An umpolung oxa-[2,3] sigmatropic rearrangement employing arynes for the synthesis of functionalized enol ethers

Article abstract of DOI:10.1021/acs.orglett.1c00911

An oxa-[2,3] sigmatropic rearrangement involving arynes is reported featuring the umpolung of ketones, where the C=O bond polarity is reversed. The in situ-generated sulfur ylides from β-keto thioethers and arynes undergo efficient rearrangement allowing the facile and robust synthesis of functionalized enol ethers in high yields and excellent functional group compatibility. Preliminary mechanistic studies rule out the possibility of Pummerer-type rearrangement operating in this case.

Full text of DOI:10.1021/acs.orglett.1c00911

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Letter
An Umpolung Oxa-[2,3] Sigmatropic Rearrangement Employing
Arynes for the Synthesis of Functionalized Enol Ethers
Rahul N. Gaykar, Malini George, Avishek Guin, Subrata Bhattacharjee, and Akkattu T. Biju*
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ABSTRACT: An oxa-[2,3] sigmatropic rearrangement involving
arynes is reported featuring the umpolung of ketones, where the
CO bond polarity is reversed. The in situ-generated sulfur ylides
from β-keto thioethers and arynes undergo efficient rearrangement
allowing the facile and robust synthesis of functionalized enol
ethers in high yields and excellent functional group compatibility.
Preliminary mechanistic studies rule out the possibility of
Pummerer-type rearrangement operating in this case.
Scheme 1. Normal/Umpolung Reactivity of Aldehydes/
Imines and the Umpolung Oxa-[2,3] Sigmatropic
Rearrangement Presented Here
he reversal of inherent polarity and hence the normal
mode of reactivity (umpolung) of well-known functional
T
groups such as carbonyls have made available new and
unconventional possibilities for carbon−carbon bond-forming
reactions.1 For instance, the CO bonds of aldehydes are
intrinsically electrophilic, and a variety of nucleophiles can add
to the electrophilic carbon, leading to various bond-forming
reactions (Scheme 1A). However, the inherent polarity of
aldehydes can be inverted by conversion into 1,3-dithianes2 or
by catalysis using cyanides3 or N-heterocyclic carbenes.4 These
reactions proceed via the generation of acyl anion equivalents,
which are intercepted by electrophiles.5 Moreover, the innate
electrophilic reactivity of imines can be reversed to
nucleophilic reactivity in enantioselective reactions pioneered
by the groups of Shi and Deng (Scheme 1B).6,7 Although the
aldehyde and imine umpolung are known, reactions proceed-
ing via the polarity reversal of ketones have not been well
demonstrated. Herein, we present an oxa-[2,3] sigmatropic
rearrangement involving arynes for the transition-metal-free
route to enol ether derivatives.8 The nucleophilic attack of β-
keto thioethers on arynes generates 1,3-zwitterion I, and an
intramolecular proton transfer could form the key sulfur ylide
II, followed by an oxa-[2,3] sigmatropic rearrangement via the
polarity reversal of the keto group allowing the mild and
transition-metal-free synthesis of functionalized enol ethers
with good functional group compatibility (Scheme 1C).
With the advent of a transition-metal-free procedure for the
formation of arynes by the 1,2-elimination of 2-(trimethylsilyl)
aryl triflates using a fluoride source (Kobayashi method),9 the
chemistry of these electrophilic intermediates has received a
resurgence of interest in the past three decades.10 This
intermediate has been widely used in pericyclic reactions,
insertion into element−element bonds,11 three-component
coupling reactions,12 and various reactions catalyzed by
transition metals.13 Additionally, numerous molecular rear-
rangements can proceed via aryne intermediates.14 The
Received: March 16, 2021
Published: April 8, 2021
https://doi.org/10.1021/acs.orglett.1c00911
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3447−3452
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In one of the preliminary experiments, treatment of β-keto
thioether 1a with the benzyne engendered from Kobayashi
triflate precursor 2a9 with the aid of KF and 18-crown-6 in
THF furnished the desired enol ether derivative 3a in 91%
yield in 1 h (Scheme 2). Product 3a was derived from the oxa-
[2,3] sigmatropic rearrangement via the in situ-generated
sulfur ylide (II).20 The reaction was slightly less efficient using
CsF (instead of KF and 18-crown-6) in CH3CN as the solvent.
