A one-pot method for the preparation of 2,5-diarylthiophene-1-oxides from arylacetylenes

Article abstract of DOI:10.1016/j.tetlet.2016.03.051

2,5-Diarylthiophene-1-oxides have been prepared from readily available arylacetylene precursors via zirconacyclopentadiene intermediates. The isolated yields of the desired thiophene-1-oxides are comparable to those obtained from the oxidation of thiophen

Full text of DOI:10.1016/j.tetlet.2016.03.051

Tetrahedron Letters 57 (2016) 1860–1862
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A one-pot method for the preparation of 2,5-diarylthiophene-1-
oxides from arylacetylenes
Robert W. Miller a, Nicholas J. Dodge a, Adam M. Dyer a, Eleanor M. Fortner-Buczala b, Adam C. Whalley a,
⇑
a Department of Chemistry, University of Vermont, Burlington, VT 05405, United States
b Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
2,5-Diarylthiophene-1-oxides have been prepared from readily available arylacetylene precursors via
zirconacyclopentadiene intermediates. The isolated yields of the desired thiophene-1-oxides are compa-
rable to those obtained from the oxidation of thiophene derivatives while avoiding the formation of
over-oxidation products. Furthermore, this route offers broader versatility than commonly used methods
by providing products outfitted with electron-donating or electron-withdrawing groups with very little
variation in isolated product yields. Finally, this strategy provides access to products containing
functional groups that are not compatible with oxidation conditions.
Received 2 March 2016
Accepted 16 March 2016
Available online 17 March 2016
Keywords:
Thiophene oxides
Aryl acetylenes
Zirconocene
Ó 2016 Elsevier Ltd. All rights reserved.
Metallole heterocycles
Diels–Alder
The [4+2] cycloaddition reaction—commonly known as the
Diels–Alder reaction—has had a profound effect on synthetic
organic chemistry due to its ability to generate 6-membered rings
with high regio- and stereochemical control.1 As a result, the reac-
tion has found utility in areas ranging from natural product synthe-
sis2 to the preparation of organic materials.3 Of particular interest
to the field of polycyclic aromatic hydrocarbons (PAHs) are cyclic
dienes that undergo Diels–Alder reactions with alkynes then sub-
sequently fragment to produce substituted benzene rings in a sin-
gle synthetic step. Although there is potential for dienes outfitted
with aryl groups at the 1- and 4-positions to act as synthons for
the fabrication of PAHs, such compounds are surprisingly uncom-
mon. While 2,5-diarylated thiophene, thiophene dioxides, and fur-
ans are synthetically accessible, these compounds typically require
the use of strongly activated dienophiles or forcing conditions
(high temperatures and/or pressures) to react by cycloaddition.4
Cyclopentadienone and isobenzofuran derivatives are inherently
more reactive but synthesizing the 2,5-diarylated analogs of these
compounds without additional substituents is nearly impossible.5
Thiophene-1-oxides,6 originally identified as intermediates in the
oxidation of thiophenes to thiophene dioxides, on the other hand,
have recently shown the potential to behave as highly reactive
dienes in the synthesis of PAHs.7 Despite these recent advances,
however, these dienes have yet to find widespread utility, likely
as a result of the absence of methodology capable of consistently
providing functionalized derivatives. To remedy this situation we
have developed a one-pot strategy that converts easily accessible
arylacetylenes into 2,5-diarylthiophene-1-oxides. Importantly,
the yields achieved through this process are comparable to those
achieved through the most commonly used oxidation strategies,
but with a much higher functional group tolerance.
Thiophene-1-oxides are commonly synthesized through the
oxidation of the corresponding thiophene derivative. The earliest
example of this strategy employed m-chloroperoxybenzoic acid
(mCPBA) as the oxidizing agent, however, this could only provide
thiophene-1-oxides bearing bulky substituents (in order to prevent
self-dimerization) in very low yields (ꢀ5%); the majority of the
material recovered from these reactions being the sulfone—the
product of over-oxidation.8 It was later realized that the introduc-
tion of either a strong Brönsted–Lowry9 or Lewis acid10 to the
oxidative conditions hinder the over-oxidation process resulting
in an improvement in reaction yields. In our studies, we were
⇑
Corresponding author. Tel.: +1 802 656 8246; fax: +1 802 656 8705.
E-mail address: Adam.Whalley@uvm.edu (A.C. Whalley).
Scheme 1. The synthesis of 2,5-diphenylthiophene-1-oxide through zirconacy-
clopentadiene intermediate.
http://dx.doi.org/10.1016/j.tetlet.2016.03.051
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

