Catalytic asymmetric hydrogenation of naphthalenes

Article abstract of DOI:10.1002/anie.201201153

Vanishing aromaticity: A chiral ruthenium complex catalyzes the hydrogenation of 2,6- or 2,7-disubstituted naphthalenes to give chiral tetralins with up to 92 % ee. The chiral catalyst is applicable to the regio- and enantioselective reduction of 6-substi

Full text of DOI:10.1002/anie.201201153

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Angewandte
Communications
DOI: 10.1002/anie.201201153
Asymmetric Hydrogenation
Catalytic Asymmetric Hydrogenation of Naphthalenes**
Ryoichi Kuwano,* Ryuichi Morioka, Manabu Kashiwabara, and Nao Kameyama
The catalytic asymmetric hydrogenation of heteroarenes has
been intensively studied during the last decade.[1] Nowadays,
various heteroaromatics, for example, indoles,[2] pyrroles,[3]
and quinolines,[4] can be reduced to the corresponding chiral
heterocycles with high stereoselectivity through asymmetric
catalysis.[5–8] Glorius and co-workers recently found that
a chiral N-heterocyclic carbene–ruthenium catalyst allowed
the site-selective hydrogenation of the carbocyclic rings of
some quinoxalines, producing chiral 5,6,7,8-tetrahydro-
quinoxalines with up to 88% ee.[9–11] However, to the best of
our knowledge, the catalytic asymmetric hydrogenation of
aromatics containing no heteroatoms remains unex-
plored.[12,13] Herein, we report the first successful enantio-
selective hydrogenation of carbocyclic arenes, naphthalenes,
through asymmetric catalysis.
Previously, we had developed the highly enantioselective
hydrogenation of N-Boc indoles with a ruthenium catalyst
generated from [{RuCl2(p-cymene)}2] and the chiral bisphos-
phine ligand, PhTrap.[2d,14] During the course of this study, we
attempted the reduction of 2-naphthylindole 1 with the
PhTrap–ruthenium catalyst (Scheme 1). To our surprise,
none of the expected product 2 was obtained. The hydro-
genation was accompanied by the partial reduction of the
naphthalene ring, yielding tetrahydronaphthylindoline 3 with
90% ee. This observation suggested that the ruthenium
complex was capable of reducing carbocyclic aromatic rings.
In this context, we began to study the catalytic asymmetric
hydrogenation of naphthalenes.
In our initial attempt, a solution of dimethyl naphthalene-
2,6-dicarboxylate (4a) in 1,4-dioxane was stirred at 608C
under hydrogen gas (50 atm) in the presence of [RuCl-
(p-cymene){(S,S)-(R,R)-PhTrap}]Cl (6)[2d] catalyst. Although
formation of the hydrogenation product 5a was observed, the
desired reaction was very sluggish and the enantiomeric
excess of 5a was only 22% ee (Table 1, entry 1). Both the
Table 1: Catalytic asymmetric hydrogenation of naphthalene-2,6-dicarb-
oxylate 4.[a]
Entry
R (4)
Additive
Solvent
Conv. [%][b]
ee [%][c]
1[d]
2[d]
3[d]
4
5
6
7
8
9
10
11
12
13
14
Me (4a)
Et (4b)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
K3PO4
KOtBu
DBU
TMG
DBU
DBU
DBU
DBU
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
toluene
EtOAc
17
18
51
14
0
24
28
67
78
22
68
69
78
–
76
77
82
81
78
81
82
86
83
iBu (4c)
iBu (4c)
iBu (4c)
iBu (4c)
iBu (4c)
iBu (4c)
iBu (4c)
iBu (4c)
iBu (4c)
iBu (4c)
iBu (4c)
iBu (4c)
66
99
EtOH
iBuOH
iPrOH
(79)[e,f]
100 (98)[e]
100
DBU
[a] Unless otherwise noted, reactions were conducted on a 0.25 mmol
scale in 1.0 mL of solvent at 408C for 24 h. The ratio of 4/6/additive was
50:1:10. [b] Determined by 1H NMR analysis. Unless otherwise noted, no
side product was detected. [c] Determined by HPLC analysis. [d] The
reactions were conducted at 608C. [e] Yields of isolated 5c are in
parentheses. [f] A 14% yield of isolated 5b was also obtained.
DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, dioxane=1,4-dioxane,
TMG=1,1,3,3-tetramethylguanidine.
Scheme 1. Asymmetric hydrogenation of 2-naphthylindole. Boc=tert-
butoxycarbonyl.
[*] Prof. R. Kuwano, R. Morioka, M. Kashiwabara, N. Kameyama
Department of Chemistry, Graduate School of Sciences, and
International Research Center for Molecular Systems (IRCMS),
Kyushu University
stereoselectivity and the reaction rate were affected by the
ester substituents of the naphthalene substrate. The reaction
of ethyl ester 4b also proceeded in low yield, but the ethyl
substituent brought about a remarkable improvement in the
stereoselectivity (entry 2). The use of 4c, which is a larger and
more flexible ester, resulted in a moderate yield of chiral
tetralin 5c (entry 3). The enantiomeric excess of 5c was
improved to 78% ee by conducting the hydrogenation at
lower temperature (entry 4). The enantioselectivity scarcely
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581 (Japan)
E-mail: rkuwano@chem.kyushu-univ.jp
Homepage: http://www.scc.kyushu-u.ac.jp/Yuki/main.html
[**] This work was supported by the Nagase Science and Technology
Foundation, the Takeda Science Foundation, and a Grant-in-Aid for
the Global COE Program “Science for Future Molecular Systems”
from MEXT.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201153.
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fluctuated with base and solvent, but these factors did
influence the catalytic activity of 6. The absence of a base
resulted in no conversion of the naphthalene substrate
(entry 5). On the other hand, using either 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) or 1,1,3,3-tetramethylguanidine
(TMG) as the base led to an increase in the yield of 5c
(entries 8 and 9). The hydrogenation product was quantita-
tively obtained from reactions carried out in EtOAc or
alcoholic solvents (entries 11–14). Isobutyl alcohol is the
solvent of choice for the asymmetric hydrogenation of 4c, as
transesterification occurred in other alcohols. Under the
optimized conditions, naphthalene 4c was converted to the
desired tetralin 5c with 86% ee (entry 13).[15] The chiral
catalyst was also able to hydrogenate 2,7-disubstituted
naphthalene 7 to the corresponding chiral tetralin 8 in high
yield, but the enantiomeric excess of the product was
moderate [Eq. (1)].
transformation. The hydrogenation of 9d afforded 11d in
high yield (entry 4). The THP groups of 11d were deprotected
by treatment with p-toluenesulfonic acid in ethanol to give
(S)-2,6-dihydroxy-1,2,3,4-tetrahydronaphthalene with 85%
ee. 2,7-Dialkoxynaphthalenes 10 were also reduced to chiral
tetralins 12 through ruthenium catalysis (entries 5–8). As with
9, ethyl or isopropyl ethers were more favorable for the
asymmetric hydrogenation of 10 than methyl ether, giving
12b or 12c with 92% ee. The chiral ruthenium complex 6 can
also catalyze the hydrogenation of bis(alkoxymethyl)naph-
thalene 13 [Eq. (2)]. However, the reaction proceeded with
moderate stereoselectivity and did not reach completion
within 48 h. Disappointingly, no reaction was observed when
a selection of symmetrical dialkylnaphthalenes were treated
with hydrogen in the presence of the PhTrap–ruthenium
catalyst. These results suggest that the coordination of an
oxygen lone pair in the naphthalene substrate to the
ruthenium atom is required for chiral catalysis, as this
coordination may induce interaction between the catalyst
and the naphthalene ring.
We tested various symmetrical disubstituted naphthalenes
in the asymmetric hydrogenation with chiral ruthenium
catalyst 6. 2,6-Dimethoxynaphtalene (9a) was quantitatively
hydrogenated to the desired tetralin 11a (Table 2, entry 1).
However, the reaction required a higher temperature than for
the hydrogenation of 4 or 7, and proceeded with 69% ee. The
enantioselectivity was enhanced to 90% ee by using an
ethoxy- or isopropoxy-substituted substrate (entries 2 and 3).
