Gold-Catalyzed Cycloisomerization of Sulfur Ylides to Dihydrobenzothiepines

Article abstract of DOI:10.1002/chem.202000622

The metal-promoted nucleophilic addition of sulfur ylides to π-systems is a well-established reactivity. However, the driving force of such transformations, elimination of a sulfide moiety, entails stoichiometric byproducts making them unfavorable in terms of atom economy. In this work, a new take on sulfur ylide chemistry is reported, an atom-economical gold(I)-catalyzed synthesis of dihydrobenzo[b]thiepines. The reaction proceeds under mild conditions at room temperature.

Full text of DOI:10.1002/chem.202000622

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Accepted Article
Title: Gold-catalyzed cycloisomerization of sulfur ylides to
dihydrobenzothiepines
Authors: Nuno Maulide, Christian Knittl-Frank, Iakovos Saridakis,
Thomas Stephens, Rafael Gomes, James Neuhaus, Antonio
Misale, Rik Oost, and Alberto Oppedisano
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To be cited as: Chem. Eur. J. 10.1002/chem.202000622
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Gold-catalyzed cycloisomerization of sulfur ylides to
dihydrobenzothiepines
Christian Knittl-Frank,[a] Iakovos Saridakis,[a] Thomas Stephens,[a] Rafael Gomes,[a] James Neuhaus,[a]
Antonio Misale,[a] Rik Oost,[a] Alberto Oppedisano[a] and Nuno Maulide*[a]
[a]
C. Knittl-Frank, I. Saridakis, T. Stephens, Dr. R. Gomes, Dr. J. Neuhaus, Dr. A. Misale, Dr. R. Oost, Dr. A. Oppedisano, Prof. Dr. N. Maulide
Institute for organic Chemistry
University of Vienna
Währinger Strasse 38, 1090 Vienna
E-mail: nuno.maulide@univie.ac.at
Web: http://maulide.univie.ac.at
Supporting information for this article is given via a link at the end of the document.
Abstract: The metal-promoted nucleophilic addition of sulfur ylides to
π-systems is a well-established reactivity. However, the driving force
of such transformations, elimination of a sulfide moiety, entails
stoichiometric byproducts making them unfavorable in terms of atom
economy. Herein, we report on a new take on sulfur ylide chemistry,
an
atom-economical
gold(I)-catalyzed
synthesis
of
dihydrobenzo[b]thiepines. The reaction proceeds under mild
conditions at room temperature.
Six decades past the pioneering work of Johnson[1–3] and
Corey,[4,5] sulfonium and sulfoxonium ylides have arguably
become textbook reagents in organic synthesis.[6–10] In particular,
they serve as one-carbon synthons for the construction of small
rings such as epoxides,[11–17] cyclopropanes[11,17–20] and
aziridines[11,17,20–23] as well as for the synthesis of more complex
cores via rearrangement reactions.[24] Whilst the majority of the
initial studies were based on non-stabilized sulfonium and
sulfoxonium ylides, modern work exploits the reactivity of their
stabilized surrogates, in which electron density from the ylidic
carbon is distributed to one or two electron-withdrawing
functionalities. This in turn enables the utilization of these sulfur
ylides as practical and bench-stable reagents as well as the
development of novel reactivity. Indeed, applications of stabilized
sulfonium and sulfoxonium ylides have been expanded to
encompass noble transition metal catalysis,[8,9,25] in particular
Au(I).
Scheme 1. Reactivity of alkenes and alkynes with sulfonium ylides under gold(I)
Recently, our group has reported that gold-catalyzed
electrophilic activation of alkenes allows the construction of highly
functionalized cyclopropane scaffolds.[25–30] Prior to that, we[31]
and others[32] have demonstrated the synthesis of multi-
substituted furan cores through gold-catalyzed activation of
alkynes in the presence of sulfonium ylides, either in intra- or
intermolecular fashion. Interestingly, the majority of these and
related transition metal-catalyzed reactions of sulfur ylides mostly
employ variations on substituents tethered to the ylidic carbon. On
the other hand, only minor variations on the sulfur substitution
have been reported,[25,30] probably due to the fact that most of
those transformations eventually result in elimination of the sulfur
tether during the reaction, thus, leading to stoichiometric sulfide
byproducts (cf. Scheme 1a ii–iv).
catalysis.
Given our recent experience in the cycloisomerizations of S-
homoallyl sulfonium ylides (Scheme 1a i),[25] we became
interested in exploring the reactivity of analogous S-
homopropargyl sulfonium ylides. In this regard, initial experiments
involved the reaction of the readily available sulfonium ylide 1a[33]
with JohnPhos Au(MeCN)SbF6 (5 mol%) in MeOH at room
temperature, aiming at the formation of a trisubstituted furan,
inspired by a prior study of our group (Scheme 1a iv).[31] To our
surprise, the obtained spectroscopic data for the major product
were not in agreement with our hypothesis. Thorough analysis
revealed that dihydrobenzo[b]thiepine 2a was formed as a major
product in lieu of the anticipated furan (Scheme 1b). This
serendipitously discovered reactivity prompted us to investigate
the scope of this atom-economical transformation, especially
since the benzothiepine scaffold is a known pharmacophore.[34]
Herein, we report on a gold-catalyzed cycloisomerization of S-
homopropargyl
sulfonium
ylides
to
functionalized
dihydrobenzo[b]thiepines.[35]
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bond (cf. also Scheme 3). Hence, the reaction of 1f and 1g yielded
2f/2f’ and 2g with the propargyl and allyl moiety remaining intact,
