Enantioselective iridium-catalyzed hydrogenation of 1- and 3-substituted isoquinolinium salts

Article abstract of DOI:10.1002/anie.201208300

Asymmetric hydrogenation: The title reaction provides an efficient and rapid access to chiral 1- and 3-substituted 1,2,3,4-tetrahydroisoquinolines with excellent enantioselectivity (see scheme; L=ligand). A preliminary mechanistic study indicates that the 1,2-hydride addition might be the initial step in the reaction. The method has been used in the synthesis of urinary antispasmodic drug (+)-solifenacin. Copyright

Full text of DOI:10.1002/anie.201208300

Angewandte
Chemie
DOI: 10.1002/anie.201208300
Synthetic Methods
Enantioselective Iridium-Catalyzed Hydrogenation of 1- and
3-Substituted Isoquinolinium Salts**
Zhi-Shi Ye, Ran-Ning Guo, Xian-Feng Cai, Mu-Wang Chen, Lei Shi, and Yong-Gui Zhou*
Chiral 1,2,3,4-tetrahydroisoquinolines are ubiquitous struc-
tural motifs in many natural alkaloids and biologically active
compounds.[1] Among the various catalytic methods devel-
oped for the construction of chiral tetrahydroisoquinolines
during the past decades,[2] asymmetric hydrogenation of
isoquinolines unquestionably serves as one of the most
straightforward and powerful methods. So far, significant
progress on the asymmetric hydrogenation of aromatic
compounds has been implemented successfully[3] for sub-
strates such as quinolines,[4] quinoxalines,[5] indoles,[6] pyr-
roles,[7] pyridines,[8] furans,[9] imidazoles,[10] thiophenes[11] and
aromatic carbocyclic rings.[12] However, the development of
the enantioselective hydrogenation of isoquinolines has met
with limited success, probably owing to lower reactivity and
Scheme 1. General strategy for asymmetric hydrogenation of 1- and 3-
substituted isoquinolines. BCDMH=1-bromo-3-chloro-5,5-dimethyl-
hydantoin.
strong coordination to the catalyst. In 2006, our group
reported the first iridium-catalyzed asymmetric hydrogena-
tion of isoquinolines, which were activated by chloroformates,
with moderate enantioselectivity and yield.[13] Very recently,
an enantioselective hydrogenation of 3,4-disubstituted iso-
quinolines employing catalyst activation was successfully
described,[14] nevertheless, this strategy is not suitable for 1-
substituted isoquinolines. Moreover, there is no report on the
asymmetric hydrogenation of 3-substituted isoquinolines
heretofore. Therefore, the development of a general and
efficient strategy for asymmetric hydrogenation of 1- and 3-
substituted isoquinolines is still a very valuable and challeng-
ing area of chemical research.
Recently, our group successfully documented the iridium-
catalyzed asymmetric hydrogenation of simple pyridinium
salts, which were formed by using benzyl bromide and possess
higher reactivity than the corresponding pyridines.[15] As part
of our ongoing efforts to promote the development of
asymmetric hydrogenation of heteroaromatic compounds,[3a,b]
and considering the similar structure of pyridine to isoquino-
line, we envisioned that activating isoquinoline as the
N-benzyl isoquinolinium salt would effectively improve the
reactivity to facilitate hydrogenation (Scheme 1). Herein, we
report the iridium-catalyzed asymmetric hydrogenation of 1-
and 3-substituted isoquinolinium salts with up to 96% ee, as
well as the application of the method to the synthesis of the
chiral drug (+)-solifenacin.
To begin the study, N-benzyl-1-phenyl isoquinolinium
bromide (1; Ar= Ph) was chosen as a model substrate for the
iridium-catalyzed asymmetric hydrogenation (Table 1). The
reaction occurred smoothly in CH2Cl2 to give the desired
product with moderate enantioselectivity and yield (entry 1).
Further assessment of solvent revealed that the transforma-
tion was very sensitive to the reaction medium. The protic
polar solvents displayed lower reactivity and enantioselectiv-
ity (entries 4 and 5). Gratifyingly, the mixed solvent system of
THF/CH2Cl2 (1:1) gave the best result in terms of enantio-
selectivity and yield (entry 7). Subsequently, exploration of
various commercially available bisphosphine ligands showed
that (Rax,S,S)-C3*-TunePhos was the best ligand with respect
to the yield and enantioselectivity (entry 13), whereas
(R)-Binap gave lower enantioselectivity despite with high
reactivity. Replacement of the bromide counterion by the
trifluoromethanesulfonate anion resulted in no reactivity. In
particular, when the CO2iPr group was introduced at the 2-
position of the benzyl group [1; Ar= 2-(iPrCO2)C6H4], the
enantioselectivity was increased slightly, possibly because of
its steric bulk and/or interaction with the iridium atom
(entry 13 versus 16).
