Nickel-Catalyzed Cyanation of Aryl Chlorides and Triflates Using Butyronitrile: Merging Retro-hydrocyanation with Cross-Coupling

Article abstract of DOI:10.1002/anie.201707517

We describe a nickel-catalyzed cyanation reaction of aryl (pseudo)halides that employs butyronitrile as a cyanating reagent instead of highly toxic cyanide salts. A dual catalytic cycle merging retro-hydrocyanation and cross-coupling enables the conversion of a broad array of aryl chlorides and aryl/vinyl triflates into their corresponding nitriles. This new reaction provides a strategically distinct approach to the safe preparation of aryl cyanides, which are essential compounds in agrochemistry and medicinal chemistry.

Full text of DOI:10.1002/anie.201707517

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Accepted Article
Title: Nickel-Catalyzed Cyanation of Aryl Chlorides and Triflates Using
Butyronitrile: Merging Retro-Hydrocyanation with Cross-coupling
Authors: Peng Yu and Bill Morandi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707517
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Nickel-Catalyzed Cyanation of Aryl Chlorides and Triflates Using
Butyronitrile: Merging Retro-Hydrocyanation with Cross-coupling
Peng Yu and Bill Morandi*
Dedicated to Robert H. Grubbs on the occasion of his 75th birthday
[10e]
Abstract: We describe here a nickel-catalyzed cyanation reaction of
aryl (pseudo)halides that employs butyronitrile as a cyanating
reagent instead of highly toxic cyanide salts. A dual catalytic cycle
merging retro-hydrocyanation and cross-coupling enables the
conversion of a broad array of aryl chlorides and aryl/vinyl triflates
into their corresponding nitriles. This new reaction provides a
strategically distinct approach to the safe preparation of aryl
cyanides, which are essential compounds in agrochemistry and
medicinal chemistry.
the reaction mixture.
Additionally, the use of this reagent
leads to the formation of metal wastes. Thus, the discovery of
novel, non-toxic reagents addressing these challenges remains
of great significance. In particular, a method employing simple,
non-hydrolysable alkyl nitriles as benign cyanating reagents
would be a complementary tool for the safe preparation of aryl
and vinyl cyanides.
Aromatic nitriles are found in
a
wide range of
pharmaceuticals, agrochemicals, natural products and organic
materials.[1] Moreover, aryl nitriles are among the most versatile
synthetic intermediates because they can be readily converted
to aldehydes, carboxylic acids, ketones, amides, amines, and
heterocycles.[2] The development of efficient and practical routes
for the synthesis of aryl nitriles has thus been a longstanding
goal of organic synthesis. To bypass the limitations of the
venerable Sandmeyer[3] and Rosenmund-von Braun reaction[4]
that employ stoichiometric amounts of CuCN, the transition-
metal catalyzed cyanation of aryl halides has been introduced.[5]
While the use of earth-abundant metals as catalysts and less
reactive aryl halides as substrates remains challenging, the most
severe drawback of the vast majority of the current protocols
continues to be the reliance upon highly toxic cyanide salts as
reagents.
Traditionally, metal cyanide salts (KCN,[6] NaCN,[7]
Zn(CN)2[8]), TMSCN[9] or acetone cyanohydrin[10] have been used
in the transition-metal-catalyzed cyanation of aryl halides
(scheme 1a). The common feature among all these reagents is
the relative ease by which the cyano group can be transferred to
the metal catalyst, ensuring a facile cyanation reaction. However,
this feature is also often responsible for catalyst deactivation
through formation of inactive catalytic species bearing multiple
cyanide ligands. More importantly, the facile release of the
cyanide anion is responsible for the high toxicity of these
reagents, which generates significant safety concerns for both
academic and industrial applications. To address these safety
concerns, K4[Fe(CN)6],[11] a nontoxic food additive, has been
introduced as a reagent for the cyanation of aryl halides by the
Beller and Weissman group.[11a, c] However, the low solubility of
this reagent in organic solvents and its low rate of
transmetallation has limited its broader application, in part
because of scalability issues due to the heterogeneous nature of
Scheme 1. Reaction design.
The installation of a cyano group through transition-metal
catalyzed activation of C–CN bonds enables the use of
inexpensive and less toxic alkyl nitriles as reagents.[12] This
strategy provides a controlled way to generate metal-cyanide
intermediates without employing metal cyanide sources,
avoiding both catalyst deactivation and exposure to toxic
reagents. Recently, our group reported a reversible nickel–
catalyzed transfer hydrocyanation through shuttle catalysis[13]
that employed a simple alkyl nitrile as a HCN donor to convert
alkenes into nitriles.[14]
Inspired by the transfer mechanism of the hydrocyanation
process, we hypothesized that simple alkyl nitriles bearing β-
hydrogens could possibly be employed as cyanating reagents in
transition-metal-catalyzed cyanation of aryl (pseudo)halides
(scheme 1b). With regard to the mechanism, we envisaged that
a transmetallation event between two independently generated
catalytic intermediates, H–Ni–CN (generated through oxidative
addition of the C−CN bond followed by β-hydride elimination)
and Ar–Ni–X (generated through oxidative addition of Ar–X),
could lead to the formation of the desired aryl cyanide after
[*]
[†]
M. Sc. Peng Yu and Dr. Bill Morandi
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
E-mail: morandi@kofo.mpg.de
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.
