Transition-Metal-Free Synthesis of C3-Arylated Benzofurans from Benzothiophenes and Phenols

Article abstract of DOI:10.1021/acs.orglett.8b03267

We report a transition-metal-free synthesis of benzofurans from benzothiophenes and phenols that exploits the unique reactivity of sulfoxides. Through a sequence involving an interrupted Pummerer reaction and [3,3] sigmatropic rearrangement, phenols can b

Full text of DOI:10.1021/acs.orglett.8b03267

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free Synthesis of C3-Arylated Benzofurans from
Benzothiophenes and Phenols
Kevin Yang, Alexander P. Pulis, Gregory J. P. Perry, and David J. Procter*
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, U.K.
S
* Supporting Information
ABSTRACT: We report a transition-metal-free synthesis of
benzofurans from benzothiophenes and phenols that exploits
the unique reactivity of sulfoxides. Through a sequence
involving an interrupted Pummerer reaction and [3,3]
sigmatropic rearrangement, phenols can be combined with
readily accessible yet synthetically unexplored benzothiophene
S-oxides to provide C3-arylated benzofuran products. The
products from this approach can undergo subsequent
functionalization to gain access to a range of important
benzofuran derivatives.
he benzofuran motif is a key structural unit found in a
variety of functional molecules, from naturally occurring
Scheme 1. (a−c) Current Methods for the Synthesis of
T
Benzofurans and (d) Using Sulfoxides for the Divergent
a
bioactive compounds to manmade organic electronics.1
Demand for this important subunit has resulted in a range of
methods for its construction.2 A common route for benzofuran
synthesis is through ring closure of ortho-substituted phenol
derivatives (Scheme 1a).3 However, the phenol generally
requires prefunctionalization (i.e., ortho-halogenated phenols I
are required), and the approach proceeds by (i) attachment of
the alkynyl/alkenyl chain via transition-metal-catalyzed cross-
coupling (I to II) followed by (ii) transition-metal-catalyzed
ring closure (II to III). More recently, efforts have targeted a
more direct synthesis of benzofurans via C−H coupling of
simple phenols with alkenes and alkynes (Scheme 1b).4
Despite this tremendous progress, most reactions require the
addition of transition metals and the development of routes to
benzofurans that do not require such metals remains an
important goal.
Synthesis of Benzothiophenes and Benzofurans
The trapping of nucleophiles by activated sulfoxides through
interrupted Pummerer-type processes has begun to spawn a
variety of useful transformations.5 In particular, this mode of
reactivity has allowed the facile transformation of C−H bonds
in the absence of transition metals.6 This mode of reactivity
has recently been harnessed by Yorimitsu and co-workers for
the synthesis of 2-methylthiobenzofurans by reaction of simple
phenols with ketene dithioacetal monoxides (Scheme 1c).7,8
We have recently described the arylation of benzothiophene
S-oxides, readily prepared from the parent benzothiophene by
simple oxidation, via an interrupted Pummerer-type reaction
(Scheme 1d, (i)).9 In this process, phenol substrates are
captured by activated benzothiophene S-oxides before [3,3]
sigmatropic rearrangement leads to the formation of the S,O-
acetals IV. Acid-mediated ring-opening of these intermediates
then provides the C3-arylated benzothiophenes through
cleavage of the C−O bond. This provides a novel route to
functionalized benzothiophenes and, importantly, does not
a
TM = transition metal.
require the use of transition-metal additives. In a proposed
divergent approach, we speculated as to whether the
intermediate thioacetals IV could also allow access to
Received: October 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03267
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Letter
benzofuran derivatives through selective cleavage of the C−S
bond (Scheme 1d, (ii)).
oxidize the thioacetal to the thioacetal S,S-dioxide. We
hypothesized that converting the sulfide to the sulfone would
render the C−S bond more susceptible to bond cleavage.10
Upon treatment of thioacetal 3a with m-CPBA, the desired
sulfone 4a was isolated in 68% yield. Both the thioacetal 3a
and the sulfone 4a could also be prepared on gram scale
without detriment to the yield.
The desired thioacetal S,S-dioxide 4a could also be directly
prepared from simple phenol and benzothiophene (Scheme
2b). Thus, following oxidation of benzothiophene 2 and
filtration, benzothiophene S-oxide 2′ was activated using
TFAA before addition of the phenol to form the thioacetal
3a in situ. The addition of m-CPBA to the same pot resulted in
the formation of the desired thioacetal S,S-dioxide 4a in 86%
overall yield. In general, the one-pot procedure provided
greater overall yields than the stepwise procedure.
Here, we describe a transition-metal-free synthesis of C3-
arylated benzofurans via the C−H functionalization of simple
phenol reagents. Our strategy represents a unique approach in
which one molecule, the benzothiophene, is deconstructed for
the assembly of another, the desired benzofuran. We also detail
how the benzofuran products can undergo further derivatiza-
tion through the use of desulfinylative cross-coupling methods.
This procedure demonstrates that a variety of synthetically
useful heterocyclic molecules can be constructed from simple
phenols and previously unexploited benzothiophene S-oxides.