In order to remove the O-alkyl group from the hydrogenation
product, THP-protected naphthalenediol 9d (THP = tetra-
hydro-2H-pyran-2-yl) was employed for the asymmetric
The low reactivities of dialkylnaphthalenes prompted us
to attempt the regio- and enantioselective hydrogenation of
unsymmetrical 6-alkyl- or 6-aryl-2-alkoxynaphthalenes 15
(Table 3). Hydrogenation preferentially occurred on the
alkoxy-substituted arene ring. In each case, the major product
16 was obtained with 91% ee. The substituent at the 6-
position had no effect on the stereoselectivity. The reaction of
2-ethoxy-6-ethylnaphthalene (15a) gave 16a and 17a in
a ratio of 79:21 (entry 1). The site-selectivity was also not
affected by replacing an ethyl group by a phenyl group at the
Table 2: Catalytic asymmetric hydrogenation of 2,6- and 2,7-dialkoxy-
naphthalenes 9 and 10.[a]
Table 3: Catalytic asymmetric hydrogenation of unsymmetrical 2,6-
disubstituted naphthalenes 15.[a]
Entry R (9 or 10)
Conv. [%][b] Product Yield [%][c] ee [%][d]
1
Me (9a)
Et (9b)
iPr (9c)
100
100
92
11a
11b
11c
11d
12a
12b
12c
12d
99
87
91
95
96
97
93
90
69
90
89
2[e]
3
4[e]
5
THP (9d)[f]
Me (10a)
Et (10b)
iPr (10c)
THP (10d)[f]
96
85 (S)[g]
73
Entry R (15)
Conv. [%][b] 16/17[b] Yield [%][c] ee [%][d]
100
100
94
6[e]
7
92
1[e]
2[g]
3
Et (15a)
Ph (15b)
2-MeC6H4 (15c)
100
94
96
79:21
79:21
96:4
65[f]
75[h]
89
91
91
91
92
8
94
86 (S)[g]
[a] Unless otherwise noted, reactions were conducted on a 0.25 mmol
scale in 1.0 mL of 2-propanol at 1008C for 48 h. The ratio of 9 or 10/6/
TMG was 50:1:10. [b] Determined by 1H NMR analysis. No side product
was detected. [c] Yield of isolated product. [d] Determined by HPLC
analysis. [e] The reaction was conducted in toluene. [f] The substrate was
a stereoisomeric mixture. [g] The enantiomeric excess was determined
after the hydrolytic removal of the THP groups. THP=tetrahydro-2H-
pyran-2-yl, TMG=1,1,3,3-tetramethylguanidine.
[a] Unless otherwise noted, reactions were conducted on a 0.25 mmol
scale in 1.0 mL of 2-propanol at 1008C for 48 h. The ratio of 15/6/TMG
was 50:1:10. [b] Determined by 1H NMR analysis. [c] Yields of isolated
products 16. [d] Enantiomeric excesses of products 16, as determined by
HPLC analysis. [e] The reaction was conducted in toluene with 4%
catalyst loading. [f] A 15% yield of isolated 17a was obtained. [g] The
reaction was conducted at 808C for 24 h. [h] A 21% yield of isolated 17b
with 81% ee was obtained.
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6-position (entry 2). The minor product 17c was barely
formed in the hydrogenation of 15c (entry 3). The o-methyl
group in 15c may sterically hinder the interaction between the
catalyst and the aryl-substituted arene ring.
In the present asymmetric hydrogenation, the reduction
of the alkoxy-substituted arene ring of naphthalene substrate
would be expected to proceed stepwise through sequential
[1] For reviews, see: a) F. Glorius, Org. Biomol. Chem. 2005, 3, 4171;
b) Y.-G. Zhou, Acc. Chem. Res. 2007, 40, 1357; c) R. Kuwano,
Heterocycles 2008, 76, 909; d) D.-S. Wang, Q.-A. Chen, S.-M. Lu,
Y.-G. Zhou, Chem. Rev. 2012, DOI: 10.1021/cr200328h.
[2] a) R. Kuwano, K. Sato, T. Kurokawa, D. Karube, Y. Ito, J. Am.
Chem. Soc. 2000, 122, 7614; b) R. Kuwano, K. Kaneda, T. Ito, K.
Sato, T. Kurokawa, Y. Ito, Org. Lett. 2004, 6, 2213; c) R. Kuwano,
M. Kashiwabara, K. Sato, T. Ito, K. Kaneda, Y. Ito, Tetrahedron:
Asymmetry 2006, 17, 521; d) R. Kuwano, M. Kashiwabara, Org.
