Catalytic Asymmetric Hydrogenation of Heteroarenes and Arenes

Article abstract of DOI:10.1080/10426507.2014.974752

A trans-chelating chiral bisphosphine, PhTRAP, allows the ruthenium-catalyzed hydrogenation of various azoles to proceed with high enantioselectivity. The PhTRAP-ruthenium catalyst transformed indoles, pyrroles, imidazoles, and oxazoles into the correspon

Full text of DOI:10.1080/10426507.2014.974752

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Catalytic Asymmetric Hydrogenation of
Heteroarenes and Arenes
Ryoichi Kuwanoa
a Department of Chemistry, Graduate School of Sciences, and
International Research Center for Molecular Systems (IRCMS), Kyushu
University, and JST ACT-C, 6-10-1 Hakozaki, Higashi-ku, 812-8581,
Fukuoka, Japan
Accepted author version posted online: 03 Nov 2014.
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To cite this article: Ryoichi Kuwano (2015) Catalytic Asymmetric Hydrogenation of Heteroarenes
and Arenes, Phosphorus, Sulfur, and Silicon and the Related Elements, 190:5-6, 715-719, DOI:
10.1080/10426507.2014.974752
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Phosphorus, Sulfur, 190:715–719, 2015
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2014.974752
CATALYTIC ASYMMETRIC HYDROGENATION
OF HETEROARENES AND ARENES
Ryoichi Kuwano
Department of Chemistry, Graduate School of Sciences, and International
Research Center for Molecular Systems (IRCMS), Kyushu University, and JST
ACT-C, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
GRAPHICAL ABSTRACT
R
R
N
Boc
N
Boc
R2
R3
R1
R2
R1
R3
R1
R1
N
N
Boc
Boc
cat. [Ru]–PhTRAP
N
N
Ph
Ph
X
X
(X = N–Boc, O)
R
R
OEt
OEt
Abstract A trans-chelating chiral bisphosphine, PhTRAP, allows the ruthenium-catalyzed hy-
drogenation of various azoles to proceed with high enantioselectivity. The PhTRAP–ruthenium
catalyst transformed indoles, pyrroles, imidazoles, and oxazoles into the corresponding chiral
heterocycles. Naphthalenes are also reduced with hydrogen by the chiral ruthenium catalyst,
exclusively giving tetralins. Some 2-alkoxytetralins were obtained with over 90% ee from the
catalytic asymmetric hydrogenation of the corresponding substituted naphthalenes.
Keywords Bisphosphine; ruthenium; asymmetric catalysis; hydrogenation; azoles;
naphthalenes
INTRODUCTION
Catalytic asymmetric hydrogenation is a powerful method for preparing optically
active compounds. Various chiral catalysts have been developed for the stereoselective
hydrogenations of prochiral alkenes, ketones, and imines. Meanwhile, heteroarenes and
Received 28 August 2014; accepted 5 October 2014.
Address correspondence to Ryoichi Kuwano, Department of Chemistry, Graduate School of Sciences, and
International Research Center for Molecular Systems (IRCMS), Kyushu University, and JST ACT-C, 6-10-1
Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan. E-mail: rkuwano@chem.kyushu-univ.jp
715