Having the optimal conditions realized, we then evaluated
the scope and limitations of this reaction. First, we checked the
variation of the β-keto thioether moiety (Scheme 3). A series
of β-benzoyl thioethers bearing electron-releasing, -neutral, and
-withdrawing substituents at the para position of the phenyl
group underwent efficient oxa-[2,3] sigmatropic rearrangement
in a short period of time (1−3 h) under the present conditions
leading to the synthesis of the enol ethers in 69−91% yields
Scheme 2. Reaction of β-Keto Thioether with Benzyne
products formed from the aryne-induced rearrangements (such
as those of Claisen,15 Smiles,16 Stevens,17 and Sommelet-
Hauser18) cannot be readily accessed using other methods
under mild conditions. Notably, all of these rearrangements
proceed without polarity reversal. In this context, we
envisioned the oxa-[2,3] sigmatropic rearrangement involving
arynes featuring the umpolung of ketones where the CO
bond polarity is reversed.19
e
Scheme 3. Substrate Scope of the Aryne Oxa-[2,3] Sigmatropic Rearrangement
a
b
1
Yield of the experiment carried out on a 2.0 mmol scale. The diastereomer ratio was established by H NMR analysis of the crude reaction.
c
d
e
1
Reaction performed on a 0.25 mmol scale. The regioisomer ratio was ascertained by H NMR analysis of the crude reaction. Reaction
conditions: 1 (0.5 mmol), 2 (0.6 mmol), KF (1.2 mmol), 18-crown-6 (1.2 mmol), THF (2.0 mL), 25 °C, reaction time in parentheses. Isolated
yields of the products are given.
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(3a−3h). This is an indication that the outcome of this
rearrangement is not affected by the electronic nature of the
benzene ring.21 Moreover, substitutions at the meta and ortho
positions of the β-aryl ring were acceptable under the
optimized conditions to furnish the expected enol ethers in
good yields of >80% in all cases (3i−3n). In addition,
thioethers having disubstitution on the β-aryl ring also
underwent smooth rearrangement allowing the synthesis of
the target enol ether derivatives (3o−3s). Notably, thiophene-
substituted thioether 1t afforded rearranged enol ether 3t in
73% yield.
Scheme 4. Experiments toward the Reaction Mechanism
Then, we varied the ester moiety of β-keto thioether 1. A
variety of substrates bearing linear, branched, and unsaturated
alkoxy moieties on the thioether reacted fine under the
optimized conditions to provide the enol ether products in
good yields (3u−3aa). Interestingly, chiral groups such as
menthol, cholesterol, and amino alcohol as well as a
monoterpenoid geraniol could be used as the alkoxy
substituent of the thioether, and in every case, the target
products were isolated in high yields (3ab−3ae). In addition,
thioethers having amide and Weinreb amide were also well
tolerated (3af and 3ag). Furthermore, thioethers with β-alkyl
groups also underwent smooth aryne-triggered rearrangement
and delivered the expected enol ethers in reasonable yields
(3ah−3al).
With regard to the variation of arynes, a series of
electronically different symmetrical benzynes produced from
the respective Kobayashi triflate substrates reacted well with β-
keto thioether 1a, and in all cases, the enol ether derivative was
isolated in good yields (3am−3ar). The symmetrical
naphthalyne produced from TMS-triflate 2g furnished 3ar in
82% yield. The unsymmetrical naphthalyne generated from
triflate 2h produced a mixture of regioisomers that are
inseparable (3ar and 3as in 84% yield and 1.2:1 ratio).
Interestingly, the unsymmetrical 3-methoxy benzyne derived
from 2i delivered a single regioisomer 3at in 84% yield. Finally,
the unsymmetrical methyl-, chloro-, and fluoro-substituted
arynes produced from the corresponding precursors 2j−2l
provided the target products as a mixture of regioisomers that
are inseparable (3au−3aw).
formation of nucleophile trapping product 6 (Scheme 4C).
