Asymmetric Transfer Hydrogenation of 1-Aryl-3,4-Dihydroisoquinolines Using a Cp*Ir(TsDPEN) Complex

Article abstract of DOI:10.1002/ejoc.201701094

We report herein a simple alternative method for the asymmetric transfer hydrogenation (ATH) of 1-aryl-3,4-dihydroisoquinolines (1-Ar-DHIQs) that are known to be challenging substrates owing to their poor reactivity. The hydrogenation protocol employs the

Full text of DOI:10.1002/ejoc.201701094

A Journal of
Accepted Article
Title: Asymmetric Transfer Hydrogenation of 1-Aryl-3,4-
Dihydroisoquinolines Using a Cp*Ir(TsDPEN) Complex
Authors: Bea Václavíková Vilhanová, Alena Budinská, Jiří Václavík,
Václav Matoušek, Marek Kuzma, and Libor Červený
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701094
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701094
Supported by

10.1002/ejoc.201701094
European Journal of Organic Chemistry
COMMUNICATION
Asymmetric Transfer Hydrogenation of 1-Aryl-3,4-
Dihydroisoquinolines Using a Cp*Ir(TsDPEN) Complex
Bea Václavíková Vilhanová,*[a] Alena Budinská,[b] Jiří Václavík,[b,c] Václav Matoušek+,[d]
Marek Kuzma,[c] Libor Červený[a]
Abstract: We report herein a simple alternative method for the
asymmetric transfer hydrogenation of 1-aryl-3,4-dihydroisoquinolines
(1-Ar-DHIQs) that are known to be challenging substrates owing to
their poor reactivity. The hydrogenation protocol employs the readily
available Cp*Ir(TsDPEN) (where Cp* = pentamethylcyclopentadienyl
available. For those reasons, protocols toward 1-Ar-THIQs
employing the Noyori-Ikariya complexes are highly attractive.
Noyori and co-workers originally showed that complex 1a
(Figure 1), bearing h6-benzene and naphthalene-1-sulfonamide
ligands, could catalyse the ATH of 6,7-dimethoxy-1-phenyl-3,4-
dihydroisoquinoline (2a) with 84% enantiomeric excess (ee).[17]
The use of 1a in the synthesis of muscle relaxant Gantacurium
was shown by the group of Boros.[12] However, Vedejs et al.[18]
observed irreproducible results with 1a and found that complex
1b (Figure 1), featuring the classic TsDPEN (N-p-
toluenesulfonyl-1,2-diphenylethylene-1,2-diamine) ligand, was
significantly more soluble under the reaction conditions and
provided reproducible results in ATH of 1-aryl-DHIQs.
Enantioselective reduction of 2a with the most popular catalyst
1c, containing p-cymene as the h6-arene (Figure 1), was tackled
by converting the substrate to an iminium salt via alkylation.[19]
2a underwent 1c catalysed ATH in aqueous methanol with
AgSbF6/La(OTf)3 activation.[20] We previously contributed to this
topic with a borneolsulfonyl-based ruthenium catalyst, achieving
reactivity comparable to that of 1a in the ATH of 1-Ar-DHIQs and
1c with 1-alkyl-DHIQs.[21] While the Cp*RhCl(TsDPEN) complex
(1d, Figure 1) provides excellent reactivity due to the rhodium
metal centre, the enantioselectivity achieved with 1-Ar-DHIQs is
close to zero.[22] The field has been developed further by the
group of Ratovelomanana-Vidal who disclosed conditions for
efficient ATH of 1-Ar-DHIQs using the 1b catalyst.[23,24] They also
reported that rhodium complex 1d and its iridium analogue 1e
(Figure 1) display good reactivity with substrate 2a, but the
product is formed as a racemate.
and TsDPEN
=
(S,S)-HNCHPhCHPhNTs2–) catalytic complex,
2-propanol and HCOOH/triethylamine mixture as the solvent and
hydrogen donor, and anhydrous phosphoric acid as an inexpensive
additive. The series of examined substrates shows a favourable
tolerance to various functional groups. Unlike 1-alkyl-DHIQs, where
the enantiomeric excess (ee) starkly changes during the course of
hydrogenation, 1-Ar-DHIQs exhibit a constant ee value, which
makes the method practical and useful for the production of fine
chemicals containing the 1,2,3,4-tetrahydroisoquinoline motif.