716
R. KUWANO
H
H
Me
Fe
Ph2P
(R,R)-(S,S)-PhTRAP
PPh2
Ph2P
Me
Fe
PPh2
(S,S)-(R,R)-PhTRAP
Fe
Fe
Me
Me
H
H
Chart 1 Structures of (R,R)-(S,S)- and (S,S)-(R,R)-PhTRAP.
arenes are attractive substrates for the catalytic asymmetric hydrogenation, because they
can directly be transformed into the corresponding chiral heterocycles. Nevertheless, the
asymmetric reductions of the aromatic compounds had been an unexplored subject in or-
ganic chemistry until a decade ago, because the substrates are highly stabilized with the
resonance of their π-electrons. In 2000, we reported a highly enantioselective hydrogena-
tion of indoles by using the chiral rhodium complex bearing chiral bisphosphine, (R,R)-
2,2ꢁꢁ-bis[(S)-1-(diphenylphosphino)ethyl]-1,1”-bifferocene [(S,S)-(R,R)-PhTRAP], which
can chelate a metal atom in a trans manner (Chart 1).1 Since then, many chemists have
made efforts to develop the chiral catalysts for the hydrogenation of heteroarenes. Nowa-
days, the asymmetric catalysis allows various heteroarene substrates to be converted to
the corresponding chiral heterocycles with high enantiomeric excesses.2 This proceeding
surveys our research on the asymmetric hydrogenation of heteroarenes and arenes with
PhTRAP–ruthenium catalyst.
RESULTS AND DISCUSSION
The hydrogenation of indoles having an acetyl or sulfonyl group on the nitrogen
proceeds with high enantioselectivity in the presence of the PhTRAP–rhodium catalyst.1,3
However, the chiral rhodium catalyst is useless for the asymmetric hydrogenation of Boc-
protected indoles, while the Boc group is readily installed in the substrates and removed
from the hydrogenation products. The hydrogenation of N-Boc-indoles proceeded with
high enantioselectivity by using {RuCl(p-cymene)[(S,S)-(R,R)-phtrap]}Cl (1) in place of
the rhodium catalyst.4 The ruthenium catalyst efficiently converted N-Boc-2-methylindole
(2) into the chiral indoline 3 with 95% ee (R) (Eq. (1)).
1 (1.0%), Cs2CO3 (10%)
Me
Me
+
H2
(1)
N
N
Boc
MeOH, 60°C, 2 h
(5.0 MPa)
Boc
2
3
99% yield, 95% ee (R)
The PhTRAP–ruthenium catalyst allows various azoles to give the corresponding
hydrogenation products with high enantioselectivities. A solution of pyrrole-2-carboxylate
4a in 2-propanol was stirred at 60◦C under 5.0 MPa of hydrogen in the presence of the
ruthenium catalyst, which was prepared in situ from [Ru(η3-methallyl)2(cod)] and (S,S)-
(R,R)-PhTRAP (Eq. (2)).5 The reaction yielded (S)-pyrrolidine-2-carboxylate 5a with 73%

CATALYTIC ASYMMETRIC HYDROGENATION OF ARENES
717
ee. The enantiomeric excess increased to 79% ee when the hydrogenation was conducted
in the presence of triethylamine. It is noteworthy that the PhTRAP–ruthenium catalyst
exhibited high enantioselectivity for the hydrogenation of 2,3,5-trisubstituted pyrroles
(Eq. (3)). The reaction of 4b newly created three chiral centers on the nitrogen-containing
5-membered ring and produced chiral pyrrolidine 5b with 96% ee as the single diastere-
omer. Furthermore, 2,3,5-triphenylpyrrolidine 4c was transformed into dihydropyrrole 6c
with 99.7% ee.
[Ru(η3-methallyl)2(cod)] (1.0%)
(S,S)-(R,R)-PhTRAP (1.1%)
CO2Me
CO2Me
+
H2
(2)
N
N
i-PrOH, 60°C, 24 h
(5.0 MPa)
Boc
Boc
4a
5a
92% yield, 73% ee (S)
92% yield, 79% ee (S)
with no base
with Et3N (10%)
[Ru(η3-methallyl)2(cod)] (2.5%)
(S,S)-(R,R)-PhTRAP (2.8%)
R2
R2
R2
R2
R1 R2
+
H2
(3)
R2
R1
R1
Et3N (25%), EtOAc
80°C, 24 h
N
N
N
(5.0 MPa)
Boc
Boc
Boc
4
5
6
4b: R1 = CO2Me, R2 = Me
4c: R1 = R2 = Ph
5b: 85% yield, 96% ee
6c: >99% yield, 99.7% ee
5b:6b = 100:0
5c:6c = 0:100
The condition for the hydrogenation of pyrroles 4 is useful for the reaction of N-
Boc-imidazoles 7 (Eq. (4)).6 The (R,R)-(S,S)-PhTRAP–ruthenium catalyst transformed
4-methyl-2-phenylimidazole 7a into chiral imidazoline (S)-8a without over-reduction of its
C–N double bond. The substituent at the 2-position strongly affects the reaction rate. The
reaction of 7b gave the desired product 8b with 86% ee, but the yield of 8b was only 35%.
As with imidazoles, oxazoles were also reduced to oxazolines with high stereoselectivity.6
2,4-Disubstituted oxazole 9a was converted to oxazoline (R)-10a with 98% ee through the
(S,S)-(R,R)-PhTRAP–ruthenium catalyst (Eq. (5)). Oxazoline (R)-10b, which has a chiral
center at its 5-position, was also obtained with 97% ee from the reaction of 9b (Eq. (6)). The
stereochemical outcomes of the asymmetric hydrogenations suggest that the Boc group on
the nitrogen scarcely participates in the chiral induction during the present hydrogenation of
7. Furthermore, the PhTRAP–ruthenium catalyst may recognize the shape of the substrate
rather than the electronic properties of two heteroatoms in the imidazole or oxazole ring.
[Ru(η3-methallyl)2(cod)] (2.5%)
(R,R)-(S,S)-PhTRAP (2.8%)
Me
Me
N
N
+
H2
(4)
R
R
N
N
Et3N (25%), EtOAc, 80°C, 24 h
(5.0 MPa)
Boc
Boc
8
7
7a: R = Ph
7b: R = Et
8a: 97% yield, 97% ee (S)
8b: 35% yield, 86% ee

