Nickel-Catalyzed Cyanation of Aryl Thioethers

Article abstract of DOI:10.1021/acs.orglett.1c02285

A nickel-catalyzed cyanation of aryl thioethers using Zn(CN)2 as a cyanide source has been developed to access functionalized aryl nitriles. The ligand dcype (1,2-bis(dicyclohexylphosphino)ethane) in combination with the base KOAc (potassium acetate) is essential for achieving this transformation efficiently. This reaction involves both a C-S bond activation and a C-C bond formation. The scalability, low catalyst and reagents loadings, and high functional group tolerance have enabled both late-stage derivatization and polymer recycling, demonstrating the reaction's utility across organic chemistry.

Full text of DOI:10.1021/acs.orglett.1c02285

pubs.acs.org/OrgLett
Letter
Nickel-Catalyzed Cyanation of Aryl Thioethers
Tristan Delcaillau,† Adrian Woenckhaus-Alvarez,† and Bill Morandi*
Cite This: https://doi.org/10.1021/acs.orglett.1c02285
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A nickel-catalyzed cyanation of aryl thioethers using
Zn(CN)2 as a cyanide source has been developed to access
functionalized aryl nitriles. The ligand dcype (1,2-bis(dicyclohexyl-
phosphino)ethane) in combination with the base KOAc
(potassium acetate) is essential for achieving this transformation
efficiently. This reaction involves both a C−S bond activation and a
C−C bond formation. The scalability, low catalyst and reagents loadings, and high functional group tolerance have enabled both
late-stage derivatization and polymer recycling, demonstrating the reaction’s utility across organic chemistry.
employed aryl thioethers or thioesters to introduce a wide
ryl nitriles are important compounds due to their
Aoccurrence in natural products, pharmaceuticals, agro- range of functional groups, such as alkyl and aryl groups,19,20
amines,21,22 functionalized thioethers,23 boryl and silyl
groups,24,25 phosphonates,26 and hydrides.27−29 However,
despite the occurrence of thioethers and the synthetic potential
of nitriles, direct methods to convert aryl sulfides to the
corresponding aryl nitriles using a metal cyanide reagent are
unknown. To date, only a functional group metathesis between
aryl nitriles and aryl thioethers has been reported to access
valuable aryl nitriles from the corresponding aryl thioethers.30
We started our investigation using thioanisole as a
benchmark substrate and Zn(CN)2 as cyanide source. Guided
by recent reports on the activation of C−S bonds and the
formation of C−CN bonds11−13,22,30 as well as the high
abundance and low price of nickel, we decided to use
Ni(COD)2 as a precatalyst and KOAc as a base. Several
bidentate ligands were tested such as XantPhos (4,5-bis(di-
phenylphosphino)-9,9-dimethylxanthene), DPEPhos ((oxydi-
2,1-phenylene)bis(diphenylphosphine)), dppm (bis(diphenyl-
phosphino)methane), and dppe (1,2-bis(diphenylphosphino)-
ethane), but no formation of the desired product was observed.
We next tested dcypm (bis(dicyclohexylphosphino)-
methane), which has previously shown its ability to break
C−S bonds;22 however, no conversion of thioanisole was
observed. When using dcype instead of dcypm, a promising
41% yield of benzonitrile could be observed by gas
chromatography analysis of the reaction mixture. This result
is in accordance with recent reports in this field, as this ligand,
in combination with a nickel precatalyst, has been used to
activate C−S bonds and to form C−CN bonds.11,12,22,30
chemicals, materials, and dyes.1,2 They are also versatile
building blocks for accessing a wide range of other functional
groups such as benzoic acid, ketone, aldehyde, and amine.3−5
Aryl nitriles were historically obtained via a Rosenmund−von
Braun6 or a Sandmeyer reaction.7 Lately, with the advent of
metal-catalyzed reactions, aryl nitriles have been synthesized
through the cross-coupling between an aryl (pseudo)halide
and an inorganic or organic cyanide species (Scheme 1).8−10
Recently, chemists have dedicated their efforts to using other
electrophiles such as phenol derivatives,11,12 esters,13 or
amides.14 Moreover, thioethers have been investigated as
electrophiles in the past decade.15−18 Several reports have
Scheme 1. Context of This Work
Received: July 8, 2021
© XXXX The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.orglett.1c02285
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Unlike Szostak and coworkers, who showed no need for the
external base in their decarbonylative cyanation of amides,14 in
our case, the absence of a base resulted in no conversion of
thioanisole. An extensive screening of different bases did not
lead to any yield improvement. (See the SI and Table 1.)
