A Radical-Initiated Fragmentary Rearrangement Cascade of Ene-Ynamides to [1,2]-Annulated Indoles via Site-Selective Cyclization

Article abstract of DOI:10.1021/acs.orglett.1c02519

Straightforward access to [1,2]-annulated indoles, key substructures in natural products, is highly desirable yet challenging. Herein, a radical triggered fragmentary cyclization cascade reaction of ene-ynamides is presented, providing a rapid access into [1,2]-annulated indoles by an intermolecular radical addition, intramolecular cyclization, desulfonylative aryl migration, and site-selective C(sp2)-N cyclization sequence. DFT calculations support oxidation of N-centered radical species to cations prior to the C-N bond formation, followed by an unusual aza-Nazarov cyclization.

Full text of DOI:10.1021/acs.orglett.1c02519

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Letter
A Radical-Initiated Fragmentary Rearrangement Cascade of Ene-
Ynamides to [1,2]-Annulated Indoles via Site-Selective Cyclization
Sifan Li, Yu Wang, Zibo Wu, Weiliang Shi, Yibo Lei, Paul W. Davies,* and Wei Shu*
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ABSTRACT: Straightforward access to [1,2]-annulated indoles, key
substructures in natural products, is highly desirable yet challenging.
Herein, a radical triggered fragmentary cyclization cascade reaction of
ene-ynamides is presented, providing a rapid access into [1,2]-
annulated indoles by an intermolecular radical addition, intra-
molecular cyclization, desulfonylative aryl migration, and site-
selective C(sp2)-N cyclization sequence. DFT calculations support
oxidation of N-centered radical species to cations prior to the C−N bond formation, followed by an unusual aza-Nazarov cyclization.
indole and require relatively linear synthesis. As a result,
he importance of annulated indole skeletons in bio-
Tlogically active molecules inspires methodology develop- alternative and versatile approaches into annulated indole
motifs that assemble the indole motif are appealing.
Ynamides have received increasing attention over the past
decade in reaction discovery, with particular utility in the
construction of N-heterocyclic systems.8 Despite the myriad
synthetic utilities of ynamides, their radical chemistry is
relatively unexplored.9 Due to our ongoing interest in ynamide
based cascade reactions10 and radical chemistry,11 we
hypothesized that a radical-initiated cascade reaction of ene-
ynamides might provide a novel way to construct [1,2]-
annulated indoles: Ynamides commonly feature stabilizing aryl
sulfonamide groups that could be incorporated into an indole
motif through a desulfonylative aryl migration and C(sp2)−N
bond formation pathway initiated by a radical induced
cyclization.
Scheme 1. Significance and Strategies to Access [1,2]-
Annulated Indoles
Moreover, the Smiles rearrangement is an intramolecular
nucleophilic substitution at the ipso-position of an activated
aromatic ring system12 that typically involves aryl sulfides,
sulfoxides, sulfones, and amides.13 Radical versions of the
Smiles rearrangement have also been demonstrated.14 In
2015, the Nevado group15 reported a copper-catalyzed
desulfonylative radical Smiles rearrangement of conjugated
tosyl amides. Ye and co-workers reported a novel photoredox-
catalyzed radical Smiles rearrangement of α-keto aniline-
derived ynamides.16 Here we represent a rapid assembly of
[1,2]-annulated indoles from simple ene-ynamides enabled by
radical fragmentary cascade cyclization reaction (Scheme 1b).
ments toward their effective preparation (Scheme 1a).1,2
Strategies for the construction of [1,2]-annulated indole
structures are commonly based on functionalization of an
already intact indole,3 by methods including transition metal-
catalyzed cyclization,4 radical cyclization reactions,5 Friedel−
Crafts alkylation,6 and N-alkylation.7 These approaches are
limited to those substitution patterns accessible on the starting
Received: August 5, 2021
https://doi.org/10.1021/acs.orglett.1c02519
© XXXX American Chemical Society
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A

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a
a substrate bearing electronically similar aryl substituents at
the alkyne and the sulfonamide group affords a ∼1:1 mixture
of inseparable regioisomers (3f, 3f′). The regioisomeric ratio
improved to 2.8:1.0 (3g:3g′) where cyclization onto the p-
tolyl group from the sulfonamide was favored over cyclization
onto the alkynes m-methoxyphenyl group. Replacing the m-
methoxyphenyl substituent on the ynamide with a fluoro-
benzene substituent led to greater selectivity (3h:3h′ =
4.0:1.0). A single product 3i was obtained from the m-fluoro-
substituted ynamide in 64% yield, demonstrating that sole
indole products might be obtained by exploiting electronic
differences between the two aryl groups.
