Enantioselective synthesis of 1-aryl-tetrahydroisoquinolines through iridium catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/ol301281s

Asymmetric hydrogenation of 1-aryl-3,4-dihydroisoquinolines using the [IrCODCl]₂/(R)-3,5-diMe-Synphos catalyst is reported. Under mild reaction conditions, this atom-economical process provides easy access to a variety of enantioenriched 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives, which are important pharmacophores found in several pharmaceutical drug candidates, in high yields and enantiomeric excesses up to 99% after a single crystallization.

Full text of DOI:10.1021/ol301281s

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3308–3311
Enantioselective Synthesis of
1-Aryl-tetrahydroisoquinolines through
Iridium Catalyzed Asymmetric
Hydrogenation
Farouk Berhal,†,‡ Zi Wu,†,‡ Zhaoguo Zhang,§, Tahar Ayad,†,‡ and
Virginie Ratovelomanana-Vidal*,†,‡
Chimie ParisTech, Laboratoire Charles Friedel (LCF), 75005 Paris, France, CNRS,
UMR 7223, 75005 Paris, France, School of Chemistry and Chemical Engineering,
Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China, and
Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
virginie-vidal@chimie-paristech.fr
Received May 9, 2012
ABSTRACT
Asymmetric hydrogenation of 1-aryl-3,4-dihydroisoquinolines using the [IrCODCl]2/(R)-3,5-diMe-Synphos catalyst is reported. Under mild
reaction conditions, this atom-economical process provides easy access to a variety of enantioenriched 1-aryl-1,2,3,4-tetrahydroisoquinoline
derivatives, which are important pharmacophores found in several pharmaceutical drug candidates, in high yields and enantiomeric excesses up
to 99% after a single crystallization.
Isoquinoline derivatives, widely present in plants and
several tissues in mammalian alkaloids, play an important
role in the field of medicinal chemistry due to their
remarkable pharmacological potential.1 Among the mem-
bers of this family, 1-aryl-substituted-1,2,3,4-tetrahydroi-
soquinoline derivatives (THIQs) constitute a major group
in this class of alkaloids. For example, compound I
(Solifenacin, YM-905) is a competitive muscarinic acetyl-
Figure 1. Bioactive 1-aryl-tetrahydroisoquinolines.
choline receptor antagonist currently used in the treatment
of overactive bladders.2 1-Phenyl-tetrahydroisoquinoline
II originally developed as a general anesthetic agent
shows phencyclidine-like stereotype behavior and ataxia,3
whereas compound III is a potent noncompetitive AMPA
† Chimie ParisTech.
receptor antagonist currently being investigated in phase
III trials as an antiepileptic agent4 (Figure 1). In view of
their high potential as pharmaceutical drug candidates,
the synthesis of 1-substituted-THIQs has attracted much
attention, and various efficient methods have been devel-
oped during the past decades.
‡ CNRS.
§ Shanghai Jiao Tong University.
Shanghai Institute of Organic Chemistry.
(1) (a) Phillipson, J. D., Roberts, M. F., Zenk, M. H., Eds. The
Chemistry and Biology of Isoquinoline Alkaloids; Springer: Berlin, 1985.
(b) Jack, D.; Williams, R. Chem. Rev. 2002, 102, 1669. (c) Bentley, K. W.
Nat. Prod. Rep. 2006, 23, 444.
(2) Naito, R.; Yonetoku, Y.; Okamoto, Y.; Toyoshimata, A.; Ikeda,
K.; Takeuchi, M. J. J. Med. Chem. 2005, 48, 6597.
