Metal-free C-H thioarylation of arenes using sulfoxides: A direct, general diaryl sulfide synthesis

Article abstract of DOI:10.1039/c6cc07627k

Metal-free C-H thioarylation of arenes and heteroarenes using methyl sulfoxides constitutes a general protocol for the synthesis of high value diaryl sulfides. The coupling of arenes and heteroarenes with in situ activated sulfoxides is regioselective, uses readily available starting materials, is operationally simple, and tolerates a wide range of functional groups.

Full text of DOI:10.1039/c6cc07627k

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DOI: 10.1039/C6CC07627K
Journal Name
COMMUNICATION
Metal-free C–H thioarylation of arenes using sulfoxides: A direct,
general diaryl sulfide synthesis
Received 00th January 20xx,
Accepted 00th January 20xx
José A. Fernández-Salas, Alexander P. Pulis, and David J. Procter*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Metal-free C-H thioarylation of arenes and heteroarenes using
methyl sulfoxides constitutes a general metal-free protocol for the
synthesis of high value diaryl sulfides. The coupling of arenes and
heteroarenes with in situ activated sulfoxides is regioselective,
uses readily available starting materials, is operationally simple,
and tolerates a wide range of functional groups.
A.The diarylsulfide moiety in important target molecules and materials
O
HO
S
S
CO2H
OH
O
O
S
N
Me
Me
H
N
! AZD4407
5-lipoxygenase inhibitor
! HIV-1 integrase
S
inhibitor
O
O
S
S
S
N
Me
NHOH
S
Diaryl sulfides are prevalent in important and high value
chemical structures such as biologically active compounds,1
organic materials2 and ligands3 that mediate an array of
chemical transformations (Scheme 1A). In addition, they are
precursors to other higher oxidation state sulfur containing
compounds that are found in similarly important chemicals.4
Due to the importance of unsymmetrical diaryl sulfides,
their synthesis has garnered much attention. For example, in
transition metal-mediated processes,5 using Pd,6 Ni,7 Rh,8 Cu,9
In,10 Fe11 and Co,12 the coupling of aryl halides (or
pseudohalides) with various sulfur based partners has been
described (Scheme 1Bi).13,14 In an attempt to improve reaction
efficiency by abolishing the need for a prefunctionalized arene
(e.g. aryl halide), C-H thioarylation mediated by transition
metals has received significant attention (Scheme 1Bii).15
However, the use of metals raises issues of supply risk16 and
contamination of products.17 In addition, these metal-
catalyzed procedures for the synthesis of diaryl sulfides
typically require elevated temperatures, that limit their
general applicability. More recently, metal-free18 C-H
thioarylation of highly electron rich arenes and heteroarenes
using electrophilic sulfur reagents and precursors, including N-
(thio)succinimides,19 sulfonyl hydrazines,20 sulfonyl chlorides,21
sodium sulfinates,22 thiols,23 disulfides,24 and others25 has
emerged, and circumvents some of the problems associated
with transition metal-mediated transformations (Scheme 1Bii).
In these reactions the active sulfur electrophile, which is often
formed in situ, is at the sulfide oxidation level and therefore
has poor electrophilicity, limiting these methods to electron
S
O
Me
S
! Vortioxetine (Brintellix®)
! BTBT & BTNT
organic semiconductors
! anti-Hepatitis C
virus activity
antidepressant
B. Approaches to unsymmetrical diaryl sulfides
i) Metal-mediated cross-coupling
! metal catalyst
! prefunctionalized ArX
Metal
"S"
X
R1
R2
+
S
X = halide, B(OH)2
ii) C-H thioarylation
H
R1
R2
"S" = SH, SCl, SSAr, SBn
Metal
or Metal-free
"S"
R1
R2
+
! high temperatures
! limited scope - highly
electron rich ArH
"S" = SH, SSAr, S(O)2Cl, S(O)2NHNH2, SO2Na,
SBn, SSO3Na, SO2H, S−succinimide
! low FG tolerance
C. This work: Direct C-H thioarylation of arenes using sulfoxides – a general,
metal-free synthesis of unsymmetrical diaryl sulfides
O
S
H
S
Tf2O, DBU
Me
R1
R2
R1
R2
+
via
OTf
Me
OTf
OTf
S
S
Me
R2
R1
R2
Ι
ΙΙ
! metal-free ! only one prefunctionalized partner ! mild conditions
! broad scope ! many commercial aryl sulfides ! bench stable S+ source
! non-malodorous S+ partner ! regioselective
Scheme 1. A. The importance of unsymmetrical diaryl sulfides. B. Conventional metal-
mediated and metal-free approaches. C. The metal-free C-H thioarylation of arenes
provides convenient and general access to unsymmetrical diarlysulfides. Tf2O
Trifluoromethanesulfonic anhydride, DBU = 1,8-Diazabicycloundec-7-ene
=
rich aryl coupling partners (typically indole or phenol/aniline
derivatives) and the requirement for high temperatures.
Herein, we report the development of a simple, general,
metal-free method for the synthesis of unsymmetrical diaryl
sulfides that exploits a bench-stable, convenient sulfur
electrophile, which has broad scope and high functional group
tolerance (Scheme 1C). The method exploits the reactivity of
activated sulfoxides, which we show to be excellent
School of Chemistry, University of Manchester, Oxford Rd, Manchester, M13 9PL,
UK, E-mail: david.j.procter@manchester.ac.uk
†
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1

