Direct asymmetric hydrosilylation of indoles: Combined Lewis base and bronsted acid activation

Article abstract of DOI:10.1002/anie.201105341

Quite a pair: The first organocatalytic direct asymmetric reduction of unprotected 1H-indoles to chiral indolines has been developed. The reaction proceeds through the generation of electrophilic indolenium ions by a Bronsted acid, and then chiral Lewis base (1) mediated enantioselective hydride transfer with HSiCl₃. A variety of chiral indolines were obtained with moderate to excellent enantioselectivity. MOM=methoxymethyl. Copyright

Full text of DOI:10.1002/anie.201105341

DOI: 10.1002/anie.201105341
Organocatalysis
Direct Asymmetric Hydrosilylation of Indoles: Combined Lewis Base
and Brønsted Acid Activation**
You-Cai Xiao, Chao Wang, Yuan Yao, Jian Sun,* and Ying-Chun Chen*
In light of their occurrence in a broad spectrum of natural
alkaloids and several important pharmaceutically active
compounds,[1] such as those outlined in Scheme 1, enantioen-
riched indolines have triggered increasing attention in both
the synthetic and medicinal chemistry communities.[2]
Feringa, Pfaltz, and others to the asymmetric hydrogenation
of indoles, but the methods usually suffer from a limited
substrate scope and relatively harsh reaction conditions.[6]
A
noteworthy breakthrough was made by Zhou, Zhang, and co-
workers who reported an elegant palladium-catalyzed enan-
tioselective hydrogenation of unprotected indoles activated
by Brønsted acids.[7] In contrast, Rueping et al. presented the
chiral Brønsted acid catalyzed transfer hydrogenation of 3H-
indoles with Hantzsch dihydropyridine as the hydrogen
source.[8] Nevertheless, to the best of our knowledge, there
is no successful precedent on the direct asymmetric reduction
of 1H-indoles to access chiral indolines under metal-free
conditions despite the fantastic progress of organocatalysis
over the past decade.[9]
Recently we discovered a highly diastereoselective intra-
molecular direct imino-ene reaction of indoles tethered to an
olefinic side chain at C3, in which a Lewis acid promoted
enamine–imine isomerization of the indole through C3 pro-
tonation was key to its success.[10] We also recognized that, for
unprotected indoles, a similar C3 protonation would occur in
the presence of suitable Brønsted acids, which would destroy
the aromaticity of indoles and result in the formation of
electrophilic indolenium ions.[11] We envisioned that the
asymmetric reduction of indoles might be realized by utilizing
a chiral organocatalytic system that is compatible with a
Brønsted acid activation process. Herein we report our
endeavors on the first direct enantioselective hydrosilylation
of prochiral 1H-indoles by combined Brønsted acid/Lewis
base activation (Scheme 2).[12]
Scheme 1. Representative chiral indoline derivatives.
While a variety of protocols, including traditional enzy-
matic or non-enzymatic kinetic resolutions,[3] and organic-
molecule- or metal-mediated asymmetric transformations[4]
have been described, the direct asymmetric reduction of
prochiral indole precursors would be one of the most
straightforward ways to make chiral indolines.[5] Thus, a few
transition metal/chiral phosphine complexes, including Rh,
Ru, and Ir, have been applied by the groups of Kuwano,
[*] Y.-C. Xiao, Y. Yao, Prof. Dr. Y.-C. Chen
Key laboratory of Drug-Targeting and Drug Delivery System of the
Education Ministry, Department of Medicinal Chemistry
West China School of Pharmacy, Sichuan University
Chengdu, 610041 (China)
E-mail: ycchenhuaxi@yahoo.com.cn
Dr. C. Wang, Prof. Dr. J. Sun
Chengdu Institute of Biology
Chinese Academy of Sciences, Chengdu, 610041 (China)
E-mail: sunjian@cib.ac.cn
Scheme 2. Proposed direct asymmetric hydrosilylation of indoles
through both Lewis base and Brønsted acid activations.
Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy, West China Hospital
Sichuan University, Chengdu, 610041(China)
The initial investigation in the direct hydrosilylation of 2-
methylindole (2a) with excess HSiCl3 was conducted by
employing N,N-dimethylformamide (1a; DMF) as the Lewis
base catalyst at 08C. One equivalent of H2O was added to
react with HSiCl3 to generate a strong Brønsted acid, HCl.[13]
The reaction was quite inspiring, and the desired indoline
product 3a was cleanly obtained in high yield after 24 hours
[**] We are grateful for the financial support from the NSFC (20972101
and 21021001; for J.S.: 20972152 and 91013006), and the National
Basic Research Program of China (973 Program, 2010CB833300).
We also thank Prof. Xiao-Mei Zhang at the Chengdu Institute of
Organic Chemistry for a gift of catalyst 1c.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105341.
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Communications
Table 1: Screening studies for the direct hydrosilylation of 2-methylindole
had obvious effects on the enantioselectivity. Whereas a
dramatically decreased ee value was observed in toluene
(Table 1, entry 12), the results could be significantly improved
in chloroform (Table 1, entry 13). The O-pivaloyl picolinoyl-
pyrrolidine catalyst 1c,[19] which was reported by Zhang and
co-workers, was also tested in chloroform, but afforded
inferior results (Table 1, entry 14). It was found that the
enantioselectivity could be improved at lower temperature by
using the catalyst 1g, but a longer reaction was required to
guarantee complete conversion (Table 1, entries 15 and 16);
however, almost no reaction occurred at À408C. Interestingly,
the N-benzyl indole 2b also showed high reactivity, but a
lower enantioselectivity was obtained under the optimal
reaction conditions (Table 1, entry 17).
Consequently, the substrate scope and limitations for
indole compounds were examined. The reactions were
generally conducted with the Lewis base catalyst 1g at
À208C for 72 hours. The results are summarized in Table 2.
For 2-methyl-substituted indole derivatives, the electron-
donating or electron-withdrawing substitution on the aro-
matic ring has marginal effects, and good data were obtained
(Table 2, entries 2 and 3). Gratifyingly, 2-methylindoles bear-
ing a variety of alkyl groups at C3 could be smoothly applied,
thus exclusively giving cis indolines with high enantioselec-
(2a).[a]
Entry
1
Solvent
Additive
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1d
1d
1d
1d
1d
1d
1e
1 f
1g
1g
1g
1c
1g
1g
1g
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
H2O
H2O
H2O
MeOH
tBuOH
(S)-binol
PhCO2H
Tf2NH
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
81
85
85
81
82
82
90
<10
77
85
86
65
85
86
87
86
82
–
À60
67
43
66
67
66
–
47
70
74
39
80
À70
85
90
70
9
10
11
12
13
14
15[d,e]
16[d,f]
17[d,f,g]
Table 2: Substrate scope in the direct asymmetric hydrosilylation of
indoles 2.[a]
[a] Unless noted otherwise, reactions were performed with 2a
(0.2 mmol), additive (0.2 mmol), catalyst 1 (0.02 mmol), and HSiCl3
(0.6 mmol) in solvent (1.0 mL) at 08C for 24 h. [b] Yield of isolated
product. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] For 72 h. [e] At À108C. [f] At À208C. [g] The indole 2b was used.
binol=2,2’-dihydroxy-1,1’-binaphthyl, MOM=methoxymethyl,
Tf2NH=trifluoromethanesulfonimide.