Lett. 2006, 8, 2653; e) A. Baeza, A. Pfaltz, Chem. Eur. J. 2010, 16,
2036; f) D.-S. Wang, Q.-A. Chen, W. Li, C.-B. Yu, Y.-G. Zhou, X.
Zhang, J. Am. Chem. Soc. 2010, 132, 8909.
=
1,2-additions of hydrogen to two C C bonds as shown in
À
Scheme 2. The less substituted C3 C4 bond is hydrogenated
[3] a) R. Kuwano, M. Kashiwabara, M. Ohsumi, H. Kusano, J. Am.
Chem. Soc. 2008, 130, 808; b) D.-S. Wang, Z.-S. Ye, Q.-A. Chen,
Y.-G. Zhou, C.-B. Yu, H.-J. Fan, Y. Duan, J. Am. Chem. Soc.
2011, 133, 8866.
[4] For representative examples, see: a) W.-B. Wang, S.-M. Lu, P.-Y.
Yang, X.-W. Han, Y.-G. Zhou, J. Am. Chem. Soc. 2003, 125,
10536; b) S.-M. Lu, Y.-Q. Wang, X.-W. Han, Y.-G. Zhou, Angew.
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c) M. Rueping, A. P. Antonchick, T. Theissmann, Angew. Chem.
2006, 118, 3765; Angew. Chem. Int. Ed. 2006, 45, 3683; d) H.
Zhou, Z. Li, Z. Wang, T. Wang, L. Xu, Y. He, Q.-H. Fan, J. Pan,
L. Gu, A. S. C. Chan, Angew. Chem. 2008, 120, 8592; Angew.
Chem. Int. Ed. 2008, 47, 8464; e) T. Wang, L.-G. Zhuo, Z. Li, F.
Chen, Z. Ding, Y. He, Q.-H. Fan, J. Xiang, Z.-X. Yu, A. S. C.
Chan, J. Am. Chem. Soc. 2011, 133, 9878.
Scheme 2. Reaction pathway of the asymmetric hydrogenation of
naphthalenes.
first to give achiral alkenyl ether 18. This step partially breaks
the aromaticity of the naphthalene, but is not accompanied by
[5] For representative reports on the catalytic asymmetric hydro-
genation of quinoxalines, see: a) C. Bianchini, P. Barbaro, G.
Scapacci, E. Farnetti, M. Graziani, Organometallics 1998, 17,
3308; b) W. Tang, L. Xu, Q.-H. Fan, J. Wang, B. Fan, Z. Zhou, K.-
h. Lam, A. S. C. Chan, Angew. Chem. 2009, 121, 9299; Angew.
Chem. Int. Ed. 2009, 48, 9135; c) Q.-A. Chen, D.-S. Wang, Y.-G.
Zhou, Y. Duan, H.-J. Fan, Y. Yang, Z. Zhang, J. Am. Chem. Soc.
2011, 133, 612; d) Q.-A. Chen, K. Gao, Y. Duan, Z.-S. Ye, L. Shi,
Y. Yang, Y.-G. Zhou, J. Am. Chem. Soc. 2012, 134, 2442.
[6] For representative reports on the catalytic asymmetric hydro-
genation of pyridines, see: a) C. Y. Legault, A. B. Charette, J.
Am. Chem. Soc. 2005, 127, 8966; b) M. Rueping, A. P. Anton-
chick, Angew. Chem. 2007, 119, 4646; Angew. Chem. Int. Ed.
2007, 46, 4562; c) X.-B. Wang, W. Zeng, Y.-G. Zhou, Tetrahedron
Lett. 2008, 49, 4922.
=
chiral induction. Following this, the remaining C C bond of
18 is rapidly reduced, creating a chiral center in the product.
The hydrogenation of 18a was carried out for the purpose of
confirming the above mechanistic consideration [Eq. (3)]. As
expected, hydrogenation of the alkenyl ether was complete
within 1 h, affording chiral tetralin 19 with 93% ee, which is
comparable to the enantioselectivities in the hydrogenations
of 2-ethoxynaphthalenes 9b, 10b, and 15a–15c. In the present
asymmetric reaction, the ruthenium complex 6 catalyzes two
kinds of hydrogenations: the dearomatizing hydrogenation of
naphthalene ring and the catalytic asymmetric hydrogenation
of cyclic alkenyl ethers.[16]
[7] For representative reports on the catalytic asymmetric hydro-
genation of benzofurans, see: a) S. Kaiser, S. P. Smidt, A. Pfaltz,
Angew. Chem. 2006, 118, 5318; Angew. Chem. Int. Ed. 2006, 45,
5194; b) N. Ortega, S. Urban, B. Beiring, F. Glorius, Angew.
