Catalytic Asymmetric Synthesis of Chiral 2-Vinylindole Scaffolds by Friedel-Crafts Reaction

Article abstract of DOI:10.1021/acs.orglett.6b03584

A chiral bis(imidazolidine)pyridine (PyBidine)-Ni(OTf)₂ complex smoothly catalyzed an asymmetric Friedel-Crafts reaction of 2-vinylindoles with nitroalkenes to give chiral indoles in a highly enantioselective manner while maintaining the 2-vinyl functionality. The chiral 2-vinylindoles offer unique chiral scaffolds for diverse transformations.

Full text of DOI:10.1021/acs.orglett.6b03584

Letter
pubs.acs.org/OrgLett
Catalytic Asymmetric Synthesis of Chiral 2‑Vinylindole Scaffolds by
Friedel−Crafts Reaction
Takayoshi Arai,* Akiko Tsuchida, Tomoya Miyazaki, and Atsuko Awata
Molecular Chirality Research Center, and Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi, Inage,
Chiba 263-8522, Japan
*
S Supporting Information
ABSTRACT: A chiral bis(imidazolidine)pyridine (PyBi-
dine)−Ni(OTf) complex smoothly catalyzed an asymmetric
2
Friedel−Crafts reaction of 2-vinylindoles with nitroalkenes to
give chiral indoles in a highly enantioselective manner while
maintaining the 2-vinyl functionality. The chiral 2-vinylindoles
offer unique chiral scaffolds for diverse transformations.
arious chiral indoles have been isolated from naturally
nitroalkenes. Because we had previously succeeded in the
development of several chiral metal catalysts for asymmetric
V
occurring alkaloids, and their structural complexity is
1
10
strongly related to their biological activity. Studies on the total
Friedel−Crafts reactions of indoles with nitroalkenes, the
synthesis of indole alkaloids and on the preparation of a
chemical library of diversified indoles have been conducted on
the indole skeleton. During the past five years in particular,
novel synthetic methodologies have been rapidly developed for
catalyst system was simply applied to the reaction of the
1
1,12
2-vinylindole 1a with nitrostyrene 2a.
When an imidazoline−
10a
aminophenol (IAP)−CuOTf catalyst was used, the desired
reaction was not promoted, and the only products isolated were
dimerized adducts of 2-vinylindole (Table 1, entries 1, 2). The
use of a valinol-derived bis(oxazolidine)pyridine (PyBodine)−
2
the construction of highly substituted chiral indoles. Among
these, alkenyl indoles have been widely utilized as reactive
substrates. Xiao reported an organocatalyzed double Michael
addition/aromatization reaction using 2-propenylindoles and
10f
Cu(OTf) complex also gave a mixture of dimerized adducts
2
of 2-vinylindole, accompanied by the Friedel−Crafts products
3a
nitroalkenes to construct tetrahydrocarbazoles (Scheme 1a).
in 16% yield (entry 3). Changing the ligand of the catalyst to
13
bis(imidazolidine)pyridine (PyBidine) to give the PyBidine−
Scheme 1. Classification of 2-Vinylindoles by Reactivity
Cu(OTf) catalyst resulted in a dramatically improved yield
2
of 4a (93%), although the enantioselectivity was only 10% ee.
Among the first-row transition metal salts we examined, metal
complexes prepared from Zn(OTf) and Ni(OTf) gave better
2
2
stereoselectivity for 4a, with 36% ee and 45% ee, respectively,
while the PyBidine−Ni(OTf) catalyst in toluene gave an
2
8
3% yield of 4a with 84% ee (entry 9). In all cases in Table 1,
the cycloadduct 3a was not detected.
Under the optimized conditions, the general application of
the catalytic asymmetric Friedel−Crafts reaction was examined,
and the results are shown in Scheme 2.
Both electron-donating and -withdrawing substituents on the
nitrostyrenes were successfully employed in the enantioselective
Friedel−Crafts reaction to give a series of chiral 2-vinylindoles.
From 1 mmol of nitrostyrene (2a) with 1.2 equiv of 2-vinylindole
(1a), the chiral 2-vinylindole 4a was obtained in 81% yield with
3
,4
Not only 2-alkenylindoles but also indoles with alkenyl
substituents at the other positions underwent a series of
cycloaddition reactions.
5
−8
Although these pioneering works
have been fruitful in the production of an array of polycyclic
indoles, the cycloaddition reactions have all resulted in loss of
the vinyl functionality from the indole products. Here, we
report a catalytic asymmetric Friedel−Crafts reaction using
-vinylindoles and nitroalkenes to produce chiral indoles while
8
4% ee. A furan-derived nitroalkene was also compatible with
the reaction, giving 4g with 79% ee. Although the reactions using
aliphatic nitroalkenes, unfortunately, resulted in low yields, the
vinyl indole products 4i−4k were obtained in all cases. The