Optically pure chiral compounds are abundant among active
pharmaceutical ingredients, agrochemicals, and fragrances. As
their interaction with chiral receptors in living organisms is
enantiospecific, each of the two enantiomers can provoke
strikingly different effects. Efficient methods for the production of
single enantiomers are thus highly sought-after and as a result,
asymmetric synthesis, where the desired stereoisomer is formed
directly, has been intensively investigated in the past decades.
Among those methods, catalytic asymmetric transfer
hydrogenation (ATH) of ketones and imines, pioneered by
Noyori et al.,[1] is now very well established.[2–10] Still, this
catalytic system has certain limitations, such as the poor
reactivity of 1-aryl-3,4-dihydroisoquinolines (1-Ar-DHIQs) as
precursors of the chiral 1-aryl-1,2,3,4-tetrahydroisoquinoline (1-
Ar-THIQ) motif present in naturally-occurring alkaloids
We wish to demonstrate here a simple and efficient method for
the ATH of 1-Ar-DHIQs employing the readily available iridium
(Cryptostylines)
and
drugs
(e.g.,
Solifenacin[11]
or
complex in its 16e– form (1e
¢
,
Figure 1) and anhydrous
Gantacurium[12]). Efficient asymmetric hydrogenation protocols
for 1-Ar-DHIQs have been reported with iridium-phosphine
complexes.[11,13–16] However, the corresponding ligands are
oxygen sensitive and the complexes may not be readily
phosphoric acid as an additive.
R1
R2
O
O
Cl Ru
NTs
Cl Ru
H2N
S
N
H2N
Ph
Ph
[a]
Bea Václavíková Vilhanová, Prof. Libor Červený
Department of Organic Technology
University of Chemistry and Technology
Technická 5, CZ-166 28 Prague 6 (Czech Republic)
E-mail: vilhanob@vscht.cz
Ph
Ph
1a
1b: R1 = H, R2 = H
1c: R1 = Me, R2 = i-Pr
[b]
[c]
Alena Budinská, Jiří Václavík
Institute of Organic Chemistry and Biochemistry
Czech Academy of Sciences
Flemingovo náměstí 2, CZ-166 10 Prague 6 (Czech Republic)
Jiří Václavík, Dr. Marek Kuzma
Laboratory of Molecular Structure Characterization
Institute of Microbiology, Czech Academy of Sciences
Vídeňská 1083, CZ-142 20, Prague 4 (Czech Republic)
Dr. Václav Matoušek
Ru
Cl
M
M
NTs
HN
Ph
NTs
Ph
HN
Ph
NTs
Ph
H2N
Ph
Ph
1c'
1d: M = Rh
1e: M = Ir
1d': M = Rh
1e': M = Ir
Figure 1. Structures of complexes discussed or investigated in this study.
[d]
[+]
CF Plus Chemicals s.r.o.
Kamenice 771/34, 625 00 Brno (Czech Republic)
CF Plus Chemicals s.r.o. (www.cfplus.cz), an ETH Zurich spin-off,
commercializes the 1-aryl-3,4-dihydroisoquinolines reported here.
Our initial investigations started with ATH of the simplest
substrate, 1-phenyl-3,4-dihydroisoquinoline (2b), using the
HCOOH/triethylamine (HCOOH/TEA) hydrogen-donor mixture.
As ruthenium complexes (1a–c) have been examined thoroughly
Supporting information for this article is given via a link at the end of
the document.
