Iridium-Catalyzed Isomerization/Cycloisomerization/Aromatization of N-Allyl-N-sulfonyl-o-(λ1-silylethynyl)aniline Derivatives to Give Substituted Indole Derivatives

Article abstract of DOI:10.1021/acs.orglett.1c01231

We have developed a one-iridium-catalyst system that transforms N-allyl-N-sulfonyl-2-(silylalkynyl)aniline derivatives, which are 1,7-enynes in which both multiple bonds have a heteroatom, to the corresponding substituted indole derivatives via isomerizat

Full text of DOI:10.1021/acs.orglett.1c01231

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Letter
Iridium-Catalyzed Isomerization/Cycloisomerization/Aromatization
of N‑Allyl‑N‑sulfonyl‑o‑(λ1‑silylethynyl)aniline Derivatives to Give
Substituted Indole Derivatives
Jiawei Qiu, Makoto Sako, Tomoyuki Tanaka, Tsuyoshi Matsuzaki, Tsunayoshi Takehara,
Takeyuki Suzuki, Shohei Ohno, Kenichi Murai, and Mitsuhiro Arisawa*
Cite This: Org. Lett. 2021, 23, 4284−4288
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ABSTRACT: We have developed a one-iridium-catalyst system that transforms N-
allyl-N-sulfonyl-2-(silylalkynyl)aniline derivatives, which are 1,7-enynes in which
both multiple bonds have a heteroatom, to the corresponding substituted indole
derivatives via isomerization/cycloisomerization/aromatization. This strategy
provides an atom-economical and straightforward synthetic approach to a series
of valuable indoles having vinyl and silylmethyl groups at the 2- and 3-positions.
Scheme 1. Previous Works on Transition-Metal-Catalyzed
Indole Syntheses Using 1,n-Enynes or -Dienes and This
Work
he substituted indole structure is a widespread hetero-
Tcyclic skeleton in natural products, optoelectronic
materials,1,2 and pharmaceutical agents (anticancer activity,
antimicrobial activity, anti-HIV activity etc.).3 Classic method-
ologies for indole synthesis have been investigated very well.4
However, these methods are not only restricted to some harsh
conditions in which strong acids (or bases) and heating are
used for transformations but also applied to a narrow scope of
substrates. On the other hand, recent transition-metal-
catalyzed indole synthesis methods have been attractive
because of their high efficiency, mild conditions, and wide
substrate scope. Among them, transition-metal-catalyzed
cyclization of enynes or dienes is one promising reaction
because of the easy transformation from an uncomplicated
acyclic structure to a multisubstituted cyclic structure.5
Especially, researchers envisioned that transition-metal-cata-
lyzed cyclization of enynes or dienes could be utilized as a
useful indole synthesis approach. Indeed, transition metal (Ru,
Fe, Pd)-catalyzed cyclization of 1,7-dienes and 1,6-enynes,
which are reactions between an enamide and a multiple bond
without a heteroatom, have been reported to yield the
corresponding indole derivatives, and further chemical trans-
formations of them are rather difficult (Scheme 1a).6,7
However, transition-metal-catalyzed cyclization between an
enamide and a multiple bond with a heteroatom, which gives
indole derivatives with a heteroatom substituent, have not been
developed except in our report of Ru-catalyzed cyclization of
1,7-enynes involving an aromatic enamide and a silylalkyne
(Scheme 1b).8 Although it is an atom-economical and efficient
method to yield 2-vinyl-3-(silylmethyl)indoles, which have
chemical transferability, two kinds of Ru catalysts and one
more extra camphorsulfonic acid for aromatization are
necessary. Also, this method cannot tolerate a more stable
and synthetically useful bulkier sulfonyl protective group on
nitrogen very well.
Received: April 11, 2021
Published: May 25, 2021
https://doi.org/10.1021/acs.orglett.1c01231
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4284−4288
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Here we report the first example of indole synthesis using
1,7-enynes in which both multiple bonds have a heteroatom
with just a single multitask catalyst, [IrCl(cod)]2.9 The
catalytic system could promote isomerization/cycloisomeriza-
tion/aromatization of N-allyl-N-sulfonyl-o-(λ1-silylethynyl)-
aniline derivatives to give the corresponding 2-vinyl 3-
silylmethylindole derivatives (Scheme 1c) and tolerates a
bulkier protecting group (a sulfonyl group) on nitrogen.
