Asymmetric transfer hydrogenation of 1-phenyl dihydroisoquinolines using Ru(II) diamine catalysts

Article abstract of DOI:10.1016/j.catcom.2013.03.004

A new [Ru(II)(η⁶-p-cymene)(1R,2R)-N-((1S,2S)-borneol-10- sulfonyl)-1,2-diphenylethylenediamine] catalyst for the asymmetric transfer hydrogenation of both 1-alkyl and 1-aryl dihydroisoquinolines has been isolated. For the first time in this type of reaction, the catalyst employs an N-alkylsulfonyl group instead of N-arylsulfonyl.

Full text of DOI:10.1016/j.catcom.2013.03.004

Catalysis Communications 36 (2013) 67–70
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Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
Asymmetric transfer hydrogenation of 1-phenyl dihydroisoquinolines
using Ru(II) diamine catalysts
Jan Přech a, Jiří Václavík a, Petr Šot a, Jan Pecháček a, Beáta Vilhanová a, Jakub Januščák a, Kamila Syslová a,
Richard Pažout b, Jaroslav Maixner b, Jakub Zápal c, Marek Kuzma c, Petr Kačer a,
⁎
a
Department of Organic technology, Institute of Chemical Technology, Technická 5, 166 28 Prague 6, Czech Republic
Central Laboratories, Institute of Chemical Technology, Technická 5, 166 28 Prague 6, Czech Republic
b
c
Laboratory of Molecular Structure Characterization, Institute of Microbiology, v.v.i., Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20 Prague 4, Czech Republic
a r t i c l e i n f o
a b s t r a c t
A new [Ru(II)(η6-p-cymene)(1R,2R)-N-((1S,2S)-borneol-10-sulfonyl)-1,2-diphenylethylenediamine] catalyst
for the asymmetric transfer hydrogenation of both 1-alkyl and 1-aryl dihydroisoquinolines has been isolated.
For the first time in this type of reaction, the catalyst employs an N-alkylsulfonyl group instead of N-arylsulfonyl.
© 2013 Elsevier B.V. All rights reserved.
Article history:
Received 2 January 2013
Received in revised form 5 March 2013
Accepted 6 March 2013
Available online 15 March 2013
Keywords:
Asymmetric transfer hydrogenation
N-alkylsulfonyl
Dihydroisoquinoline
Ruthenium
1. Introduction
catalysts, there is only one example of a complex which is able to
catalyze the ATH of 6,7-dimethoxy-1-phenyl-DHIQ (2a) to corresponding
Chiral amines are important building blocks in the fine-chemical,
agrochemical and pharmaceutical industries. As the natural resources
of optically pure substances are limited, their synthesis from achiral
precursors is strongly in demand. The asymmetric reduction of corre-
sponding imines is nowadays a prevalent procedure of their preparation
[1].
Chiral ruthenium(II)-diamine catalysts (for instance 1a and 1b in
Fig. 1) together with the formic acid-triethylamine azeotropic mixture
(HCOOH-TEA) as a hydrogen donor represents an efficient and popular
system for the asymmetric transfer hydrogenation (ATH) of various
imines and ketones [2–4]. Regarding imine substrates, this catalytic
system is capable of reducing the C_N double bonds of aryl-N-benzyl
imines, β-carbolines and 1-alkyl- or 1-benzyl-3,4-dihydroisoquinolines
(DHIQs). On the other hand, the ATH of 1-phenyl-DHIQs represents a con-
siderable challenge since catalysts bearing the N-p-toluenesulfonyl-1,
2-diphenylethylenediamine (TsDPEN) ligand (like 1a) fail to catalyze
this reduction under standard reaction conditions.
tetrahydroisoquinoline under the original conditions. Catalyst 1a, bearing
the N-naphthalene-1-sulfonyl-DPEN ligand (NpsDPEN), was first pro-
posed and tested by Noyori [10] and subsequently used by Vedejs and
Boros [11–13].