1
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701094
European Journal of Organic Chemistry
COMMUNICATION
by others (vide supra), we turned our attention to Rh- and Ir-
based complexes. Adopting the reaction conditions previously
established on 1-methyl-DHIQs,[25] complex 1d, as well as its
enabled us to find two optimal ratios of HCOOH:TEA. While with
the molar ratio of 2.5:1 we obtained 3b in 80% conversion and
71% ee (Table S1, entry 5), equimolar ratio of HCOOH:TEA
gave 72% conversion, but a higher ee value of 77% (Table S1,
entry 12) after 24 h. The latter combination was selected for
further refinement.
16e– congener 1d
¢
(Figure 1), afforded only trace amounts of the
THIQ product 3b (Table 1, entries 1 and 2). Changing the
solvent to anhydrous 2-propanol (i-PrOH) provided 64–66%
conversion, but only 3% ee (Table 1, entries 3 and 4), which is
consistent with previous findings made for 1d in
dichloromethane (DCM).[22,23]
Applying the synthetic procedure for the preparation of complex
1d[22] in the synthesis of 1e, we arrived directly at its 16e– form
1e . Under the same ATH conditions, 1e provided the product
¢ ¢
3b in 83% conversion and 60% ee (Table 1, entry 5). Leaving
out TEA caused lower reactivity (Table 1, entries 6 and 8). Test
experiments without HCOOH (Table 1, entries 7 and 8) resulted
in practically zero conversion, excluding the possibility that
i-PrOH might serve as the reductant. Likewise, other solvents
tested (acetonitrile, DCM, DMSO, hexafluoro-2-propanol) did not
lead to further improvements (Table 1, entries 9–12).
Various additives were tested in order to enhance the reactivity
and/or enantioselectivity (Table S2). L-Proline as a chiral additive
caused a notable decrease of ee (Table S2, entries 1 and 2).
Lewis-acidic aluminium chloride led to lower reactivity (Table S2,
entries 3 and 4). Out of the Brønsted acids tested (trifluoroacetic
acid, tetrafluoroboric acid, and 85% aq. orthophosphoric acid –
Table S2, entries 5–15), the 85% aq. solution of orthophosphoric
acid helped increase the ee to 82% (Table S2, entry 14).
Therefore, orthophosphoric acid was investigated further,
including the anhydrous phosphoric acid (APA)[11] prepared by
mixing the 85% H3PO4 with stoichiometric amounts of
phosphorus pentoxide (Table S2, entries 16–28). With this
additive and anhydrous i-PrOH as a solvent, the ee was
increased to 86% at full conversion (Table S2, entry 26 and
Table 2, entry 1). Interestingly, APA obtained from a commercial
source gave consistently lower reactivity (Table S2, entries 22
and 24).
Optimization of the ratios of HCOOH, TEA and 2b (Table S1)
Table 1. Screening of complexes 1d, 1d
¢
and 1e
¢
in the ATH of imine 2b in
various solvents.[a]
Test experiment without APA (Table 2, entry 2) gave 65%
conversion and 77% ee. Reactions without HCOOH (Table 2,
1
N
NH
∗
HCOOH/TEA, solvent
30 °C, 24 h
Ph
Ph
2b
3b
Table 2. Screening of complexes 1c, 1c
imine 2b with APA as additive.[a]
¢
, 1d, 1d
¢
, and 1e in the ATH of
¢
Entry
1
1
Solvent
MeCN
MeCN
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
MeCN
DCM
Conversion [%][b]
ee [%][c]
n.d.[d]
n.d.[d]
3
1
N
NH
∗
HCOOH/TEA, APA
i-PrOH, 30 °C, 24 h
1d
1d
1d
1d
3
Ph
Ph
2b
3b
2
¢
¢
2
3
64
66
83
54
1
Entry
1
1
Conversion [%][b]
ee [%][c]
86
4
3
1e
1e
1e
1e
1e
1c
1c
¢
¢
¢
¢
¢
>99
65
4
2[d]
3[e]
4[f]
5[h]
6
77
5
1e
1e
1e
1e
1e
1e
1e
1e
¢
¢
¢
¢
¢
¢
¢
¢
60
6[e]
7[f]
8[g]
9
34
6
n.d.[d]
n.d.[d]
10
0
n.d.[g]
n.d.[g]
n.d.[g]
n.d.[g]
3
0
0
87
57
4
1
10
11
12[h]
7
7
¢
1
DMSO
HFIP[i]
n.d.[d]
n.d.[d]
8
1d
1d
8
0
9
¢
11
3
[a] Conditions: 2b (0.15 mmol), 1 (0.0015 mmol, 1 mol% vs. 2b), HCOOH
(36 µL, 0.95 mmol), TEA (53 µL, 0.38 mmol), HCOOH:TEA = 2.5, total
volume: 2 mL, 30 °C, 24 h. Amine product was obtained by alkalization and
extraction. [b] Determined by GC. [c] Determined by GC using pre-column
derivatization.[25] [d] Not determined due to low conversion. [e] Without TEA.