At first, we subjected starting material 1a having
trimethylsilylalkyne and allylsulfonylamide groups to several
sets of reaction conditions using a variety of organometallic
catalysts, ligands, and additives (Table 1). As a result, we
However, the yield of 2a was not improved (73% and trace;
entries 7 and 8). On the basis of the ligand screening results,
we fixed SPhos as the best ligand and continued the
optimization, focusing on metal salt additives to activate the
iridium catalyst species and promote the reaction. We chose
silver salts (AgOTf and AgSbF6) and added them to the above
reaction mixtures.11 As a result, the yield of 2a sharply
decreased to trace and 18%, respectively (entries 9 and 10).
Next, the effects of the catalyst loading, solvent, and
concentration were examined. At first, we decreased the
catalyst loading of iridium to 5 mol % (entry 11). As a result,
only a 56% yield of 2a and a 28% yield of isomerized
1
intermediate 1a′ were obtained, as confirmed by H NMR
Table 1. Optimization of the Reaction Conditions
spectroscopy. To perform the reaction at a higher temperature,
α,α,α-trifluorotoluene was chosen because of its higher boiling
point and same electrostatic constant as (CH2Cl)2. The yield
of 2a was improved to 88% (4 mol % [IrCl(cod)]2), even
within 12 h (entry 12). We then examined the concentration of
the reaction mixture (0.05 and 0.02 M) in this Ir-catalyzed
cascade reaction, and 2a was obtained in 92% and 80% yield,
respectively (entries 13 and 14). In a control experiment in the
e
entry
ligand
PCy3
P(t-Bu)3
XPhos
RuPhos
L1
SPhos
L2
L3
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
SPhos
additive
NaBArF
solvent (M)
yield (%)
1
2
3
4
5
6
7
8
9
(CH2Cl)2 (0.1)
(CH2Cl)2 (0.1)
(CH2Cl)2 (0.1)
(CH2Cl)2 (0.1)
(CH2Cl)2 (0.1)
(CH2Cl)2 (0.1)
(CH2Cl)2 (0.1)
(CH2Cl)2 (0.1)
(CH2Cl)2 (0.1)
(CH2Cl)2 (0.1)
(CH2Cl)2 (0.1)
C6H5CF3 (0.1)
C6H5CF3 (0.05)
C6H5CF3 (0.02)
C6H5CF3 (0.1)
C6H5CF3 (0.1)
22
0
trace
72
75
78
73
trace
trace
18
4
absence of NaBArF , the reaction did not proceed at all (entry
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
AgOTf
AgSbF6
NaBArF
NaBArF
NaBArF
NaBArF
−
4
4
4
4
4
4
4
4
15), and when [Ir(cod)2]BArF was used in place of
4
[IrCl(cod)]2 and NaBArF , only a trace yield of 2a was
4
obtained (entry 16). In addition, we confirmed that other
metal catalyst systems ([Rh(cod)2]BF4 and Ni(cod)2), which
showed excellent cycloisomerization activities in the past,12,13
did not work well.
We next examined the effect of substituents on the alkyne or
nitrogen (Scheme 2). Silylalkyne derivatives 1b, 1c, 1e, and 1f
(with SiEt3, SiMe2Ph, SiMe2Bn, and SiPh2Me groups,
respectively) gave the corresponding indoles in yields of 75%
(2b), 79% (2c), 82% (2e), and 83% (2f). In contrast,
10
11
a
56
4
4
4
4
bc
,
12
13
14
15
16
88
bc
,
f
92 (89 )
bc
,
80
0
trace
a
Scheme 2. Effect of Substituents on the Alkyne or Nitrogen
d
−
a
5 mol % [IrCl(cod)]2, 10 mol % SPhos, and 10 mol % NaBArF
4
b
(ArF= 3,5-bis(trifluoromethyl)phenyl). 4 mol % [IrCl(cod)]2, 8 mol
c
d
% SPhos, and 8 mol % NaBArF . 12 h. 8 mol % [Ir(cod)2]BArF , 8
4
4
e
mol % SPhos. NMR yields were determinded using 1,3,5-
trimethoxybenzene as an internal standard. The isolated yield is
shown in parentheses. ORTEP drawing of L3 at the 50% probability
f
g
level (CCDC 2075648).
obtained the desired 2,3-disubstituted indole 2a in 22% yield
when we refluxed a dichloroethane solution of 1a, [IrCl(cod)]2
(10 mol %), PCy3 (20 mol %), and NaBArF (20 mol %)
4
(entry 1). Then, in order to improve the yield of 2a, we
screened a P(t-Bu)3 ligand, which has a slightly bigger cone
angle than PCy3, along with other phosphine ligands that are
sterically bulky (XPhos) or electron-rich (RuPhos, L1, and
SPhos).10 The product 2a was obtained in yields of 0%, trace,
72%, 75%, and 78%, respectively (entries 2−6). Furthermore,
we designed L2 and L3, which have different steric
configurations and more electron-donating groups on the
biphenyl core, and tried to perform the same reaction as above.
a
b
Isolated yields are shown. 6 mol % [IrCl(cod)]2, 12 mol % SPhos,
12 mol % NaBArF .