To begin our investigation, we set about synthesizing the key
thioacetal intermediate 3a (Scheme 2). Using our previously
Scheme 2. (a) Preparation, Isolation, and X-ray
With an efficient method for the preparation of sulfones 4 in
hand, we assessed the generality of this sequence. The yields
provided in Scheme 3 are the result of the one-pot procedure,
Crystallographic Analysis of Thioacetal 3a and Thioacetal
S,S-Dioxide 4a and (b) One-Pot Synthesis of Thioacetal S,S-
Dioxide 4a
a
Scheme 3. Scope of the One-Pot Synthesis of Thioacetal
a
S,S-Dioxides
a
Reaction conditions. [O]: benzothiophene (1.0 equiv), m-CPBA
(1.2 equiv), BF3·OEt2 (8.0 equiv) then filtration. Sulfone formation:
TFAA (1.5 equiv), phenol (1.5 equiv), then m-CPBA (2.4 equiv).
reported conditions, we found that thioacetal 3a could be
prepared through activation of the benzothiophene S-oxide 2′
with trifluoroacetic anhydride (TFAA) followed by addition of
phenol 1. This provided the thioacetal 3a in 60% isolated yield.
The benzothiophene S-oxides 2′ were easily prepared from the
corresponding benzothiophenes 2. After oxidation of the
benzothiophene 2, the crude material was filtered to provide
the benzothiophene S-oxide 2′ as a solution in CH2Cl2 suitable
for use in subsequent steps. Importantly, isolation of the
sulfoxide was not required.
With the desired thioacetal in hand, we then considered
methods for cleaving the C−S bond in favor of the C−O bond.
From our previous report, we had observed cleavage of the C−
O bond in the presence of acid, which led to the formation of
C3-arylated benzothiophene products (Scheme 1d).9 Our
strategy for selective cleavage of the C−S bond was to first
a
Reaction conditions. [O]: benzothiophene (1.0 equiv), m-CPBA
(1.2 equiv), BF3·OEt2 (8.0 equiv) then filtration. Sulfone formation:
TFAA (1.5 equiv), phenol (1.5 equiv), then m-CPBA (2.4 equiv).
though we have also prepared and fully characterized each
thioacetal intermediate 3.11 A range of electron-deficient
phenols reacted well under the reaction conditions (4b−h).
Substituents in both the ortho and para positions of the phenol
were tolerated, although the para-substituted phenols provided
superior yields, likely due to less steric hindrance around the
B
DOI: 10.1021/acs.orglett.8b03267
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Letter
a
Scheme 4. Scope of the Transition Metal-Free Synthesis of Benzofurans
a
b
c
Reaction conditions: thioacetal S,S-dioxide 2 (1.0 equiv), NaOMe (1.5 equiv), MeI (1.5 equiv). R4−X (3.0 equiv). tBuOK used instead of
NaOMe.
point of bond formation (4a−g). When meta-substituted
phenols were used, a mixture of regioisomeric products was
formed, although the major isomer (4h) could be isolated in
41% yield.12 The least sterically crowded regioisomer was
favored in this case. Phenols bearing electron-donating
functional groups were poor substrates in this reaction;
however, 3,5-dimethylphenol gave a respectable yield of the
desired sulfone 4i.
We also investigated the scope with respect to the
benzothiophene S-oxide. As seen for the phenol substrates, a
range of electron-donating and electron-withdrawing sub-
stituents were tolerated at each position (C4, C5, C6, and C7)
of the benzothiophene S-oxide (4j−n). The use of C2-
substituted benzothiophene S-oxides led to thioacetal S,S-
dioxides bearing a quaternary carbon center (4o−q). The
presence of electron-releasing methoxy groups on the benzene
ring of the benzothiophene typically leads to less efficient
arylation as the stability and electrophilicity of the activated S-
oxide is reduced.9a In addition to halide substituents, we have
previously shown that electron-withdrawing nitro groups are
compatible with the arylation.9a
the bond lengths in the crystal structures of the thioacetal 3r
and thioacetal S,S-dioxide 4b supported our hypothesis
(Scheme 2). For example, the C−O and C−S bonds of the
thioacetal 3r are 1.458 and 1.799, respectively. Oxidation with
m-CPBA resulted in the formation of thioacetal S,S-dioxide 4b,
which possesses a shorter C−O bond (1.421) and a longer C−
S bond (1.847) compared to thioacetal 3r.
The addition of NaOMe resulted in the formation of the
desired C3-arylated benzofuran products (Scheme 4). The
sulfinate products were converted in situ to the corresponding
sulfones by treatment with MeI. Using these conditions, we
transformed each of the sulfones (Scheme 3) to the
corresponding benzofurans in good to very high yields. We
were pleased to observe the formation of products bearing a
halo group (5e, 5h, 5j, 5l−n) as these would likely undergo
competing reactions in more conventional approaches
involving transition metal catalysts. Products 5o−q revealed
that the C2 substituent, which initially resides on the
benzothiophene substrate, can be efficiently transferred to
the benzofuran. This allowed access to C2,C3-disubstituted
benzofurans from simple phenol starting materials. We also
demonstrated that a range of electrophiles other than MeI
could be used to quench the sulfinate upon completion of the
base-mediated bond cleavage event (5r−t).