respectively.
Furthermore, the acetylacetone derivative 1h afforded the
corresponding benzo[b]thiepine in moderate yield. It is noteworthy
that 2h resided solely in its enol form (in chloroform), whilst the
rest of the synthesized dihydrobenzo[b]thiepines 2 were present
in both tautomeric forms.
Finally, we surveyed the functionality tolerance on the southern
domain of the sulfonium ylides. Hence, different para- and ortho-
substituted S-aryl moieties were examined, and gratifyingly
delivered the desired benzothiepines 2i–l in modest to good
yields.
Figure 1. Scope of the Au(I)-catalyzed dihydrobenzo[b]thiepine synthesis. All
yields are isolated yields after column chromatography. Reactions were carried
out in 0.2 mmol scale. [a] Formation of isomer 2’ resulted in an inseparable
mixture. Given ratios determined by NMR after isolation. [b] Reaction at 50 °C.
Whilst minute amounts (5%) of the furan product could be
detected in initial setups, the addition of silver triflate and
employment of a binary solvent system (isopropanol/water 4:1
v/v) suppressed it entirely and was optimal for the
dihydrobenzo[b]thiepine formation (see SI for details). Hence, 2a
(along with its isomer 2a’) was isolated in 77% yield.[36]
Scheme 2. Probed chemoselectivity of propargylic and allylic esters 1f and 1g.
Conditions as in Figure 1.
To investigate the scope of our reaction we first screened
variations in the northern 1,3-dicarbonyl substituent. We found
that electron-neutral, -rich, and -poor aromatics were all well
tolerated (Figure 1, 2a–c). Interestingly, the p-NO2 substituted
sulfonium ylide 1c required higher temperature (50 °C) than the
rest of the substrates to reach full conversion. This might be
ascribed to the decreased nucleophilicity of the ylidic carbon, due
to better delocalization of its formal negative charge. Moreover,
the aliphatic β-keto esters 1d and 1e delivered the benzothiepine
in satisfying yields, too.
From a mechanistic point of view, we envisaged that the
reaction starts with activation of the alkyne by π-coordination to
the gold catalyst,[37] as shown in intermediate A (Scheme 3). An
intramolecular 5-exo-dig attack of the ylidic carbon to the internal
alkyne C-atom leads to a gold-vinyl complex B,[38] which
undergoes a charge-accelerated sulfonium [3,3]-sigmatropic re-
arrangement[24,35c,39] to furnish the seven-membered thiepine ring
C. Finally, rearomatization and protodeauration[40] deliver the
dihydrobenzo[b]thiepines 2, completing the catalytic cycle.
We then devised a competition experiment by subjecting the
sulfonium ylides 1f and 1g, bearing a propargyl and an allyl ester-
substituted ylidic C-atom to our reaction conditions, respectively.
In previously reported gold(I)-catalyzed processes, propargyl-
and allyl-tethered diphenylsulfonium ylides were readily
transformed
into
the
corresponding
furans[31]
and
cyclopropanes,[29] respectively. Following this reactivity, 1f would
react to the corresponding furan 2f’’ via an initial 5-exo-dig attack
of the ylidic carbon onto the gold(I)-activated triple bond followed
by a 5-endo-trig cyclization along with sulfide release (Scheme
2a).[31] Likewise, 1g would form cyclopropane 2g’’ after an initial
5-exo-trig attack of the ylidic C-atom onto the gold(I)-activated
double bond with a subsequent 3-exo-tet cyclization concomitant
with sulfide release (Scheme 2b).[29] In contrast to those reports,
the presence of the S-homopropargyl group completely shut
down this pathway in both cases examined. Thus, under our
reaction conditions we observed complete selectivity towards the
formation of dihydrobenzo[b]thiepines, via an initial attack of the
ylidic carbon onto the gold(I)-activated S-homopropargyl triple
Scheme 3. Proposed catalytic cycle for the formation of benzo[b]thiepines.
In
conclusion,
a
Au(I)-catalyzed
synthesis
of
dihydrobenzo[b]thiepines was developed. The mild conditions of
the cycloisomerization and the simple accessibility of the
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sulfonium ylide starting materials are distinctive characteristics of
this process. Interestingly, this process appears to supersede the
previously reported Au(I)-catalyzed intramolecular furan and
cyclopropane syntheses. The retention of the sulfur atom onto the
final product after the reaction is an unusual trait of metal-
catalyzed transformations of sulfonium ylides and enables the
development of atom-economical synthetic transformations.
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Generous support of this research by the FWF (DK MolTag
W1232), the ERC (StG FLATOUT and CoG VINCAT 682002 to
N.M.) and the SOCRATES-Erasmus program (fellowship to T.S.)
is acknowledged. We are very grateful to the University of Vienna
for continued support of our research programs. We also thank S.
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Keywords: alkynes • benzothiepines • gold • rearrangement •
sulfonium ylides
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Entry for the Table of Contents
Readily available S-homopropargyl sulfonium ylides are transformed to substituted dihydrobenzo[b]thiepines under Au(I) catalysis. This
atom-efficient transformation takes place under very mild conditions at ambient temperature and proceeds via a charge-accelerated
sulfonium [3,3]-sigmatropic rearrangement.
Institute and/or researcher Twitter usernames: @MaulideLab
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