Asymmetric chlorocyclization of indole-3-yl-benzamides for the construction of fused indolines

Article abstract of DOI:10.1021/ol5007532

(DHQD)₂PHAL catalyzed enantioselective chlorocyclization of indole-3-yl-benzamides was realized. Fused indolines containing a continuous quaternary carbon center and tertiary carbon center were obtained in good yields with excellent enantioselectivity (up to 98% yield and >99% ee).

Full text of DOI:10.1021/ol5007532

Letter
pubs.acs.org/OrgLett
Asymmetric Chlorocyclization of Indole-3-yl-benzamides for the
Construction of Fused Indolines
Qin Yin and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Lu, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: (DHQD)2PHAL catalyzed enantioselective
chlorocyclization of indole-3-yl-benzamides was realized.
Fused indolines containing a continuous quaternary carbon
center and tertiary carbon center were obtained in good yields
with excellent enantioselectivity (up to 98% yield and >99%
ee).
symmetric functionalization of indoles has attracted broad
interest, as the resulting chiral indole or indoline scaffolds
Scheme 1. Chlorocyclization of Indoles Bearing an
Embedded Nucleophile
A
are important components of numerous biologically active
alkaloids.1 Asymmetric dearomatization of indole derivatives
with an embedded nucleophile at either the C2 or C3 position
provides a facile and efficient route to construct spiro or fused
indoline motifs.2 However, highly enantioselective synthesis of
these privileged structures containing continuous chiral centers
remains a formidable challenge and is therefore highly
desirable.3 On the other hand, asymmetric halofunctionaliza-
tion of alkenes has become a research focus during the past
several years.4 The highly enantioselective halolactonization,5
haloetherification,6 haloaminocyclization,7 halogenation/semi-
pinacol rearrangement,8 and other halofunctionalization re-
actions9 of alkenes have been realized. Enantioselective
halocyclization reactions of indoles are synthetically attractive
as they could quickly construct enantioenriched spiro or fused
indoline motifs with the simultaneous formation of a
stereodefined C−X (Br, Cl, F) bond. However, highly
enantioselective examples concerning asymmetric halocycliza-
tion of indole derivatives are rare.10 This predicament could be
ascribed to the very unstable chirality of the halonium ion
intermediate, as a rapid olefin-to-olefin transfer process exists
between the enantiomerically enriched halonium ion and
electron-rich indole substrate.11 We envisaged that regulation
of the electronic property of the 2,3-double bond of indole
might provide a benefit for the stereocontrol. This design has
been applied in the enantioselective chloro- and bromocycliza-
tion of substituted indoles.12 Herein we report the reaction
between indole-derived benzamides with 1,3-dichloro-5,5-
dimethylhydantoin (DCDMH) under the catalysis of
(DHQD)2PHAL, providing an efficient synthesis of fused
indolines with continuous stereogenic centers including a C−Cl
bond containing a quaternary carbon center (Scheme 1).13
We began our studies by testing the reactions of indole-
derived benzamide 1 with DCDMH under the catalysis of
commercially available (DHQD)2PHAL (Table 1). To our
delight, the reaction could proceed smoothly via a 6-endo-trig
cyclization to generate a fused dihydrooxazine when a tosyl-
protected indole substrate was utilized. The corresponding
product could be obtained in a moderate yield with good
enantioselectivity (65% yield, 86% ee, entry 1, Table 1). In
contrast, indole-derived benzamides with a weaker electron-
withdrawing group such as Ac or Boc gave much complicated
reaction mixtures with only a trace of the desired product
(entries 2−3, Table 1). These experimental results suggested
that the electronic property of the 2,3-double bond of indole
was critical for the reactivity and enantioselectivity. Screening of
the solvents displayed that CHCl3 and DCE could remarkably
enhance the yield to 80% or 90%, respectively, without erosion
of the enantioselectivity (87% ee, entries 4−5, Table 1).
However, a dramatic decrease of the yield was observed when
CCl4 was utilized (entry 6, Table 1). The desired product was
obtained in 23% yield in a racemic form when toluene was
used, while no conversion was observed in THF (entries 7−8,
Table 1). Further screening disclosed that polar solvents such
as acetonitrile and alcohols gave better results in terms of yield
and enantioselectivity (entries 9−12, Table 1). Excellent yields
and enantioselectivity were obtained when MeOH or EtOH
was utilized in an open flask (87−90% yields, 95−97% ee,
entries 10−11, Table 1). Gratifyingly, an enantiopure product
was obtained in 93% yield within 5 min when trifluoroethanol
was employed as the solvent (entry 12, Table 1). The absolute
configuration of the product was determined as (4aS, 9aS) by a
Received: March 18, 2014