9
5-methyl 2-vinylindole adduct 4f was obtained with 85% ee
2
retaining the 2-vinyl functionality (Scheme 1b).
Inspired by Xiao’s pioneering work, this study began by
3a
Received: December 1, 2016
targeting the cycloaddition reaction of 2-vinylindoles with
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03584
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Catalyst Screening for the Reaction of 2-Vinylindole (1a) with Nitrostyrene (2a)
a
yield (%)
4a
entry
ligand
IAP1
metal salt
solvent
time (h)
3a
5a/6a/7a
ee of 4a (%)
b
1
2
3
4
5
6
7
8
CuOTf
CH Cl2
4
trace
trace
trace
trace
−
−
−
−
−
4
28/4/4
33
−
2
b
IAP2
CuOTf
CH Cl2
2
trace
16
8/12/17
2
PyBodine
PyBidine
PyBidine
PyBidine
PyBidine
PyBidine
PyBidine
Cu(OTf)2
Cu(OTf)2
Zn(OTf)2
Ni(OTf)2
CH Cl2
3
trace/22/35
−47
10
36
45
−
2
CH Cl2
40
4
93
trace
−
−
−
−
2
CH Cl2
81
2
CH Cl2
7
68
2
c
Ni(OAc)2
Ni(OTf)2
Ni(OTf)2
CH Cl2
17
6
trace
73
2
toluene
toluene
83
d
9
16
83
−
84
a
b
c
d
Isolated yield. (CuOTf) −C H was used. Tetrahydrate was used. 1.2 equiv of 1a was added to 2a at 25 °C.
2
6
6
Scheme 2. General Application of Friedel−Crafts Reaction
The stereochemistry of the (R)-enriched formation of 4d
using (S,S)-PyBidine−Ni(OTf)2 was unequivocally deter-
mined by X-ray crystallographic analysis, as shown in Figure 1.
Catalyzed by PyBidine−Ni(OTf)
2
Figure 1. X-ray crystallographic analysis of 4d.
It should be noted that the use of (S,S)-PyBidine gives
(
S)-enriched 4a due to the prioritization rule, when the indoles
attack from the re-face of nitroalkenes.
The synthetic utility of the chiral 2-vinylindoles is shown in
Scheme 3. The nitro group of 4a was successfully reduced using
a zinc nanopowder to give chiral tryptamine derivative 8, and
the amine 8 was tosylated to give 9 while maintaining the
2
-vinyl functionality.
The vinyl group could be exchanged for other olefin
substituents using a Grubbs−Hoveyda II catalyst. From the
metathesis adduct 10 obtained from methyl acrylate, an intra-
molecular nitro-Michael reaction proceeded by DBU to give
the carbocycle 11 in a diastereoselective manner (d.r. = 80:20).
in 83% yield, and the racemic 5-bromo 2-vinylindole adduct 4l
was obtained in 90% yield under the same catalyst system.
B
DOI: 10.1021/acs.orglett.6b03584
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Organic Letters
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Scheme 3. Transformations of Chiral 2-Vinylindole 4a
2-vinyl indole does not easily undergo [4 + 2]-cycloaddition
3a
(
Scheme 4(1)). In Xiao’s work on [4 + 2]-cycloaddition using
-vinyl indoles, steric repulsion between the methyl substituent
2
on the nitrogen and the alkene substituent at the 2-position
deflects the equilibrium toward the s-cis form, allowing the
[4 + 2]-cycloaddition reaction to proceed (Scheme 4(2)).
When the reaction of 2-vinylindole 1a with nitrostyrene 2a was
examined using Xiao’s catalyst, only the Friedel−Crafts product
4a was generated (Scheme 4(3)), which strongly suggested this
scenario.
In conclusion, the chiral bis(imidazolidine)pyridine (PyBidine)−
Ni(OTf) complex is the first general catalyst for asymmetric
2
Friedel−Crafts reactions of 2-vinylindoles with nitroalkenes.
Because various chemical transformations of the 2-vinyl
functionality are possible, the chiral 2-vinyl indoles are expected
to be useful chiral scaffolds for diverse possibilities in organic
synthesis.
The stereochemistry of the major isomer of 11 was determined
by the X-ray crystallographic analysis (Figure 2). The vinyl group
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03584.
1
General procedure, synthetic and analytical data, H and
13
C NMR, HPLC data (PDF)
Crystallographic data (CIF, CIF)
AUTHOR INFORMATION
Corresponding Author
■
Figure 2. X-ray crystallographic analysis for major isomer of 11.
*
E-mail: tarai@faculty.chiba-u.jp.
ORCID
Scheme 4. Reaction Pathway for (1) Friedel−Crafts
Reaction and (2) [4 + 2]-Cycloaddition
Takayoshi Arai: 0000-0001-9490-3988
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research is supported by JSPS KAKENHI Grant Number
JP16H01004 in Precisely Designed Catalysts with Customized
Scaffolding, and by a Leading Research Promotion Program
“Soft Molecular Activation” of Chiba University, Japan. We offer
sincere thanks to Prof. Kazuhiro Yoshida in Chiba University and
Prof. Masamichi Ogasawara in Tokushima University for the
generous gift of the Grubbs−Hoveyda II catalyst.
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