Although the original Noyori-type ATH catalysts always bear an
N-arylsulfonyl substituent, Ohkuma et al. [14], Ikariya et al. [15]
and others [16–18] showed that Ir and Ru catalysts containing
methanesulfonyl-DPEN (MsDPEN) hydrogenate various aryl-N-benzyl
imines, N-sulfonylimines and aryl ketones with molecular hydrogen.
Carreira and co-workers followed with their work on the ATH of β-keto
esters in water catalyzed by an Ir(III)-MsDPEN complex [19]. The MsDPEN
ligand belongs to a very small group of N-alkylsulfonyl diamines that
proved utilizable in asymmetric (transfer) hydrogenation. Another
such ligand is alicyclic N-(camphor-10-sulfonyl)-DPEN (CsDPEN) that
has been employed in the ATH of various ketones [20–23]. However,
to the best of our knowledge, no N-alkylsulfonyl diamines have applied
in the ATH of imines such as DHIQs.
Some homogeneous catalysts have been described for the asymmetric
hydrogenation of 1-phenyl substituted DHIQs, such as Rh(III)-diamine
catalysts structurally similar to 1a [5] and Ir(III)-phosphine complexes
[6,7]. Catalytic activity was also reached in aqueous environment with
the substrate in the form of iminium over modified 1a [8], and with 1a
upon activation with AgSbF6/La(OTf)3 [9]. Among ruthenium-based
We report here a CsDPEN-based Ru(II) catalyst that is suitable for
the reduction of both 1-alkyl- and 1-phenyl-DHIQ substrates.
2. Experimental
2.1. General information
⁎
Corresponding author. Tel.: +420 220 444 158.
E-mail addresses: petr.kacer@vscht.cz (P. Kačer), richard.pazout@vscht.cz (R. Pažout),
[RuCl(η6-p-cymene)(1R,2R)-N-((1S,2S)-borneol-10-sulfonyl)-1,2-
diphenylethylenediamine] (5) and [RuCl(η6-benzene) (1R,2R)-N-
kuzma@biomed.cas.cz (M. Kuzma).
1566-7367/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2013.03.004

68
J. Přech et al. / Catalysis Communications 36 (2013) 67–70
O
O
O
O
O
O
S
S
S
Cl Ru
H2N
Cl Ru
H2N
Cl Ru
H2N
N
N
N
HO
Ph
Ph
Ph
Ph
Ph
Ph
1a
1c
1b
Fig. 1. Structures of Ru(II) half-sandwich complexes 1a–1c used in this work.
(naphthalene-1-sulfonyl)-1,2-diphenylethylenediamine] (1b) were
prepared from corresponding diamine ligands and [RuCl2(η6-p-cymene)]2
and [RuCl2(η6-benzene)]2, respectively, as described previously [10]. All
starting materials were of commercial origin (Sigma-Aldrich, Germany
or Penta, Czech Republic). 1H and 13C NMR spectra were recorded on
Bruker AVANCE III 400 MHz, 600 MHz and 700 MHz spectrometers
with reference to the residual signal of solvent as an internal standard.
Kinetic samples were analyzed by a GC instrument with an FID detec-
tor and Varian VF-1 non-polar capillary column. Enantiomeric excess
(ee) was determined by GC using pre-column derivatization with
(R)-(−)-menthyl chloroformate. For complete NMR data please refer
to the supporting information.
2.2.3. Synthesis of [RuCl(η6-p-cymene) (1R,2R)-N-((1S,2S)-borneol-10-
sulfonyl)-1,2-diphenyl-ethylenediamine] (1c)
[RuCl2(η6-p-cymene)]2 (139 mg, 0.227 mmol), (1R,2R)-N-((R)-camphor-
10-sulfonyl)-1,2-diphenylethylenediamine (168 mg, 0.394 mmol) and
TEA (126 μL; 0.91 mmol) were dissolved in propan-2-ol (5 mL) and
heated for 3 h at 85 °C under an argon atmosphere. The resulting
dark red solution was evaporated to dryness and crude product
was washed with water (20 mL) on sintered glass and dried in a
desiccator for a period of 2 days. The catalyst was recrystallized
from boiling ethanol:methanol (1:1) mixture and red crystals were
washed with a small amount of cold solvents. Yield: 125.5 mg (after
recrystallization), 43%.
