Nickel-Catalyzed Thiolation of Aryl Nitriles

Article abstract of DOI:10.1002/chem.202101273

A nickel-catalyzed thiolation of aryl nitriles has been developed to access functionalized aryl thioethers. The ligand dcype (1,2-bis(dicyclohexylphosphino)ethane) as well as the base KO^tBu (potassium tert-butoxide) are essential to achieve this transformation. This scalable and practical process involves both a C?C bond activation and a C?S bond formation. Furthermore, this reaction shows a high functional-group tolerance and enables the late-stage functionalization of important molecules.

Full text of DOI:10.1002/chem.202101273

Accepted Article
Accepted Article
Title: Nickel-Catalyzed Thiolation of Aryl Nitriles
Authors: Tristan Delcaillau and Bill Morandi
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To be cited as: Chem. Eur. J. 10.1002/chem.202101273
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01/2020

10.1002/chem.202101273
Chemistry - A European Journal
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Nickel-Catalyzed Thiolation of Aryl Nitriles
Tristan Delcaillau[a] and Bill Morandi*[a]
In Memory of Prof. François Diederich
[a]
T. Delcaillau, Prof. Dr. B. Morandi
Laboratorium für Organische Chemie
ETH Zꢀrich
Vladimir-Prelog-Weg 3, HCI, 8093 Zꢀrich, Switzerland
Supporting information for this article is given via a link at the end of the document.
evaluated several ligands such as monodentate and bidentate
phosphine ligands, as well as N-heterocyclic carbenes (NHC).
Abstract: A nickel-catalyzed thiolation of aryl nitriles has been
developed to access functionalized aryl thioethers. The ligand dcype
(1,2-Bis(dicyclohexylphosphino)ethane) as well as the base KOtBu
(potassium tert-butoxide) are essential to achieve this transformation.
This scalable and practical process involves both a C–C bond
activation and a C–S bond formation. Furthermore, this reaction
shows a high functional-group tolerance and enables the late-stage
functionalization of important molecules.
Initial
experiments
relied
on
LiHMDS
(Lithium
bis(trimethylsilyl)amide) as a base, because it had proven to be
efficient in our previously reported aryl thioether metathesis.[11]
First positive results were observed with dppe (1,2-
bis(diphenylphosphino)ethane) as ligand, affording the
corresponding aryl thioether in 10% yield. Gratifyingly, the use of
dcype (1,2-bis(dicyclohexylphosphino)ethane) increased the
yield up to 33%. This ligand was previously reported to be
Aryl nitriles are of great interest to the scientific community.
Indeed, this moiety is found in many natural products as well as
pharmaceuticals.[1,2] Aryl nitriles can be readily transformed into
several other functional groups such as carboxylic acids, ketones,
aldehydes, or benzylamines derivatives (Scheme 1A).[3] The rise
of modern cross-coupling reactions has facilitated the access to
aryl nitriles. The use of Pd, Ni or Cu as catalysts in combination
with a metal cyanide reagent has enabled the efficient access to
diversified aryl nitriles from aryl (pseudo)halides.[4In contrast, the
concept of using the cyano group as an atypical electrophile in
cross-coupling has only been developed in the past two decades.
For instance, the formation of valuable bi-aryl compounds, aryl
amines, aryl boronic esters, aryl organo silicons, aryl phosphines
and hydro-aryls using aryl nitriles as electrophiles has expanded
the synthetic potential of this functional group (Scheme 1B).[5] On
the other hand, the synthesis of aryl thioethers, which are
important compounds in medicinal chemistry[6] and materials
science,[7] has also taken advantage of modern organic chemistry
and the associated generalization of metal-catalyzed reactions.
Aryl (pseudo) halides have served as versatile platforms to rapidly
generate diversified libraries of aryl thioethers by using either Pd,
Ni or Cu catalysts (Scheme 1C).[8] An interesting feature of
thioethers is their facile conversion to other valuable functional