(3) Gray, N. M.; Cheng, B. K.; Mick, S. J.; Lair, C. M.; Contreras,
P. C. J. Med. Chem. 1989, 32, 1242.
(4) Gitto, R.; Barreca, M. L.; De Sarro, G.; Ferreri, G.; Quartarone,
S.; Russo, E.; Constanti, A.; Chimirri, A. J. Med. Chem. 2003, 46, 197.
r
10.1021/ol301281s
Published on Web 06/13/2012
2012 American Chemical Society

However, most of these methods, involve the use of
chiral starting building blocks or rely on diastereoselective
reactions using a stoichiometric amount of chiral sources.5
Consequently, the development of new efficient catalytic
enantioselective methods to give 1-substituted-THIQ fra-
meworks is required. To date, only a few approaches are
based on catalytic asymmetric reactions.5,6 Among them,
asymmetric hydrogenation of 1-substituted 3,4-dihydroi-
soquinoline derivatives (DHIQs) constitutes one of the
most direct and viable strategies for the synthesis of such
compounds. Over the past two decades, significant pro-
gress in the development of transition-metal catalyzed
asymmetric hydrogenation7 and asymmetric transfer
hydrogenation8 has been done in this area. However, since
the seminal work of Buchwald et al.9 and Noyori et al.,10
using a chiral ansa-titanocene catalyst and a Ru/TsDPEN
catalyst for the asymmetric reduction of the 1-methyl-3,
4-dihydro-6,7-dimethoxyisoquinoline (95 and 96% ee,
respectively), only a few efficient catalytic systems have
been reported to give 1-alkyl-THIQs in high enantio-
selectivity.11h,k,l Surprisingly, most of the catalytic systems
provide low to moderate selectivity for the hydrogenation
of more challenging 1-aryl-substituted-DHIQs, which has
been attributed to greater steric hindrance arising from
the adjacent aromatic ring. So far, only two examples of
catalytic enantioselective reduction of 1-aryl-substituted-
3,4-dihydroisoquinolines have been described in the litera-
ture. Vedejs et al.11m reported excellent ee values, ranging
from 94 to 99%, via asymmetric transfer hydrogenation
using the Noyori Ru/TsDPEN catalyst with the substrate
scope limited to a few 1-ortho-substituted aryl-3,4-dihy-
dro-7,8-dimethoxyisoquinolines. In 2011, Zhang et al.11k
described the asymmetric hydrogenation of 1-alkyl- and
1-aryl-3,4-dihydroisoquinolines with excellent conversions
and high enantioselectivities using the iodine-bridged
dimeric iridium complex [{Ir(H)[(S,S)-(f)-binaphane]}2-
(μ-I)3]þIꢀ. We report herein the efficient enantioselective
synthesis of various 1-aryl-THIQ derivatives 2 through
Ir/(R)-3,5-diMe-Synphos catalyzed asymmetric hydroge-
nation of the corresponding 1-aryl-DHIQs 1.
Initial investigations began with the hydrogenation of
1-phenyl-DHIQ 1aas a standard substrate using 0.5 mol %
of [IrCODCl]2 in the presence of various diphosphines
L1ꢀL8 at 40 °C in THF under 30 bar of H2 for 18 h (Table 1).
