C O M M U N I C A T I O N S
Table 2. Asymmetric Hydrogenation of Unprotected Indolesa
carbon-carbon double bond and the hydrogenation of iminium salt,
which is in fact a dynamic kinetic resolution process. To obtain
high ee, it should meet the equation of k1. k2. The above
mechanism study indicated that rate of protonation, k1, is faster
than rate of hydrogenation, k2.
entry
R1
R2
R3
yield (%)b
ee (%)c
Scheme 3. Hydrogenation Mechanism of 2,3-Disubstituted Indoles
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
n-Bu
n-pentyl
88 (2a)
82 (2b)
89 (2c)
90 (2d)
85 (2e)
89 (2f)
99 (2g)
84 (2h)
95 (2i)
82 (2j)
78 (2k)
84 (2l)
81 (2m)
91 (2n)
83 (2o)
96 (2p)
84 (2q)
91 (R)
93 (R)
92 (R)
95 (S)
cyclohexyl
cyclopentyl
phenethyl
Bn
2-MeC6H5CH2-
3-MeC6H5CH2-
4-MeC6H5CH2-
1-naphthylCH2-
Me
95 (S)
93 (R)
95 (R)
94 (R)
94 (R)
93 (R)
96 (R)
88 (R)
84 (R)
91 (R,R)
96 (R,R)
90 (R,R)
92 (R,R)
9
10
11
12
13
14
15
16
17d
H
H
5-F
5-Me
H
7-Me
H
Gratifyingly, the above asymmetric hydrogenation strategy could
also be extended to 2,3-disubstituted indoles. For the 2,3-fused
indoles, hydrogenation proceeded smoothly to give the cis-indolines
with 90-96% ee (Table 2, entries 14-16). For the simple 2,3-
dimethylindole, by elevating the temperature and lowering the
pressure, cis-product was also obtained with 92% ee.
In summary, we developed the first highly enantioselective
hydrogenation of simple indoles using Pd(OCOCF3)2/(R)-H8-
BINAP with a Brønsted acid as an activator. The present study
provides an efficient route to make chiral indolines. Further study
on extending this strategy to other heteroaromatic compounds is
in progress.
Me
-(CH2)4-
-(CH2)4-
-(CH2)5-
Me
H
Me
a Conditions: 0.25 mmol 1, L-CSA (0.25 mmol), Pd(OCOCF3)2 (2
mol %), (R)-H8-BINAP (2.4 mol %), 3 mL of solvent, 24 h, RT.
b Isolated yield. c Determined by HPLC. d With oil bath of 50 °C and H2
(300 psi).
substituents on the benzene ring (entries 7-11). Substrates
bearing groups at the 5-position displayed slightly lower ee’s
(84-88% ee, entries 12-13). It is noteworthy that very low
reactivity was observed for 2-indole-carboxylic acid or its ester,
and the reason is not clear.
Acknowledgment. Financial support from NSFC (20921092),
MOST (973 #2010CB833300), and NIH (GM58832 for X.Z.).
To probe the mechanistic information, two isotopic labeling
experiments were carried out. When the hydrogenation was
carried out in deuterated TFE, H NMR analysis of the crude
Supporting Information Available: Spectroscopic data and ex-
perimental details. This material is available free of charge Via the
1
hydrogenated product showed that two deuterium atoms were
incorporated to the 3-position (eq 2, Scheme 2), which suggested
that a reversible process of protonation and deprotonation existed
(eq 1, Scheme 1), and the equilibrium was faster than hydro-
genation.12 Thus, two deuterium atoms were imported to the
3-position of the 2-methylindoline before hydrogenation oc-
curred. When 2-methylindole was subjected to D2, 2-deuterio-
2-methylindoline with 92% incorporation was obtained, and
deuterium at the 3-position was not observed (eq 3, Scheme 2).
These results confirmed that the simple unprotected indole can
be activated by a Brønsted acid to form iminium in situ, which
was then hydrogenated by the Pd-catalyst.
References
(1) For some reviews, see: (a) Southon, I. W.; Buckingham, J. In Dictionary
of Alkaloids; Chapman and Hall: New York, 1989. (b) Neuss, N.; Neuss,
M. N. In The Alkaloids; Brossi, A., Suffness, M., Eds.; Academic Press:
San Diego, 1990; p 229. (c) Gueritte, F.; Fahy, J. In Anticancer Agents
from Natural Products; Cragg, G. M., Kingstom, D. G. I., Newman, D. J.,
Eds.; CRC Press: Boca Raton, 2005; p 123. (d) Modern Alkaloids;
Fattorusso, E., Taglialatela-Scafati, O., Eds.; Wiley-VCH: Weinheim, 2008
and references therein.
(2) (a) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14264. (b) Hou,
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Tetrahedron: Asymmetry 2009, 20, 2193, and references therein.
(3) For recent reviews on hydrogenation of aromatic compounds, see: (a)
Glorius, F. Org. Biomol. Chem. 2005, 3, 4171. (b) Lu, S.-M.; Han, X.-W.;
Zhou, Y.-G. Chin. J. Org. Chem. 2005, 25, 634. (c) Dyson, P. J. Dalton
Trans. 2003, 2964. (d) Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357. (e)
Kuwano, R. Hetereocycles 2008, 76, 909. For recent examples: (f) Zhou,
H.-F.; Li, Z.-W.; Wang, Z.-J.; Wang, T.-L.; Xu, L.-J.; He, Y.-M.; Fan,
Q.-H.; Pan, J.; Gu, L.-Q.; Chan, A. S. C. Angew. Chem., Int. Ed. 2008, 47,
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Chem. Soc. 2008, 130, 808. (i) Kaiser, S.; Smidt, S. P.; Pfaltz, A. Angew.
Chem., Int. Ed. 2006, 45, 5194.
Scheme 2. Isotopic Labeling Experiments Using D2 and d3-TFE
(4) (a) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem.
Soc. 2000, 122, 7614. (b) Kuwano, R.; Kaneda, K.; Ito, T.; Sato, K.;
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M.; Sato, K.; Ito, T.; Kaneda, K.; Ito, Y. Tetrahedron: Asymmetry 2006,
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Chem.sEur. J. 2010, 16, 2036.
(5) Pfaltz and coworkers tried asymmetric hydrogenation of 2-methylindole
using Ir/N,P catalyst, but low reactivity and poor enantioselectivity were
obtained; see the Supporting Information of reference 4f.
(6) (a) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int.
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51, 3014.
(7) For recent examples using a Brønsted acid as an additive in hydrogenation,
see: (a) Hou, G. H.; Gosselin, F.; Li, W.; McWilliams, J. C.; Sun, Y. K.;
Weisel, M.; O’Shea, P. D.; Chen, C. Y.; Davies, I. W.; Zhang, X. M. J. Am.
For the asymmetric hydrogenation of 2,3-disubstituted indoles
activated by a Brønsted acid, the mechanism was slightly different
from that of 2-substituted indoles (Scheme 3). The hydrogenation
of an intermediate iminium salt of 2-substituted indole is the
enantioselectivity-controlled step, while the enantioselectivity-
controlled step of 2,3-disubstituted indole is the protonation of the
9
8910 J. AM. CHEM. SOC. VOL. 132, NO. 26, 2010