Ruthenium-catalyzed asymmetric hydrogenation of N-Boc-indoles

Article abstract of DOI:10.1021/ol061039x

Highly enantioselective hydrogenation of various N-Boc-indoles proceeded successfully in the presence of the ruthenium complex generated from an appropriate ruthenium precursor and a trans-chelate chiral bisphosphine PhTRAP. Various 2- or 3-substituted indoles were converted into chiral indolines with high enantiomeric excesses (up to 95% ee). The PhTRAP-ruthenium catalyst was able to promote the hydrogenation of 2,3-dimethylindoles, giving cis-2,3-dimethylindolines with 72% ee.

Full text of DOI:10.1021/ol061039x

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2653-2655
Ruthenium-Catalyzed Asymmetric
Hydrogenation of N-Boc-Indoles
Ryoichi Kuwano* and Manabu Kashiwabara
Department of Chemistry, Graduate School of Sciences, Kyushu UniVersity,
6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
rkuwascc@mbox.nc.kyushu-u.ac.jp
Received April 28, 2006
ABSTRACT
Highly enantioselective hydrogenation of various N-Boc-indoles proceeded successfully in the presence of the ruthenium complex generated
from an appropriate ruthenium precursor and a trans-chelate chiral bisphosphine PhTRAP. Various 2- or 3-substituted indoles were converted
into chiral indolines with high enantiomeric excesses (up to 95% ee). The PhTRAP
of 2,3-dimethylindoles, giving cis-2,3-dimethylindolines with 72% ee.
−ruthenium catalyst was able to promote the hydrogenation
Catalytic asymmetric hydrogenation is now regarded as a
powerful method for the preparation of optically active
compounds.1 The asymmetric catalysis has been used to
prepare a variety of optically active molecules from prochiral
olefins, ketones, and imines. Meanwhile, asymmetric hy-
drogenation of heteroaromatics is rare, although the stereo-
selective transformation will be useful for the construction
of optically active heterocyclic skeletons.2 2-Methylquinoxa-
line,3 2-alkylquinolines,4 and pyridines5,6 have been success-
fully hydrogenated with over 90% ee to date. Additionally,
we accomplished the highly enantioselective hydrogenation
of indoles with a rhodium complex modified with PhTRAP
(Figure 1),7 a chiral bisphosphine ligand that is able to form
a trans-chelate complex with a transition-metal atom.8
(1) (a) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029-3069. (b)
Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.; Studer, M.
AdV. Synth. Catal. 2003, 345, 103-151. (c) Kitamura, M.; Noyori, R. In
Ruthenium in Organic Synthesis; Murahashi, S.-i., Ed.; Wiley-VCH:
Weinheim, 2004; pp 3-52. (d) Chi, Y.; Tang, W.; Zhang, X. In Modern
Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH:
Weinheim, 2005; pp 1-31.
(2) Glorius, F. Org. Biomol. Chem. 2005, 3, 4171-4175.
(3) (a) Bianchini, C.; Barbaro, P.; Scapacci, G.; Farnetti, E.; Graziani,
M. Organometallics 1998, 17, 3308-3310. (b) Henschke, J. P.; Burk, M.
J.; Malan, C. G.; Herzberg, D.; Peterson, J. A.; Wildsmith, A. J.; Cobley,
C. J.; Casy, G. AdV. Synth. Catal. 2003, 345, 300-307.
Figure 1. Structure of (S,S)-(R,R)- and (R,R)-(S,S)-PhTRAP.
(4) (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G.
J. Am. Chem. Soc. 2003, 125, 10536-10537. (b) Yang, P.-Y.; Zhou, Y.-G.
Tetrahedron: Asymmetry 2004, 15, 1145-1149. (c) Lu, S.-M.; Han, X.-
W.; Zhou, Y.-G. AdV. Synth. Catal. 2004, 346, 909-912. (d) Lu, S.-M.;
Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006, 45,
2260-2263. (e) Xu, L.; Lam, K. H.; Ji, J.; Wu, J.; Fan, Q.-H.; Lo, W.-H.;
Chan, A. S. C. Chem. Commun. 2005, 1390-1392. (f) Lam, K. H.; Xu, L.;
Feng, L.; Fan, Q.-H.; Lam, F. L.; Lo, W.-h.; Chan, A. S. C. AdV. Synth.
Catal. 2005, 347, 1755-1758.
This paper describes a new chiral ruthenium catalyst for
the asymmetric hydrogenation of indoles. The ruthenium
(5) Legault, C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966-
8967.
10.1021/ol061039x CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/18/2006

