[4] furans,[5] pyrroles,[6] pyridines,[7]
imidazoles,[8] and aromatic carbocycles can now be trans-
formed through asymmetric hydrogenation.[9] Despite ach-
ievements made, the asymmetric hydrogenation of isoquino-
line still remains an important unmet challenge. Hydrogena-
tion reactions involving this substrate have been plagued by
catalyst deactivation owing to the strong coordinating ability
of the substrate and the product. So far, only one example of
an enantioselective hydrogenation of isoquinoline has been
reported by our research group.[10] N-protected 1-substituted
1,2-dihydroisoquinolines were obtained in moderate yield
and enantioselectivity in the presence of stoichiometric
amounts of chloroformate as the substrate activator
(Scheme 1). However, several obvious limitations remain,
such as the need for a stoichiometric amount of activating
reagent and inorganic base, and that current methods only
lead to products containing one stereogenic center, which is
usually the C1 position. Given the prevalence of the chiral
1,2,3,4-tetrahydroisoquinoline motif in natural alkaloids and
pharmaceutical molecules,[11] the development of an efficient
method for the direct hydrogenation of isoquinolines is highly
desirable. Herein, we describe a highly efficient direct
enantioselective iridium-catalyzed hydrogenation of 3,4-dis-
ubstituted isoquinolines.
Recent results from our research group[2a] and that of
others[7b,12] have demonstrated that iodine can significantly
improve the performance of an iridium catalyst in asymmetric
hydrogenation. We wanted to investigate whether isoquino-
line could be amenable to asymmetric hydrogenation cata-
lyzed by an iodine-activated iridium complex. Initially, ethyl
3-methylisoquinoline-4-carboxylate 1a was chosen as model
substrate. Upon exposure to 500 psi H2 in the presence of
a chiral iridium complex, which is generated in situ from
[Ir(cod)Cl]2/(R)-synphos and iodine at 508C, isoquinoline 1a
underwent enantioselective hydrogenation to afford product
2a with full conversion, excellent diastereoselectivity
(d.r.>20:1) and moderate enantioselectivity (59% ee;
Table 1, entry 2); when iodine was omitted, only the 1,2-
hydrogenation product was observed (Table 1, entry 1).
Encouraged by this promising result, we initially inves-
tigated the effect of the identity of the solvent on the substrate
conversion and enantioselectivity. The substrate conversion
was, in most solvents, uniformly good, whereas the ee value of
2a exhibited a dramatic dependence upon the solvent identity
(Table 1, entries 2–5). The use of toluene as the solvent was
the most beneficial in terms of the enantioselectivity of the
hydrogenation (80% ee, Table 1, entry 6). Next, the effect of
the nature of the additive was investigated using various
halogen sources (Table 1, entries 6–10). Each additive pro-
moted this transformation, thus leading to full conversion of
substrate and similar enantioselectivity. Among these addi-
tives, the use of 1-bromo-3-chloro-5,5-dimethyl-hydantoin
(BCDMH) led to the isolation of product with slightly
superior ee value (83% ee; Table 1, entry 10). The effect of
the nature of the ligand on the reaction was then investigated
by employing BCDMH as the halogen source in combination
with iridium catalysts that were generated from [Ir(cod)Cl]2
and a diverse array of commercially available ligands
(Table 1, entries 10–13). Disappointingly, no ligand gave
a better result than the ligand used in the initial screening
of reaction conditions (L1).
Scheme 1. Asymmetric hydrogenation of isoquinoline.
[*] Dr. L. Shi, Z.-S. Ye, L.-L. Cao, R.-N. Guo, Y. Hu, Prof. Y.-G. Zhou
State Key Laboratory of Catalysis
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
Dalian 116023 (China)
Dynamic kinetic resolution (DKR), which is a powerful
tool for accessing enantioenriched compounds, has been
successfully applied in asymmetric hydrogenation.[13] In our
previous research on asymmetric hydrogenation of
2,3-disubstituted quinolines and indoles, an interesting DKR
phenomenon was also observed.[2f,4h] For the asymmetric
hydrogenation of 3,4-disubstituted isoquinolines, a dynamic
kinetic resolution process was involved (see below). In
E-mail: ygzhou@dicp.ac.cn
[**] Financial support from the National Natural Science Foundation of
China (21032003 and 21125208) and National Basic Research
Program of China (2010CB833300).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203647.
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Table 1: Optimization of the hydrogenation reaction.[a]
Entry
Ligand
H2 [psi]
Solvent
Additive
ee [%][b]
1[c]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[d]
17[e]
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
500
500
500
500
500
500
500
500
500
500
500
500
500
100
40
THF
THF
DCM
none
I2
I2
I2
I2
I2
NBS
NCS
DBDMH
BCDMH
BCDMH
BCDMH
BCDMH
BCDMH
BCDMH
BCDMH
BCDMH
–
59
52
67
70
80
77
77
76
83
75
32
53
87
89
91
93
EtOAc
benzene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
40
40
Scheme 2. Iridium-catalyzed enantioselective hydrogenation of 3,4-dis-
ubstituted isoquinolines. [a] The absolute configuration was deter-
mined by single-crystal X-ray diffraction analysis of the corresponding
N-tosyl derivative. [b] The reaction was carried out at 808C. cod=1,5-
cyclooctadiene.
[a] Reaction conditions: 0.2 mmol of 1a, 1.0 mol% [Ir(cod)Cl]2,
2.2 mol% ligand, 10 mol% additive, 3.0 mL of solvent, 508C. Reaction
conversion and d.r. were determined by 1H NMR spectroscopy. In all
cases, the reaction conversion was >95% and the d.r. >20:1.
