Palladium-Catalyzed Late-Stage Direct Arene Cyanation

Article abstract of DOI:10.1016/j.chempr.2018.09.027

Methods for direct benzonitrile synthesis are sparse, despite the versatility of cyano groups in organic synthesis and the importance of benzonitriles for the dye, agrochemical, and pharmaceutical industries. We report the first general late-stage aryl C–H cyanation with broad substrate scope and functional-group tolerance. The reaction is enabled by a dual-ligand combination of quinoxaline and an amino acid-derived ligand. The method is applicable to direct cyanation of several marketed small-molecule drugs, common pharmacophores, and organic dyes. Benzonitriles are some of the most versatile building blocks for organic synthesis, in particular in the pharmaceutical industry, but general methods to make them by direct C–H functionalization are unknown. In this issue of Chem, Ritter and coworkers describe a late-stage aryl C–H cyanation with broad substrate scope and functional-group tolerance, enabled by a palladium-dual-ligand catalyst system. The reaction may serve for the late-stage modification of drug candidates. Aryl nitriles constitute an important class of organic compounds that are widely found in natural products, pharmaceuticals, agricultural chemicals, dyes, and materials. Moreover, nitriles are versatile building blocks to access numerous other important molecular structure groups. However, no general method for direct aromatic C–H cyanation is known. All approaches to date require either an appropriate directing group or reactive electron-rich substrates, such as indoles, which limit their synthetic applications. Here we describe an undirected, palladium-catalyzed late-stage aryl C–H cyanation reaction for the synthesis of complex aryl nitriles that would otherwise be more challenging to produce. The wide substrate scope and good functional-group tolerance of this reaction provide direct and quick access to structural diversity for pharmaceutical and agrochemical development.

Full text of DOI:10.1016/j.chempr.2018.09.027

Article
Palladium-Catalyzed Late-Stage Direct Arene
Cyanation
Da Zhao, Peng Xu, Tobias Ritter
ritter@mpi-muelheim.mpg.de
HIGHLIGHTS
Late-stage direct arene cyanation
with arene as limiting reagent
Broad substrate scope enabled by
a dual-ligand system
Electron-rich and -poor arenes as
well as common pharmacophores
tolerated
Benzonitriles are some of the most versatile building blocks for organic synthesis,
in particular in the pharmaceutical industry, but general methods to make them by
direct C–H functionalization are unknown. In this issue of Chem, Ritter and
coworkers describe a late-stage aryl C–H cyanation with broad substrate scope
and functional-group tolerance, enabled by a palladium-dual-ligand catalyst
system. The reaction may serve for the late-stage modification of drug candidates.
Zhao et al., Chem 5, 1–11
January 10, 2019 ª 2018 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2018.09.027

Please cite this article in press as: Zhao et al., Palladium-Catalyzed Late-Stage Direct Arene Cyanation, Chem (2018), https://doi.org/10.1016/
j.chempr.2018.09.027
Article
Palladium-Catalyzed Late-Stage
Direct Arene Cyanation
Da Zhao,1,2 Peng Xu,1,2 and Tobias Ritter1,3,
*
SUMMARY
The Bigger Picture
Aryl nitriles constitute an
Methods for direct benzonitrile synthesis are sparse, despite the versatility of
cyano groups in organic synthesis and the importance of benzonitriles for the
dye, agrochemical, and pharmaceutical industries. We report the first general
late-stage aryl C–H cyanation with broad substrate scope and functional-group
tolerance. The reaction is enabled by a dual-ligand combination of quinoxaline
and an amino acid-derived ligand. The method is applicable to direct cyanation
of several marketed small-molecule drugs, common pharmacophores, and
organic dyes.
important class of organic
compounds that are widely found
in natural products,
pharmaceuticals, agricultural
chemicals, dyes, and materials.
Moreover, nitriles are versatile
building blocks to access
numerous other important
molecular structure groups.