In all cases, the hydrogenation product 2a was isolated in
good to excellent yields. The use of Difluorphos ligand
L112 and the Sunphos family of ligands L2ꢀL4,13 which
both share similar dihedral angles but opposite electronic
profiles, gave moderate enantioselectivities ranging from
35 to 39% (Table 1, entries 1ꢀ4). The data in Table 1
clearly showed that the steric properties of the dipho-
sphine, in particular the substituents at the phosphorus
atom, greatly influencedthe stereochemicaloutcome of the
reaction. This steric effect was revealed by a comparison of
the selectivity of the reaction carried out with catalysts
bearing the Synphos family of ligands14 (Table 1, entries
5ꢀ8). The Synphos ligand L5 and the corresponding
4-Me-C6H4 substituted diphosphine L6 afforded slightly
better selectivities compared to ligands L1ꢀL4, with 46
and 42% ee, respectively (Table 1, entries 5 and 6), while
ligands L7 and L8 having 3,5-dialkyl-substituents on the
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48, 1831. (h) Li, C.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 13208. (i) Yan,
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Q. Q.; Yuan, K. X.; Zhou, Q. L. ACS Catal. 2012, 2, 561. For
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Org. Lett., Vol. 14, No. 13, 2012
3309

Table 1. Ligand Screening for Asymmetric Hydrogenation of1aa
Table 2. Optimization of the Reaction Conditions for Asym-
metric Hydrogenation of 1aa
yield (%)b
additive/
base
temp
P
ee 3a
(%)c
entry
(°C) (bar)
2a
3a
1
2
3
4
5
6
7
8
(Boc)2O/none
(Ac)2O/none
(PhCO)2O/none
(EtOCO)2O/none
TsCl/none
TsCl/K2CO3
TsCl/DIPEA
TsCl/Et3N
TsCl/proton sponge
TsCl/proton sponge
TsCl/proton sponge
TsCl/proton sponge
TsCl/proton sponge
40
40
40
40
40
40
40
40
40
60
20
40
40
30
30
30
30
30
30
30
30
30
30
30
50
10
0
0
0
0
46
30
20
20
0
0
0
0
0
94
92
94
96
45
65
77
75
95
95
92
94
95
84
83
70
81
92
84
84
84
92
92
87
92
94
yield
(%)b
ee
entry
ligand
solvent
THF
THF
THF
THF
THF
THF
THF
THF
toluene
Et2O
dioxane
CH2Cl2
ClCH2CH2Cl
EtOAc
MeOH
(%)c
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L8
L8
L8
97
90
89
75
95
93
91
95
93
92
95
89
90
89
87
38
35
39
39
46
42
69
71
55
65
73
41
38
65
18
9
10
11
12
13
9
10
11
12
13
14
15
a All reactions were performed using 1 mmol of substrate 1a with
1 mol % of Ir-catalyst. b After flash column chromatography. c Deter-
mined by chiral stationary phase-supercritical fluid chromatography.
increased remarkably to 92% ee when TsCl (1 equiv) was
used. However, 3a was obtained in only 45% yield along
with the nonprotected THIQ compound 2a in similar yield
(Table 2, entry 5). To avoid the formation of 2a, which
probably resulted from the reduction of the hydrogen
chloride salt of 1a produced during the reaction, as pre-
viously observed by Zhou et al.11j for the asymmetric
hydrogenation of quinolines activated by chloroformates,
we studied the effect of several bases (Table 2, entries 6ꢀ9).
Gratifyingly, the amount of 2a was completely suppressed
when the sequestering proton sponge was used, giving the
desired product 3a in 95% yield and 92% ee.16
a All reactions were performed using 1 mmol of substrate 1a with
1 mol % of Ir-catalyst. b After flash column chromatography. c Deter-
mined by chiral stationary phase-supercritical fluid chromatography.
enantioselectivity regardless of the electronic nature of the
substituents (Table 1, entries 7 and 8, 69 and 71% ee). This
result is another manifestation of what Pregosin et al.15
have named the “3,5-meta-dialkyl effect”.
Further examinations focused on the solvent employed
(Table 1, entries 8ꢀ15). Although the hydrogenation could be
performed in all tested solvents, the best results with regard to
both selectivity and reactivity were achieved in ethereal
solvents, and dioxane was found to be the solvent of choice,
giving 2a in 95% isolated yield and 73% ee (Table 1, entry 11).