Chem. 2012, 124, 1742; Angew. Chem. Int. Ed. 2012, 51, 1710.
[8] For a report on the catalytic asymmetric hydrogenation of azoles,
see: R. Kuwano, N. Kameyama, R. Ikeda, J. Am. Chem. Soc.
2011, 133, 7312.
[9] S. Urban, N. Ortega, F. Glorius, Angew. Chem. 2011, 123, 3887;
Angew. Chem. Int. Ed. 2011, 50, 3803.
[10] For asymmetric hydrogenation by a non-chiral catalyst on
quinolines bearing a chiral auxiliary, see: M. Heitbaum, R.
Frçhlich, F. Glorius, Adv. Synth. Catal. 2010, 352, 357.
In conclusion, we have found that naphthalenes can be
hydrogenated to tetralins by PhTrap–ruthenium catalyst 6.
Furthermore, the chiral ruthenium complex allows the hydro-
genation of 2,6- and 2,7-disubstituted naphthalenes to pro-
ceed with high enantioselectivity. In particular, 2-alkoxynaph-
thalenes were converted to the corresponding chiral tetralins
with over 90% ee. To our knowledge, the present enantiose-
lective reaction is the first success in the catalytic asymmetric
hydrogenation of aromatics containing no heteroatoms.[17]
[11] A site-selective hydrogenation of the carbocyclic ring in benz-
fused pyridines has been reported by Borowski and Sabo-
Etienne: A. F. Borowski, S. Sabo-Etienne, B. Donnadieu, B.
Chaudret, Organometallics 2003, 22, 1630.
[12] The hydrogenation of benzene rings has been attempted by
using ruthenium nanoparticles modified with chiral N-donor
ligands: a) S. Jansat, D. Picurelli, K. Pelzer, K. Philippot, M.
Gꢀmez, G. Muller, P. Lecante, B. Chaudret, New J. Chem. 2006,
30, 115; b) A. Gual, M. R. Axet, K. Philippot, B. Chaudret, A.
Denicourt-Nowicki, S. Cacchi, S. Castillon, C. Claver, Chem.
Commun. 2008, 2759.
Received: February 11, 2012
Published online: March 13, 2012
Keywords: asymmetric catalysis · hydrogenation ·
.
naphthalenes · ruthenium · tetralins
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[13] For reports on the asymmetric hydrogenation of o-disubstituted
benzenes bearing a chiral auxiliary, see: a) M. Besson, B. Bianc,
M. Champelet, P. Gallezot, K. Nasar, C. Pinel, J. Catal. 1997, 170,
254; b) M. Besson, S. Neto, C. Pinel, Chem. Commun. 1998,
1431; c) V. S. Ranade, R. Prins, J. Catal. 1999, 185, 479; d) M.
Besson, F. Delbecq, P. Gallezot, S. Neto, C. Pinel, Chem. Eur. J.
2000, 6, 949.
[14] a) M. Sawamura, H. Hamashima, M. Sugawara, R. Kuwano, Y.
Ito, Organometallics 1995, 14, 4549; b) R. Kuwano, M. Sawa-
mura in Catalysts for Fine Chemical Synthesis, Vol. 5 (Eds.: S. M.
Roberts, J. Whittall), Wiley, Chichester, 2007, p. 73.
[15] Very little formation of 5c was observed in the asymmetric
hydrogenations of 4c using chiral bisphosphine ligands other
than PhTrap. For details, see the Supporting Information.
[16] A. Paptchikhine, K. Itto, P. G. Andersson, Chem. Commun.
2011, 47, 3989.
[17] We believe that the present hydrogenations of naphthalenes
proceed through molecular catalysis, because a high degree of
enantiocontrol was achieved in the asymmetric reaction. How-
ever, we cannot completely rule out the possibility that the
hydrogenation took place through catalysis by colloidal ruthe-
nium at this time. For information on colloidal ruthenium
catalysis, see: P. J. Dyson, Dalton Trans. 2003, 2964.
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