Pd-catalyzed asymmetric hydrogenation of unprotected indoles activated by bronsted acids

Article abstract of DOI:10.1021/ja103668q

The first highly enantioselective hydrogenation of simple indoles was developed with a Brnsted acid as an activator to form the iminium intermediate in situ, which was hydrogenated using Pd(OCOCF₃)₂/(R)-H8- BINAP catalyst system with up to 96% ee. The present method provides an efficient route to enantioenriched 2-substituted and 2,3-disubstituted indolines.

Full text of DOI:10.1021/ja103668q

Published on Web 06/16/2010
Pd-Catalyzed Asymmetric Hydrogenation of Unprotected Indoles Activated by
Brønsted Acids
Duo-Sheng Wang,† Qing-An Chen,† Wei Li,‡ Chang-Bin Yu,† Yong-Gui Zhou,*,† and Xumu Zhang*,‡
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian 116023, China, and Department of Chemistry, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received April 29, 2010; E-mail: ygzhou@dicp.ac.cn; xumu@rutgers.edu
Chiral indolines are ubiquitous structural motifs in naturally
occurring alkaloids and many biological active molecules.1 Some
catalytic methods have been developed to obtain such molecules
on the basis of the kinetic resolution.2 Asymmetric hydrogenation
of indoles is the most straight and powerful approach to make chiral
indolines in terms of simplicity and atom efficiency. Despite the
progress achieved in asymmetric hydrogenation of indoles and other
heteroaromatic compounds in the past decade,3 efficient hydrogena-
tion of simple unprotected indoles remains a great challenge in
organic synthesis. Kuwano and Ito developed the first highly
effective hydrogenation of a series of N-protected indoles by
application of a Rh or Ru complex.4a-d Feringa and co-workers
reported Rh-catalyzed hydrogenation of 2-substituted N-protected
indoles with moderate enantioselectivity.4e Very recently, the Pfaltz
group revealed Ir/N,P-catalyzed hydrogenation of N-protected
indoles with high ee but low reactivity.4f To the best of our
knowledge, no report on asymmetric hydrogenation of unprotected
indoles has appeared despite the operational simplicity.5 Herein,
we describe a new strategy for highly enantioselective Pd-catalyzed
hydrogenation of unprotected indoles with a Brønsted acid as the
activator with up to 96% ee.
Initially, 2-methylindole was selected as a model substrate
for optimization of the conditions. Recently, chiral palladium
complexes have been successfully applied to asymmetric hy-
drogenation of activated imines by us9 and other groups,10 due
to similarity between iminium salt and activated imine, and thus
Pd(OCOCF3)2/(R)-SegPhos was used as the catalyst. In a control
experiment, without the addition of a Brønsted acid, the reaction
did not occur. When the stoichiometric amount of trifluoroacetic
acid was added, the reaction proceeded smoothly to give the
expected 2a with full conversion and 8% ee. Screening of
different acids found that L-camphorsulfonic acid (L-CSA) gave
the best result (Table 1, entry 1).11,12 Solvent experiments
showed that mixture solvent DCM/TFE was the best choice
(entry 8, 85% ee). Subsequently, various commercially available
chiral bisphosphine ligands were tested (entries 10-14), and (R)-
H8-BINAP gave the highest 91% ee (entry 14). The change of
temperature and pressure of hydrogen has no obvious effect on
ee at 2% catalyst loading; low ee (84%) and full conversion
were obtained when the reaction was run at 50 °C at 0.5%
catalyst loading. Therefore, the optimal conditions: Pd(O-
COCF3)2/(R)-H8-BINAP/L-CSA/DCM-TFE/RT.
Table 1. Optimization for Asymmetric Hydrogenation of Indole 1aa
Scheme 1. Activation Strategy of Indoles with a Brønsted Acid
entry
ligand
solvent
convn.b
ee (%)c
1
(R)-SegPhos
(R)-SegPhos
(R)-SegPhos
(R)-SegPhos
(R)-SegPhos
(R)-SegPhos
(R)-SegPhos
(R)-SegPhos
(R)-SegPhos
(R)-SynPhos
(R)-MeOBiPhep
(R)-C4-TunePhos
(R)-BINAP
TFE
TFE
toluene
THF
MeOH
DCM
>95
44
57
<5
19
71 (R)
66 (R)
57 (R)
-
40 (R)
73 (R)
82 (R)
85 (R)
80 (R)
86 (R)
84 (R)
84 (R)
85 (R)
91 (R)
2d
3
4
5
6
7
8
9
10
11
12
13
14
89
For the asymmetric hydrogenation of aromatics, the main
challenge is the low reactivity.3 Recently, our group developed two
kinds of substrate activation strategies for the asymmetric hydro-
genation of six-membered heteroaromatics with a Brønsted acid
and chloroformate as activators, respectively.6 Another breakthrough
in hydrogenation of imines is through formation of iminium by
addition of a Brønsted acid.7 We envision that in searching
hydrogenation of five-membered heteroaromatic unprotected in-
doles, development of a new activation strategy is highly desirable.
Considering that the simple unprotected indoles can react with a
strong Brønsted acid to form the iminium salt by protonation of
the carbon-carbon double bond,8 and the aromaticity of indole is
destroyed, the in situ formed iminium salts would be prone to be
hydrogenated (Scheme 1).
DCM/TFE (2/1)
DCM/TFE (1/1)
DCM/TFE (1/2)
DCM/TFE (1/1)
DCM/TFE (1/1)
DCM/TFE (1/1)
DCM/TFE (1/1)
DCM/TFE (1/1)
>95
>95
>95
>95
>95
>95
>95
>95
(R)-H8-BINAP
a Conditions: 0.25 mmol 1a, L-CSA (0.25 mmol), Pd(OCOCF3)2 (2
mol %), ligand (2.4 mol %), 3 mL of solvent, 24 h, RT. b Determined
by H NMR. c Determined by HPLC. d With D-CSA instead of L-CSA.
1
Under the optimized conditions, a variety of 2-alkylsubstituted
indoles were hydrogenated smoothly with excellent yields and
84-96% ee, regardless of the length or steric hindrance of the
side chain (Table 2, entries 1-6). For 2-benzyl-substituted
indoles, 93-96% ee were obtained with little effect from
† Chinese Academy of Sciences.
‡ Rutgers.
9
10.1021/ja103668q  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 8909–8911 8909

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
Internet at http://pubs.acs.org.
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.
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9
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(12) The equivalent TsOH-H2O was added to 2-methylindole in CDCl3, the
signal of the 2-methyl and hydrogen in the 3-position become broad peaks,
and the N-H peak disappeared. For detailed information, see the Supporting
Information.
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