Scheme 2. Scope of Aryl Thioethers
Table 1. Optimization of the Ni-Catalyzed Cyanation of
a
Aryl Thioethers
b
entry
deviation from standard conditions
yield (%)
1
2
3
4
5
6
7
8
9
10
none
L1 instead of L6
L2 instead of L6
L3 instead of L6
L4 instead of L6
L5 instead of L6
no base
K2CO3 instead of KOAc
1,4-dioxane instead of PhMe
0.5 mL of 1,4-dioxane instead of 1.5 mL of toluene
41
0
0
0
0
0
0
20
70
89
a
PhSMe (0.25 mmol), Zn(CN)2 (0.6 equiv), Ni(COD)2 (5 mol %),
b
dcype (10 mol %), PhMe (1.5 mL), 110 °C, 16 h. GC yield using n-
dodecane as an internal standard.
However, switching the solvent to 1,4-dioxane drastically
improved the outcome of the reaction, affording benzonitrile in
70% yield. A further examination of the molarity of the
reaction led to product formation in 89% yield using a
concentration of 0.5 mol/L.
With the best conditions in hand, we explored the substrate
scope of this synthetic transformation (Scheme 2). We started
the investigation by subjecting several electron-neutral (2a, 2b)
and electron-rich thioanisoles (2c−2h) to the reaction
conditions. Gratifyingly, all of them gave the corresponding
product in good to excellent yield. An aryl thioether bearing an
alkene, which could have deactivated the catalyst via
chelation,31 was also tolerated (2i). Sterically hindered
substrates worked well under the reaction conditions (2j,
2k). Furthermore, aryl sulfides bearing electron-withdrawing
functional groups, such as nitrile (2l), morpholine, and
piperazine amides (2m, 2n), methyl and tert-butyl esters (2o,
2p), ketone (2q), and a sulfone (2r), worked smoothly under
the reaction conditions (49−97%). Importantly, fluoro-
containing thioanisole was also a competent partner in this
reaction (2s). We next tested the ability of this transformation
toward naphthalene units (2t, 2u), which worked in moderate
yields (41−45%). Several aromatic heterocycles, such as
carbazole (2v), which is an important class of compounds in
organic electronics,32 benzofuran (2w), quinoline (2x, 2y), a
pyrimidine bearing an azepane moiety (2z), and a
phenothiazine possessing a free aniline group (2aa), were
readily accommodated. Furthermore, nonaromatic hetero-
cycles such as a thioanisole bearing a 2-oxabicyclo[2.1.1]-
hexane moiety (2ab), a water-soluble bioisostere of benzene,33
gave the desired product in good yield. To further demonstrate
the synthetic potential of this transformation, we subjected aryl
a
Yield of isolated product. ArSMe (0.25 mmol), Zn(CN)2 (0.6
equiv), KOAc (1.24 equiv), Ni(COD)2 (5 mol %), dcype (10 mol %),
b
c
1,4-dioxane (0.5 M), 110 °C, 16 h. NMR yield. 150 °C.
B
https://doi.org/10.1021/acs.orglett.1c02285
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
thioethers bearing important functional groups to the reaction
conditions. To our delight, aryl sulfides containing a
phthalimide (2ac), benzyl-protected and unprotected amides
(2ad, 2ae), a boronic ester (2af), a silyl (2ag), a styrene (2ah),
an acetal-protected aldehyde (2ai), and an aliphatic ester (2aj)
worked efficiently under the reaction conditions (47−89%).
We next performed some competition reactions. Aliphatic and
benzyl nitriles (2ak, 2al) were not reactive toward the nickel
catalyst, confirming the need for a Lewis acid to activate
them.34,35
Furthermore, an aliphatic thioether (2am) was inert to the
conditions and led to selective cyanation of the aryl sulfide in
excellent yield. Double coupling of an arene bearing two
thioether moieties (2an) worked smoothly. Finally, we
completed this study by performing the late-stage derivatiza-
tion of commercial molecules. Gratifyingly, the synthesis of the
benzyl-protected donitriptan intermediate (2ao), an antimi-
graine drug, worked in excellent yield (95%). Letrozole (2ap),
a drug used in the treatment of breast cancer, was also
successfully transformed to the dicyano compound in 29%
yield and the monocyano in 42% yield, showing the ability of
this transformation to generate libraries of interesting
derivatives. A cholestanol derivative (2aq) was obtained in
high yield. Furthermore, clofibrate, a drug controlling high
cholesterol and triacylglyceride levels in the blood, could also
be readily functionalized (2ar). The late-stage cyanation of a
commercial photoinitiator, MMMP, was also successful,
affording the corresponding product (2as) in 88% yield.