The scope of the reaction was then explored with
consideration of the electronic properties between two aryl
groups. First, a series of ynamides containing p-alkyl and p-
alkoxy substituents on the sulfonamide and electron-with-
drawing substituents on the aryl ethynyl portion were
examined. Exclusive formation of the indole products resulting
from cyclization onto the sulfonamide-derived aryl unit was
observed. Halide (3j−3n), ester (3o), including those derived
from (−)-menthol and (+)-fenchol (3r; 3s), and nitrile (3p;
3q) groups on the other aryl ring were well tolerated.
Selective cascade reactions that deliver a different skeletal
assembly can also be realized by inverting the electronic
properties of the two aryl groups: Substrates with more
electron-deficient aryl groups on the sulfonamide and
electron-donating substituents on the aryl ethynyl moiety
see the latter aryl group incorporated into the indole (3t−3ad,
43%−70%). Alkyl-, alkoxy-, and thioether substituents are all
tolerated. The use of p-substituted aryl groups lead to 6-
substituted indoles, while a 3,5-dimethylbenzene derivative
provides access to the 5,7-substituted indole 3aa. Aryl
sulfonamides bearing o-, m-, and p-halo, 3,5-difluoro, p-
trifluoromethyl, and p-nitro groups were all effective in the
reaction. The reaction also proceeded using an ynamide with a
monosubstituted alkene to generate a tertiary stereocenter
(3y). In addition, a pyridine-containing substrate also
functioned well in the reaction, with cyclization observed
onto the p-methoxyphenyl unit derived from the alkyne
substituent (3ad).
Table 1. Optimization Studies
b
entry
deviation from standard conditions
yield of 3a (%)
1
none
72 (63)
67
67
n.d.
n.d.
46
59
47
n.d.
n.d.
55
2
3
4
5
6
7
8
9
CuBr instead of CuCl
CuI instead of CuCl
Cu(OAc)2 instead of CuCl
Cu(OTf)2 instead of CuCl
room temperature instead of 60 °C
80 °C instead of 60 °C
DCM instead of CH3CN
THF instead of CH3CN
DMA instead of CH3CN
Togni reagent II instead of 2
0.05 M in CH3CN
10
11
12
13
14
62
47
n.d.
0.02 M in CH3CN
no CuCl
a
Standard conditions: 1a (0.1 mmol), 2 (0.12 mmol, 1.2 equiv), CuCl
(20 mol %) in CH3CN (3 mL) in a Schlenk tube at 60 °C under N2
b
atmosphere for 2 h. Yields were determined by 1H NMR
spectroscopy of the crude reaction mixture using mesitylene as an
internal standard; an isolated yield is shown in parentheses. Togni
reagent II: 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one. n.d. = not
detected.
We started our study with ynamide 1a, using Togni’s
reagent 2 as the radical source for the putative cascade. After
evaluation of various reaction parameters, the annulated
indole product 3a was achieved in 72% 1H NMR yield
using CuCl (20 mol %) in CH3CN (0.033 M) at 60 °C
(Table 1, entry 1). CuBr and CuI were also efficient catalysts
in this transformation, albeit giving slightly lower yields (Table
1, entries 2−3). Copper(II) complexes such as Cu(OAc)2 and
Cu(OTf)2 failed to deliver the desired product 3a (Table 1,
entries 4−5). An elevated temperature of 60 °C improved the
efficiency of the reaction (46% yield at room temperature,
Table 1, entry 6) but lower yields were seen at higher
temperature (Table 1, entry 7). Other solvents were not
suitable for this transformation (Table 1, entries 8−10).