It is well-known that the presence of a second coordinat-
ing group attached to the nitrogen atom is a critical
element for achieving both high reactivity and selectivity
in the asymmetric hydrogenation of CdN bonds.7 We thus
decided to evaluate the effect of various activating reagents
for the hydrogenation of 1a. The results of these experi-
ments are reported in Table 2. With the exception of
(PhCO)2O, the reduction of 1a under 30 bar of H2 at
40 °C using dioxane in the presence of anhydride deriva-
tives (1 equiv) proceeded smoothly to afford the desired
product 3a in excellent yield and with significant higher
enantioselectivity than those obtained when the reaction
is performed without an activator (Table 2, entries 1ꢀ4,
70ꢀ84% ee). To our delight, the enantiomeric excess of 3a
Finally, variation of the hydrogen pressure and reaction
temperature has only little effect on the catalytic activity
(Table 2, entries 9ꢀ13).
To assess the substrate scope, a full set of 1-aryl- DHIQ
derivatives1aꢀrweresynthesizedandhydrogenated under
the optimized reaction conditions (Table 3). High yields
were obtained for all substrates, with good to excellent
enantioselectivities ranging from 81% to 94%. The stereo-
chemical outcome of the reaction was largely influenced by
the substitution pattern on the aromatic rings. For exam-
ple, compounds 1 with an ortho substituent on the1-phenyl
group gave uniformly lower enantioselectivities compared
to the nonsubstituted DHIQ 1a, probably due to the
unfavorablesteric hindrancebetween the ortho-substituted
group of the substrate and the catalyst during the reac-
tion (Table 3, compare entry 1 vs entries 2, 5, and 8,
80ꢀ83% ee). Similar results were obtained with sub-
strates possessing an electron-withdrawing group (Table 3,
(15) Trabensinger, G.; Albinati, A.; Feiken, N.; Kunz, R. W.;
Pregosin, P. S.; Tschoerner, M. J. Am. Chem. Soc. 1997, 119, 6315.
(16) For mechanism discussion, see Supporting Information.
3310
Org. Lett., Vol. 14, No. 13, 2012

Table 3. Asymmetric Hydrogenation of 1-Aryl-Substituted 3,4-Dihydroisoquinolines 1aꢀra
a All reactions were performed using 1 mmol of substrate 1 with 1 mol % of Ir-catalyst. b After flash chromatography. c Determined by chiral
stationary phase-supercritical fluid chromatography. Absolute configuration was determined to be R by comparison of the specific rotation with
reported data. d Number ee values after a single crystallization.
entries 9ꢀ11, 81ꢀ84% ee), whereas compounds with an
electron-donating group tend to give significantly better
selectivity (Table 3, entries 4, 6, and 7, 90% ee). When the
benzene ring of the dihydroisoquinoline moiety was sub-
stituted by a methyl group, enantioselectivities between 84
to 88% ee were obtained (Table 3, entries 12ꢀ14), whereas
the presence of one or two methoxy groups gave higher
enantiofacial discrimination (Table 3, entries 15ꢀ18,
88ꢀ92% ee). It is also worth noting that the enantiomeric
excesses of all hydrogenated products 3aꢀr could be easily
upgraded to 90ꢀ99% after a single crystallization, as
outlined in Table 3. Moreover, the tosyl protecting group
of 3a was easily removed without affecting the stereoche-
mical integrity, giving 2a in quantitative yield and with
94% ee.17
In summary, we have demonstrated that the (R)-3,5-
diMe-Synphos is an efficient ligand for the Ir-catalyzed
asymmetric hydrogenation of challenging 1-aryl-3,
4-dihydroisoquinolines under mild reaction conditions.
This method provides an atom economical and attractive
route to pharmaceutically relevant chiral 1-aryl-THIQ com-
pounds in high yields and excellent enantioselectivities up to
>99%, after a single crystallization.
Acknowledgment. Z.W. thanks the CNRS and the Min-
ꢀ
istere de l’Education et de la Recherche for financial support.
Supporting Information Available. Full experimental
details and characterization data. This material is avail-
able free of charge via Internet at http://pubs.acs.org.
(17) Ankner, T.; Hilmersson, G. Org. Lett. 2009, 11, 503.
Org. Lett., Vol. 14, No. 13, 2012
The authors declare no competing financial interest.
3311