[f] Without HCOOH. [g] Without HCOOH and TEA. [h] Reaction time of 3 h. [i]
HFIP = hexafluoro-2-propanol.
[a] Conditions: 2b (0.15 mmol), 1 (0.0015 mmol, 1 mol% vs. 2b), HCOOH
(11 µL, 0.3 mmol), TEA (41 µL, 0.3 mmol), HCOOH:TEA = 1, APA (2 equiv
to 2b), i-PrOH, total volume: 2 mL, 30 °C, 24 h. Amine product was obtained
by basification and extraction. [b] Determined by GC. [c] Determined by GC
using pre-column derivatization.[26] [d] Without APA. [e] Without HCOOH. [f]
Without TEA. [g] Not determined due to low conversion. [h] Without HCOOH
and TEA.
2
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701094
European Journal of Organic Chemistry
COMMUNICATION
entry 3), TEA (Table 2, entry 4) or both HCOOH and TEA (Table
the course of the reaction, sometimes even leading to
enantionselectivity reversal at higher conversions. The authors
explain this unusual phenomenon by different kinetics of
formation of each enantiomer – while the (R) isomer is formed in
a first-order reaction with reaction rates decreasing exponentially,
the formation of the opposite (S) enantiomer follows a zero order
kinetics.[28]
2, entry 5) did not proceed. Other catalysts (1c, its 16e– complex
1c
shows that the reaction conditions were indeed tailored for the
iridium-based 1e
, 1d, and 1d ) exhibited poor activity (Table 2, entry 6–9). This
¢ ¢
¢
.
Next, we set out to explore the structure-activity trends by
hydrogenating imines 2a–l with the same basic scaffold that
differ by position and type of various functional groups (Figure 2).
As an extension, we also incorporated 3,4-dihydro-b-carboline
2m from the family of harmala alkaloids.
[a]
Table 3. ATH of substrates 2a–m catalysed by complex 1e .
¢
1e'
N
NH
∗
HCOOH/TEA, APA,
i-PrOH, 30 °C
R5
R5
R1 R2 R3
R4 R5
Ar
2a–m
Ar
3a–m
2a
2b
2c
2d
2e
2f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
N
H
H
H
H
H
H
H
H
H
H
H
R1
R2
H
NO2
CF3
OMe
Me
Br
Entry
1[e]
2
Substrate
Time [h]
Conversion [%][b]
Yield [%][c]
ee [%][d]
72 (+)
H
R4
H
R3
88[g]
>99
98
–
H
[h]
2a
2b
2c
2d
2e
2f
3
3
3
6
3
3
3
3
18
6
6
6
3
2a–l
2g
2h
2i
H
H
CO2Me H
90
90
79
92
87
86
90
77
86[i] (–)
64 (–)
CF3
H
H
H
H
H
2j Me
N
Ph
N
H
3
2k
2l
H
OMe OMe OMe H
OMe OMe OMe OMe OMe
2m
4
95
73[i] (–)
79[i] (–)
83[i] (–)
76[i] (–)
77[i] (–)
80 (–)
Figure 2. Structures of substrates 2a–m tested in ATH catalysed by 1e .