Higher or lower concentration of solvent gave diminished
yields (Table 1, entries 12−13). A control experiment showed
that CuCl was indispensable in this transformation (Table 1,
entry 14).
With the optimized reaction conditions in hand, we then set
out to evaluate the generality of this approach (Scheme 2).
Annulated indoles were obtained in good yields from a series
of ynamides with matching p-substituted aryl groups on both
the ethynyl and sulfonamide regions of the ynamide (3b−3e,
45%−71%). The structure of 3e was confirmed by single
crystal X-ray diffraction. The practicality and ready imple-
mentation of this method is demonstrated by the preparation
of 3e on one gram scale.
Isomeric sets of starting materials (4a/4a′ and 4b/4b′,
Scheme 3a) showed very similar reaction efficiencies under
standard reaction conditions and converged to the same
regioisomers (5a and 5b, respectively), with more electron-
rich p-methoxyphenyl group embedded in the indole
regardless of its original position. Hence starting materials
can be designed and prepared on the basis of synthetic
accessibility.
More diverse [1,2]-annulated indole skeletons can also be
prepared by this approach. Pyrido[1,2-a]indole and azepino-
[1,2-a]indole (7a−7c) are accessed by increasing the alkyl
chain length between the alkene and the nitrogen (Scheme
n
3b). Unbranched and butyl branched alkene groups are also
tolerated. In all cases site-selective C(sp2)−N bond formation
occurs onto the more electron-rich aryl group.
Next, we examined the reaction efficiency of this cascade
process under photoredox-catalyzed conditions with different
radical precursors. Analogous [1,2]-annulated indole systems
could be formed under iridium photoredox-catalysis allowing
the introduction of the α,α-difluoroamidyl and α,α-difluor-
ocarbonyl functional groups (8a−8e, Scheme 3c). The site-
selective arylation was also retained under these photoredox
conditions (8d and 8e). Keto-ynamide 9 underwent fast
Initial studies with ynamides containing different aryl
groups on the sulfonamide and alkyne showed that isomeric
products could be realized from these reactions. Either aryl
group can be incorporated into the indole motif. For example,
B
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a
Scheme 2. Substrate Scope
a
Standard conditions: 1 (0.2 mmol), 2 (1.2 equiv, 0.24 mmol), CuCl (20 mol %), and CH3CN (6 mL) in a Schlenk tube at 60 °C under N2
b
atmosphere for 2 h. Isolated yields are reported. Unless otherwise stated, the regioisomeric ratio is >20:1. Reaction was performed at room
c
d
temperature. See Supporting Information for details. Ratio was determined by 19F NMR spectroscopy of the crude reaction mixture. tBu = tert-
i
butyl, Pr = iso-propyl.
decomposition under the copper-catalyzed conditions but
afforded the desired 3-acyl pyrrolo[1,2-a]indole 10a using the
photoredox conditions alongside a small amount of 10b
resulting from otho-vinylation of the sulfonamide after the
initial cyclization step.
extended cation IV and regenerate the copper(I) catalyst (or
IrIII catalyst). The electrocyclization occurs selectively through
the 4π system incorporating the more electron-rich aryl group
to give V,18 affording the indole 3 on deprotonation.
In summary, a straightforward access to pyrrolo[1,2-
DFT calculations verified that an aza-Nazarov type
cyclization is responsible for the excellent site-selectivity
observed in the C(sp2)-N bond forming step (see Supporting
Information for details). On the basis of the results and
literature precedent,15,16 a proposed mechanism is depicted in
Scheme 4. First, the radical precursor undergoes single
electron transfer with copper(I) complex (or the photoexcited
*IrIII catalyst) to generate a copper(II) species (or IrIV
species) and radical ·X (·CF2R) which then undergoes
intermolecular addition to the alkene part in the ynamide 1
furnishing alkyl radical intermediate I.17 Intramolecular
cyclization to generate vinyl radical intermediate II precedes
ipso-cyclization onto the sulfonamide and desulfonylation to
generate the N-centered radical intermediate III. Oxidation of
III by copper(II) complex (or IrIV species) would generate the
a]indole, pyrido[1,2-a]indole, and azepino[1,2-a]indole motifs
has been achieved using a nontrivial radical-initiated
fragmentary rearrangement cascade of ene-ynamides. This
strategy provides a novel approach for the skeletal assembly of
these important heterocyclic structures from readily assemble
ynamides. The new transformation provides ready access into
molecules displaying biological activities allowing for potential
application in medicinal chemistry. The reaction represents a
unique example of a site-selective C(sp2)−N arylation, with
DFT calculations supporting aza-Nazarov type cyclization
following a radical Smiles rearrangement process.