Having investigated the generality of the procedure we now
looked to collapse these structures to form the desired
benzofuran products 5. We proposed that the C−S bond in
the sulfone would be more susceptible to bond cleavage than
the C−O bond upon treatment with base. Indeed, analysis of
Based on previous reports, we have proposed a mechanism
for the formation of the benzofuran products from
C
DOI: 10.1021/acs.orglett.8b03267
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Letter
benzothiophenes and phenols (Scheme 5).9 The process
begins with oxidation of the benzothiophene 2 to the
Scheme 6. Scope of the Palladium-Catalyzed Desulfinative
Coupling of Sulfones 4 with Aryl Bromides
a
Scheme 5. Mechanism for the Formation of Benzofurans
a
from Phenols and Benzothiophenes
a
Reaction conditions: thioacetal S,S-dioxide 4 (2.0 equiv), NaOMe
(3.0 equiv), Pd(OAc)2 (10 mol %), PCy3 (20 mol %) K2CO3 (1.5
equiv), ArBr (1.0 equiv).
a
Colors indicate one-pot processes.
benzothiophene S-oxide 2′. The phenol is then captured by
the activated sulfoxide V in an interrupted Pummerer-type
process. The resultant aryloxysulfonium salt VI then undergoes
spontaneous [3,3] sigmatropic rearrangement and cyclization
to form the thioacetal intermediate 3. Oxidation of the
thioacetal provides sulfone 4 before addition of base gives
access to the desired benzofuran product 5.
material provides selective access to C3-arylated benzothio-
phenes or C3-arylated benzofurans through a divergent
strategy.
ASSOCIATED CONTENT
* Supporting Information
■
S
Sulfinate salts are a class of versatile compounds that have
recently found use as coupling partners in palladium-catalyzed
cross-coupling reactions.13 We therefore envisioned a sub-
sequent desulfinative cross coupling of aryl halides with our
sulfinate-containing benzofuran products. If successful, this
would establish sulfoxides as a traceless activating group for
C−H functionalization in this method. Thus, the intermediate
aryl sulfinates, formed from treatment of the sulfones 4 with
base, underwent desulfinative palladium-catalyzed cross-cou-
pling in the same pot to provide the desired biphenyl
benzofurans 6 (Scheme 6). This procedure gave good to
very high yields for all substrates tested. A range of aryl
bromides were applicable including electron-deficient (6b, 6f),
electron-rich (6d), and heteroaromatic bromides (6c, 6e). In
addition, ortho-, meta-, and para-substituted (6b, 6d, 6f)
substrates all gave similarly high yields. The formation of 6d
was particularly impressive as it represents an efficient process
for the cross-coupling of two sterically encumbered ortho-
substituted reagents.14 We believe this displays the potential
for accessing a range of substituted benzofuran derivatives
from benzothiophene S-oxides and phenols. Importantly, no
trace of the sulfoxide group that is present in the starting
material remained upon formation of the product.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03267.
Experimental procedures, X-ray data, and NMR spectra
(PDF)
Accession Codes
CCDC 1872998−1872999 contain the supplementary crys-
tallographic 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 Author
*E-mail: david.j.procter@manchester.ac.uk.
ORCID
Alexander P. Pulis: 0000-0003-1754-527X
David J. Procter: 0000-0003-3179-2509
Notes
We have reported on the synthesis of benzofurans from
simple phenol starting materials. The reaction utilizes the
unique reactivity of benzothiophene S-oxides to promote the
C−H functionalization of phenols without the requirement for
transition metal catalysts. The approach grants access to a
variety of C3-arylated benzofurans that can also undergo
further derivatization. In combination with our previous
studies, we have shown that a common sulfoxide starting
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC (Established Career Fellowship to
D.J.P.; EP/M005062/1) and the University of Manchester
(Lectureships to A.P.P. and G.J.P.P). We thank the Man-
chester X-ray crystallography service.
D
DOI: 10.1021/acs.orglett.8b03267
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Letter
Mechanistic Insights on Orthogonal Selectivity in Heterocycle
Synthesis. ACS Catal. 2018, 8, 10111−10118.
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(10) We also attempted C−S bond cleavage of the thioacetal 3
through the addition of N-iodosuccinimide (NIS); however, the
desired benzofuran product was not observed. Veeneman, G. H.; van
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cleavage of the C−S bond in thioacetal 3 using MeOTf also failed to
give the desired benzofuran product.
(11) See the Supporting Information for the synthesis and
characterization of the thioacetal intermediates.
(12) After the first step, the thioacetal 3 could be isolated in 73%
yield as a 74:26 regioisomeric mixture (3h/3h′). The minor thioacetal
S,S-dioxide regioisomer 4h′ was not isolated.
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DOI: 10.1021/acs.orglett.8b03267
Org. Lett. XXXX, XXX, XXX−XXX