¢
5
97
6
97
The substrate scope study (Table 3) started with imine 2a
bearing two methoxy groups in positions 6 and 7. After 3 h, the
conversion to amine 3a was 88% (Table 3, entry 1) and the
reaction did not proceed any further after 24 h. Such a
suppressed reactivity (compared to 2b in Table 3, entry 2) was
surprising to us since in the 1-methyl-DHIQ series, the 6,7-
dimethoxy derivatives are known to be more reactive.[27] In
contrast, varying the para-substitution of the 1-phenyl moiety did
not alter the reactivity to a significant extent as seen from high
conversions of 2c–h (Table 3, entries 3–8). Trifluoromethyl
group in the meta-position (substrate 2i) caused slightly
diminished catalytic activity (Table 3, entry 9) and ortho-methyl-
substituted derivative (2j) showed poor reactivity (Table 3, entry
10), consistent with findings of Perez et al.[24] in ATH of ortho-
halogenated substrates with complex 1b. Derivative 2k bearing
3,4,5-trimethoxyphenyl group also required longer time for
complete reaction compared with 2b (Table 3, entries 2 and 11).
Moreover, the highly methoxylated substrate 2l showed a stark
decrease in reactivity (Table 3, entry 12), similarly as in the case
of 2a (Table 3, entry 1). Therefore, these two structural features,
i.e., 6,7-dimethoxy substitution of the DHIQ core together with
ortho-substitution of the 1-phenyl substituent, can be considered
key factors inhibiting the ATH reaction under given conditions.
Additionally, 3,4-dihydro-b-carboline 2m was tested (Table 3,
entry 13), giving excellent reactivity but mediocre ee – unlike
DHIQs 2a–l that were hydrogenated with fair to good
enantioselectivity (Table 3, entries 1–12). Remarkably, using this
catalytic system, substrates 2b, 2e and 2f (79–86% ee) were
hydrogenated with higher ees than using the Ru-based complex
1b, where only 29–39% ee was achieved.[24]
7
2g
2h
2i
96
8
97
9
93
10[f]
11
12[f]
13
2j
55[g]
96
–
77[i] (–)
84 (–)
[h]
2k
2l
90
46[g]
>99
–
76 (+)
[h]
2m
92
50 (–)
[a] Conditions: substrate 2 (0.15 mmol), 1e (0.0015 mmol, 1 mol% vs.
¢
substrate), HCOOH (11 µL, 0.3 mmol), TEA (41 µL, 0.3 mmol), HCOOH:TEA
= 1, APA (2 equiv to substrate), total volume: 2 mL, 30 °C. Amine product was
obtained by basification and extraction. [b] Determined by 1H NMR. [c] Isolated
yield taking into account conversion as purity. [d] Determined by HPLC. [e]
Loading of 1e : 2 mol%. [f] Loading of 1e : 5 mol%. [g] The same value
¢ ¢
observed after 24 h. [h] Not isolated due to incomplete conversion. [i]
Determined by GC using pre-column derivatization.[26]
We observed the same behaviour with
4 and 1e under
¢
optimized conditions, although the effect was even more
pronounced in some cases (Figure 3). In fact, the other isomer
of the product 5 can be formed depending on the reaction
conditions. For instance, in acetonitrile with APA, the ee of 5
changed from –14 to –45% (i.e., the (S)-THIQ isomer was
formed) in 2 h. Leaving out the APA led to attenuated reactivity
and also less pronounced ee changes during the course of
reaction, decreasing from +77% ee to +58% ee with (R)-isomer
formed. Similar experiments in anhydrous i-PrOH revealed a
dramatic change from +43% ee to –56% ee with APA and only
+80% ee to +74% ee without APA (Figure 3).