catalyst bearing a PhTRAP ligand converted N-Boc-protected
(Boc ) tert-butoxycarbonyl) indoles into chiral indolines
with high enantiomeric excess. In general, the Boc group is
readily attached to an indole substrate and detached from
an indoline product.9 In our earlier work, the PhTRAP-
rhodium-catalyzed hydrogenation required an N-acetyl or
N-sulfonyl protective group to achieve high stereoselectivity.7
Asymmetric hydrogenation of N-Boc-2-methylindole (1a)
was attempted with the (S,S)-(R,R)-PhTRAP-rhodium-Cs2-
CO3 catalyst system (Table 1, entry 1), but the desired chiral
complexes prepared from BINAP and DIOP gave a trace of
2a with 13% and 24% ee, respectively. No hydrogenation
of 1a occurred when most commercially available chiral
phosphines were used in place of PhTRAP. In contrast,
enantioselectivity was not affected by ligands of ruthenium
catalyst precursors. Ruthenium precursors [RuCl2(benzene)]2
and Ru(η3-2-methylallyl)2(cod)10 were comparable to [RuCl2-
(p-cymene)]2 (entries 6 and 7). Cesium carbonate seemed
to act as a base because the hydrogenation product 2a was
quantitatively obtained with 93-95% ee from the reaction
using potassium carbonate, triethylamine, or 1,8-diazabicyclo-
[5,4,0]undec-7-ene (DBU) in place of cesium carbonate. The
PhTRAP-[RuCl2(p-cymene)]2 complex did not work well
as a chiral catalyst for the asymmetric hydrogenation in the
absence of base (entry 8).
Table 1. Screening of Catalysts for Asymmetric
Hydrogenation of 1aa
The reaction of [RuCl2(p-cymene)]2 with (S,S)-(R,R)-
PhTRAP yielded a brown amorphous solid containing a
single ruthenium species. The structure of the ruthenium
complex was supposed to be [RuCl(p-cymeme){(S,S)-(R,R)-
PhTRAP}]Cl (3) by analogy with the reaction of [RuCl2-
(arene)]2 and other bisphosphines.11 The 1H NMR spectrum
of the complex indicated that one p-cymene and one
PhTRAP were bound to ruthenium. The 31P NMR of the
ruthenium complex showed a pair of doublet peaks at 9.0
and 25.1 ppm with a JP-P value of 42 Hz.12 The isolated
PhTRAP-ruthenium complex 3 exhibited catalytic activity
and stereoselectivity at the same level as the in-situ-generated
ruthenium catalyst (Table 2, entry 1).
entry
[M]
yield, %b
ee, %c
1
2
3
4
5d
6d
7d
8d,e
[Rh(nbd)2]SbF6
[RhCl(cod)]2
100
100
14
100
100
100
100
7
78 (R)
73 (R)
28 (S)
92 (R)
95 (R)
96 (R)
95 (R)
63 (R)
[IrCl(cod)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(benzene)]2
Ru(η3-2-methylallyl)2(cod)
[RuCl2(p-cymene)]2
a Reactions were conducted on a 0.5 mmol scale in 1.0 mL of 2-propanol.
b Determined by 1H NMR analysis of crude product. c Determined by chiral
HPLC. d The reactions were conducted in methanol. e The reaction was
conducted without Cs2CO3.
Table 2. Catalytic Asymmetric Hydrogenation of 2-Substituted
Indoles 1a
indoline 2a was obtained with 78% ee (R).7c To improve
enantioselectivity, a variety of catalyst precursors were
evaluated for the reaction of 1a as summarized in Table 1.
Use of rhodium catalyst precursors other than [Rh(nbd)2]-
SbF6 provided (R)-2a with 71-78% ee (e.g., entry 2). When
[Ir(cod)Cl]2 was used as a catalyst precursor, S-enriched 2a
was obtained with 28% ee in low yield (entry 3). Palladium,
molybdenum, and tungsten complexes failed to catalyze the
hydrogenation of the N-Boc-indole. Hydrogenation of 1a
yielded (R)-2a with 92% ee in the presence of the ruthenium
complex generated in situ from [RuCl2(p-cymene)]2 and
PhTRAP (entry 4). The enantiomeric excess of the hydro-
genation product was enhanced to 95% when methanol was
used in place of 2-propanol (entry 5). The chosen chiral
phosphine ligand was crucial for achieving a high yield as
well as a high enantiomeric excess of 2a. The ruthenium
entry
R1
R2
1
time, h
2
yield, %b ee, %c
1
2
3
4d
5d,e
6d,e
7e
8e
Me
Me
Me
Bu
H
1a
2
2
2
2a
2b
2c
2d
2e
2f
99
97
96
94
92
99
95
91
95
91
90
92
87
95
93
90
OMe 1b
F
1c
1d
1e
1f
1g
1h
H
H
H
H
H
2
c-C6H11
Ph
C6H4-p-F
CO2Me
48
24
4
2g
2h
2
a Reactions were conducted on a 0.5 mmol scale in 1.0 mL of methanol.
b Isolated yield. c Determined by chiral HPLC analysis. d The reactions were
conducted in the presence of the enantiomeric catalyst [RuCl(p-cymene){(R,R)-
(S,S)-PhTRAP}]Cl (3′). e The reactions were conducted in 2-propanol.
(6) Glorius, F.; Spielkamp, N.; Holle, S.; Goddard, R.; Lehmann, C. W.
Angew. Chem., Int. Ed. 2004, 43, 2850-2852.
(7) (a) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am.
Chem. Soc. 2000, 122, 7614-7615. (b) Kuwano, R.; Kaneda, K.; Ito, T.;
Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004, 6, 2213-2215. (c) Kuwano,
R.; Kashiwabara, M.; Sato, K.; Ito, T.; Kaneda, K.; Ito, Y. Tetrahedron:
Asymmetry 2006, 17, 521-535.
(8) (a) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron: Asymmetry
1991, 2, 593-596. (b) Sawamura, M.; Hamashima, H.; Sugawara, M.;
Kuwano, R.; Ito, Y. Organometallics 1995, 14, 4549-4558.
(9) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
As shown in Table 2, a wide range of 2-substituted N-Boc-
indoles were hydrogenated with high enantioselectivity by
(10) (a) Geneˆt, J. P.; Mallart, S.; Pinel, C.; Juge, S.; Laffitte, J. A.
Tetrahedron: Asymmetry 1991, 2, 43-46. (b) Geneˆt, J. P.; Pinel, C.;
Ratovelomanana-Vidal, V.; Mallart, S.; Pfister, X.; Can˜o De Andrade, M.
C.; Laffitte, J. A. Tetrahedron: Asymmetry 1994, 5, 665-674.
(11) Mashima, K.; Kusano, K.-h.; Sato, N.; Matsumura, Y.-i.; Nozaki,
K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.;
Takaya, H. J. Org. Chem. 1994, 59, 3064-3076.
2654
Org. Lett., Vol. 8, No. 12, 2006