X-ray diffraction data were measured at 190 K on a four-circle
CCD diffractometer Gemini of Oxford Diffraction Ltd. with graphite
monochromated CuKα radiation (λ = 1.5418 Å). Data reduction
including empirical absorption correction by using spherical harmonics
was performed with CrysAlis-Pro (Oxford Diffraction, England). The
crystal structure was solved by the charge-flipping method using the
program Superflip [24] and refined with the Jana2006 program package
[25] by full-matrix least-squares technique on F. The non-hydrogen
atoms were refined anisotropically and the hydrogen atoms were posi-
tioned geometrically and refined by using the riding model. The
molecular-structure plots were prepared by using ORTEP III [26] and
the intermolecular interactions were viewed in Mercury software [27].
2.2.4. [RuCl(η6-benzene)(1R,2R)-N-(naphthalene-1-sulfonyl)-1,2-diphenyl-
ethylenediamine] (1b)
The compound was prepared according to the procedure de-
scribed above using (1R,2R)-N-(naphthalene-1-sulfonyl)-1,2-diphenyl-
ethylenediamine. Yield: 104 mg, 50%.
2.3. General procedure for asymmetric transfer hydrogenation
The formic acid-triethylamine azeotropic mixture (218 μL; 6.3 eq
of formic acid with respect to the imine) was charged into a round-
bottom flask (10 mL), followed by the catalyst (0.01 eq) dissolved
in acetonitrile (1 mL). The resulting mixture was stirred for 10 min to
activate the catalyst. The imine (0.42 mmol) dissolved in acetonitrile
(1 mL) was introduced at once and the mixture was stirred at 30 °C.
The samples of the reaction mixture (60 μL) were collected at 10, 20,
30, 40, 50, 90, 120 and 180 min.
Each sample was quenched by using saturated solution of Na2CO3
(1 mL) and extracted with diethyl ether (3 × 1 mL). Combined extracts
were dried over anhydrous sodium sulfate and the solvent was stripped
off in a stream of nitrogen. The dry sample was dissolved in acetonitrile
(1 mL) and analyzed.
2.2. Synthesis of chiral ligands and catalysts
2.2.1. Synthesis of (1R,2R)-N-((S)-camphor-10-sulfonyl)-1,
2-diphenylethylenediamine (ligand for catalyst 1c)
(S)-Camphor-10-sulfonic acid (500 mg, 2.15 mmol) was treated with
SOCl2 (0.625 mL, 8.61 mmol) for 1.5 h at 120 °C to get (S)-camphor-
10-sulfonyl chloride. Excess SOCl2 was evaporated twice with toluene
(5 mL) at reduced pressure.
The solution of (S)-camphor-10-sulfonyl chloride (215 mg,
0.85 mmol) in acetonitrile (20 mL) was added dropwise into a solution
of (R,R)-1,2-diphenylethylene-1,2-diamine (DPEN; 200 mg, 1.1 eq)
and triethylamine (TEA; 240 μL, 4 eq) in acetonitrile (40 mL) at 0 °C
for 30 min. After further 60 min of the reaction, the white precipitate
of TEA∙HCl was filtered off and the reaction mixture was diluted with
dichloromethane and evaporated at 40 °C at reduced pressure. The
product was dissolved in 0.1 M solution of NaOH (30 mL) and extracted
with dichloromethane (3 × 10 mL). Combined extracts were dried
over anhydrous Na2SO4 and evaporated. The crude product was purified
by flash column chromatography using Silicagel 60 and mobile phase
consisting of ethyl acetate/hexane/TEA (1/1/0.02) yielding ochre crystals
of pure (1R,2R)-N-((S)-camphor-10-sulfonyl)-1,2-diphenylethylene-1,
2-diamine. Yield: 280 mg, 77%; purity: 98%.
3. Results and discussion
3.1. Catalyst development and performance
At the beginning of our study, we tested catalyst 1b in the ATH of a
series of 1-phenyl-DHIQs 2a–2d and two 1-alkyl-DHIQs (2e and 2f)
(Table 1, entries 1–6). We found out that this system showed signifi-
cantly lower catalytic activity (expressed as turnover frequency, TOF)
and selectivity (expressed by ee) in the ATH of 1-alkyl-DHIQs (2e and
2f) compared to catalyst 1a (entries 7 and 8), which, however, does
not reduce 1-phenyl-DHIQs (2a–2d).