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reductive elimination. Reaction of H–Ni–X with a base could
then regenerate the catalytically active Ni(0) species (scheme
1b). However, we anticipated that few challenges would have to
be overcome to realize this strategy: (1) a single catalyst must
be able to mediate all the elementary steps involved in two
distinct catalytic cycles; (2) the rate of both catalytic cycles
should be adjusted appropriately to make the transmetallation
kinetically accessible.
yields of 3aa or no product formation, indicating that an
aluminium Lewis acid plays a critical role in the activation of the
C–CN bond. Likewise, other bases or reducing agent had a
deleterious effect on the outcome of the
Table 2: Scope of nickel-catalyzed transfer cyanation of aryl chlorides.[a]
Table 1: Optimization of reaction conditions.[a]
Entry
1
Deviation from standard conditions
none
3aa (%)[b]
88
<5
0
2
DPEPhos instead of Xantphos
PPhCy2 instead of Xantphos
NiCl2·glyme instead of Ni(acac)2
NiBr2·glyme instead of Ni(acac)2
Ni(COD)2 instead of Ni(acac)2
AlMe2Cl instead of Al(isobutyl)3
AlMe3 instead of Al(isobutyl)3
AlCl3 instead of Al(isobutyl)3
K2CO3 instead of K3PO4
Et3N instead of K3PO4
3
4
32
37
25
27
71
0
5
6
7
8
9
10
11
12
13
21
59
27
Mn instead of Zn
[a] Yields of isolated products. [b] n = 7.5. [c] n = 10. [d] n = 12.5. [e] n = 15.
2.0 equivalent of 2a
22 (52[c]
)
reaction (entries 10-12). Lower yields of 3aa were obtained
when the reaction was treated with fewer equivalents of 2a
(entry 13), probably reflecting the slower rate of retro-
hydrocyanation relative to the oxidative addition of the aryl
chloride.
As shown in table 2, substrates bearing electron donating or
withdrawing substituents, whether they were at the para, meta or
even ortho position, reacted well (3ba-3ja), revealing a good
tolerance to steric and electronic effects. Naphthyl and 9-
phenanthryl chlorides can also be converted to the
corresponding aryl nitriles in good yields (3la, 3ma). Several
nitrogen and oxygen heterocycles relevant to the drug discovery
processcould be efficiently tolerated by the catalytic system
(3oa-3sa).
We next aimed to extend the scope to another important
class of electrophiles, aryl and vinyl triflates. Despite the fact that
triflate electrophiles, which can be easily accessed from phenols
or aliphatic ketones, are retrosynthetically complementary to
halides, they have not been frequently used in transition-metal
catalyzed cyanation reactions.[16] In particular, few examples of
nickel-catalyzed cyanation of aryl triflates have been reported,[17]
[a] Reaction conditions: 1a (0.1 mmol), 2a (1.0 mmol), Ni(acac)2 (5 mol%),
Xantphos (5 mol%), Al(isobutyl)3 (20 mol%), Zn (15 mol%), K3PO4 (2.0 eq.),
toluene (0.5 mL) at 120 oC, 12 h. [b] GC yields. [c] 2a (6.0 eq.).
