Radical Cascade Reaction of Aryl Alkynoates at Room Temperature: Synthesis of Fully Substituted α,β-Unsaturated Acids with Chalcogen Functionality

Article abstract of DOI:10.1021/acs.orglett.8b01474

A radical-based cascade reaction has been devised for oxidative difunctionalization of aryl alkynoates at room temperature to access stereodefined fully substituted α,β-unsaturated acids bearing a chalcogen functionality in high yields (up to 95%). The protocol is operationally simple, metal-free, scalable, and suppresses the usual CO₂ exclusion phenomenon. The utility of this method was showcased in the synthesis of vinyl halides, vinyl selenides, and 3,3-disubstituted indanones.

Full text of DOI:10.1021/acs.orglett.8b01474

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Radical Cascade Reaction of Aryl Alkynoates at Room Temperature:
Synthesis of Fully Substituted α,β-Unsaturated Acids with Chalcogen
Functionality
Harekrishna Sahoo, Saibal Singh, and Mahiuddin Baidya*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, Tamil Nadu, India
S
* Supporting Information
ABSTRACT: A radical-based cascade reaction has been
devised for oxidative difunctionalization of aryl alkynoates at
room temperature to access stereodefined fully substituted
α,β-unsaturated acids bearing a chalcogen functionality in high
yields (up to 95%). The protocol is operationally simple,
metal-free, scalable, and suppresses the usual CO2 exclusion
phenomenon. The utility of this method was showcased in the
synthesis of vinyl halides, vinyl selenides, and 3,3-disubstituted indanones.
ryl alkynoates are reliable coupling partners in atom transfer
radical cascade reactions, and various molecular frameworks
have been constructed taking advantage of the radical acceptor
property of the activated alkyne functionality.1−3 Recently, this
radical cascade has been advanced for 1,4-aryl migration that
resembles Smiles rearrangement (see Scheme 1a).4,5 All of these
synthesis of tetrasubstituted α,β-unsaturated acids decorated
with four different substituents is highly challenging, because of
difficulties in controlling the stereoselectivity. The situation
becomes particularly more daunting where acyclic systems with
sensitive functional groups and heteroatom substitutions are
concerned. In our approach, an exquisite stereo control is
expected, as both radical addition and 1,4-aryl migration steps
would proceed in a highly regioselective fashion.
Molecules comprising C−Se and C−S bonds, or organo-
chalcogenides, represent an important structural motif in
bioactive molecules.7 They are pivotal building blocks in
synthetic organic chemistry and have found extensive
applications in functional materials.8 Consequently, synthetic
methods that efficiently install a chalcogen functionality into
organic molecules are highly desirable. With our continuous
interest in organochalcogenide chemistry,9 herein, we report an
unprecedented metal-free atom transfer radical cascade reaction
for difunctionalization of aryl alkynoates with diselenides and
thiols en route to fully susbtituted α,β-unsaturated acids
embracing a chalcogen functionality at room temperature (see
Scheme 1b). The synthetic utility of this protocol was further
highlighted through the production of vinyl selenides, vinyl-
halides, and 3,3-disubstituted indanones.
A
Scheme 1. Radical-Based Rearrangement of Aryl Alkynoates
and Synthesis of Substituted Olefins and α,β-unsaturated
acids
We commenced our investigation with the reaction of aryl
alkynoate 1a with diphenyldiselenides 2a. Gratifyingly, when the
mixture of 1a and 2a was stirred in the presence of tert-butyl
hydroperoxide (TBHP) as the oxidant at room temperature in
acetonitrile solvent, selenium-radical-induced cascade rearrange-
ment with 1,4-aryl migration from the oxygen center to the
carbon center occurred smoothly to deliver desired tetrasub-
stituted alkene 3a in 95% isolated yield (Table 1, entry 1). The
compound 3a was crystallized, and X-ray analysis unambiguously
established the structure of the acid. It also supports the
radical-based rearrangements were primarily performed at
elevated temperature, and only trisubstituted olefins were
obtained after the decarboxylation process (Path I, Scheme
1a).6 We envisioned that the decarboxylation step would be
interrupted if the radical-based Smiles rearrangement process can
be executed under mild conditions. If successful, the protocol will
not only disclose a new mode of radical cascade of aryl
alkynoates, but also deliver unsymmetrically tetrasubstituted
acyclic olefins embracing carboxylic acid as one of the
substituents (Path II, Scheme 1a). Note that the presence of a
carboxylate functionality is advantageous, since it can be easily
transformed to a broad range of functional groups, indicating
wide application prospects in chemical production. Furthermore,
Received: May 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01474
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Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope for Radical Cascade Selenylation
of Aryl Alkynoates
a
entry
deviation from optimal conditions
yield (%)
1
2
none
95
68
DCE instead of MeCN
THF instead of MeCN
toluene instead of MeCN
DMSO instead of MeCN
DMF instead of MeCN
MeOH instead of MeCN
DCP instead of TBHP
DTBP instead of TBHP
H2O2 instead of TBHP
under air atmosphere
3
44
4
56
5
trace
27
6
7
32
8
15
9
trace
trace
77
10
11
12
13
14
15
16
1.5 equiv of TBHP was used
1.0 equiv of TBHP was used
without TBHP
75
48
0
1.5 equiv of PhSeSePh was used
1.0 equiv of PhSeSePh was used
81
54
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), TBHP in
decane solution (0.4 mmol), MeCN (1.5 mL), room temperature (rt),
24 h. Isolated yields. TBHP = tert-butyl hydrogen peroxide; DCP =
dicumyl peroxide; DTBP = di-tert-butyl peroxide.