Entry
1
R1
R2
R3
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1c
1c
1c
1c
1c
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
-(CH2)4-
-(CH2)3-
H
H
H
H
Me
Me
Et
nBu
Bn
H
Me
Br
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a: 86
3c: 89
3d: 83
3e: 88
3 f: 85
3g: 92
3h: 87
3i: 87
3j: 82
3k: 82
3k: 80
3l: 87
3m: 91
3n: 80
3o: 81
3p: 78
3p: 87
3q: 82
3r: 82
3s: 80
3t: 78
90[d]
90
85
90[d]
86
(Table 1, entry 1). It should be addressed that the reduction
did not take place in the absence of either H2O or 1a, thus
indicating that both the Brønsted acid and Lewis base
activations were necessary. Subsequently, a variety of chiral
Lewis base organocatalysts, which have been effectively
utilized in several asymmetric hydrosilylation reactions with
HSiCl3 over the past years,[14] were extensively screened to
induce chirality in the product.[15] Pleasingly, both chiral
picolinoylpyrrolidine[16] (1b) and N-formyl l-pipecolin-
amide[17] (1d) exhibited high catalytic activity, and more
importantly, promising enantioselectivity (Table 1, entries 2
and 3). We next explored the effects of an array of proton
additives with catalyst 1d (Table 1, entries 4–8). Though the
ee value was significantly diminished when H2O was replaced
by MeOH (Table 1, entry 4), similar data was generally
obtained, even when a chiral (S)-binol was used (Table 1,
entry 6). It seems that the acid additive just supplies a proton,
and might not be involved in the key asymmetric reduction
step.[18] Nevertheless, almost no reaction occurred in the
presence of Tf2NH (Table 1, entry 8). In addition, the
modified catalysts 1e–1g that are based on 1d were tested
(Table 1, entries 9–11); 1g, having an MOM ether moiety
delivered better enantiocontrol (Table 1, entry 11). Solvent
93
86
88
85
88
87
84
70
55
46
23
À76
À75
À90
À88
À88
9[e]
10[e]
11[e,f]
12[g]
13[g]
14
iPr
CH2CH2CO2Me
CH CHCO2Me
=
Bn
15[e]
16
H
CH2CH2CO2Et
H
H
H
Me
Me
Et
nBu
nBu
Bn
Et
nPr
nPr
17[e,h]
18[e,h]
19[e]
20[e]
21[e]
[a] Unless noted otherwise, reactions were performed with 2 (0.2 mmol),
H2O (0.2 mmol), catalyst 1 (0.02 mmol), and HSiCl3 (0.6 mmol) in
CHCl3 (1.0 mL) at À208C for 72 h. [b] Yield of isolated product.
[c] Determined by HPLC analysis on a chiral stationary phase; d.r. >99:1
by 1H NMR analysis (where applicable). [d] The absolute configuration
was determined by comparison of the specific optical rotations with
those reported in the literature. The other products were assigned by
analogy. [e] At 08C. [f] HSiCl3 (0.8 mmol) was used. [g] At À308C. [h] For
24 h.
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C. Cheesman, S. Rosenzweig-Lipson, CNS Drug Rev. 2006, 12,
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carboxylate group was compatible with the current catalytic
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=
Importantly, a conjugated C C bond was found to be
simultaneously reduced (Table 2, entry 11). A good ee value
was delivered for cyclohexyl[b]indole (Table 2, entry 12),
whilst lower enantiocontrol was attained for cyclopentyl[-
b]indole even at À308C (Table 2, entry 13). The dynamic
kinetic reduction of 3-substituted indoles could be realized,
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Unfortunately, the 1g-based catalytic system was not suitable
for indoles having a larger 2-alkyl group, and very low
enantioselectivity was obtained for 2-nbutylindole (Table 2,
entry 16).
Subsequently, we re-screened various Lewis base cata-
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alkyl group. To our gratification, the chiral picolinamide
catalyst 1c afforded a much better ee value in the reduction of
2-nbutylindole (Table 2, entry 17).[15] Thus, more indole sub-
strates were explored using the catalyst 1c. A similar
moderate enantioselectivity was obtained for 2-benzylindole
(Table 2, entry 18). Fortunately, high ee values with excellent
diastereoselectivity could be attained by introducing another
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In conclusion, we have developed the first organocatalytic
direct asymmetric reduction of unprotected 1H-indoles to
access chiral indoline scaffolds. The reaction proceeds
through the generation of electrophilic indolenium ions by
C3 protonation with the in situ formed HCl acid, and
subsequent chiral Lewis base mediated enantioselective
hydrosilylation with HSiCl3. A variety of chiral indolines
were efficiently obtained in moderate to excellent enantiose-
lectivity (up to 93% ee), and remarkably, the exclusive
diastereocontrol was observed for 2,3-disubstituted ones.
We hope that this study will help to open an avenue for the
direct asymmetric reduction of indoles under metal-free
reaction conditions. Currently more applications using the
reported catalytic strategy are under investigation in this
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Received: July 29, 2011
Revised: August 16, 2011
Published online: September 20, 2011
Keywords: asymmetric catalysis · Brønsted acids · heterocycles ·
.
Lewis bases · reduction
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2a, indicating that HSiCl2OR (produced from HSiCl3 and proton
additive ROH) might not be involved in the asymmetric
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[21] Indoles carrying a phenyl or carboxylate group at either C2 or
C3 showed no reactivity under current catalytic conditions; this
is probably due to the failure of the C3-protonation process.
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