Thioether-Directed Selective C4 C-H Alkenylation of Indoles under Rhodium Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b02038

A thioether-directed Rh(III)-catalyzed C4 selective C-H alkenylation of indoles via the formation of 5-membered metallacycle intermediates is reported. This protocol allows a wide functional group compatibility and broad substrate scope. The directing group can be readily removed or transformed into other functional groups after the C-H functionalization event. The catalytic method is also applicable to related heterocyclic systems involving benzo[b]thiophene and benzo[b]furan scaffolds.

Full text of DOI:10.1021/acs.orglett.8b02038

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Thioether-Directed Selective C4 C−H Alkenylation of Indoles under
Rhodium Catalysis
Chandrababu Naidu Kona,† Yuji Nishii,‡ and Masahiro Miura*,†
‡
†Department of Applied Chemistry and Frontier Research Base for Global Young Researchers, Graduate School of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: A thioether-directed Rh(III)-catalyzed C4
selective C−H alkenylation of indoles via the formation of
5-membered metallacycle intermediates is reported. This
protocol allows a wide functional group compatibility and
broad substrate scope. The directing group can be readily
removed or transformed into other functional groups after the
C−H functionalization event. The catalytic method is also
applicable to related heterocyclic systems involving benzo-
[b]thiophene and benzo[b]furan scaffolds.
he indole motif is one of the most widely studied
heterocycles to date because of its unique biological
T
activities as well as substantial importance in material science.
The past decades have witnessed a rapid advancement in novel
synthetic methods for the elaboration of an indole scaffold to
meet the increasing demand in the medicinal chemistry field.1
Meanwhile, transition-metal-catalyzed regioselective aro-
matic C−H bond functionalization has attracted much interest
due to its atom- and step-economic benefits.2 For the
functionalization of the indole nucleus,3,4 the C4−C7-selective
reactions over the C2−C3 positions have been a challenging
task since the benzo ring has inherently poor reactivity relative
to the pyrrole skeleton. The direct C−H activation at the C4
position among others has been achieved with the aid of
directing groups placed at the C3 position. As an early
example, Jia and co-workers reported a Pd-catalyzed direct C4
alkenylation of tryptophan derivatives where the amine moiety
could act as the directing function.5 Besides this seminal
achievement, a series of direct C4 functionalization methods
were developed with Pd, Ru, Ir, and Rh catalysts mainly
employing carbonyl-based directing groups.4 In these reac-
tions, formation of 6-membered metallacycles rather than 5-
membered ones is the key to attaining significant regiose-
lectivity (Figure 1a).
Figure 1. Schematic representation of regioselective C−H activation
of indole derivatives.
exhibits tolerance of a wide range of coupling substrates, and
thereafter, the sulfur directing group is readily converted into
other functional groups (Figure 1b). Furthermore, related
heterocyclic motifs such as benzo[b]thiophene and benzo[b]-
furan can be accommodated.
We commenced our investigation with the optimization
study for a model reaction of 1-methyl-3-(methylthio)indole
(1a)10 with butyl acrylate (2c) in the presence of a Rh(III)
catalyst (Table 1). Initially, the C4-alkenylated product 3ac
was obtained in 35% yield by using a cationic complex
[Cp*Rh(CH3CN)3][SbF6]2 (5 mol %) together with AgOAc
(10 mol %) and Cu(OAc)2·H2O (1.0 equiv) in MeOH at 100
°C (entry 1). Solvent screening was then conducted and the
yield was improved to 55% with DCE (entry 3), whereas
increase in the reaction temperature to 120 °C had a minimal
In recent years, considerable attention has been paid to
thioether directing groups owing to their labile nature. They
can be easily removed under reductive conditions6 or
catalytically converted into other synthetically useful func-
tions.7 Our group has been developing Rh-catalyzed direct C−
H functionalization reactions using sulfur-containing directing
groups8 and recently reported a thioether-directed peri-
selective C−H alkenylation of acenes though a 5-membered
metallacycle.9 Consequently, we have taken steps to develop a
C4-selective functionalization of indole derivatives employing
thioether directing groups. We herein describe an effective Rh-
catalyzed direct C4 alkenylation protocol. This catalytic system
Received: June 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02038
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
alkenylated products 3aa−ag were selectively obtained in good
to high yields. The regioselectivity and trans-configuration of
the alkene moiety was further evidenced by the single-crystal
X-ray analysis of 3af. Additionally, the present reaction system
was applicable to acrylonitrile (2h), vinyl phosphonate (2i),
and styrene derivatives 2j−l and allowed us to deliver the
corresponding C4-alkenylated products in moderate to high
yields. The reaction with ethyl crotonate did not occur.