This result is also an indication that the present aryne reaction
is not proceeding via the Pummerer-type rearrangement.25
Moreover, intermolecular competition experiments carried out
using 1a and allyl thioether 7 provided an ∼1:1 ratio of oxa-
[2,3] sigmatropic rearrangement product 3a and [2,3]
sigmatropic rearrangement derivative 8, indicating that both
rearrangements proceed at a similar rate (Scheme 4D).
The present oxa-[2,3] sigmatropic rearrangement is not
limited to β-keto thioethers bearing an ester moiety, but
instead, β-diketo thioether 9a can be employed in this reaction
to furnish rearranged product 10a in 95% yield (Scheme 5A).
The functionalization of the enol ether products was also
carried out (Scheme 5B). Treatment of 3 with MeNH2
afforded amide products 11 and 12 in good yields. The
structure of 11 was further established unambiguously by X-ray
studies.26 Moreover, the ester hydrolysis and a subsequent
intramolecular cyclization in tandem furnished 1,3-dioxolan-4-
one derivatives 13 and 14 in reasonable yields and high
diastereoselectivity.
Mechanistically, sulfur ylide II derived from the initially
generated 1,3-zwitterion I [formed from 1 and aryne (Scheme
1C)] could undergo the oxa-[2,3] sigmatropic rearrangement
to furnish enol ether derivative 3a (Scheme 4A, path 1).
Alternatively, ylide II could undergo a fragmentation thus
generating a sulfonium species III and an enolate IV in a
Pummerer-type rearrangement.22 Recombination of intermedi-
ates III and IV could result in the formation of product 3 (path
2). This pathway proceeds without the umpolung of ketones.
To shed light on the reaction mechanism, some mechanistic
experiments were carried out. Crossover experiments carried
out using different thioethers 1h and 1u with benzyne
generated from 2a under optimized conditions furnished
products 3h and 3u in 73% and 92% yields, respectively
1
[determined by H NMR spectroscopy (Scheme 4B)]. Under
these conditions, crossover products 3ax and 3ay are not
observed. The formation of no crossover products is likely an
indication that the Pummerer pathway is not operating in the
case presented here.20,23 To gain further insight, the treatment
of 1a and 2a in the presence of an external nucleophile (4) was
performed, in an effort to intercept intermediate III.
Interestingly, this experiment furnished enol ether 3a in 94%
yield and aryne-inserted derivative 524 in 9% yield without the
In summary, we have presented a facile and robust oxa-[2,3]
sigmatropic rearrangement featuring the umpolung of ketones.
The in situ-generated sulfur ylides from β-keto thioethers and
arynes undergo efficient rearrangement allowing the synthesis
of enol ether derivatives in moderate to good yields with
relatively short reaction times. A series of thioethers and
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Scheme 5. Synthetic Utility of the Method
ACKNOWLEDGMENTS
■
Generous financial support by the Science and Engineering
Research Board (SERB), Government of India (File EMR/
2016/007021), is gratefully acknowledged. R.N.G. thanks IISc
(for SRF), A.G. MHRD (for PMRF), and S.B. CSIR (for SRF)
for s research fellowships. The authors thank Dr. Tony Roy
(CSIR-NCL) for fruitful discussion and Mr. Sujit Kamilya
(SSCU, IISc) and Dr. M. Venkateswarulu (IPC, IISc) for
collecting the crystal data of 11.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00911.
Detailed experimental procedures, characterization, and
NMR spectra of functionalized enol ethers (PDF)
Accession Codes
CCDC 2058553 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, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
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Corresponding Author
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Akkattu T. Biju − Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India; orcid.org/
0000-0002-0645-8261; Email: atbiju@iisc.ac.in
Authors
Rahul N. Gaykar − Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India
Malini George − Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India
Avishek Guin − Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560012, India
Subrata Bhattacharjee − Department of Organic Chemistry,
Indian Institute of Science, Bangalore 560012, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00911
Notes
The authors declare no competing financial interest.
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Organic Letters
pubs.acs.org/OrgLett
Letter
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(20) For details, see the Supporting Information.
(21) Product 3a was formed in 88% yield in 2 h when the reaction
was performed on a 2.0 mmol scale, indicating that this method is
scalable.
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performed using β-keto thioethers 1b and 1u.
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(25) The reaction carried out using ethyl acetoacetate as the external
nucleophile provided similar results.
(26) CCDC 2058553 (11) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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