R. W. Miller et al. / Tetrahedron Letters 57 (2016) 1860–1862
1861
Table 1
Reaction substrate scope
An alternate strategy for the synthesis of thiophene-1-oxides
relies on the reaction of zirconacyclopentadiene precursors with
either thionyl chloride11 or sulfur dioxide.12 This method is
particularly attractive as it avoids the undesired over-oxidation
discussed above and exhibits a greater functional group tolerance.
Although a vast array of metallole heterocycles have been derived
from zirconacyclopentadiene intermediates,11,13 these reactions
almost exclusively employ disubstituted acetylenes for the gener-
ation of tetrasubstituted species. Terminal acetylenes, on the other
hand, have only been employed on a handful of occasions14 likely
due to the fact that such systems have been observed to lead to
mixtures of the regioisomeric 2,4- and 2,5-disubsituted products.15
Surprisingly, the conditions presented herein produce only the 2,5-
diarylated product and we did not observe any of the undesired
isomers from our reactions mixtures.16
A simple example of the one-pot synthesis of 2,5-diarylthio-
phene-1-oxides is displayed in Scheme 1. Initially, ‘Cp2Zr’ was
generated by the slow addition of n-BuLi to Cp2ZrCl2 at À78 °C
under a nitrogen atmosphere. The reaction mixture was allowed
to warm to room temperature until a dark red solution developed.
Phenylacetylene (1a) was then added at 0 °C to generate the
diphenylzirconacyclopentadiene intermediate (2a). The reaction
mixture was then cooled back down to À78 °C and thionyl chloride
was added drop-wise to the reaction mixture affording a bright
yellow solution. The cold reaction mixture was directly added to
a plug of silica and the product (3a) was eluted in 30% yield
(Table 1, entry 1).
It is important to note that our initial attempts to perform these
reactions using standard Negishi workup conditions resulted in
surprisingly low (ca. 5%) yields of the desired thiophene-1-
oxides.17 Additionally, crude reaction mixtures that were left in a
À20 °C freezer overnight were devoid of the desired product upon
subsequent analysis. We suspect that byproducts resulting from
the thermal decomposition18 of the ‘Cp2Zr’ (namely 1-butene and
cyclopentadiene), are capable of reacting in a Diels–Alder fashion
with our desired product. Unfortunately, we were unable to con-
firm the existence of such adducts through mass spectral analysis
of the crude reaction mixture. Nonetheless, considerably better
yields can be achieved by filtering the cold reaction mixture
through a plug of silica and eluting any potentially reactive inter-
mediates with hexanes prior to isolating the desired compound
using more polar eluents. The isolated products undergo slight
decomposition when left in organic solvents for extended periods
of time but they can be stored as solids at 0 °C for months with lit-
tle to no decomposition.
Having established that the desired reactivity could be achieved
we were excited to find that the reaction is tolerant of a range of
electronically diverse functional groups, as observed in Table 1.
When electron-donating functionality was introduced to the para
position of the aryl ring of the arylacetylene—such as the methyl
(1b) and methoxyl (1c) substituted derivatives—we observed the
formation of products 3b and 3c in yields that were nearly identi-
cal to that of the unsubstituted precursor (3a). When the methoxyl
group is shifted meta to the alkyne (1d), where it is theoretically
less able to donate electron-density into the triple-bond, surpris-
ingly no decrease in yield is observed. Even the veritrole-based sys-
tem (1e) equipped with two electron-donating methoxyl groups
displays only a minor increase in the yield of 3e compared to the
less electron-rich systems. At the opposite end of the spectrum,
we observe a slight but significant decrease in the yield when
mildly electron-withdrawing fluorine groups are installed on the
aryl ring (1f) and a complete loss of reactivity when nitro groups
are incorporated (1g). To investigate this observation we used den-
sity functional theory (DFT) calculations to generate electrostatic
potential maps (see Supporting information) of each of the ary-
lacetylenes listed in Table 1.19 These maps indicate the presence
Entry Substrate
Product
Yielda
(%)
1
30
30
29
28
32
23
0
2
3
4
5
6
7
8
9
27
29
10b
10
a
Isolated yield obtained by quenching with thionyl chloride.
Isolated yield obtained by quenching with SO2.
b
surprised to find, however, that these oxidation strategies were
intolerant of a variety of functional groups installed on the aryl
rings of 2,5-diarylthiophenes, most notably alkoxy and alkyl moi-
eties. Furthermore, for the compounds that could be successfully
oxidized, the reactions had to be monitored closely to limit the
formation of the sulfone and as a result the yields of these reac-
tions varied significantly.

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R. W. Miller et al. / Tetrahedron Letters 57 (2016) 1860–1862
of a distinctly negative environment surrounding the alkyne for
each of the compounds except for 1g, which has a noticeably posi-
tive electrostatic potential surrounding the triple bond. Based on
this evidence, it is reasonable to conclude that the strongly
electron-withdrawing nature of the nitro group renders the alkyne
sufficiently electron-poor such that it is unable to react with the
generated ‘Cp2Zr’ species.
References and notes
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the 3- and 4-positions of each of the thiophene rings.
In summary, we have presented a convenient one-pot method
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from oxidation strategies while providing the desired products in
comparable yields. The methodology discussed in this Letter is tol-
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Acknowledgments
16. The position of the aryl substituents on each of the thiophene-1-oxide products
was confirmed using Heteronuclear Single Quantum Coherence (HSQC)
spectroscopy. The carbon alpha to the sulfoxide on the thiophene-1-oxide
ring has a characteristic downfield shift of ca. 150 ppm and for each substrate it
was confirmed that this carbon atom was not directly attached to a proton.
HSQC are provided in the SI.
The authors thank Monika Ivancic in the University of Vermont
NMR Laboratory for her assistance with 2D NMR experiments and
Bruce O’Rourke for HRMS analysis. Support for the HRMS instru-
mentation was provided in part by the NIH, Grant #S10-
OD018126. Summer support for E.M.F. was provided by a Noyce
Summer Internship (NSF DUE-0934714). A.C.W. thanks the Univer-
sity of Vermont for generous start-up funding.
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(b) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124.
18. Dioumaev, V. K.; Harrod, J. F. Organometallics 1997, 16, 1452.
19. Electrostatic potential maps were generated using DFT calculations (B3LYP
functional, LACVP** basis set for bromine and 6-31G** basis set for all other
atoms) performed using Jaguar (see Jaguar: Version 8.3, Maestro: Version 9.8,
Schrödinger, LLC, New York, USA, 2014) software package.
Supplementary data
20. Despite reports that the yields of similar systems were increased by replacing
thionyl chloride with sulfur dioxide (see Ref. 12a) this was not observed for our
substrates. However, reactions carried out under these conditions tended to
afford notably cleaner crude reaction mixtures.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.03.
051.