We next turned our attention to the effect of protecting
groups and examined the reaction of indoles bearing benzyl
(Bn, 1b), p-methoxybenzyl (PMB, 1c), and p-tolylsulfonyl (Ts,
1d) groups on the nitrogen atom (Scheme 2). The relatively
Table 1. Optimization Studies
d
entry
catalyst
solvent
temp (°C) 3ac (%)
a
1
[Cp*Rh(CH3CN)3][SbF6]2
[Cp*Rh(CH3CN)3][SbF6]2
[Cp*Rh(CH3CN)3][SbF6]2
[Cp*Rh(CH3CN)3][SbF6]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
MeOH
PhCF3
DCE
DCE
DCE
100
100
100
120
95
95
95
95
35
25
55
54
76
78
n.d.
n.d.
n.d.
a
2
a
3
a
4
b
5
Scheme 2. Substrate Scope with Respect to the Directing
a
b
6
DCE
Group and the Protecting Group
b
b
b
,c
7
8
9
MeOH
tAmOH
dioxane
PhCF3
[Cp*RhCl2]2
[Cp*RhCl2]2
95
95
b
10
31
a
Reaction conditions: 1a (0.2 mmol), 2a (0.8 mmol), [Cp*Rh-
(CH3CN)3][SbF6]2 (5.0 mol %), AgOAc (10 mol %), and
b
Cu(OAc)2·H2O (0.2 mmol) in solvent (2 mL). Reaction conditions:
1a (0.2 mmol), 2a (0.8 mmol), [Cp*RhCl2]2 (2.5 mol %), AgSbF6
c
(10 mol %), and Cu(OAc)2·H2O (0.2 mmol) in solvent (2 mL). 2.0
d
equiv (0.4 mmol) of Cu(OAc)2·H2O was used; Isolated yield; nd =
not detected.
impact on the reaction efficiency (entry 4). After further
modifications, the highest 76% yield was achieved by
employing a [Cp*RhCl2]2/AgSbF6 catalyst at 95 °C (entry
5). A small increase in the yield of 3ac was found by use of 2.0
equiv of the Cu(II) oxidant (entry 6). Decreasing the amount
of DCE to 1.0 mL did not affect the product yield, while it
considerably dropped to 54% by using 4.0 mL of the solvent
(not shown).
a
All reactions were carried out on a 0.2 mmol scale.
With the optimized conditions in hand, we examined the
scope of alkenes using 1a as the representative substrate
(Scheme 1). With acrylates 2a−g, the corresponding C4-
electron-rich indoles 1b and 1c reacted smoothly to furnish the
alkenylated products 3bc and 3cc in 95% and 96% yields,
respectively. While the electron-withdrawing Ts on 1d
retarded the reaction with acrylate 2c as well as with styrene
2j, the desired compounds 3dc and 3dj were produced in
synthetically usable yields. It is worth noting that these
protecting groups are of genuine synthetic utility, as they can
be readily removed under mild conditions.
a
Scheme 1. Substrate Scope for Alkenes
Subsequently, we conducted a quick survey on the scope of
thioether directing groups. Under the standard reaction
conditions, the directing ability of the SCy (Cy = cyclohexyl)
and SPh groups was tested with acrylates. Interestingly, we
found that the SCy group also acted as an efficient directing
group with exclusive C4 selectivity to give the desired products
3ec, 3ed, and 3eg in excellent yields. In contrast, the use of an
SPh directing group in 1f resulted in the considerable drop of
yields in the reaction with 2c (47%) and 2d (49%). The
present catalytic protocol was successfully scaled up; when the
reaction of indole 1a with acrylate 2c was carried out on a 1.0
mmol scale, the coupling product 3ac was isolated in 81% yield
as the sole product (Scheme 3).
We next investigated the scope of various functionalized
indoles with butyl acrylate (2c) (Scheme 4). Indoles bearing 5-
Cl 1e and 5-Br 1f were well tolerated under the conditions and
converted into the C4-alkenylated products 3gc and 3hc as the
a
All reactions were carried out on a 0.2 mmol scale.
B
DOI: 10.1021/acs.orglett.8b02038
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scale-up Experiment
Scheme 5. C4 Alkenylation of Benzo[b]thiophene and
Benzo[b]furan Derivatives
a
Scheme 4. Substrate Scope for Indoles
Scheme 6. Transformation of the SMe-Directing Group of
a
3aj
a
All reactions were carried out on a 50 mg scale.
mixture of E/Z isomers. In contrast, 5-OMe indole 3i was
obtained exclusively in the E form with a good yield.
