Journal of the American Chemical Society
Communication
would also considerably expand the scope of the emerging class
of single-bond metathesis reactions (Scheme 1D).
We also applied this methodology to a thioanisole bearing a 2-
oxabicyclo[2.1.1]hexane moiety (3ag), which was recently
shown to be a water-soluble bioisostere of benzene.53
Gratifyingly, the expected nitrile product was obtained in
excellent yield (91%).
On the basis of the recent success in activating both C−CN
and C−SR bonds under nickel catalysis,41−47 we reasoned that
a Ni-based catalytic manifold could provide an appropriate
platform to develop this reaction. However, two main
challenges were identified: (1) a single catalyst and set of
reaction conditions need to be competent for two distinct and
reversible oxidative additions; (2) a suitable transfer
mechanism, such as a direct crossover between two oxidative
addition complexes, needs to be kinetically accessible. We
initially explored this process by evaluating a range of ligands,
in combination with a Ni(COD)2 precatalyst, for the
metathesis between thioanisole and 4-methylbenzonitrile.
Traces of 4-methylthioanisole and benzonitrile were observed
by employing 1,2-bis(dicyclohexylphosphino)ethane (dcype)
as a ligand (details in the SI), which has been shown previously
to enable the activation and the formation of C−SR and C−
CN bonds.45,48−50 After an extensive study (details in the SI),
Ni(COD)2 (10 mol %) and a slight excess of dcype (15 mol
%) in o-xylene at 140 °C for 24 h were found to be most
effective at reaching the equilibrium of the reaction, namely, to
get the same product distribution in the forward and reverse
reactions.
Finally, we subjected several commercially relevant mole-
cules to the reaction conditions. To our delight, the late-stage
derivatization of photoinitiator MMMP (3ah)54 and fexinida-
zole (3ai), a drug used to treat sleeping sickness,55 proceeded
smoothly. Furthermore, the synthesis of the nitrile derivative of
celecoxib (3aj), a COX-2 inhibitor,56 and the late-stage
derivatization of thioridazine (3ak) were successfully achieved.
We could also access a drug used in the treatment of breast
cancer, letrozole (3al),57 in an efficient way (63% yield),
showing the possibility to transfer two cyanides in a single-step
protocol. We finally synthesized a derivative of δ-tocopherol
(3am) with this catalytic manifold in a synthetically useful
yield of 51%.
The reverse reaction (i.e., the conversion of an aryl nitrile to
an aryl thioether) was next explored (Table 2). We found that
both 4-methoxythioanisole (donor C) and 4-morpholine-
thioanisole (donor D) were suitable donors for this reaction
due to their electron-donating properties that thermodynami-
cally favor the donation of the SMe group. Similar to the
forward reaction, the functional group tolerance proved to be
high. Indeed, thioanisoles bearing an alkyl (4a), trifluoro-
methyl (4b), difluoro (4c), sulfone (4d), amide (4e), ketone
(4f), ester (4g), or cyano (4h) group were obtained in good to
quantitative yield (60−99%). Several heterocycles and bicycles,
such as quinoline (4i), pyridine (4j), 1,3,4-oxadiazole (4k),
benzothiophene (4l), and 2-naphtalene (4m), worked in
modest to excellent yield (26−86%). Furthermore, menthol
(4n), a fluorine-containing substrate (4p), proline (4q), and
cholesterol derivatives (4r) were all found to be competent
partners. Notably, an aryl nitrile bearing an alkyl nitrile (4o)
worked smoothly under the reaction conditions, confirming
that aliphatic carbon−cyanide bonds do not react with nickel
in the absence of Lewis acids.58 We next explored the substrate
scope of alkyl thioethers. To our delight, thioethers bearing
either an ethyl (4s), an alkyl nitrile (4t), an alkyl CF3 (4u), or
an azetidine (4v) group were efficiently transferred to the
metathesis products in moderate to excellent yield (41−96%).
A derivative of probenecid (4w) was successfully obtained in
95% yield, as well as the late-stage derivatized fadrozole (4x,
62%). Finally, the synthesis of widely used photoinitiator
MMMP (4y) was performed, affording the desired product in
good yield (74%).52
We next investigated different nitrile donors to find suitable
conditions to shift the equilibrium of this reversible and
thermodynamically controlled reaction toward the product
(Ar−CN) side. We reasoned that an electronic mismatch
could serve as a potent driving force for the reaction.39 For
electron-neutral and -rich aryl thioether acceptors, 2.0 equiv of
methyl 4-cyanobenzoate (donor A) were competent to achieve
the transformation in high yield, whereas for electron-poor aryl
thioethers, 2.0 equiv of 1,4-dicyanobenzene (donor B) were
employed. We next explored the scope of the reaction (Table
1). To our delight, a wide range of thioanisole derivatives
worked efficiently under the reaction conditions. Indeed, both
electron-neutral and electron-rich substrates (3a−3i) worked
well, affording the corresponding products in good to excellent
yield (56−94%). A citronellol-based ether, bearing an alkene
that could possibly deactivate the catalyst through coordina-
tion, afforded the expected product (3j) in 76% yield.51
Sterically hindered aryl thioethers bearing an ortho substituent
(3k and 3l) also proved to be competent partners in affording
the desired product in 56 and 85% yields, respectively. We
then applied the optimal conditions by using the other donor,
1,4-dicyanobenzene (donor B), to different electron-poor
thioanisoles. Gratifyingly, many electron-withdrawing func-
tional groups, such as fluoride (3m), amide (3n), ketone (3o),
ester (3p), and sulfone (3q), were tolerated. In all cases, the
desired product was obtained in moderate to excellent yield
(50−87%). Bicyclic compounds such as 2- and 1-naphthyl
derivatives (3r and 3s) reacted smoothly under the reaction
conditions (88 and 37%). We then successfully subjected
several arenes bearing common functional groups, including
acetal (3t,), benzyl-protected amide (3u), vinyl (3v), pinacol
boronic ester (3w), and phthalimide-protected amine (3x), to
our reaction. Furthermore, several heterocycles, such as a
thiophene (3y), a benzofuran (3z), a dibenzofuran (3aa), a
pyrimidine bearing an azepane moiety (3ab), a phenothiazine
possessing a free aniline (3ac), a carbazole (3ad), which is an
Inspired by Yamaguchi and co-workers’ recent work, the
ester dance on an aromatic ring,59 we explored the possibility
of scrambling the cyano and thioether groups located on a
single substrate (Scheme 2A). We thus subjected starting
material 5a, bearing one electron-rich and one electron-poor
aromatic ring, to the optimized conditions to obtain the clean
formation of three new products in addition to the starting
material. Gratifyingly, we were able to separate the four
different compounds which were further characterized. This
result shows the potential of this methodology to generate a
library of derivatives through late-stage nitrile/thioether
metathesis diversification.
We next turned our attention to the intrinsic electronic
properties of both functional groups and their influence on
Friedel−Crafts acylation (Scheme 2B). The thioether group
usually directs the reaction to the para position,7−9 while the
important class of compounds in organic electronics,52
a
quinolone (3ae), and a 1,3,4-oxadiazole (3af), all afforded the
metathesis product in moderate to excellent yield (40−94%).
3725
J. Am. Chem. Soc. 2021, 143, 3723−3728