However, no general method for
direct aromatic C–H cyanation is
known. All approaches to date
require either an appropriate
directing group or reactive
electron-rich substrates, such as
indoles, which limit their synthetic
applications. Here we describe an
undirected, palladium-catalyzed
late-stage aryl C–H cyanation
reaction for the synthesis of
complex aryl nitriles that would
otherwise be more challenging to
produce. The wide substrate
scope and good functional-group
tolerance of this reaction provide
direct and quick access to
INTRODUCTION
Aromatic nitriles are found as privileged motifs in numerous dyes, agrochemicals,
herbicides, and natural products (Scheme 1A).1–4 Moreover, the cyano group is a
versatile precursor for a multitude of important functional groups such as amines,
amidines, tetrazoles, aldehydes, amides, and carboxylic acids.5,6 Conventional
methods for aromatic cyanation rely on classical approaches such as the Sandmeyer
reaction,7,8 the Rosenmund-von Braun reaction,9 or transition-metal-catalyzed cyan-
ation of aryl (pseudo)halides.10,11 Despite their practical importance, such strategies
require prefunctionalized substrates. An ideal way for aromatic nitrile production
would be direct aromatic C–H cyanation without the requirement for chelation assis-
tance; however, such methods are still scarce, and none is currently available that has
a large substrate scope with respect to the electronic structure of the arene.12
Most advances in aromatic C–H cyanation have been accomplished through a che-
lation-assisted transition-metal-catalyzed C–H activation strategy (Scheme 1B,
Equation 1).13–27 Despite its potential to control site selectivity, directing groups
are required that may not be present in a given molecule, or must be introduced
and subsequently removed.28–30 A nondirected C–H cyanation method can func-
tionalize sites that are not accessible by a directed approach.31,32 Direct cyanation
methods exist for simple, electron-rich arenes, such as indole and anisole, but the
synthetic application remains rather limited, especially for structurally complex
molecules. Electrophilic cyanating reagents (+CN) have been shown to react with
electron-rich arenes, but sometimes lead to significant by-product formation.33–37
Alternatively, oxidative cyanation via a sequence of single electron transfer (SET)
from electron-rich arenes with subsequent cyanide addition can be used effectively
(Scheme 1B, Equation 2).38–41 The groups of Kita38 and Wang39 independently re-
ported hypervalent iodine(III)-mediated oxidative cyanation of electron-rich arenes.
In 2017, McManus and Nicewicz reported a direct arene C–H cyanation reaction of
electron-rich arenes via photoredox catalysis.40 In all known modern nondirected
aromatic cyanation reactions, the arene substrate must be sufficiently electron-rich
(no less electron-rich than toluene) for the oxidation to occur.12,15 Alternatively,
structural diversity for
pharmaceutical and agrochemical
development.
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two-step transformations can access benzonitriles from arenes, such as the efficient
two-step-one-pot C–H borylation-cyanation sequence developed by the Hartwig
group.42
One long-standing challenge in nondirected aromatic C–H functionalization is the
lack of sufficiently active metal catalysts. This challenge is illustrated by the very
limited reports on transition-metal-catalyzed C–H functionalization with arene as
the limiting reagent.43–51 In 2017, Yu and coworkers reported a palladium (Pd)-
catalyzed, pyridone-ligand-enabled Fujiwara-Moritani olefination reaction with
arenes as limiting reagent.43 Shortly thereafter, van Gemmeren reported the
same transformation using a combination of a pyridine ligand and a mono-N-pro-
tected amino acid (MPAA) ligand.45 An additional challenge for the development
of cyanation reactions is catalyst deactivation through formation of strong metal–
CN bonds, which renders the development of direct C–H cyanations difficult, as
electrophilic metal centers are required. Common cyanating reagents such as
metal cyanide salts (e.g., KCN, NaCN, Zn(CN)2, and CuCN) and trimethylsilyl
cyanide (Me3SiCN) have high potential for forming free cyanide in solution, which
can serve as a strong ligand to metals52–56 that in turn are no longer sufficiently
electrophilic for C–H metalation. Both challenges make general nondirected
cyanation difficult. To avoid catalyst deactivation, electrophilic cyanating reagents
such as N-cyano-N-phenyl-para-toluenesulfonamide (NCTS)17,21–23 and less reac-
tive reagents such as acetonitrile (CH3CN),57 nitromethane (CH3NO2),58 dimethyl-
formamide (DMF),16,26,27 or tert-butyl isocyanide (tBuNC)59–61 have also been
utilized in conventional C–H cyanation reactions. In all described transition-
metal-catalyzed direct C–H cyanation, the substrates are limited to reactive
electron-rich arenes such as indoles or anisoles, and high temperatures (>130ꢀC)
are usually required (Scheme 1B, Equation 3).
Thus far, a general approach for direct aromatic C–H cyanation of electron-poor
arenes, complex molecules, marketed small-molecule drugs, or common pharmaco-
phores has yet to be achieved (Scheme 1C). Such an approach would constitute a
powerful tool for late-stage diversification of drug candidates, agrochemicals, and
natural products. Herein, we report a Pd-catalyzed late-stage aromatic C–H cyana-
tion reaction with broad substrate scope and functional-group tolerance (Scheme
1D, Equation 4). In addition, we provide a dual-catalyst system that provides a con-
ceptual entry into efficient C–H functionalization chemistry.