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electrophiles, and as such allows the straightforward reaction Heteroaromatics, such as indole (3x), dibenzothiVoiepwhAertnicele O(3nlyin)e,
to proceed under mild conditions with a variety of arene benzothiophene (3z and 3aa), thiopheneD(O3Ia: 1c0).1a0n3d9/fCu6rCaCn0(736a27dK)
coupling partners in a highly regioselective manner.
were also successfully applied. We have used benzothiophene
Based on the seminal studies by Balenkova26 and recent 3z in a formal synthesis of an anti-Hepatitis-C drug candidate
work by us27 and others28 on the reactivity of sulfoxonium salts (see Scheme 1A for structure).32 Also of note, 3aa is a known
with a variety of nucleophiles,29 we postulated that activated precursor15a to BTBT organic semiconductors (see Scheme 1A
aryl methyl sulfoxides (I) would serve as efficient sulfur based for structure).
electrophiles for the C-H thioarylation of arenes to afford
sulfonium salts II (Scheme 1C). The intermediates II could then
be demethylated in situ to afford a straightforward, metal-free
synthesis of unsymmetrical diaryl sulfides. Thus, we treated
methyl phenyl sulfoxide 1a with trifluoromethanesulfonic
anhydride, which formed the activated sulfoxide (cf. I).
Addition of by p-xylene 2a led to the formation of an isolable
sulfonium salt (cf. II),30 that smoothly underwent
demethylation with DBU to yield diaryl sulfide 3a in 91%
isolated yield (Scheme 2).31
Scheme 2. Scope of the methyl aryl sulfoxide coupling partner in the metal-free C–H
thioarylation approach to diaryl sulfides. Isolated yields stated.
We furthered investigated the scope of the metal-free C-H
thioarylation process with regard to the aryl methyl sulfoxide
partner (Scheme 2).
A range of methyl sulfoxides 1,
commercially available or readily prepared from the
corresponding commercial sulfides, were employed in the
study. Electron-donating (3b and 3c) and electron-withdrawing
(3d-k) substituents were well tolerated and diaryl sulfides
were obtained in excellent isolated yields. More hindered
ortho substituted sulfoxides (forming 3c, 3f and 3g), as well as
a variety of important and/or functionalizable groups, such as
methoxyl (3b), chloro (3d), trifluoromethyl (3e and 3g), bromo
(3f), nitro (3h), sulfone (3i), ketone (3j) and aldehyde (3k) were
amenable to the process. It is important to note that the
presence of halides would typically be incompatible with
metal-mediated diaryl sulfide syntheses.
Next we turned to investigating the scope with regards to
the aryl-H partner 2 and found that the metal-free C–H
thioarylation embraced a variety of aromatics with complete
regioselectivity observed in all cases (Scheme 3). Less activated
arenes, such as toluene (3l), iodobenzene (3m) and even
benzene (3n) underwent smooth C-H thioarylation, in stark
contrast to other metal-free C-H thioarylation approaches to
diaryl sulfides. More hindered m-xylene (3o), naphthalene (3p)
and 1-bromo naphthalene (3q) were well tolerated, as well as
arenes containing oxygen substitution (3r-v and 3ab), including
those with versatile bromo (3s and 3t), acetal (3t), alkenyl
(3ab), ester (3u, 3w and 3ab) and aldehyde (3v) functionality.
Scheme 3. Scope of the arene and heteroarene coupling partner in the metal-free C–H
thioarylation approach to diaryl sulfides and metal-free C–H thioarylation for scaffold
construction and late-stage modification. Isolated yields stated. [a] TFAA used as
activator. [b] 2 equiv. of 1a and 2.1 equiv. of Tf2O.
We further evaluated the efficacy of the process in the
late-stage diversification of a range of molecular scaffolds. Aryl
sulfide 3ae was formed from an established coumarin based
fluorophore, useful in the study of biological systems.33
Pyrene, a common motif in dyes, also efficiently formed diaryl
sulfide 3af, an intermediate in the synthesis of fluorescent
chemosensors.34 Dimethyl BINOL, bearing the ubiquitous
binaphthyl chiral scaffold, smoothly underwent a one-pot
double C-H thioarylation with two equivalents of activated
sulfoxide without reduction in efficiency (3ag). The metal-free
protocol was applied to estrone methyl ether, an estrogenic