4
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derivatives 1d and 1g having bulky silyl groups were converted
to 2d and 2g in 68% and 37% yield, respectively. Carbon-
substituted derivatives (R1 = Me (S1a), Ph (S1b)) were not
transformed to the corresponding indoles, which implied the
importance of the electron-donating silyl substituent on the
alkyne in this Ir-catalyzed cyclization. To know the effect of the
substituent on nitrogen, we also performed the same reaction
using substrates 1h−j with other sulfonyl protecting groups
and obtained the corresponding indole derivatives in yields of
91% (2h), 80% (2i), and 82% (2j). In addition, we prepared
formyl and benzoyl derivatives (R2 = CHO (S1c), Bz (S1d))
and subjected them to the optimized conditions, but only trace
amounts of the corresponding products were obtained.
The reaction was also tested on a 2.08 mmol scale (Scheme
3a). When we performed the reaction under standard
Scheme 3. Reaction on a 2.08 mmol Scale and Chemical
Transformations
The effect of substituents on the benzene ring was
investigated by subjecting substrates 1k−u to the optimized
reaction conditions (Table 2). The indole products 2k−m, 2o,
Table 2. Effect of Substituents on the Benzene Ring
a
entry
1
R
2
yield (%)
1
2
3
4
5
6
7
8
9
1a
1k
1l
1m
1n
1o
1p
1q
1r
H
3-Cl
4-Cl
5-Cl
2a
2k
2l
2m
2n
2o
2p
2q
2r
89
59
39
82
0
85
79
0
trace
80
73
78
conditions using 2.08 mmol of 1a, the corresponding product
2a was obtained in 81% yield. Moreover, the obtained
compound 2a was applied to chemical transformations
(Scheme 3b). When 2a was treated with paraformaldehyde
and CsF, the one-carbon extension product 3 was formed.
Another fluoride reagent (e.g., n-Bu4NF) decomposed the
substrate and did not give the desired compound. In addition,
we tried deprotection of 2a under Mg/MeOH conditions and
obtained product 4 in 78% yield.
To study the reaction mechanism, we used electrospray
ionization mass spectroscopy (ESI-MS) to obtain some
information about the iridium species in this reaction. The
reaction with a stoichiometric amount of iridium species (1
equiv) was performed within 5 min and then was analyzed.
Consequently, we detected a peak for C47H58IrNO4PSSi at m/
z 984.3222 (see Figures S2 and S4), which possibly
corresponds to intermediate C with further elimination of
two hydrogens. Its exact mass (984.3222) is 2 fewer than the
simulation mass (986.3374), probably because of the trend to
keep a stable state (C′ or C″) by elimination during ESI-MS
analysis (Figure 2). Also, we found a peak for C34H47IrO2P at
m/z 711.2943 (see Figures S2 and S3), corresponding to the
iridium complex [Ir]+ in Figure 2.
6-Cl
4-Me
5-Me
4,6-Me2
4-CN
4-OMe
5-CO2Me
5-F
10
11
12
1s
1t
1u
2s
2t
2u
a
Isolated yields.
2p, and 2s−u were obtained in high or moderate yields
(entries 2, 3, 4, 6, 7, 10, 11, and 12). However, substrates 1n
and 1q, having a substituent at the 6-position, did not adapt
themselves to the reaction conditions, probably because of
their steric hindrance toward the iridacycle intermediate
(entries 5 and 8). Substrates 1r and 1s were converted to
the corresponding cyclized indole products 2r and 2s in trace
and 80% yield, respectively (entries 9 and 10). These results
suggest that an electron-withdrawing group at the 4-position
disturbed the key coordination of the silylalkyne to iridium
metal.
We also examined the effect of the alkene substituent using
1v and 1w (Figure 1) and found that the cyclization of 1v or
1w to give the corresponding indoles did not proceed at all
under the optimal reaction conditions, which means that a
methyl substituent on the alkene impedes the reaction.