RESULTS AND DISCUSSION
An unusual ligand combination of readily available quinoxaline and N-acetyl-L-
alanine (Ac-Ala-OH)62–68 proved uniquely suitable with ferricyanate as cyanide
donor to effect direct cyanation of arenes (Table 1, see also Tables S1–S8). Our
goal was to provide a sufficiently stable and reactive Pd(II) center for metalation
(amino acid ligand), combined with a second ligand that is sufficiently coordinating
to prevent catalyst deactivation by cyanide ligation, and at the same time does not
inhibit the electrophilicity for metalation (quinoxaline). Cyanation of ortho-xylene
was accomplished in 78% isolated yield under the optimized conditions shown in
1Max-Planck-Institut fur Kohlenforschung,
¨
Kaiser-Wilhelm-Platz 1, 45470 Mulheim an der
¨
Table 1, in which copper(II) acetate functions as stoichiometric oxidant. Control ex-
Ruhr, Germany
periments showed that both ligands are essential for high catalytic activity. The
69–72
2These authors contributed equally
3Lead Contact
choice of K3Fe(CN)6
as cyanating reagent is crucial for a productive reaction;
K4Fe(CN)6 resulted in lower conversion. Although some pyridine-based ligands
(e.g., 3,5-dicholorpyridine and 2,6-dimethylpyridine) were found to be effective in
the cyanation of electron-rich arenes such as ortho-xylene, for more challenging
*Correspondence: ritter@mpi-muelheim.mpg.de
https://doi.org/10.1016/j.chempr.2018.09.027
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j.chempr.2018.09.027
A
NH2
NC
NC
Br
O
Me
Me
O
N
O
N
N
Me
N
H
N
N
S
CN
Me
Me
F
CN
citalopram
etravirine
periciazine
antipsychotic, neuroleptic
selective serotonin
transporter inhibitor
antiretroviral agent
O
Me
O
CN
CN
NH
Me
OH
CN
OH
O
HN
N
N
N
O
N
OH
CN
letrozole
Cromakalim
epanolol
beta blocker
antineoplastic
bicalutamidpotassium
aromatase inhibitor
channel-opening vasodilator
B
DG
DG
DG
TM
[TM]
H
DG
TM
CN
CN or
DG
CN
or
(1)
(2)
(3)
or
C–H
activation
CN
H
CN
SET
CN
EDG
EDG
EDG
H
TM
CN
[TM]
CN
CN or
R2
R2
R2
C–H activation
N
N
N
R1
R1
R1
C
OMe
Me
H
Cl
CO2Me
CF3
N
Me
known
unexplored
this work
D
cat. [PdII]
cat. quinoxaline
cat. MPAA
CN
K3Fe(CN)6
+
R
R
oxidant CuII or AgI
(4)
arene
1.0 equiv
R = EDG & EWG
O
R'
N
· broad scope
O
· late-stage cyanation
Me
N
H
· safe cyanating reagent
· commercially available ligands
N
OH
MPAA, R' = Me or sec-Butyl
quinoxaline
Scheme 1. Aromatic C–H Cyanation
(A) Pharmaceutically important benzonitriles.
(B) Summary of prior art.
(C) Electronic substrate scope of transition-metal-catalyzed direct C–H cyanation.
(D) This work.
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Table 1. Optimization of Reaction Conditions
10 mol % Pd(OPiv)2
B
20 mol % Ac-Ala-OH
30 mol % quinoxaline
Me
Me
Me
CN
A
K3Fe(CN)6
0.17 equiv.
1.0 equiv. KTFA,
2.0 equiv. Cu(OAc)2
HFIP, 85°C, 24 hr
Me
1.0 equiv.
1
Entry
Change of Reaction Conditionsa
none
Yield (%)b
1
2
81 (78)c
0
no Pd(OPiv)2
3
no quinoxaline
38
4
pyridine instead of quinoxaline
3,5-dicholoropyridine instead of quinoxaline
no Ac-Ala-OH
24
5
45
6
58
7
NaOAc instead of KTFA
DMF instead of HFIP
56
8
11
9
K4Fe(CN)6 instead of K3Fe(CN)6
Ag2CO3 instead of Cu(OAc)2
49
10
14
DMF, dimethylformamide; HFIP, hexafluoroisopropanol; Ac-Ala-OH, N-acetyl-L-alanine. See also
Tables S1–S8.
aReaction conditions: ortho-xylene (0.50 mmol), K3Fe(CN)6 (0.17 equiv), Pd(OPiv)2 (10 mol %), Ac-Ala-OH
(20 mol %), quinoxaline (30 mol %), KTFA (1.0 equiv), Cu(OAc)2 (2.0 equiv) in 0.65 mL of HFIP, at 85ꢀC for
24 hr.
bGC yield determined using mesitylene as internal standard.
cIsolated yield. Ratio A/B = 3:1.
electron-deficient arenes, such pyridine-based ligands as well as those reported to
be effective in other Pd-catalyzed C–H functionalization reactions43,45,73–79 did not
show promising results (see Supplemental Information).