Stirling et al. have recently demonstrated that when performing
the ATH of a 1-alkyl-substituted DHIQ (6,7-dimethoxy-1-methyl-
3,4-dihydroisoquinoline 4) catalysed by 1e, the ee decreases in
3
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701094
European Journal of Organic Chemistry
COMMUNICATION
Remarkably, however, this phenomenon was virtually absent
when identical experiments were performed with 1-Ph-DHIQ 2b
– the ee was more or less constant in the course of the reaction
(Figure S1). On the contrary, the absence of APA led to either
no (acetonitrile) or sluggish (i-PrOH) reactivity. These
experiments thus further confirmed the necessity of an acid
additive.
[1]
[2]
R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97–102.
N. Fleury-Brégeot, V. de la Fuente, S. Castillón, C. Claver,
ChemCatChem 2010, 2, 1346–1371.
[3]
[4]
J.-H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111, 1713–1760.
J. Václavík, P. Kačer, M. Kuzma, L. Červený, Molecules 2011, 16,
5460–5495.
[5]
[6]
J. Václavík, P. Šot, B. Vilhanová, J. Pecháček, M. Kuzma, P. Kačer,
Molecules 2013, 18, 6804–6828.
MeO
MeO
MeO
MeO
1e' (1 mol%)
J. Václavík, P. Šot, J. Pecháček, B. Vilhanová, O. Matuška, M.
Kuzma, P. Kačer, Molecules 2014, 19, 6987–7007.
F. Foubelo, M. Yus, Chem. Rec. 2015, 15, 907–924.
D. Wang, D. Astruc, Chem. Rev. 2015, 115, 6621–6686.
M. Wills, Top. Curr. Chem. (Z) 2016, 374, 14.
N
NH
∗
HCOOH/TEA, (APA),
solvent, 30 °C
4
5
[7]
i-PrOH
MeCN
[8]
100
80
60
40
20
0
100
80
60
40
20
0
[9]
[10]
H. G. Nedden, A. Zanotti-Gerosa, M. Wills, Chem. Rec. 2016, 16,
2619–2639.
[11]
[12]
M. Ružič, A. Pečavar, D. Prudič, D. Kralj, C. Scriban, A. Zanotti-
Gerosa, Org. Proc. Res. Dev. 2012, 16, 1293–1300.
V. Samano, J. A. Ray, J. B. Thompson, R. A. Mook, D. K. Jung, C.
S. Koble, M. T. Martin, E. C. Bigham, C. S. Regitz, P. L. Feldman, et
al., Org. Lett. 1999, 1, 1993–1996.
0
20 40 60 80 100 120
0
20 40 60 80 100 120
t [min]
t [min]
80
60
80
60
40
40
[13]
[14]
[15]
M. Chang, W. Li, X. Zhang, Angew. Chem. Int. Ed. 2011, 50,
10679–10681.
20
0
-20
-40
-60
-80
20
0
-20
-40
-60
-80
20 40 60 80 100 120
20 40 60 80 100 120
F. Berhal, Z. Wu, Z. Zhang, T. Ayad, V. Ratovelomanana-Vidal, Org.
Lett. 2012, 14, 3308–3311.
t [min]
t [min]
A. Iimuro, K. Yamaji, S. Kandula, T. Nagano, Y. Kita, K. Mashima,
Angew. Chem. Int. Ed. 2013, 52, 2046–2050.
with APA
without APA
with APA
without APA
[16]
[17]
R. Schwenk, A. Togni, Dalt. Trans. 2015, 44, 19566–19575.
N. Uematsu, A. Fujii, S. Hashiguchi, T. Ikariya, R. Noyori, J. Am.
Chem. Soc. 1996, 118, 4916–4917.
Figure 3. Time-conversion and time-ee plots of ATH of imine 4 in acetonitrile
and i-PrOH catalysed by 1e
¢
.
[18]
[19]
[20]
[21]
E. Vedejs, P. Trapencieris, E. Suna, J. Org. Chem. 1999, 64, 6724–
6729.
To sum up, we have developed a simple protocol for the ATH of
1-aryl-substituted DHIQs using anhydrous phosphoric acid as
the key additive and a readily available iridium catalytic complex.