A plausible mechanism for the iridium-catalyzed cyclization
is shown in Scheme 4. The cationic iridium complex reacts
with the substrate to form the isomerized product 1a′.14 Then
the double bond and triple bond coordinate to the Ir species to
form intermediate B. Iridacycle intermediate C is generated via
Figure 1. Structures of 1v and 1w.
Figure 2. Structures of reaction intermediates predicted by ESI-MS.
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Letter
Makoto Sako − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan;
orcid.org/0000-0002-4268-7002
Scheme 4. Plausible Catalytic Cycle
Tomoyuki Tanaka − Graduate School of Pharmaceutical
Sciences, Osaka University, Suita, Osaka 565-0871, Japan
Tsuyoshi Matsuzaki − Comprehensive Analysis Center, The
Institute of Scientific and Industrial Research, Osaka
University, Ibaraki, Osaka 567-0047, Japan
Tsunayoshi Takehara − Comprehensive Analysis Center, The
Institute of Scientific and Industrial Research, Osaka
University, Ibaraki, Osaka 567-0047, Japan; orcid.org/
0000-0002-4113-7578
Takeyuki Suzuki − Comprehensive Analysis Center, The
Institute of Scientific and Industrial Research, Osaka
University, Ibaraki, Osaka 567-0047, Japan; orcid.org/
0000-0002-2137-0276
Shohei Ohno − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan
Kenichi Murai − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan;
orcid.org/0000-0002-1689-6492
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01231
oxidative cyclization, and subsequent β-H elimination gives
intermediate D. Finally, aromatization and reductive elimi-
nation proceed to give the corresponding 2,3-disubstituted
indole 2a.
Notes
The authors declare no competing financial interest.
In conclusion, we have found the first example of single-
iridium-catalyst-catalyzed isomerization/cycloisomerization/
aromatization of N-allyl-N-sulfonyl-o-(λ1-silylethynyl)aniline
derivatives, in which both multiple bonds have a heteroatom,
to give substituted indole derivatives. This methodology
enabled the synthesis of a series of 2,3-disubstituted indoles
having vinyl and silylmethyl groups at the 2- and 3-positions,
respectively. In addition, some information about the iridium
species in this reaction was obtained by ESI-MS.
ACKNOWLEDGMENTS
■
This study was partially supported by a Grant-in-Aid from
JSPS KAKENHI (JP 15KT0063), by the Platform Project for
Supporting Drug Discovery and Life Science Research (Basis
for Supporting Innovative Drug Discovery and Life Science
Research (BINDS)) from AMED (Grant JP21am0101084),
and by the Cooperative Research Program of the Network
Joint Research Center for Materials and Devices of the
Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT).
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REFERENCES
The Supporting Information is available free of charge at
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■
(1) (a) Sundberg, R. J. Indoles; Academic Press: San Diego, CA,
1996. (b) Bandari, C.; Scull, E. M.; Bavineni, T.; Nimmo, S. L.;
Gardner, E. D.; Bensen, R. C.; Burgett, A. W.; Singh, S. FgaPT2, a
biocatalytic tool for alkyl-diversification of indole natural products.
MedChemComm 2019, 10, 1465−1475.
(2) For a recent review, see: Urieta-Mora, J.; García-Benito, I.;
Molina-Ontoria, A.; Martín, N. Hole transporting materials for
perovskite solar cells: a chemical approach. Chem. Soc. Rev. 2018, 47,
8541−8571.
(3) (a) Jordan, M. A.; Wilson, L. Microtubules as a target for
anticancer drugs. Nat. Rev. Cancer 2004, 4, 253−265. (b) Smart, B. P.;
Oslund, R. C.; Walsh, L. A.; Gelb, M. H. The first potent inhibitor of
mammalian group X secreted phospholipase A2: elucidation of sites
for enhanced binding. J. Med. Chem. 2006, 49, 2858−2860.
(c) Kochanowska-Karamyan, A. J.; Hamann, M. T. Marine indole
alkaloids: potential new drug leads for the control of depression and
anxiety. Chem. Rev. 2010, 110, 4489−4497.
(4) Taber, D. F.; Tirunahari, P. K. Indole synthesis: a review and
proposed classification. Tetrahedron 2011, 67, 7195−7210.
(5) Yamamoto, Y. Transition-metal-catalyzed cycloisomerizations of
α,ω-dienes. Chem. Rev. 2012, 112, 4736−4769.