718
R. KUWANO
[Ru(η3-methallyl)2(cod)] (2.5%)
(S,S)-(R,R)-PhTRAP (2.8%)
Ph
Ph
N
N
+
H2
(5)
TMG (25%), i-BuOH, 80°C, 4 h
Ph (5.0 MPa)
Ph
O
O
10a
>99% yield, 98% ee (R)
9a
[Ru(η3-methallyl)2(cod)] (2.5%)
(S,S)-(R,R)-PhTRAP (2.8%)
N
N
+
H2
(6)
Ph
Ph
Ph
Ph
toluene, 80°C, 24 h
O
O
(5.0 MPa)
10b
97% yield, 97% ee (R)
9b
To our surprise, the PhTRAP–ruthenium catalyst hydrogenated naphthalenes to
tetralins. The hydrogenations of naphthalene-2,6-dicarboxylates 11 were conducted with
catalyst 1 (Eq. (7)).7 Methyl ester 11a failed to give the desired chiral tetralin 12a in
moderate yield as well as with good enantioselectivity because of its low solubility. How-
ever, the low yield and selectivity were remarkably improved by replacing the methyl by
isobutyl. The hydrogenation product 12b was obtained with 86% ee in 98% yield under
the optimized condition. The ruthenium-catalyzed hydrogenation of 11b was attempted
by using various purchasable cis-chelating bisphosphines in place of PhTRAP, but tetralin
12b was formed in less than 10% yield. Consequently, the trans-chelating property of the
bisphosphine ligand may be crucial for the ruthenium catalysis.
RO2C
RO2C
1 (2.0%), base (20%)
+
H2
(7)
*
(5.0 MPa) 1,4-dioxane, 60°C, 24 h
CO2R
CO2R
11
12
11a: R = Me
11b: R = i-Bu
base = Cs2CO3
base = Cs2CO3
base = DBU (in i-BuOH, at 40°C)
12a: 17% convn., 22% ee
12b: 51% convn., 69% ee
12b: 98% yield, 86% ee
The hydrogenation of 2-alkoxynaphthalenes 13 proceeded with high enantioselectiv-
ity through the chiral catalysis (Eq. (8)). The PhTRAP–ruthenium catalyst converted 2,6-
and 2,7-dialkoxynaphthalenes, 13a and 13b, to tetralins 14a and 14b with 90% ee and 92%
ee, respectively. In the reaction of 13c, the alkoxy-substituted ring was selectively reduced
to give 14c in high yield. Coordination of the oxygen lone pair in the naphthalene substrate
to the ruthenium atom may assist the interaction between the naphthalene ring and the
catalyst.
R
R
R
1 (2.0%), TMG (20%)
6
7
+
H2
(8)
toluene, 100°C, 48 h
(5.0 MPa)
OEt
OEt
OEt
13
14
15
13a: R = 6-EtO
13b: R = 7-EtO
14a: 87% yield, 90% ee
14b: 97% yield, 92% ee
13c: R = 6-(2-MeC6H4)
14c: 89% yield, 91% ee (14c:15c = 96:4)

CATALYTIC ASYMMETRIC HYDROGENATION OF ARENES
719
CONCLUSION
The ruthenium catalyst bearing the trans-chelating bisphosphine, PhTRAP, was
proved to be useful for the asymmetric hydrogenation of various azoles. Indoles, pyrroles,
imidazoles, and oxazoles were converted to the chiral indolines, pyrrolidines (or dihy-
dropyrroles), imidazolines, and oxazolines with high enantiomeric excesses. Furthermore,
the chiral catalyst allows the hydrogenation of naphthalenes to proceed with moderate
reaction rate. Several chiral 2-alkoxytetralins were obtained with over 90% ee through the
PhTRAP–ruthenium catalysis. The trans-chelating property of the chiral bisphosphine is
crucial for achieving the hydrogenation of the carbocyclic arenes.
FUNDING
This work was partly supported by ACT-C (JST).
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