Metal-Free CH-CH-Type Cross-Coupling of Arenes and Alkynes Directed by a Multifunctional Sulfoxide Group

Article abstract of DOI:10.1021/jacs.5b12579

A metal-free CH-CH-type coupling of arenes and alkynes, mediated by a multifunctional sulfoxide directing group, exploits nonprefunctionalized coupling partners, proceeds under mild conditions, is operationally simple, and exhibits high functional group t

Full text of DOI:10.1021/jacs.5b12579

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Communication
Metal-free CH–CH-type cross coupling of arenes and
alkynes di-rected by a multi-functional sulfoxide group
José A. Fernández-Salas, Andrew J. Eberhart, and David J. Procter
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b12579 • Publication Date (Web): 08 Jan 2016
Downloaded from http://pubs.acs.org on January 11, 2016
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Metal-free CH–CH-type cross coupling of arenes and alkynes di-
rected by a multi-functional sulfoxide group
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José A. Fernández-Salas, Andrew J. Eberhart, David J. Procter*
School of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
and delivering8 the pronucleophilic alkyne partner, con-
ABSTRACT: A metal-free CH–CH-type coupling of
trolling the regiochemical outcome of the coupling, and
ensuring that no over reaction takes place to give by-
products (Scheme 1B).9,10 Key to successful coupling is
the proposed formation and rearrangement of alkenyl
sulfonium salt intermediates I.11 The products of cross
coupling are challenging targets for current metal-
mediated methods.
arenes and alkynes, mediated by a multi-functional sul-
foxide directing group, exploits non-prefunctionalized
coupling partners, proceeds under mild conditions, is
operationally simple, and exhibits high functional group
tolerance. The products of the CH–CH coupling are
highly versatile and the metal-free process can be used
for the construction and late-stage modification of im-
portant molecular scaffolds.
Carbon-carbon bond formation is a challenging objec-
tive that is essential in almost any synthetic endeavor
that involves the construction or manipulation of molec-
ular architecture.1,2 In particular, metal-catalyzed C–H
functionalization has become an established and more
atom-economical way to construct C–C bonds with a
wide selection of directing groups available to control
processes involving C–H bonds on aromatic rings
(Scheme 1A).3 Furthermore, CH–CH-type cross cou-
pling, so called cross-dehydrogenative coupling (CDC),
has been developed that obviates the need for pre-
functionalization of either coupling partner,4 although
issues of chemo- and regioselectivity, and a dependence
on harsh conditions and stoichiometric oxidants remain
issues that limit the broad take-up of such technology
(Scheme 1B).4 The majority of C–H cross coupling pro-
cesses are mediated by platinum group metals and this
leads to potential issues of supply risk5 and metal con-
tamination of products.2a-c,6,7 Thus, despite remarkable
recent advances in C–H cross coupling, the development
of complementary, metal-free CH–CH-type cross cou-
pling processes that use readily available non-
prefunctionalized starting materials and that operate un-
der mild conditions, is an outstanding challenge.
Scheme 1. A. Metal-catalyzed C–H and CH–CH cross
coupling. B. Metal-free, CH–CH-type cross coupling of
arenes and alkynes mediated by a sulfoxide directing
group (DG). X–X = electrophilic activator of sulfoxide.
Our study began by investigating the cross coupling
reaction between arene sulfoxide 1a and butyne 2a (See
Supporting Information for optimization studies). Aim-
ing to develop an operationally simple protocol, we ex-
plored the use of commercially available Tf2O (1,1,1-
trifluoromethanesulfonic anhydride) and 2,6-lutidine to
mediate the proposed metal-free cross coupling.8a Unfor-
tunately, in both MeCN and CH2Cl2, only traces of the
desired product 3a were observed. The role of the base
and the temperature at which the activating agent was
added were then investigated. Interestingly, if Tf2O was
added at –78 ºC in the presence of K2CO3, the desired
Here we report a metal-free CH–CH-type strategy that
allows the selective coupling of aromatic centers to pro-
pargylic centers in alkynes at the expense of two C–H
bonds – CAr(sp2)–H and C(sp3)–H bonds. A sulfoxide
directing group in the arene plays a multi-functional role
in the metal-free cross coupling, capturing, activating
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process was observed and a 65% isolated yield of the coupling (preparation of 3j and 3k). Pleasingly, chal-
lenging metal-free couplings involving secondary sp3-
propargylic C–H bonds were possible and resulted in
new C–C bonds despite significant steric congestion:
alkynes 2d, 2e, 2h and 2i underwent coupling to give
branched coupling products 3d, 3e’, 3h, 3i, 3o and 3p in
moderate to high yield. Finally, an arene bearing a me-
thyl sulfinyl directing group could also be used in the
cross coupling: treatment of 1b with alkynes 2b, 2f, 2g,
2h and 2i gave the desired coupling products 3l-p, re-
spectively (Table 1).