the chiral ruthenium catalyst 3. Neither electron-donating nor
-withdrawing substituents at the 5-position of 1 caused a
significant decrease in the enantiomeric excess of the
hydrogenation product 2 (entries 2 and 3). The enantio-
selectivity was scarcely affected by the substituent at the
2-position. Indoles 1d-h bearing primary and secondary
alkyl, aryl, or ester groups were transformed into the desired
indolines 2d-h with 87-95% ee (entries 4-8). Of note,
2-cyclohexylindoline 2e was obtained with 87% ee in high
yield. The PhTRAP-rhodium catalyst, which was developed
by us previously, failed to promote the hydrogenation of
2-cyclohexylindole.7c However, no hydrogenation of 2-(tert-
alkyl)indole occurred with the ruthenium catalyst.
Scheme 2. Catalytic Asymmetric Hydrogenation of
2,3-Dimethylindole 6
observed when the PhTRAP-rhodium complex was used
as a catalyst. In contrast, ruthenium catalyst 3 promoted the
hydrogenation of 6, resulting in 50% yield of cis-2,3-
dimethylindoline (-)-7 with 65% ee. No diastereomer of 7
The chiral catalyst 3 is effective for the asymmetric
reductions of 3-substituted N-Boc-indoles 4 as well as 1
(Scheme 1). The hydrogenation of 3-methylindole 4a yielded
1
was detected in the reaction mixture by H NMR. The ee
value of 7 was improved to 72% using the PhTRAP-
ruthenium catalyst generated in situ from Ru(η3-2-methylallyl)2-
(cod).
Scheme 1. Catalytic Asymmetric Hydrogenation of
3-Substituted Indoles 4
We have developed a new chiral ruthenium catalyst 3 for
the asymmetric hydrogenation of indoles. When the PhTRAP
ligand was replaced with other phosphine ligands, the
ruthenium catalyst failed to give the hydrogenation product.
The present ruthenium catalyst enabled highly enantioselec-
tive hydrogenation of various N-Boc-protected indoles to give
chiral indolines which are useful chiral synthons in organic
synthesis. Moreover, the hydrogenation of a 2,3-disubstituted
indole proceeded successfully with significant enantioselec-
tivity using the PhTRAP-ruthenium catalyst.
(S)-3-methylindoline 5a with 87% ee. The stereochemistry
of the product indicates that the hydrogen delivery occurs
from the re face of the alkene which is opposite to what is
observed in the case of 1. Similarly, optically active
3-phenylindoline 5b was obtained with 94% ee.
Furthermore, the asymmetric hydrogenation of 2,3-disub-
stituted indole 6 was attempted using the PhTRAP-
ruthenium catalyst (Scheme 2). The reaction can create two
vicinal chiral centers simultaneously. No formation of 7 was
Acknowledgment. This work was supported by the
Uehara Memorial Foundation and a Grant-in-Aid for Sci-
entific Research on Priority Area (Nos. 17035062 and
18032056) from MEXT. We thank Dr. Tatsuya Uchida and
Prof. Tsutomu Katsuki (Kyushu University) for the ESI-MS
spectrum of 3 and Mr. Yasuhiro Ueda (Kyushu University)
for preparation of 4b.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds
(PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) The coupling constant indicates that PhTRAP coordinates the
ruthenium in a cis chelation manner. The cis geometry of the two
phosphoruses of PhTRAP may be enforced by the η6-arene ligand of 3.
The arene ligand would be liberated from the ruthenium on starting the
asymmetric hydrogenation; therefore, the geometry of PhTRAP would be
kept trans during the reaction.
OL061039X
Org. Lett., Vol. 8, No. 12, 2006
2655