Interestingly, the reaction worked in a lower but good yield on
a 5 mmol scale, with 20% of the starting material recovered,
demonstrating both the scalability and the excellent mass
balance of this otherwise byproduct-free reaction.
attention to the depolymerization of a commercial thermo-
plastic polymer PPS (polyphenylene sulfide).36,37 After a re-
evaluation of the reaction conditions, the polymer was
successfully depolymerized in 58% yield to obtain dicyano-
benzene (Scheme 3B). These results show the potential of this
transformation for upcycling polymer wastes. Moreover, we
also demonstrated the utility of our reaction in orthogonal
reactions. Under palladium catalysis, the C−Br bond of
compound 3d was selectively functionalized in a Suzuki−
Miyaura cross-coupling.22 Compound 3e could then be further
converted into a nitrile under nickel catalysis (Scheme 3C,
top). Furthermore, this selective bond activation was also
shown in a Miyaura borylation.38 Compound 3g, was indeed
selectively borylated at the C−Br bond position using a
palladium catalyst. The corresponding boronic ester (3h)
could then be transformed into the corresponding nitrile under
the developed reaction conditions in 89% yield (Scheme 3C,
bottom).
Nickel, in combination with dcype, was previously
demonstrated to be competent in the cleavage of C(sp2)−S
bonds.22,23,30 Furthermore, Rueping and coworkers showed
the ability of this nickel catalyst to undergo transmetalation
with Zn(CN)2 under basic conditions.13 The nickel/dcype
catalytic manifold has also been reported to enable C−CN
bond formation.11,12,30 Hence, the plausible mechanism of this
transformation starts with active catalyst M1. Subsequently, the
complex is oxidized to Ni(II) in the presence of thioanisole,
followed by transmetalation with M−CN leading to complex
M3 and the generation of M−SMe salt. This complex
undergoes reductive elimination with the help of an extra
ligand to generate back complex M1 and release the
corresponding aryl nitrile (Scheme 4).
We then shifted our focus to synthetic applications. First, we
applied our reaction to the two-step synthesis of compound 3b
in 59% yield, which could not be accessed otherwise with this
substitution pattern through the direct Friedel−Crafts
acylation of benzonitrile (Scheme 3A). We next turned our
Scheme 4. Proposed Mechanism
Scheme 3. Synthetic Applications
In summary, we have developed the first nickel-catalyzed
direct cyanation of aryl thioethers using a slight excess of zinc
cyanide and potassium acetate. This transformation showed
great efficiency toward many aryl sulfides as well as high
functional group tolerance. The reaction is scalable and user-
friendly due to the lower toxicity on Zn(CN)2 compared with
other metallic cyanide sources.39 Furthermore, late-stage
derivatizations in combination with synthetic applications
showed its potential as a new tool to access densely
functionalized aryl nitriles.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02285.
a
Yield of isolated product (%). For details, see the SI.
C
https://doi.org/10.1021/acs.orglett.1c02285
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(12) Takise, R.; Itami, K.; Yamaguchi, J. Cyanation of Phenol
Derivatives with Aminoacetonitriles by Nickel Catalysis. Org. Lett.
2016, 18, 4428−4431.
Experimental details and nuclear magnetic resonance
spectra (PDF)
(13) Chatupheeraphat, A.; Liao, H. H.; Lee, S. C.; Rueping, M.
Nickel-Catalyzed C−CN Bond Formation via Decarbonylative
Cyanation of Esters, Amides, and Intramolecular Recombination
Fragment Coupling of Acyl Cyanides. Org. Lett. 2017, 19, 4255−
4258.
(14) Shi, S.; Szostak, M. Decarbonylative Cyanation of Amides by
Palladium Catalysis. Org. Lett. 2017, 19, 3095−3098.
(15) Lou, J.; Wang, Q.; Wu, P.; Wang, H.; Zhou, Y. G.; Yu, Z.
Transition-Metal Mediated Carbon-Sulfur Bond Activation and
Transformations: An Update. Chem. Soc. Rev. 2020, 49, 4307−4359.
(16) Wang, L.; He, W.; Yu, Z. Transition-Metal Mediated Carbon−
Sulfur Bond Activation and Transformations. Chem. Soc. Rev. 2013,
42, 599−621.