To test our hypothesis, we selected butyronitrile 2a as an
inexpensive reagent (~80€/L) to cyanate aryl chloride 1a (Table
1). The choice of 2a as cyanating agent is accounted for its low
price, low-molecular weight and high volatility of the
corresponding alkene by-product. After careful evaluation of
reaction parameters,[15] we found that
a combination of
inexpensive and bench-stable Ni(acac)2, Xantphos, Al(isobutyl)3
as co-catalyst, Zn as reducing agent to generate Ni(0) and
K3PO4 as base in toluene at 120oC gave the best result within 12
hours, delivering 3aa in 88% GC yield (entry 1). It is noteworthy
that undesired homodimerization or Heck-type reactions were
not observed under the reaction conditions. The use of a
bidentate ligand with a smaller bite angle hampered the
reactivity of this cyanation reaction, and no product was
detected when the reaction was treated with a monodentate
phosphine ligand (entries 2 and 3). As shown in entries 4-9, the
use of other precatalysts or co-catalysts resulted either in lower
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and these protocols all rely on highly toxic KCN as cyanating
reagent. After a small modification of the reaction conditions, we
found that several aryl and vinyl triflates can be successfully
converted to the corresponding cyano products in good to
excellent yields (62-97%) under mild reaction conditions
(Ni(cod)2, Xantphos, AlCl3, Et3N in toluene at 50-110 oC for 3-12
hours). The fact that AlCl3, in contrast to the aryl chloride case,
performed best could be explained by the stark influence of the
Lewis-acid on the rate of retro-hydrocyanation. As shown in
table 3, substrates bearing either electron deficient (3ta, 3ua) or
electron donating groups (3fa, 3ca, 3ea, 3va) can be efficiently
converted to aryl nitriles in excellent yields. Ortho substituted
substrates reacted well under our reaction conditions, even
though slightly lower yields were obtained (3ea, 3xa). A
chemoselective reaction of the triflate electrophile could be
realized in the presence of a chloride, furnishing the desired
products in good yields (3ya, 3za). Heterocycles such as
pyrrolidine, dioxole, carbazole, pyrazole and quinoline were well
tolerated under our conditions (3ab, 3qa, 3bb, 3cb, 3db). Even
unprotected indole and carbazole substrates could be well
tolerated (3eb, 3fb). Interestingly, vinyl triflates efficiently
afforded synthetically versatile vinyl nitriles in excellent yields
(3gb). A few natural products, such as δ-tocopherol, cholesterol
and estrone, were then transformed into the corresponding
triflates before being subjected to the transfer cyanation
conditions to obtain excellent yields of the desired products
(3hb-3jb). Notably, the amount of the reagent can be reduced
from 10 equiv. to 2 equiv. when the electrophile is slowly added
to the reaction mixture (3aa).
Table 3: nickel-catalyzed transfer cyanation of aryl and vinyl triflates.[a]
The method could also be employed on a preparative scale
when the reaction was performed in an open system to facilitate
the rapid release of the propene side-product (Scheme 2).
[a] Yields of isolated products. [b] GC yields. [c] 4 (0.5 mmol), 2a (1.0 mmol),
toluene (1.5 mL), 50 oC, 3h, triflate added over 2h. [d] 4 (0.5 mmol), 2a (1.5
mmol), toluene (1.5 mL), 70 oC, 5h, triflate added over 4h. [e] N-Xantphos (10
mol%), 110 oC. [f] Ni(COD)2 (20 mol%), Xantphos (20 mol%), AlCl3 (120
mol%), Et3N (4.0 eq.). [g] 80 oC.
control experiments using a simple ammonium cyanide salt or
acetone cyanohydrin as reagents did not give any conversion,
further suggesting that our reaction is not proceeding through
the in situ generation of an ammonium cyanide reagent
(Scheme 3, eq. 3 and 4). Taken altogether, these experiments
are best explained by a double catalytic cycle as presented in
Scheme 1b. Within this mechanistic context, the ability to
drastically decrease the amount of butyronitrile reagent when
the electrophile is slowly added to the reaction mixture (vide
supra) highlights the critical importance of matching the rate of
retro-hydrocyanation with that of aryl (pseudo)halide oxidative
addition.
Scheme 2. Gram scale experiment.
Several control reactions were then performed to gather
preliminary information about the mechanism. We demonstrated
the occurrence of the proposed retro-hydrocyanation step
through the detection of undecene isomers resulting from the
retro-hydrocyanation of dodecanitrile (Scheme 3, eq. 1).
We next explored whether retro-hydrocyanation proceeds in
the absence of electrophile. In this experiment, only small
amounts of alkene isomers were observed, showing that retro-
hydrocyanation cannot be performed efficiently in the absence of
the electrophile. The normal reaction course resumed after
addition of the electrophile, further suggesting that a direct
transfer of the cyanide anion between two nickel(II)-species is
the main pathway of the reaction (Scheme 3, eq. 2). Additional
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Scheme 3. Control experiments.
In conclusion, a new nickel-catalyzed cyanation reaction has
been developed, enabling the conversion of a broad range of
aryl chlorides and aryl/vinyl triflates into aryl/vinyl nitriles. The
use of nontoxic and inexpensive butyronitrile as a cyanating
agent not only addresses the safety issues encountered with
most of the current cyanation reactions, but also overcome other
drawbacks by preventing catalyst deactivation and ensuring
homogeneity of the reaction mixture. We believe that the new
concept delineated in this work, namely the merger of transfer
hydrofunctionalization and cross-coupling, will open new
avenues in synthetic organic chemistry.
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Generous funding from the Max-Planck-Society and the Max-
Planck-Institut für Kohlenforschung is acknowledged. We thank
Prof. Dr. Benjamin List for sharing analytical equipment. P.Y.
thanks the China Scholarship Council for a scholarship.
Keywords: Cross-coupling • Cyanation • Aryl chloride • Aryl
triflate • Retro-hydrocyanation
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