C
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Scheme 3. a) Regioconvergent Methods; b) Access to Pyrido[1,2-a]indole and Azepino[1,2-a]indole Motifs; c) Reactions
under Photoredox-Catalyzed Conditions
Scheme 4. Proposed Mechanism
tional details, Cartesian coordinates, crystal data, and
copies of NMR spectra for all products (PDF)
Accession Codes
CCDC 2043669−2043672 and 2043674 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
■
Corresponding Authors
Paul W. Davies − School of Chemistry, University of
Birmingham, Birmingham B15 2TT, U.K.; orcid.org/
0000-0002-0340-2414; Email: p.w.davies@bham.ac.uk
Wei Shu − Shenzhen Grubbs Institute, Department of
Chemistry, and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
a
Substrate 1 with Ar1 = electron-rich aryl group, Ar2 = electron-
Shenzhen, Guangdong, P.R. China; orcid.org/0000-
deficient aryl group was taken as example for clarity. n = 1, 2, 3.
0003-0890-2634; Email: shuw@sustech.edu.cn
Authors
Sifan Li − Shenzhen Grubbs Institute, Department of
Chemistry, and Guangdong Provincial Key Laboratory of
Catalysis, Southern University of Science and Technology,
Shenzhen, Guangdong, P.R. China; School of Chemistry,
University of Birmingham, Birmingham B15 2TT, U.K.
Yu Wang − Shenzhen Grubbs Institute, Department of
Chemistry, and Guangdong Provincial Key Laboratory of
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02519.
■
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Experimental procedures, mechanistic investigations,
characterization data, energy level diagrams, computa-
D
https://doi.org/10.1021/acs.orglett.1c02519
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Catalysis, Southern University of Science and Technology,
pubs.acs.org/OrgLett
Letter
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Shenzhen, Guangdong, P.R. China
Zibo Wu − Key Laboratory of Synthetic and Natural
Functional Molecule of the Ministry of Education, College of
Chemistry and Materials Science, Northwest University,
Xi’an, Shaanxi, P.R. China
Weiliang Shi − Key Laboratory of Synthetic and Natural
Functional Molecule of the Ministry of Education, College of
Chemistry and Materials Science, Northwest University,
Xi’an, Shaanxi, P.R. China
Yibo Lei − Key Laboratory of Synthetic and Natural
Functional Molecule of the Ministry of Education, College of
Chemistry and Materials Science, Northwest University,
Xi’an, Shaanxi, P.R. China
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https://pubs.acs.org/10.1021/acs.orglett.1c02519
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We sincerely acknowledge NSFC (21971101 and 21801126),
Thousand Talents Program for Young Scholars, Guangdong
Basic and Applied Basic Research Foundation
(2019A1515011976), The Stable Support Plan Program of
Shenzhen Natural Science Fund (No. 20200925152608001),
The Pearl River Talent Recruitment Program
(2019QN01Y261), and Guangdong Provincial Key Labora-
tory of Catalysis (No. 2020B121201002) for financial support.
The calculations were performed at the chemical HPC center
of NMU. P.W.D. gratefully acknowledges the Royal Society
and Leverhulme Trust for the award of a Senior Research
Fellowship (SRF\R1\191033). We acknowledge the assis-
tance of SUSTech Core Research Facilities. We thank Dr.
Xiaoyong Chang (SUSTech) for X-ray crystallographic
analysis of 3e (CCDC 2043670), 3m (CCDC 2043671), 3t
(CCDC 2043669), 10a (CCDC 2043672), 10b (CCDC
2043674) and Dr. Mingshang Liu (SUSTech) for reproducing
the results of 3d, 3j, 3w and 5b.
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