[*] Z.-S. Ye, R.-N. Guo, X.-F. Cai, M.-W. Chen, L. Shi, Prof. Y.-G. Zhou
State Key Laboratory of Catalysis, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (China)
E-mail: ygzhou@dicp.ac.cn
Homepage: http://www.lac.dicp.ac.cn/
With the optimized reaction conditions in hand, we turned
our attention to investigate the scope of 1-substituted
isoquinolinium salts, and the results are summarized in
Table 2. It is noteworthy that various 1-substituted isoquino-
linium salts proved to be good substrates under the standard
reaction conditions. The transformation proceeded with
excellent enantioselectivity and yield regardless of the
[**] Financial support from the National Natural Science Foundation of
China (21202162 and 21125208) and the National Basic Research
Program of China (2010CB833300) is acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208300.
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Table 1: Evaluation of reaction parameters for asymmetric hydrogena-
Table 2: Iridium-catalyzed asymmetric hydrogenation of 1-substituted
isoquinolinium salts 1.[a]
tion of 1-phenyl isoquinolinium salts.[a]
Entry
R
Ar
Yield [%][b]
ee [%][c]
Entry Solvent
Ar
Ligand Yield ee
[%][b] [%][c]
1
2
3
4
Ph
Ar1
Ph
Ph
Ph
99 (2a)
99 (2b)
97 (2c)
99 (2d)
99 (2e)
99 (2 f)
99 (2g)
97 (2h)
99 (2i)
99 (2j)
99 (2k)
96 (2l)
99 (2m)
99 (2n)
93 (R)
94 (À)
92 (À)
70 (+)
74 (+)
96 (À)
95 (À)
95 (À)
94 (À)
94 (À)
94 (À)
93 (À)
94 (À)
90 (À)
4-MeOC6H4
4-CF3C6H4
Me
iPr
Ph
4-MeC6H4
3-MeC6H4
4-MeOC6H4
3-MeOC6H4
4-ClC6H4
4-CF3C6H4
4-FC6H4
3,5-F2C6H3
1
2
CH2Cl2
THF
Ph
Ph
Ph
Ph
Ph
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L6
L6
83
99
39
7
84
83
80
8
3
4
5
PhMe
MeOH
EtOH
5[d]
6
Ph
2-(iPrCO2)C6H4
2-(iPrCO2)C6H4
2-(iPrCO2)C6H4
2-(iPrCO2)C6H4
2-(iPrCO2)C6H4
2-(iPrCO2)C6H4
2-(iPrCO2)C6H4
2-(iPrCO2)C6H4
2-(iPrCO2)C6H4
11
96
99
97
92
97
95
96
99
<5
<5
99
65
83
86
81
87
90
55
92
93
–
7
8
9
10
11
12
13
14
6
7
8
9
10
11
12
13
14[d]
15[e]
16
THF/CH2Cl2 (2:1) Ph
THF/CH2Cl2 (1:1) Ph
THF/CH2Cl2 (1:2) Ph
THF/CH2Cl2 (1:1) Ph
THF/CH2Cl2 (1:1) Ph
THF/CH2Cl2 (1:1) Ph
THF/CH2Cl2 (1:1) Ph
THF/CH2Cl2 (1:1) Ph
THF/CH2Cl2 (1:1) Ph
THF/CH2Cl2 (1:1) Ph
[a] 1 (0.25 mmol), [{Ir(cod)Cl}2] (1 mol%), (Rax,S,S)-C3*-TunePhos
(2.2 mol%), H2 (600 psi), THF/CH2Cl2 (1:1, 3 mL), 20 h, 308C. [b] Yield
of isolated product. [c] Determined by HPLC. [d] [{Ir(cod)Cl}2] (2 mol%),
(Rax,S,S)-C3*-TunePhos (4.4 mol%).