regioselective outcome, which is consistent with the postulated
reaction mechanism depicted in Scheme 1. Screening of other
solvents, such as tetrahydrofuran (THF), methyl alcohol
(MeOH), dimethyl sulfoxide (DMSO), and dimethyl formamide
(DMF), instead of CH3CN, gave inferior results (Table 1, entries
2−7). The reaction was very sluggish when oxidants such as
dicumyl peroxide (DCP), di-tert-butyl peroxide (DTBP), and
hydrogen peroxide (H2O2) were tested, and the starting material
1a was recovered for all these cases (Table 1, entries 8−10). The
yield was also reduced from 95% to 77%, when the reaction was
carried out in open air (Table 1, entry 11). The output was highly
governed by tert-butyl hydrogen peroxide (TBHP) loading; the
reaction yields gradually decreased with the lowering of the
amount of TBHP and was completely shut down in the absence
of TBHP (Table 1, entries 12−14). Examination of the amount
of diselenide 2a in the reaction revealed that the yield dropped
significantly with the reduction of diselenide loading (Table 1,
entries 15 and 16).
With the optimized conditions in hand, the scope of the
cascade process was explored (see Scheme 2). The reaction was
quite general for a wide range of aryl alkynoates having electron-
donating substituents such as methyl (3c and 3i), alkoxy (3d and
3k) and electron-withdrawing substituents, such as bromo (3e),
cyano (3f), fluoro (3g), and trifluoromethyl (3h) at the para- and
meta-positions of the O-aryl ring, delivering fully substituted α,β-
unsaturated acids in high yields (61%−93%). Satisfyingly, ortho-
substituted hindered aryl alkynoates also produced desired
products 3k and 3l in 62% and 55% yields, respectively. Naphthyl
and biphenyl substitutions did not hamper the radical cascade
process to offer 3m and 3n in good yields. Variation in the alkyne
aryl substituent was also considered; para (3o−3q), meta (3r),
and ortho (3s) substituted alkynoates provided the desired
products in good yields (57%−92%).
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), TBHP in
decane solution (0.4 mmol), MeCN (1.5 mL), rt, 24 h. Yields of
isolated products are given.
The reaction efficiency of different diselenides was also
investigated (see Scheme 2). Diaryl diselenides with different
halogens (3t and 3u), ethyl (3v), and trifluoromethyl (3w)
substituents furnished products in moderate to high yields
(55%−89%). Interestingly, when thio-bis(4,1-phenylene)bis(3-
phenylpropiolate) (1x) was exposed to the standard reaction
conditions, a 2-fold cascade rearrangement occurred efficiently
and the olefin 3x with a thio ether link was isolated in 52% yield.
The scaleup was also compatible and a gram-scale reaction of
alkynoate 1y rendered the desired product 3y in 78% yield (see
Scheme 2).
The versatility of the protocol was further tested using
different organochalcogenides. While the exposure of PhSSPh to
aryl alkynoate 1a under standard reaction conditions was unable
to deliver sulfur-substituted acid 5a, the sulfenyl radical-based
cascade rearrangement with stipulated regioselectivity occurred
smoothly with simple thiophenol under the same conditions
B
DOI: 10.1021/acs.orglett.8b01474
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(Scheme 3). Further optimization revealed that the utilization of
TBHP for the installation of sulfenyl functionality was not
The synthetic utility of the protocol was further highlighted
through the synthesis of substituted indanones, which are
important scaffolds. Accordingly, product 3y was treated with
triflic acid at 100 °C in toluene and chlorobenzene solvents
separately, furnishing 3,3-disubstituted indanones 10a and 10b,
in 98% and 66% yields, respectively (see Scheme 5). Here, an
intramolecular cyclization involving a 1,4-addition reaction of
solvent molecules occurred (details are included in the
Supporting Information (page S6)).