AUTHOR INFORMATION
■
Corresponding Author
Bill Morandi − ETH Zu
̈
rich, 8093 Zurich, Switzerland;
̈
orcid.org/0000-0003-3968-1424; Email: bill.morandi@
org.chem.ethz.ch
Authors
Tristan Delcaillau − ETH Zu
Adrian Woenckhaus-Alvarez − ETH Zu
Switzerland
̈
rich, 8093 Zu
̈
rich, Switzerland
rich,
̈
rich, 8093 Zu
̈
(17) Pan, F.; Shi, Z. J. Recent Advances in Transition-Metal-
Catalyzed C-S Activation: From Thioester to (Hetero)Aryl
Thioether. ACS Catal. 2014, 4, 280−288.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02285
(18) Otsuka, S.; Nogi, K.; Yorimitsu, H. C−S Bond Activation. Top
Curr. Chem. (Z) 2018, 376, 13.
Author Contributions
†T.D. and A.W.-A. contributed equally.
(19) Zhu, D.; Shi, L. Ni-Catalyzed Cross-Coupling of Aryl
Thioethers with Alkyl Grignard Reagents via C−S Bond Cleavage.
Chem. Commun. 2018, 54, 9313−9316.
Notes
The authors declare no competing financial interest.
(20) Someya, C. I.; Weidauer, M.; Enthaler, S. Nickel-Catalyzed
C(Sp2)−C(Sp2) Cross Coupling Reactions of Sulfur-Functionalities
and Grignard Reagents. Catal. Lett. 2013, 143, 424−431.
(21) Sugahara, T.; Murakami, K.; Yorimitsu, H.; Osuka, A.
Palladium-Catalyzed Amination of Aryl Sulfides with Anilines.
Angew. Chem., Int. Ed. 2014, 53, 9329−9333.
̈
(22) Bismuto, A.; Delcaillau, T.; Muller, P.; Morandi, B. Nickel-
Catalyzed Amination of Aryl Thioethers: A Combined Synthetic and
Mechanistic Study. ACS Catal. 2020, 10, 4630−4639.
ACKNOWLEDGMENTS
■
This project received funding from the Swiss National Science
Foundation (SNSF 184658). We also thank ETH Zu
̈
rich. We
rich for
thank the NMR and MS departments of ETH Zu
technical assistance as well as our group for critical
proofreading of this manuscript. T.D. thanks Philip Boehm
̈
̈
(ETH Zurich) for the synthesis of several starting materials.
(23) Delcaillau, T.; Bismuto, A.; Lian, Z.; Morandi, B. Nickel-
Catalyzed Inter- and Intramolecular Aryl Thioether Metathesis by
Reversible Arylation. Angew. Chem., Int. Ed. 2020, 59, 2110−2114.
(24) Uetake, Y.; Niwa, T.; Hosoya, T. Rhodium-Catalyzed Ipso-
Borylation of Alkylthioarenes via C−S Bond Cleavage. Org. Lett.
2016, 18, 2758−2761.
REFERENCES
■
(1) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D.
Pharmaceutical Substance: Synthesis, Patents and Applications of The
Most Relevant AIPs, 5th ed.; Thieme: Stuttgart, Germany, 2008; pp 1−
1800.
(25) Bhanuchandra, M.; Baralle, A.; Otsuka, S.; Nogi, K.; Yorimitsu,
H.; Osuka, A. Palladium-Catalyzed Ipso-Borylation of Aryl Sulfides
with Diborons. Org. Lett. 2016, 18, 2966−2969.
(2) Brunton, L.; Chabner, B.; Knollman, B. Goodman and Gilman’s
The Pharmacological Basis of Therapeutics; MacGraw-Hill: New York,
2010.
(3) Trost, B. M.; Fleming, I. Comprehensive Organic Synthesis;
Pergamon Press: Oxford, U.K., 1991.
(4) Larock, R. C. Comprehensive Organic Transformations; Wiley:
New York, 1999.
(5) Rappoport, Z. The Chemistry of the Cyano Group; Wiley: New
York, 1971.
(6) von Braun, J.; Manz, G. Fluoranthen und seine Derivate. III.
Mitteilung. Liebigs Ann. Chem. 1931, 488, 111−126.
(7) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges. B 1919, 52,
1749.
(8) Neetha, M.; Afsina, C. M. A.; Aneeja, T.; Anilkumar, G. Recent
Advances and Prospects in the Palladium-Catalyzed Cyanation of Aryl
Halides. RSC Adv. 2020, 10, 33683−33699.
(9) Mills, L. R.; Graham, J. M.; Patel, P.; Rousseaux, S. A. L. Ni-
Catalyzed Reductive Cyanation of Aryl Halides and Phenol
Derivatives via Transnitrilation. J. Am. Chem. Soc. 2019, 141,
19257−19262.