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product of CH–CH-type coupling 3a was obtained.
When 2,6-lutidine was used as base and added at 0 ºC
after 45 min, the cross coupling proceeded, delivering 3a
in good isolated yield (ca. 75%) after 16 h at 65 ºC (or 3
h with microwave heating).
Table 1. Alkyne substrate scope in the metal-free CH–CH-
type cross coupling of alkynes with arenes bearing a sul-
foxide directing group.a
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Cross coupling proceeded efficiently between a range
of readily available starting arenes bearing a variety of
substituents and alkynes 2a, 2f and 2g. Arenes bearing
electron-donating methoxy groups showed lower reac-
tivity, leading to coupled products 3q and 3r in moderate
yield. Less electron releasing methyl substituents on the
arene were tolerated and 3y was obtained in 60% yield.
Electron-withdrawing groups on the arene partner were
well tolerated in the metal-free CH–CH type cross cou-
pling. For example, arene substrates bearing CF3 groups
in ortho, meta and para positions led to coupled prod-
ucts in excellent yield (3s–3u). Arenes containing bro-
mide and chloride substituents also underwent coupling
with high efficiency (3v, 3w and 3x). It is important to
note that the presence of halides is often incompatible
with metal-mediated cross coupling procedures.
Table 2. Study of arene substrate scope in the metal-free
CH–CH-type cross coupling of arenes with alkynes.a
aTf2O (1.3 equiv.) was added to a mixture of 1 (0.15 mmol)
and 2 (1.3 equiv.) in CH2Cl2 (0.2 M) at –78 °C. After 15 min
at the same temperature, the mixture was stirred at 0 °C for 30
min. 2,6-Lutidine (3 equiv.) was then added. The reaction
mixture was heated at 65 °C for 16 h
.
Having optimized the reaction conditions, we next in-
vestigated the scope of the metal-free CH–CH-type
cross coupling with regard to the alkyne partner. A range
of readily available, simple and functionalized alkyne
partners 2a–k were employed in the study (Table 1).
Arene sulfoxide 1a underwent efficient coupling with
sterically demanding 4,4-dimethylpent-2-yne 2b and
benzyl-substituted alkyne 2c to give good isolated yields
of the desired products 3b and 3c, respectively. Similar-
ly, silyl-substituted alkynes 2f and 2g underwent effi-
cient cross coupling to give versatile alkyne products 3f
and 3g. Attractively, protected alkyne coupling products
allow access to a range of products via deprotection and
derivatization. Important bromide and CF3 substituents
in the alkyne were also compatible with the metal-free
b
aSee Table 1 for conditions. Isolated yields. Ratio in brackets
refers to regioselectivity. Alkylation away from the meta sub-
stituent gives the major product
.
Nitro and sulfone substituents were also tolerated and
arenes bearing these groups underwent successful cou-
pling to give 3z and 3aa. The metal-free CH–CH-type
cross coupling also proceeded in the presence of unpro-
tected ketones and aldehydes: adducts 3ab, 3ac, 3af and
3ag were obtained in 61-82% yield. Substitution in the
aryl unit of the sulfoxide-directing group was also toler-
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ated with coupling taking place selectively on the more
uct of a formal metal-free, C–H Sonogashira-type reac-
tion (Scheme 3A).16
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electron-rich ring (formation of 3ad). Finally, heterocy-
clic coupling partners also underwent coupling with al-
kynes to give 3ae, 3af, 3ag and 3ah in moderate to good
yield thus illustrating the potential of the process for the
manipulation of heteroarene platforms (Table 2).