The change of the N-arylsulfonyl substituent from p-toluenesulfonyl
(present in 1a) to naphthalene-1-sulfonyl in 1b thus enabled the cata-
lytic activity in the ATH of substrates 2a–2d. Noyori et al. showed that
catalysts bearing N-benzoyl and N-acetyl DPEN ligands are inactive in
ATH [10]. Our computational studies revealed that the sulfonyl group
plays a crucial role in the reaction mechanism by forming an N\H⋯S_O
hydrogen bond with the protonated imine [28]. The low reactivity of
1-aryl DHIQs is attributed to the fact that the aromatic ring and the
2.2.2. Synthesis of (1R,2R)-N-(naphthalene-1-sulfonyl)-1,
2-diphenylethylenediamine (ligand for catalyst 1b)
The compound was prepared according to the procedure described
above using commercial naphthalene-1-sulfonyl chloride. Yield:
722 mg, 49%; purity: 97%.

J. Přech et al. / Catalysis Communications 36 (2013) 67–70
69
Table 1
ATH of 1-phenyl (2a–2d) and 1-methyl (2e and 2f) substituted DHIQs over catalysts 1a–1c.
Entry
Substrate
Catalyst
TOF (h−1
)
ee (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2e
2f
2a
2b
2c
2d
2e
2f
1b
1b
1b
1b
1b
1b
1a
1a
1c
1c
1c
1c
1c
1c
1c
4.1
3.8
4.8
5.7
5.9
73
39
40
49
61
80
82
94
74
45
171
261
3.7
b1
b1
9
a
10
11
12
13
14
15
–
a
–
6.7
63
82
87
97
226
265
11.5
Acetophenone
a
ee was not determined due to low conversion.
C_N bond are in conjugation, which affects its electron density and po-
larization. This effect is further manifested through the N\H⋯S_O in-
teraction which has an impact on the catalytic activity. These
considerations led us to the idea of changing the structure of the catalyst
in order to enhance its activity and selectivity for both 1-alkyl and 1-aryl
DHIQs.
was rather low despite very high ee. The reduction of other ketones
has been reported elsewhere [20–23].
3.2. XRD structure analysis of 1c
The single crystal structure of compound 1c is built up by discrete
moieties in the orthorhombic space group P212121 with one formula
unit in the asymmetric unit. Basic crystallographic information is
given in Table 2.
The camphor fragment was selected as the substituent of the sulfonyl
group due to its inherent chirality. By reacting (S)-camphor-10-sulfonyl
chloride with (R,R)-DPEN, we obtained (1R,2R)-N-((S)-camphor-10-
sulfonyl)-DPEN (CsDPEN). The ligand was further reacted with [Ru(II)
Cl2(η6-p-cymene)]2. During the reaction, the complex underwent ste-
reoselective transfer auto-hydrogenation of the carbonyl group in
the N-camphorsulfonyl part of the molecule to give a complex of
N-borneolsulfonyl-DPEN. As the reaction was performed in propan-2-ol,
the solvent served as a hydrogen source. The isolated crystalline material
contained only one isomer (borneolsulfonyl, not isoborneolsulfonyl as
evidenced from the crystallographic analysis, vide infra). This ligand
has been shown applicable in the ATH of a ketone [21] but its isolated
complex has not been characterized. The reaction conditions towards
the non-reduced analog were not examined since the synthesis of such
complex has already been reported [20].
The Ru atom in 1c has a pseudo-octahedral geometry, being coor-
dinated to a η6-p-cymene occupying three facial coordination sites, a
five-membered chelate ring with neutral amine and anionic sulfon-
amide moieties (occupying two coordination sites) and a chloride
ligand. The chelate ring is formed by two-carbon-symmetric bidentate
diphenylethylenediamine ligand. The distance of the Ru atom from
the center of the η6-p-cymene ring is 1.676 Å and the average Ru\C
distance is 2.191 Å. The Ru1\C28 distance is significantly longer
than the rest of Ru\C bonds (2.227 Å compared to 2.17–2.19 Å).