Scheme 3. Substrate Scope for Radical Cascade Sulfenylation
a
of Aryl Alkynoates
Scheme 5. Synthesis of 3,3-Disubstituted Indanones
In order to gain mechanistic insight, various control
experiments were performed (see Scheme 6). The reaction was
Scheme 6. Control Experiments
a
Reaction conditions: 1 (0.2 mmol), 4 (0.4 mmol), O2 balloon,
MeCN (1.5 mL), rt, 24 h. Yields of isolated products are given.
mandatory and the reaction was fruitful in the presence of
molecular oxygen only, producing 5a in 77% yield (Scheme 3).
Irrespective of the substitution patterns, both electron-rich and
electron-deficient aryl thiols delivered the desired sulfur-
substituted α,β-unsaturated acids 5a−5j in uniformly high yields
(68%−81%; see Scheme 3).
The formed tetrasubstituted alkenes with a carboxylate
functional group demonstrated versatile reactivity. Treatment
of 3y with NIS or NBS in the presence of DTBP at 120 °C
triggered a decarboxylative cross-coupling process to give
selenylated vinyl iodide (6a) and bromide (7), respectively
(see Scheme 4). With the product 3a having different β-aryl
unproductive in the presence of radical scavengers such as
TEMPO and butylated hydroxytoluene (BHT), suggesting the
involvement of a radical species in the reaction pathway (Scheme
6a). The reaction of aryl alkynoate 1z having a bis ortho-
substituted aromatic ring gave the desired product in 44% yield,
refuting classical neighboring group participation process
(Scheme 6b).6a Also, when 1za was subjected to the standard
reaction conditions, no 1,4-migration product 3za was observed;
instead, a diselenylated product 3za′ was isolated in 20% yield
(see Scheme 6c). All these findings favor a spiro-cyclic
intermediate6b for the radical-based cascade process.
Scheme 4. Post-functionalization of the Selenylated Products
Post-functionalization of the Selenylated Product
Based on these findings and previous reports,6 a plausible
reaction mechanism is outlined in Scheme 7. The aryl chalogen
radical generated upon treatement with TBHP or O2 reacts with
Scheme 7. Plausible Reaction Mechanism
groups, iodinated compound 6b was isolated in a 1:1 mixture of
regioisomers.6g The halogen functionalities provide a good
synthetic handle for further synthetic modifications. When the
decarboxylative cross-coupling was performed with diselenide
2a, geminal diselenoether 8 was formed in 75% yield. In the
absence of any cross-coupling partner, vinyl selenide 9 was
isolated in 84% yield (Scheme 4).10
C
DOI: 10.1021/acs.orglett.8b01474
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In conclusion, we have developed a metal-free radical-based
cascade reaction of aryl alkynoates at room temperature to
provide a series of unsymmetrically tetrasubstituted α,β-
unsaturated acids with a chalcogen functionality in good to
excellent yields. The process involves the construction of C−Se/
S, C−C bonds and the cleavage of a C−O bond in a single
operation and overcomes the well-known CO2 exclusion
phenomenon. The protocol is operationally simple, scalable,
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efficiently utilized for a novel decarboxylative radical cross-
coupling to access vinyl halides, vinyl selenides, and geminal
diselenoethers, and in the synthesis of 3,3-diaryl indanones.
Control experiments support a radical mechanism for this
process. Further applications of this strategy in other carbon−
heteroatom bond forming reactions are currently being pursued
in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01474.
Complete experimental details, characterization data for
the prepared compounds (PDF)
Accession Codes
14480. (g) Quint, V.; Morlet-Savary, F. M.; Lohier, J.-F.; Lalevee
́
, J.;
CCDC 1825820 and 1825821 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
Gaumont, A.-C.; Lakhdar, S. J. Am. Chem. Soc. 2016, 138, 7436.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mbaidya@iitm.ac.in.
ORCID
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Mahiuddin Baidya: 0000-0001-9415-7137
Notes
Chemistry of the Elements; Oxford University Press: New York, 2001.
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(c) Debnath, S.; Chithiravel, S.; Sharma, S.; Bedi, A.; Krishnamoorthy,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge DST-India (No. EMR/2014/
000225) and IIT-Madras (No. CHY1819853RFIRMDMA) for
financial support. H.S. thanks IIT-Madras for HTRA.
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DOI: 10.1021/acs.orglett.8b01474
Org. Lett. XXXX, XXX, XXX−XXX