Scheme 3. Sulfoxide-directed metal-free CH–CH-
type cross coupling for scaffold construction and late-
stage modification.
A possible mechanism for coupling with but-2-yne 2a
is shown in Scheme 2. The alkyne partner is captured
and activated by the triflated sulfoxide II at low temper-
ature8-10 giving rise to vinyl triflate IV (cf. I in Scheme
1B). In the presence of base, IV may be deprotonated to
give sulfonium ylide V and [3,3]-sigmatropic rear-
rangement of V13 at elevated temperature followed by
rearomatization delivers CH–CH-type cross coupling
product 3. In support of the above, quenching reactions
between sulfoxide-bearing arenes 1a and 1b and alkyne
2a at 0 °C prior to the addition of base, resulted in com-
plete conversion to alkenylsulfonium salts (see Support-
ing Information).11,12
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Scheme 2. Proposed mechanism for the metal-free
CH–CH-type cross coupling of but-2-yne 2a with
arenes bearing a sulfoxide directing group.
Pleasingly, a sulfur atom in a validated drug scaffold
can be used to direct the metal-free CH–CH cross cou-
pling. Sulfide scaffold 6 is an intermediate in the synthe-
sis of the topical retinoid Tazarotene (Tazorac®) 10.17
Activation of 6 by sulfur oxidation and CH–CH cross
coupling with alkyne partner 2g gave 8 in good yield.
High yielding deprotection/isomerization then gave al-
kynylation product 9. Attractively, the metal-free sulfox-
ide directed CH–CH coupling is orthogonal to the Pd-
catalyzed alkynylation of the C–Br bond used in the
preparation of the drug (Scheme 3B).17,18 Functionalized
benzothiophene 11 is a key intermediate in the synthesis
of the antipsychotic drug 12: an agonist of the G-protein
coupled receptor 52.19 The crucial C–C bond in 11 is
typically prepared by stoichiometric metallation of the
arene.20 The sulfoxide-directed CH–CH process allows
medicinally-relevant benzothiophene 11 to be prepared
from 1i in 4 metal-free steps: CH–CH cross coupling,
TBAF deprotection, I2-mediated heterocyclization,21 and
NaBH4 reduction of the intermediate benzothiophene
aldehyde delivers 11 in 57% overall yield (Scheme 3C).
The selective onwards reaction of alkenylsulfonium in-
termediate IV (R1 = Me) is key to the success of the
cross coupling. Alkynes bearing large substituents are
particularly effective as they control the regiochemistry
of the addition to the activated sulfoxide II and give rise
to alkenylsulfonium intermediates IV bearing large R2
groups.14 These large R2 groups block undesired depro-
tonation and nucleophilic demethylation of the SMe
group, and hydrolysis of the triflate in IV.11
The products of cross coupling are versatile building
blocks for organic synthesis and are difficult to access
selectively using current methods. Focusing on metal-
free transformations,15 deprotection of adduct 3n deliv-
ered 4 or isomerization product 5, depending on the
conditions employed. Notably, arylalkyne 5 is the prod-
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In summary, we have developed an operationally sim-
ple, metal-free CH–CH-type cross coupling of arenes
and alkynes that proceeds under mild conditions. The
process is mediated by a sulfoxide-directing group that
captures and activates the alkyne coupling partner before
delivery to the arene and C–C bond formation. The
products of cross coupling are difficult to access using
current metal-mediated procedures and are rich in syn-
thetic potential. For example, they are readily converted
to products of formal metal-free arene C–H alkynylation
and to important benzothiophene motifs, as exemplified
by the metal-free synthesis of a precursor to an antipsy-
chotic drug. Furthermore, sulfur in a validated heterocy-
clic drug scaffold can be used to direct metal-free CH–
CH cross coupling thus facilitating late-stage scaffold
elaboration.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on
the ACS Publications website. Optimization table, mecha-
nistic studies, experimental details, characterization data
and spectra are in the Supplementary Information (PDF).
AUTHOR INFORMATION
Corresponding Author
david.j.procter@manchester.ac.uk
ACKNOWLEDGMENT
EPSRC (Established Career Fellowship to D. J. P.; Postdoc-
toral Fellowship to J. A. F-S.; Doctoral Prize to A. J. E.)
and The Leverhulme Trust (Fellowship to D. J. P.).
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