The method very well tolerates various functional groups,
following a relatively simple structure-activity pattern. Although
with a 1-alkyl-substituted substrate the enantioselectivity rapidly
changes and can even be reversed during the course of the
J. Wu, F. Wang, Y. Ma, X. Cui, L. Cun, J. Zhu, J. Deng, B. Yu,
Chem. Commun. 2006, 1766–1768.
L. Evanno, J. Ormala, P. M. Pihko, Chem. Eur. J. 2009, 15, 12963–
12967.
J. Přech, J. Václavík, P. Šot, J. Pecháček, B. Vilhanová, J.
Januščák, K. Syslová, R. Pažout, J. Maixner, J. Zápal, et al., Catal.
Commun. 2013, 36, 67–70.
reaction, 1-aryl-DHIQs are hydrogenated with
a practically
constant ee. The Ir-based anhydrous phosphoric acid promoted
system thus represents an attractive and practical alternative to
the few other existing methods for ATH of 1-aryl-DHIQs.
[22]
[23]
J. Mao, D. C. Baker, Org. Lett. 1999, 1, 841–843.
Z. Wu, M. Perez, M. Scalone, T. Ayad, V. Ratovelomanana-Vidal,
Angew. Chem. Int. Ed. 2013, 52, 4925–4928.
[24]
[25]
M. Perez, Z. Wu, M. Scalone, T. Ayad, V. Ratovelomanana-Vidal,
European J. Org. Chem. 2015, 2015, 6503–6514.
J. Pecháček, J. Václavík, J. Přech, P. Šot, J. Januščák, B.
Vilhanová, J. Vavřík, M. Kuzma, P. Kačer, Tetrahedron: Asymmetry
2013, 24, 233–239.
Acknowledgements
The work was financially supported by the Czech Science
Foundation (GA15-08992S), specific university research (MSMT
[26]
[27]
[28]
J. Přech, V. Matoušek, J. Václavík, J. Pecháček, K. Syslová, P. Šot,
J. Januščák, B. Vilhanová, M. Kuzma, P. Kačer, Am. J. Anal. Chem.
2013, 4, 125–133.
No 20-SVV/2017), the Operational Programme Prague
–
Competitiveness (CZ.2.16/3.1.00/24501), and National Program
of Sustainability (NPU I LO1613, MSMT-43760/2015). We thank
Prof. Dr. Antonio Togni (ETH Zürich) and Dr. Petr Beier (IOCB
CAS Prague) for providing their laboratories and Dr. Jiří
Rybáček (IOCB CAS Prague) for providing the HPLC instrument.
J. Václavík, J. Pecháček, B. Vilhanová, P. Šot, J. Januščák, V.
Matoušek, J. Přech, S. Bártová, M. Kuzma, P. Kačer, Catal. Lett.
2013, 143, 555–562.
M. J. Stirling, G. Sweeney, K. MacRory, A. J. Blacker, M. I. Page,
Org. Biomol. Chem. 2016, 14, 3614–3622.
Keywords: 1-aryl-3,4-dihydroisoquinolines • asymmetric
synthesis • hydrogenation • iridium • phosphoric acid
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701094
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Layout 2:
COMMUNICATION
Asymmetric Hydrogenation
Bea Václavíková Vilhanová,* Alena
Budinská, Jiří Václavík, Václav
Matoušek, Marek Kuzma, Libor Červený
Page No. – Page No.
A method for the asymmetric transfer hydrogenation of 1-aryl-3,4-
Asymmetric Transfer Hydrogenation
of 1-Aryl-3,4-Dihydroisoquinolines
Using a Cp*Ir(TsDPEN) Complex
dihydroisoquinolines is reported. Employing the Cp*Ir(TsDPEN) catalytic complex
with anhydrous phosphoric acid additive, high yields and good-to-high enantiomeric
excess (ee) can be achieved. The ee is constant during the reaction, unlike in the
case of 1-alkyl-3,4-dihydroisoquinolines where it changes dramatically.
5
This article is protected by copyright. All rights reserved.