Experimental details, characterization data, and copies of
1H and 13C NMR spectra (PDF)
Accession Codes
CCDC 2075648 contains the supplementary 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Mitsuhiro Arisawa − Graduate School of Pharmaceutical
Sciences, Osaka University, Suita, Osaka 565-0871, Japan;
orcid.org/0000-0002-7937-670X; Email: arisaw@
phs.osaka-u.ac.jp
(6) (a) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Selective
isomerization of a terminal olefin catalyzed by a ruthenium complex:
the synthesis of indoles through ring-closing metathesis. Angew.
Chem., Int. Ed. 2002, 41, 4732−4734. (b) Xia, X.; He, W.; Zhang, G.;
Authors
Jiawei Qiu − Graduate School of Pharmaceutical Sciences,
Osaka University, Suita, Osaka 565-0871, Japan
4287
https://doi.org/10.1021/acs.orglett.1c01231
Org. Lett. 2021, 23, 4284−4288

Organic Letters
pubs.acs.org/OrgLett
Letter
Wang, D. Iron-catalyzed reductive cyclization reaction of 1,6-enynes
for the synthesis of 3-acylbenzofurans and thiophenes. Org. Chem.
Front. 2019, 6, 342−346. (c) Zhang, P.; Wang, C.; Cui, M.; Du, M.;
Li, W.; Jia, Z.; Zhao, Q. Synthesis of difluoroalkylated benzofuran,
benzothiophene, and indole derivatives via palladium-catalyzed
cascade difluoroalkylation and arylation of 1,6-enynes. Org. Lett.
2020, 22, 1149−1154.
(7) Ohno, S.; Arisawa, M. Cyclizations of benzo-fused substrates
involving two multiple bonds, including heteroatom-substituted
unsaturated bonds. J. Org. Chem. 2020, 85, 6831−6843.
(8) Takamoto, K.; Ohno, S.; Hyogo, N.; Fujioka, H.; Arisawa, M.
Ruthenium-catalyzed 1,6-aromatic enamide−silylalkyne cycloisomeri-
zation: approach to 2,3-disubstituted indoles. J. Org. Chem. 2017, 82,
8733−8742.
(9) Inprung, N.; James, M. J.; Taylor, R. J. K.; Unsworth, W. P. A
Thiol-Mediated Three-Step Ring Expansion Cascade for the
Conversion of Indoles into Functionalized Quinolines. Org. Lett.
2021, 23, 2063−2068.
(10) (a) Milne, J. E.; Buchwald, S. L. An extremely active catalyst for
the Negishi cross-coupling reaction. J. Am. Chem. Soc. 2004, 126,
13028−13032. (b) Jover, J.; Cirera, J. Computational assessment on
the Tolman cone angles for P-ligands. Dalton Trans 2019, 48, 15036−
15048.
(11) (a) Hanasaka, F.; Fujita, K.; Yamaguchi, R. Organometallics
2006, 25, 4643−4647. (b) Cheng, H.; Yang, D. Iridium-catalyzed
asymmetric ring-opening of oxabenzonorbornadienes with phenols. J.
Org. Chem. 2012, 77, 9756−9765. (c) Feng, Y.; Li, Y.; Yu, Y.; Wang,
L.; Cui, X. Iridium-catalysed direct sulfamidation of quinazolinones.
RSC Adv. 2018, 8, 8450−8454.
(12) Okamoto, R.; Okazaki, E.; Noguchi, K.; Tanaka, K. Rhodium-
catalyzed olefin isomerization/enantioselective intramolecular alder-
ene reaction cascade. Org. Lett. 2011, 13, 4894−4897.
(13) Ohno, S.; Qiu, J.; Miyazaki, R.; Aoyama, H.; Murai, K.;
Hasegawa, J.; Arisawa, M. Ni-catalyzed cycloisomerization between 3-
phenoxy acrylic acid derivatives and alkynes via intramolecular
cleavage and formation of the C−O bond to give 2,3-disubstituted
benzofurans. Org. Lett. 2019, 21, 8400−8403.
(14) Biswas, S.; Huang, Z.; Choliy, Y.; Wang, D. Y.; Brookhart, M.;
Krogh-Jespersen, K.; Goldman, A. S. Olefin Isomerization by Iridium
Pincer Catalysts. Experimental Evidence for an η3-Allyl Pathway and
an Unconventional Mechanism Predicted by DFT Calculations. J. Am.
Chem. Soc. 2012, 134, 13276−13295.
4288
https://doi.org/10.1021/acs.orglett.1c01231
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