–
THF/CH2Cl2 (1:1) 2-(iPrCO2)C6H4 L6
96
[a] 1 (0.25 mmol), [{Ir(cod)Cl}2] (1 mol%), L (2.2 mol%), H2 (600 psi),
solvent (3 mL), 20 h, 308C. [b] Yield of isolated product. [c] Determined
by HPLC. [d] 10 mol% I2 was added. [e] Br counterion was replaced by
OTf anion. cod=cyclo-1,5-octadiene, Tf=trifluoromethanesulfonyl,
THF=tetrahydrofuran.
Figure 1. Iridium-catalyzed asymmetric hydrogenation of 3-substituted
isoquinolinium salts 3.
of the optical rotation of the deprotected product 5a with data
reported literature (Scheme 2).[16,17]
To gain insight into the reaction mechanism, a series of
control experiments were conducted (Scheme 3). On the basis
of our previous reports[13,14a] and research from other groups
on the 1,2-addition of N-alkyl or N-acyl isoquinolinium
salts,[2h–k] we speculated that the hydrogenation may start with
a 1,2-hydride addition.[18] Unfortunately, we were unable to
detect the corresponding intermediate in the hydrogenation
of 1-substituted isoquinolinium salts. Nevertheless, when the
electronic properties of the substituent at C1 of the aromatic
ring (entries 2, 3, 9, and 12). Although the 1-alkylisoquino-
linium salts performed very well in the transformation to give
2d and 2e, respectively, moderate enantioselectivities were
obtained (entries 4 and 5).
Subsequently, 3-substituted isoquinolinium salts were also
evaluated to demonstrate the generality of our methodology
(Figure 1). As expected, the hydrogenation proceeded
smoothly with the present catalytic system. Notably, the 3-
arylisoquinolinium salts 3a and 3b furnished the desired
products in good enantioselectivities. However, the 3-alkyl-
isoquinolinium salt 3c only gave a moderate 43% ee with full
conversion.
The absolute configuration of the hydrogenation product,
N-benzyl-1-phenyl 1,2,3,4-tetrahydroisoquinoline (2a; which
can be increased to 99% ee by a simple recrystallization with
n-hexane), was determined to be R by comparison of the sign
Scheme 2. The determination of the absolute configuration of 2a.
2
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Scheme 5. Synthesis of the chiral drug (+)-solifenacin.
Finally, to demonstrate the utility of this method, we
focused on the synthesis of the urinary antispasmodic drug
(+)-solifenacin (Scheme 5).[22] Synthesis of this chiral drug
requires an optical resolution of the racemic 1-phenyl
tetrahydroisoquinoline using tartaric acid in industry.[23]
Hydrogenolysis of the hydrogenation product 2a afforded
the product 5a in the presence of a Pd/C catalyst without loss
of enantioselectivity. Subsequent acylation and transesterifi-
cation with (R)-3-quinuclidinol furnished the (+)-solifenacin
in 85% overall yield.
Scheme 3. Mechanistic investigation of the iridium-catalyzed asymmet-
ric hydrogenation of 1- and 3-substituted isoquinolinium salts.
hydrogenation of the 3-substituted isoquinolinium salt 3d was
stopped after 1.5 hours, and the reaction mixture was
analyzed by 1H NMR spectroscopy, the reaction mixture
was found to contain the intermediate 7d, a product of the
1,2-hydrogenation. Additionally, hydrogenation of the enam-
ine intermediate 7d, the most probable intermediate in the
second reduction, failed to proceed in the absence of HBr.
Almost one deuterium atom was incorporated into the C4-
position when 3d was hydrogenated in THF/[D8]-iPrOH (4:1)
as the solvent, thus suggesting that the hydrogenation of the
enamine intermediate 7d was conducted via an iminium
intermediate and the tautomerization process of enamine to
In summary, an iridium-catalyzed asymmetric hydroge-
nation of 1- and 3-substituted isoquinolinium salts was
successfully developed with up to 96% ee. Preliminary
mechanistic studies indicate that the reaction involves a 1,2-
hydride addition, isomerization between enamine and imi-
nium intermediate, and hydrogenation of the iminium. More-
over, this methodology was also employed as the key step for
the synthesis of urinary antispasmodic drug (+)-solifenacin.