In the case of the indoles with a functionality on the C6
position, the reaction proceeded smoothly to afford products
3jc−lc in 90−96% yields. A benzo-fused indole 2m as well as
C7-substituted indoles 2n−p were also suitable substrates for
the present reaction and were effectively transformed to the
corresponding products 3mc−pc in excellent yields. The
structure of 3pc was unambiguously determined by X-ray
crystallography. It should be noted that phenyl and 2-naphthyl
substituents on the C2 position did not affect the
regioselectivity, giving 3qc and 3rc as the single products,
and no reaction on the C2 aryl rings was observed.
It is worth noting that some of the present products were
found to be highly luminescent. Compounds 3af and 3pc are
representative and showed their emission maxima at 529 nm in
CHCl3 solutions with quantum yields of 0.59 and 0.45,
respectively (see the Supporting Information).
The significance of the current method was not limited to
indoles, but it could be adapted to benzo[b]thiophene and
benzo[b]furan derivatives (Scheme 5). The reactions of 4 with
2c and 2j and of 6 with 2c afforded the corresponding
products 5c, 5j, and 7c in moderate to high yields,
demonstrating the generality of the present catalytic protocol.
In order to demonstrate the potential advantage of the
methylthio directing group, we have performed some
derivatization reactions of 3aj as the representative compound
(Scheme 6). It can be easily oxidized by using H2O2/Tf2O to
the corresponding sulfoxide 3aj-1.11 Interestingly, when the
a
St = E-styryl.
indole was oxidized with I2/NaHCO3 in the presence of water,
an isatin (indole-2,3-dione) derivative 3aj-2 was obtained as
the major product along with 3aj-1.12 The methylthio group
can be removed by selective reduction using Ni(COD)2 and
triethylsilane, giving 3aj-3.6a Additionally, the methylthio
group was successfully converted to methyl (3aj-4) and phenyl
(3aj-5) groups by a Ni-catalyzed coupling reaction with the
corresponding Grignard reagents.13
In summary, we have developed a thioether directed C4-
selective C−H alkenylation of indoles under rhodium catalysis.
The protocol allows a broad substrate scope and can be
extended to the other heterocycle systems such as benzo[b]-
furan and benzo[b]thiophene derivatives. Some of the
products exhibit relatively strong fluorescence. Additionally,
the thioether directing group can be readily removed or
transformed into other functional groups, acting as a traceless
directing group.
C
DOI: 10.1021/acs.orglett.8b02038
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Tan, L.; Ma, D. Angew. Chem., Int. Ed. 2016, 55, 321. (n) Borah, A. J.;
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02038.
■
S
(7) Recent reviews on catalytic C−S bond transformations:
(a) Wang, L.; He, W.; Yu, Z. Chem. Soc. Rev. 2013, 42, 599.
(b) Modha, S. G.; Mehta, V. P.; van der Eycken, E. V. Chem. Soc. Rev.
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(d) Gao, K.; Otsuka, S.; Baralle, A.; Nogi, K.; Yorimitsu, H.; Osuka, A.
Yuki Gosei Kagaku Kyokaishi 2016, 74, 1119. (e) Ortgies, D. H.;
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2016, 2016, 408.
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17, 704. (b) Yokoyama, Y.; Unoh, Y.; Bohmann, R. A.; Satoh, T.;
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(c) Unoh, Y.; Satoh, T.; Hirano, K.; Miura, M. ACS Catal. 2015, 5,
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Org. Lett. 2016, 18, 5436.
Detailed experimental procedures, spectroscopic data,
NMR spectra (PDF)
Accession Codes
CCDC 1852275 and 1852277−1852278 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
(9) Shigeno, M.; Nishii, Y.; Satoh, T.; Miura, M. Asian J. Org. Chem.
2018, 7, 1334.
(10) Tudge, M.; Tamiya, M.; Savarin, C.; Humphrey, G. R. Org. Lett.
2006, 8, 565.
Corresponding Author
*E-mail: miura@chem.eng.osaka-u.ac.jp.
ORCID
(11) Khodaei, M. M.; Bahrami, K.; Karimi, A. Synthesis 2008, 2008,
1682.
(12) Liu, P.; Guo, J.; Wei, W.; Liu, X.; Sun, P. Eur. J. Org. Chem.
2016, 2016, 2105.
Masahiro Miura: 0000-0001-8288-6439
Notes
The authors declare no competing financial interest.
́
(13) (a) Baralle, A.; Otsuka, S.; Guerin, V.; Murakami, K.;
Yorimitsu, H.; Osuka, A. Synlett 2015, 26, 327. (b) Murakami, K.;
ACKNOWLEDGMENTS
■
Yorimitsu, H.; Osuka, A. Bull. Chem. Soc. Jpn. 2014, 87, 1349.
This work was supported by JSPS KAKENHI Grant No. JP
17H06092 (Grant-in-Aid for Specially Promoted Research) to
M.M.
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D
DOI: 10.1021/acs.orglett.8b02038
Org. Lett. XXXX, XXX, XXX−XXX