groups such as alkyl groups, amines, boryl moieties or
sulfoximines.[9] Despite the synthetic utility of thioethers and the
widespread occurrence of aryl nitriles, methods to convert nitriles
to the corresponding aryl thioethers are extremely scarce. To date
only one method, proceeding through functional group metathesis,
has been reported using an aryl thioether as a formal thioether
donor.[10] However, a traditional catalytic approach for the direct
conversion of an aryl cyanide to a thioether using an organic thiol
has not yet been reported (Scheme 1D).
effective in the activation of C–CN bonds and the formation of C–
S bonds.[11,12] After an extensive screening of different reaction
conditions, we found that 1,4-dioxane as solvent in combination
with KOtBu as a base afforded the expected product in 86% yield.
To our delight, a slight excess of thiol and base (1.1 equiv & 1.2
equiv. respectively) was sufficient to obtain the product in high
yield (90%).
Scheme 1. Context of the work.
With the optimized conditions in hand, we started to explore the
substrate scope with respect to aryl nitriles (Table 2). A wide
range of benzonitrile derivatives worked efficiently under the
reaction conditions. Indeed, electron-neutral and rich arenes (3a,
3b, 3c, 3d, 3e, 3f, 3g and 3h) were compatible, affording the
desired products in moderate to excellent yield (50-94%).
We started our investigation by using benzonitrile and n-
dodecanethiol as benchmark substrates. In combination with
Ni(COD)2 (Bis(1,5-cyclooctadiene)nickel(0)) as metal catalyst, we
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10.1002/chem.202101273
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Moreover, sterically hindered aryl nitriles proved to be competent
(3i), providing the ortho-methyl aryl thioether derivative in 71%
yield. We also tested the scalability of this reaction by employing
2.0 mmol of 4-(tert-butyl)benzonitrile. For that purpose, we
examined the reaction with decreased catalyst loadings (5 and 10
mol% of Ni/dcype), which provided 3d in synthetically useful
yields (66 and 79%).
compounds (3m and 3n), as well as on a bicyclic aryl nitrile (3o).
All of them afforded the expected products in high yields (74-85%).
We concluded this exploration of aryl nitriles by performing the
late-stage derivatization of the drug Fadrozole (3p) which is used
for the treatment of breast cancer.[13] Gratifyingly, the
corresponding aryl thioether was obtained in 42%. Moreover, the
synthesis of a derivative of MMMP (3q), a widely used
photoinitiator,[14] could be obtained in 82% yield. Thus,
demonstrating the potential of this transformation to derivatize
commercial molecules.
Table 1. Optimization of the reaction conditions.[a]
Table 2. Substrate scope with respect to aryl nitriles.[a]
Deviation from standard
Entry
Yield [%]b
conditions
None
1
2
33
0
L1 instead of L8
L2 instead of L8
L3 instead of L8
L4 instead of L8
L5 instead of L8
L6 instead of L8
L7 instead of L8
L9 instead of L8
10 mol% L8 instead of 5 mol%
3
0
4
5
5
10
16
22
0
6
7
8
9
0
10
34
10 mol% L8 and Ni(COD)2 instead of 5
11
52
mol%
15 mol% L8 and Ni(COD)2 instead of 5
12
13
14
15
74
75
86
90
mol%
KOtBu instead of LiHMDS
KOtBu/1,4-dioxane instead of LiHMDS/o-
xylene
1.1 equiv. of thiol and 1.2 equiv. of KOtBu
[a] 1a (0.25 mmol), 2a (2.0 equiv.), Ni(COD)2 (5 mol%), o-xylene, 140 °C, 16
h. [b] GC yields using n-dodecane as internal standard.
[a] Yield of isolated product. Aryl nitrile (0.25 mmol, 1.0 equiv.), n-dodecanethiol
(0.275 mmol, 1.1 equiv.), KOtBu (0.3 mmol, 1.2 equiv.), Ni(COD)2 (0.0375 mmol,
15 mol%), dcype (0.0375 mmol, 15 mol%), 1,4-dioxane (0.75 mL), 110 °C, 16
h. [b] the HCl salt was used in combination with 2.5 equiv. of KOtBu.
With the optimized amount of catalyst (15 mol%), a similar yield
of the product was obtained as for the trials on 0.25 mmol scale,
showcasing the potential of this transformation for larger scale
reactions. Next, several electron-poor arenes, bearing electron-