Further studies on the extension of the strategy to other
heteroaromatic compounds are ongoing in our laboratory.
iminium salt is slower than the hydrogenation of iminium Experimental Section
salt.[19,20]
Based on the above experimental results, a possible
mechanism is proposed to account for the asymmetric
hydrogenation of isoquinolinium salts (Scheme 4). The reac-
Typical procedure for asymmetric hydrogenation of isoquinolinium
salts: In a nitrogen-filled glove box, a mixture of [{Ir(cod)Cl}2]
(1.7 mg, 0.0025 mmol) and (Rax,S,S)-C3*-TunePhos (3.4 mg,
0.0055 mmol) in THF/CH2Cl2 (1:1, 1.0 mL) was stirred at room
temperature for 20–30 min. The mixture was then transferred by
a syringe to a stainless steel autoclave, in which substrate 1 or 3
(0.25 mmol) was placed beforehand. The hydrogenation was per-
formed at 308C under H2 (600 psi) for 20–24 h. After carefully
releasing the hydrogen, saturated NaHCO3 was added and the
mixture was stirred for 15–30 min. The organic layer was separated
and extracted with CH2Cl2 twice, and the combined organic extracts
were dried over Na2SO4 and concentrated. Purification was per-
formed by a silica gel column [eluent: n-hexane/ethyl acetate (10:1)]
to give the desired product. The enantiomeric excesses were
determined by HPLC analysis using a chiral stationary phase.
Scheme 4. Proposed hydrogenation mechanism.
Received: October 16, 2012
Revised: January 18, 2013
Published online: && &&, &&&&
tion is initiated by 1,2-hydride addition to give the partially
hydrogenated intermediate, 1,2-dihydroisoquinoline, with
subsequent isomerization of 1,2-dihydroisoquinoline to the
iminium salt in the presence of in situ generated HBr. The salt
then undergoes rapid hydrogenation to deliver the desired
product. In addition, an alternative mechanism that involves
initial direct 1,4-reduction of isoquinolinium salt cannot
currently be ruled out.[21]
Keywords: heterocycles · hydrogenation · iridium ·
.
reaction mechanisms · synthetic methods
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nation of the absolute configuration of the hydrogenation
product 4a.
[18] The 3,4-hydride addition could be excluded as the first
reduction. See the Supporting Information for the details.
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=
[19] Compared with C C bonds, iridium complexes were shown to
=
prefer the hydrogenation of C N bonds. See Ref. [2l] and
a) J. H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Soc. Rev. 2012, 41,
4126; b) A. J. Minnaard, B. L. Feringa, L. Lefort, J. G. de Vries,
Acc. Chem. Res. 2007, 40, 1267; c) G.-H. Hou, J.-H. Xie, L.-X.
Wang, Q.-L. Zhou, J. Am. Chem. Soc. 2006, 128, 11774.
4
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Angewandte
Chemie
[20] C.-B. Yu, K. Gao, D.-S. Wang, L. Shi, Y.-G. Zhou, Chem.
Commun. 2011, 47, 5052.
M. B. Onaran, C. T. Seto, Org. Lett. 2010, 12, 2690; c) W. Leithe,
Monatsh. Chem. 1929, 53, 956.
[21] Initial 1,4-reduction of isoquinolinium salts affords a partially
hydrogenated intermediate, 1,4-dihydroisoquinolinium, which
then undergoes rapid isomerization to deliver the 1,2-dihydro-
isoquinoline intermediate.
[22] a) R. Naito, Y. Yonetoku, Y. Okamoto, A. Toyoshimata, K.
Ikeda, M. J. Takeuchi, J. Med. Chem. 2005, 48, 6597; b) S. Wang,
[23] a) N. Mealy, J. Castaner, Drugs Future 1999, 24, 871; b) M.
Takeuchi, R. Naito, M. Hayakawa, Y. Okamoto, Y. Yonetoku, Y.
Isomura, EP0801067A1, 1997; c) V. T. Mathad, J. D. Lilakar, G.
Gilla, S. Kikkuru, R. R. Chinta, S. Dudipala, WO/2008/
011462A2, 2008.
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.
Angewandte
Communications
Communications
Synthetic Methods
Z.-S. Ye, R.-N. Guo, X.-F. Cai, M.-W. Chen,
L. Shi, Y.-G. Zhou*
&&&& — &&&&
Enantioselective Iridium-Catalyzed
Hydrogenation of 1- and 3-Substituted
Isoquinolinium Salts
Asymmetric hydrogenation: The title
reaction provides an efficient and rapid
access to chiral 1- and 3-substituted
1,2,3,4-tetrahydroisoquinolines with
excellent enantioselectivity (see scheme;
L=ligand). A preliminary mechanistic
study indicates that the 1,2-hydride addi-
tion might be the initial step in the
reaction. The method has been used in
the synthesis of urinary antispasmodic
drug (+)-solifenacin.
6
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