[b] Determined by HPLC using a chiral stationary phase. [c] Only 1,2-
hydrogenation occurred. [d] 608C. [e] 708C.
the presence of a longer alkyl group at the C3 position caused
a small decrease in product ee value, presumably because the
isomerization of the imine to the enamine intermediate was
relatively slow. For a similar reason, the 3-phenyl-substituted
tetrahydroisoquinolines 2i was obtained with only moderate
64% ee; raising the reaction temperature from 708C to 808C
can lead to satisfactory enantioselectivity (2e–j except for 2i).
Moreover, 3,4-dialkyl-substituted tetrahydroisoquinolines 2l
and 2m were prepared with good ee value. This result suggests
that the presence of an ester group is not necessary for
achieving satisfactory results, thus further highlighting the
generality of this method.
To demonstrate that the chiral cis-disubstituted products
could be used for preparing the corresponding trans com-
pounds, compound 3 was treated with lithium diisopropyla-
mide (LDA) to give the trans epimer 4 (Scheme 3), which is
generally difficult to obtain through direct asymmetric
hydrogenation.
general, efficient DKR requires rapid interconversion of two
enantiomeric intermediates. In asymmetric hydrogenations of
the type described herein, such a condition can usually be
ensured by conducting the reaction at high temperature and
by using low hydrogen pressure. As expected, further
improvement of enantioselectivity was realized when
a lower hydrogen pressure was used (Table 1, entries 14 and
15). Simultaneously lowering the hydrogen pressure and
raising the reaction temperature led to further increases in
enantioselectivity and, ultimately, product was obtained in
93% ee when the hydrogenation was carried out at 708C and
at a hydrogen pressure of 40 psi (Table 1, entry 17).
To explore the mechanism further, the hydrogenation
reaction was carried out at room temperature and was then
As a demonstration of the practicality of this reaction,
various 3,4-disubstituted tetrahydroisoquinolines were
accessed with complete conversion from substrate and with
high ee value (up to 96% ee) when the optimized reaction
conditions were used (Scheme 2). Notably, the size of the
isoquinoline substituents influenced the enantioselectivity of
reaction. The presence of a bulky ester at the C4 position or
Scheme 3. LDA-mediated conversion of cis-(3R,4R)-3 into epimeric
trans-(3R,4S)-4.
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stopped when half of the substrate was converted. The
resulting reaction mixture was then analyzed by 1H NMR
spectroscopy. The analysis showed that 1,2-dihydroisoquino-
line 5 is an intermediate in the hydrogenation reaction
(Scheme 4). When 5 was freshly prepared and subjected to
k-1 @ k2 @ k3. A high reaction temperature should accelerate
the rate of isomerization, and a low pressure of hydrogen gas
should decrease the rate of hydrogenation of 6.
In summary, we have successfully developed the first
efficient method for the enantioselective hydrogenation of
3,4-disubstituted isoquinolines. When the isoquinolines are
treated with [Ir(cod)Cl]2/(R)-synphos in the presence of 1-
bromo-3-chloro-5,5-dimethylhydantoin, the corresponding
chiral 3,4-disubstituted tetrahydroisoquinoline derivatives
were obtained with ee values as high as 96%. We are
currently conducting advanced mechanistic studies on the
effect of the additive and applying this method in the
synthesis of 1,2,3,4-tetrahydroisoquinoline alkaloids.
Experimental Section
General procedure for the enantioselective hydrogenation of 3,4-
disubstited isoquinolines:
A mixture of [Ir(cod)Cl]2 (1.3 mg,
Scheme 4. Control experiments for the elucidation of mechanism.
0.002 mmol), (R)-synphos (2.8 mg, 0.0044 mmol) in toluene (3 mL)
was stirred at room temperature for 10 min in a glove box. BCDMH
(4.8 mg, 0.02 mmol) was then added to the mixture. After stirring the
mixture for another 10 min, isoquinoline (0.2 mmol) was added to the
mixture. The resulting mixture was transferred to an autoclave. The
hydrogenation was performed at 708C or 808C under H2 (40 psi) for
24 h. After carefully releasing the hydrogen gas, the autoclave was
opened and the reaction mixture was directly purified by column
chromatography on Al2O3 using a mixture of MeOH and CH2Cl2 as
eluent to give the corresponding chiral tetrahydroisoquinolines.
the hydrogenation using the optimized reaction conditions,
the desired product cis-(3R,4R) 2a was obtained with greater
than 95% conversion from substrate and in 93% ee
(Scheme 4), which are almost identical to those of the direct
transformation of 1a. Based on this result, a stepwise hydro-
genation process was proposed (Scheme 5). Firstly,
=
1,2-hydride addition to the 1,2-C N bond, which is the least
Received: May 11, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · hydrogenation · iridium ·
.
isoquinoline · 1,2,3,4-tetrahydroisoquinoline
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=
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Communications
Asymmetric Hydrogenation
Reining in the outliers: An efficient
approach for enantioselective hydroge-
nation of 3,4-disubstituted isoquinolines
was successfully developed. When iso-
quinolines are treated with [Ir(cod)Cl]2/
(R)-synphos in the presence of 1-bromo-
3-chloro-5,5-dimethyl-hydantoin
(BCDMH), the chiral 3,4-disubstituted
tetrahydroisoquinoline derivatives are
obtained with ee values as high as 96%
(see scheme; cod=1,5-cyclooctadiene).
L. Shi, Z.-S. Ye, L.-L. Cao, R.-N. Guo,
Y. Hu, Y.-G. Zhou*
&&&& — &&&&
Enantioselective Iridium-Catalyzed
Hydrogenation of 3,4-Disubstituted
Isoquinolines
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