withdrawing functional groups such as an amide (3j) and a ketone
(3k), were examined. Both led to the formation of product in high
yields (91 and 88%). Furthermore, fluorine-containing aryl nitriles
also worked smoothly under the reaction conditions (3l, 72%).
Subsequently, we tested the methodology on heterocyclic
We next evaluated the versatility of this reaction with regards to
thiols (Table 3). Readily available aryl nitriles bearing cyclic
aliphatic thiols (4a, 4b & 4c) proved to be competent partners,
providing the respective products in high yields (91, 94 and 88%).
A sterically hindered thiol also worked efficiently under the
reaction conditions affording the desired adamantyl aryl thioether
(4d) in 91%. We next shifted our focus to densely functionalized
thiols. First, we used a thiol bearing an aliphatic nitrile group (4e).
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10.1002/chem.202101273
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To our delight, the desired product was obtained in good yield
(63%) without any reaction on the aliphatic nitrile group occurring,
thus demonstrating the selective activation of C(sp2)–CN bonds
with this catalytic manifold.[4e,15] Furthermore, thiols containing an
aliphatic amide (4f), ether (4g) and thioether (4h) gave the desired
product in good to excellent yield (82-95%). Non-aromatic
heterocycles bearing a strongly coordinating amine such as
pyrrolidine (4i) and azetidine (4j) were also tolerated under the
reaction conditions, affording the expected thioethers in moderate
to good yields (85 and 54%). Moreover, performing the double
coupling reaction on 1,4-dicyanobenzene (4k) afforded the di-
sulfide product in a satisfactory 78% yield. Finally, we completed
this study by using a thiol-derivative of vitamin E (4l). This
compound proved to be competent in the here described reaction,
delivering the natural product-derivative in 84%, thus showing the
potential of this transformation for late-stage diversification.
We hence propose the following mechanism: dissociation of one
of the COD of Ni(COD)2 in the presence of dcype provides the
active catalyst 1. Subsequently, the catalyst undergoes oxidative
addition by cleaving the C–CN of the aryl nitrile, followed by
transmetallation with the potassium thiolate leading to complex 3.
The ligand then facilitates the reductive elimination, generating
back complex 1 and releasing the aryl thioether (Scheme 2).
Scheme 2. Plausible mechanism.
Table 3. Substrate scope with respect to thiols.[a]
In summary, we have developed a nickel-catalyzed thiolation of
aryl nitriles. Because of the wide occurrence and availability of
these compounds, this transformation complements the toolbox
of useful methods available for the transformation of the cyano
group into other functional groups. The methodology shows a
good functional-group tolerance, enabling the late-stage
diversification of important molecules. Moreover, we showed that
the reaction is a scalable and practical tool to access highly
valuable aryl thioethers.
Acknowledgements
This project received funding from the Swiss National Science
Foundation (SNSF 184658). We also thank ETH Zürich. We thank
the NMR and MS departments of ETH Zürich for technical
assistance as well as our group for critical proofreading of this
manuscript. We thank Philip Boehm for reproducing some scope
entries and our group for critical proofreading.
Keywords: Nickel • nitrile • thioethers • catalysis • late-stage
[a] Yield of isolated product. Aryl nitrile (0.25 mmol, 1.0 equiv.), thiol (0.275
mmol, 1.1 equiv.), KOtBu (0.3 mmol, 1.2 equiv.), Ni(COD)2 (0.0375 mmol, 15
mol%), dcype (0.0375 mmol, 15 mol%), 1,4-dioxane (0.75 mL), 110 °C, 16 h.
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Tristan Delcaillau[a] and Bill Morandi[a]*
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Nickel-Catalyzed Thiolation of Aryl
Nitriles
Text for Table of Contents
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