(26) Yang, J.; Xiao, J.; Chen, T.; Yin, S. F.; Han, L. B. Efficient
Nickel-Catalyzed Phosphinylation of C−S Bonds Forming C-P
Bonds. Chem. Commun. 2016, 52, 12233−12236.
(27) Barbero, N.; Martin, R. Ligand-Free Ni-Catalyzed Reductive
Cleavage of Inert Carbon - Sulfur Bonds. Org. Lett. 2012, 14, 796−
799.
(28) Matsumura, T.; Niwa, T.; Nakada, M. Pd-Catalyzed Reductive
Cleavage of Alkyl Aryl Sulfides with Triethylsilane That Is Accelerated
by Trialkylsilyl Chloride. Tetrahedron Lett. 2012, 53, 4313−4316.
(29) Fang, S.; Wang, M.; Liu, J.; Li, B.; Liu, J. Y. Theoretical Study
on the Reaction Mechanism of “Ligandless” Ni-Catalyzed Hydro-
desulfurization of Aryl Sulfide. RSC Adv. 2017, 7, 51475−51484.
(30) Delcaillau, T.; Boehm, P.; Morandi, B. Nickel-Catalyzed
Reversible Functional Group Metathesis between Aryl Nitriles and
Aryl Thioethers. J. Am. Chem. Soc. 2021, 143, 3723−3728.
(31) Vogt, M.; de Bruin, B.; Berke, H.; Trincado, M.; Grutzmacher,
̈
H. Amino Olefin Nickel(I) and Nickel(0) Complexes as Dehydrogen-
ation Catalysts for Amine Boranes. Chem. Sci. 2011, 2, 723−727.
(32) Liu, N.; Mei, S.; Sun, D.; Shi, W.; Feng, J.; Zhou, Y.; Mei, F.;
Xu, J.; Jiang, Y.; Cao, X. Effects of Charge Transport Materials on
Blue Fluorescent Organic Light-Emitting Diodes with a Host-Dopant
System. Micromachines 2019, 10, 344.
(10) Chen, H.; Sun, S.; Liu, Y. A.; Liao, X. Nickel-Catalyzed
Cyanation of Aryl Halides and Hydrocyanation of Alkynes via C−CN
Bond Cleavage and Cyano Transfer. ACS Catal. 2020, 10, 1397−
1405.
(11) Heravi, M. M.; Panahi, F.; Iranpoor, N. Nickel-Catalyzed
Deoxycyanation of Activated Phenols via Cyanurate Intermediates
with Zn(CN)2: A Route to Aryl Nitriles. Org. Lett. 2018, 20, 2753−
2756.
(33) Levterov, V. V.; Panasyuk, Y.; Pivnytska, V. O.; Mykhailiuk, P.
K. Water-Soluble Non-Classical Benzene Mimetics. Angew. Chem., Int.
Ed. 2020, 59, 7161−7167.
D
https://doi.org/10.1021/acs.orglett.1c02285
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(34) Fang, X.; Yu, P.; Morandi, B. Catalytic Reversible Alkene-
Nitrile Interconversion through Controllable Transfer Hydrocyana-
tion. Science 2016, 351, 832−836.
(35) Yu, P.; Morandi, B. Nickel-Catalyzed Cyanation of Aryl
Chlorides and Triflates Using Butyronitrile: Merging Retro-Hydro-
cyanation with Cross-Coupling. Angew. Chem., Int. Ed. 2017, 56,
15693−15697.
(36) Lian, Z.; Bhawal, B. N.; Yu, P.; Morandi, B. Palladium-
Catalyzed Carbon-Sulfur or Carbon-Phosphorus Bond Metathesis by
Reversible Arylation. Science 2017, 356, 1059−1063.
(37) Minami, Y.; Matsuyama, N.; Matsuo, Y.; Tamura, M.; Sato, K.;
Nakajima, Y. Catalytic Reductive Cleavage of Poly(Phenylene
Sulfide) Using a Hydrosilane. Synthesis 2021, 5−8.
(38) Lipshutz, B. H.; Moser, R.; Voigtritter, K. R. Miyaura
Borylations of Aryl Bromides in Water at Room Temperature. Isr. J.
Chem. 2010, 50, 691−695.
(39) Molski, M. Theoretical modeling of structure-toxicity relation-
ship of cyanides. Toxicol. Lett. 2021, 349, 30−39.
E
https://doi.org/10.1021/acs.orglett.1c02285
Org. Lett. XXXX, XXX, XXX−XXX