hormone derivative, leading selectively to sulfide 3ah. In
addition, dextromethorphan,35 a drug of the morphinan class
commonly sold in over-the-counter cold and cough medicines,
led to the corresponding diaryl sulfide 3ai in good yield.
These late stage modifications (3ae-ai), general scope of
the sulfoxide 1 (3a-k) and aryl-H coupling partner 2 (3l-ad)
2 | J. Name., 2012, 00, 1-3
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underscore some key features of this metal-free C-H
COMMUNICATION
We thank EPSRC (Postdoctoral Fellowship Viteow ArJt.icAle.FO.n-lSin.e;
thioarylation protocol: 1) the reaction has broad functional Established Career Fellowship to D.J.P.) DaOnId: 1T0h.1e03U9/nCi6vCeCrs0i7t6y27oKf
group tolerance, including halides, methoxy, carbonyl Manchester (Lectureship to A.P.P.).
derivatives, nitro, sulfone, and basic nitrogen atoms; 2)
electron withdrawing groups on the aryl-H partner and
electron neutral aryl-H partners are well tolerated in contrast
Notes and references
to other metal-free protocols; 3) the reaction yields diaryl
sulfides with complete regioselectivity; and 4) over C-H
thioarylation is impossible due to intermediate sulfonium salt
II being deactivated to further SEAr with another molecule of
activated sulfoxide I. These facets are made possible by the
superior reactivity of activated sulfoxides as sulfur
electrophiles, meaning the reaction does not require harsh
conditions and elevated temperatures.
1
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2
3
4
5
For a recent review, see: R. G. Arrayás and J. C. Carretero,
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K.-M. Roy, Sulfones and Sulfoxides. Ullmann's Encyclopedia
of Industrial Chemistry, Wiley-VCH, Weinheim, 2000.
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P. Beletskaya and V. P. Ananikov, Chem. Rev., 2011, 9, 1596;
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Scheme 4. Metal-free, iterative C-H thioarylation in the synthesis of diaryl sulfides from
the union of two aryl-H coupling partners and DMSO as the sulfur source.
6
7
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The chemical union of two biologically active molecules is
of significant interest to medicinal chemists.36 We reasoned
that we could use our approach in an iterative C-H
thioarylation to link two biologically active aryl-H partners via a
sulfur atom (Scheme 4). In order to explore iterative C-H
thioarylation we reacted estrone methyl ether 2ah with
activated DMSO,26 which after dealkylation and oxidation gave
estrone derived methyl sulfoxide 1ah in high yield over two
steps (79%). The generated sulfoxide 1ah then served as the
sulfur partner in the metal-free C-H thioarylation of another
molecule of estrone methyl ether 2ah, giving dimeric estrone
methyl ether 3aj in a convenient three-step, metal-free
procedure from two non-prefunctionalized aryl-H coupling
partners and DMSO37 as the sulfur source. This strategy would
also be useful when the required methyl aryl sulfoxide 1 (or
corresponding methyl sulfide) is not commerically available.38
In summary, we have developed a general, operationally
simple metal-free synthesis of diaryl sulfides that proceeds
under mild conditions. The C-H thioarylation process is made
possible by the use of readily available sulfoxides that once
activated, form sulfoxonium salts that serve as excellent sulfur
electrophiles for coupling with a variety of aryl-H partners,
including those that are not electronically biased, with
universally high regioselectivity. The method allows the
incorporation of a variety of functional groups in either
coupling partner, and as such is suitable for the construction of
complex diaryl sulfides that have broad applications. In
addition, we have described an iterative C-H thioarylation
approach to complex diaryl sulfides utilising two aryl-H
partners and DMSO as the sulfur source.
8
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38 See ESI† for other examples of iterative C-H thioarylation
using this method.
4 | J. Name., 2012, 00, 1-3
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