The borneolsulfonyl group is connected to the N1 atom by a three-
membered S-shaped chain S1\C15\C16 and contains
a strong
The resulting complex, [Ru(II)Cl(η6-p-cymene)(1R,2R)-N-((1S,2S)-
borneol-10-sulfonyl-DPEN)] (1c), was tested in the ATH of a series of
DHIQs and a ketone (Table 1, entries 9–15). In the reduction of
1-phenyl-DHIQs containing electron-donating groups (2a and 2d,
entries 9 and 12), the catalyst's performance was comparable with
that of 1b (entries 1, 4, 9 and 12). On the contrary, substrates lacking
electron-donating groups (2b, entry 10) or even containing an electron
withdrawing group (2c, entry 11) displayed very low catalytic activity.
In the case of 1-phenyl-DHIQs, the catalytic activity (dependent on the
electronic distribution in the C_N bond) was hampered by the conju-
gation of the C_N bond with the aromatic ring. When electron-
donating groups like CH3O- and CH3- were present in the molecule, the
catalytic activity was higher than in an opposite case. The sensitivity of
1c to this effect was evidently more pronounced than in the case of 1b.
In the ATH of imines 2e and 2f, the reactivity was much higher
than with 1b, and slightly exceeding the activity of 1a. The catalyst
was also active in the ATH of acetophenone (entry 11). The reactivity
Table 2
Crystal data and structure refinement of catalyst 1c.
Empirical formula
C34H45ClN2O3RuS
Formula weight
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions
a (Å)
698.4
1.5418
Orthorhombic
P212121
12.4647 (2)
16.3344 (3)
17.1478 (5)
3491.35 (13)
4
1.3282
5.16
1456
45295/7330
0.0409, 0.0543
b (Å)
c (Å)
Volume (Å3)
Z
Calculated density
Absorption coefficient
F(000)
Reflections collected/unique
R1, wR2

70
J. Přech et al. / Catalysis Communications 36 (2013) 67–70
Fig. 2. Solid-state molecular structure of 1c (25% probability ellipsoids).
intramolecular hydrogen bond O1\H1O3⋯O3 with the H⋯A distance of
2.33(7) Å. This hydrogen bond makes the system more rigid and causes
a synergistic effect with other steric and electronic properties leading to
the catalytic results achieved. The X-ray crystallographic structure is
given in Fig. 2 and selected bond lengths and angles are summarized
in Table 3.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.catcom.2013.03.004.
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4. Conclusions
In conclusion, the novel ruthenium-arene complex containing
(1R,2R)-N-((1S,2S)-borneol-10-sulfonyl)-DPEN proved to be a robust
ATH catalyst since it is able to reduce both 1-methyl and 1-phenyl-
DHIQs with performance comparable with the reported catalysts. To
the best of our knowledge, this is the first N-alkylsulfonyl-DPEN catalyst
which can catalyze the ATH of cyclic imines. This study opens the way to
other active and selective Ru catalysts for the asymmetric hydrogen
transfer reductions of imines and ketones.
Acknowledgment
This work has been financially supported by the Grant Agency of
the Czech Republic (grant GACR 104/09/1497 and P106/12/1276),
and by grant for long-term conceptual development of Institute of
Microbiology RVO: 61388971.
Table 3
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Selected bond lengths [Å] and bond angles [°] in 1c.
Ru1\C27
Ru1\Cl1
Ru1\N1
Ru1\N2
S1\N1
2.185(5)
2.4247(1)
2.138(3)
2.117(4)
1.615(4)
1.450(4)
1.448(3)
1.808(4)
2.331(6)
Cl1\Ru1\N1
Ru1\N1\S1
O1\S1\N1
N1\S1\C15
S1\C15\C16
N1\Ru1\N2
87.46(1)
120.19(2)
110.45(2)
106.4(2)
116.00(1)
79.29(1)
S1\O1
S1\O2
S1\–15
O1\H1O3