Published: April 14, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope for Chlorocyclization of 1
b
c
entry
R
solvent
DCM
time
4 h
yield (%)
ee (%)
1
R = Ts, 1a
R = Ac, 1aa
R = Boc, 1ab
R = Ts, 1a
R = Ts, 1a
R = Ts, 1a
R = Ts, 1a
R = Ts, 1a
R = Ts, 1a
R = Ts, 1a
R = Ts, 1a
R = Ts, 1a
65
86
−
−
87
87
55
0
2
DCM
4 h
trace
trace
80
donating group (2b−2d, 84−93% yields, >99% ee) or an
electron-withdrawing group (2e−2f, 85−91% yields, >99% ee)
at the meta or para position of the benzamide (R1) was well
tolerated. In addition, 2-naphthamide 1g and 1h containing
heteroarylamide were also suitable substrates (2g−2h, 95−98%
yields, >99% ee). In all cases, the corresponding products were
obtained in enantiomerically pure forms. To be noted,
cinnamamide 1i was also well tolerated, leading to product 2i
in 68% yield and 98% ee. A decreased ee, however, was
obtained when benzamide was replaced with pivalamide (2j,
65% yield, 53% ee). A decrease in the reaction temperature
could slightly enhance the enantioselectivity to 71% ee.
3
DCM
4 h
4
CHCl3
DCE
12 h
12 h
24 h
24 h
24 h
2 h
5
90
6
CCl4
18
7
toluene
THF
23
8
−
82
−
9
CH3CN
MeOH
EtOH
80
95
97
>99
10
11
12
5 min
5 min
<5 min
87
90
CF3CH2OH
93
a
Reactions were performed with 1a (0.1 mmol), DCDMH (0.15
b
mmol) and 10 mol % of (DHQD)2PHAL at rt in open flask. Isolated
yield. Determined by HPLC.
c
To further broaden the substrate scope, substrates with
various substituents on the indole core were also tested. As
displayed in Scheme 3, substrates with a chlorine atom at either
single crystal X-ray analysis of enantiopure 2a (see the
Supporting Information).
Encouraged by the high efficiency of this chlorocyclization
reaction, we further screened the loading of (DHQD)2PHAL.
As depicted in Table 2, when the catalyst loading was decreased
Scheme 3. Further Expansion of Substrate Scope
a
Table 2. Evaluation of the Catalyst Loading
b
c
entry
catalyst loading
time
yield (%)
ee (%)
1
2
3
4
5
5 mol %
<5 min
<5 min
5 min
10 min
1 h
92
93
92
73
37
>99
>99
99
1 mol %
0.5 mol %
0.1 mol %
0.01 mol %
94
90
a
Reactions were performed with 1a (0.1 mmol), DCDMH (0.15
b
c
the C5 or C6 position of indole were well tolerated, and the
corresponding products could be obtained in good yields and
excellent ee (2k−2l, 79−80% yields, >99% ee). When
substrates with electron-donating groups on the indole core
were tested, the enantioselectivity of the corresponding
products remained at excellent levels (2m−2o, 65−88% yields,
93−95% ee).
mmol) in CF3CH2OH at rt in open flask. Isolated yield. Determined
by HPLC.
from 10 to 0.5 mol %, comparable results were achieved.
However, a further decrease of the catalyst loading led to a
decline in terms of both yield and enantioselectivity. Finally, a 1
mol % catalyst loading was chosen for examination of the
substrate scope.
With the optimized reaction conditions in hand, the scope of
the dearomative chlorocyclization reaction was explored. The
results are summarized in Scheme 2. Either an electron-
To evaluate the practicality of this catalytic process, a gram-
scale reaction was carried out. As shown in Scheme 4, product
2a could be obtained in 81% yield and 99% ee.
In summary, we have developed a highly efficient method for
the construction of fused indoline skeletons by enantioselective
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Organic Letters
Letter
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Scheme 4. Gram-Scale Experiment
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chlorocyclization of indole derived benzamides. With 1 mol %
(DHQD)2PHAL, enantiopure products were obtained in
excellent yields. The reaction features high efficiency, a low
catalyst loading, and operationally simple procedures. Further
synthetic application and mechanistic studies of this trans-
formation are currently under investigation.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and analysis data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
(n) Wilking, M.; Muck-Lichtenfeld, C.; Daniliuc, C. G.; Hennecke, U.
̈
J. Am. Chem. Soc. 2013, 135, 8133.
*E-mail: slyou@sioc.ac.cn.
Notes
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M. J. Am. Chem. Soc. 2003, 125, 15748. (b) Hennecke, U.; Muller, C.
̈
H.; Frohlich, R. Org. Lett. 2011, 13, 860. (c) Huang, D.; Wang, H.;
̈
The authors declare no competing financial interest.
Xue, F.; Guan, H.; Li, L.; Peng, X.; Shi, Y. Org. Lett. 2011, 13, 6350.
(d) Denmark, S. E.; Burk, M. T. Org. Lett. 2012, 14, 256. (e) Zeng, X.;
Miao, C.; Wang, S.; Xia, C.; Sun, W. Chem. Commun. 2013, 49, 2418.
(f) Zhao, Y.; Jiang, X.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2013, 52,
8597.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China (973
Program 2010CB833300) and National Natural Science
Foundation of China (21025209, 21121062, 21272253,
21332009) for financial support.
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