The demonstrated substrate scope of the dual-ligand-enabled C–H cyanation is
large (Table 2; see also Figures S12–S58). Cyanation can proceed on arenes as elec-
tron-rich as anisole (2). Whereas previous nondirected methods work only for arenes
no less electron-rich than toluene, our method is capable of efficient cyanation of
electron-deficient arenes such as 1,2-dichlorobenzene (10), benzamides (11 and
12), methyl benzoate (13), and trifluorotoluene (14). In these cases, the copper(II)
oxidant must be replaced by a Ag(I) oxidant to achieve high yields (condition II in
Table 2). Heterocycles such as a substituted pyridine (15), thiophene (16), pyrrole
(17), and indoles (18 and 19) are also suitable substrates for cyanation, and alde-
hydes are tolerated (20).
To demonstrate the potential utility of this Pd-catalyzed aromatic cyanation, we
evaluated late-stage cyanation of complex molecules (Table 3; see also Figures
S59–S134). Structurally complex small-molecule substrates, marketed drug mole-
cules, and common pharmacophores (23–32) can be cyanated to afford valuable
derivatives that are not readily available otherwise. The dual-ligand protocol is high-
ly tolerant of functional groups such as sulfonamides (21), esters (e.g., 22 and 33),
amides (25 and 29), unprotected hydroxyl groups (26), and ketones (30). Starting
material remained as mass balance for substrates with lower yields (e.g., 25 and
30). The fluorescein derivative 35 was cyanated smoothly at the alkenyl C–H posi-
tion, although the conditions are not generally successful in accessing acrylonitrile
4
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Table 2. Substrate Scope of Simple Arenes
MPAA, mono-N-protected amino acid; HFIP, hexafluoroisopropanol; Ac-Ala-OH, N-acetyl-L-alanine; Ac-Ile-OH, N-acetyl-L-isoleucine; DMSO, dimethyl sulf-
oxide. See also Figures S12–S58.
aReaction conditions I: arene (1.0 equiv), K3Fe(CN)6 (0.17 equiv), Pd(OPiv)2 (10 mol %), Ac-Ala-OH (20 mol %), quinoxaline (30 mol %), KTFA (1.0 equiv), Cu(OAc)2
(2.0 equiv) in 0.65 mL of HFIP, at 85ꢀC for 24 hr.
bReaction conditions II: arene (1.0 equiv), K3Fe(CN)6 (0.20 equiv), Pd(OAc)2 (15 mol %), quinoxaline (45 mol %), Ac-Ile-OH (30 mol %), KTFA (1.0 equiv), Ag2CO3
(2.0 equiv) in 1.0 mL of HFIP, at 80ꢀC for 24 hr.
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Table 2. Continued
cYield determined by 1H NMR.
d6-(Trifluoromethyl)quinoxaline (45 mol %) instead of quinoxaline, CsTFA (2.0 equiv) instead of KTFA.
eReaction performed in 0.1 mL of HFIP.
fReaction performed in 0.65 mL of DMSO.
analogs. In most cases, the cyanation reaction affords at least two constitutional iso-
mers; all products shown in Table 3 have been isolated as analytically pure, individ-
ual constitutional isomers. Although high positional selectivity is generally desired in
C–H functionalization reactions, mixtures of constitutional isomers in late-stage
diversification of agrochemical and drug candidates can afford several constitutional
isomers, which are each valuable for evaluation because they do not require costly
and laborious de novo synthesis.80
Few ligands have been reported as effective in Pd-catalyzed C–H functionalization
with arenes as the limiting reagent. We have discovered significantly improved
reactivity with quinoxaline. The intricate role of the quinoxaline is not currently
well understood in detail, but preliminary experiments indicate its role as an impor-
tant ligand on Pd. Coordination to Pd, as opposed to copper, is likely because no
desired cyanation product was observed when quinoxaline and copper(II) acetate
were mixed for likely complex formation before addition of the other reaction ingre-
dients (see Supplemental Information). We could not find support for the possibility
that both nitrogen atoms of quinoxaline were involved in binding to Pd because
electron-poor quinolines also served as promising ligands, albeit with lower yield.
We determined that electron-poor pyridine-based ligands increased the efficiency
of the transformation, and that some steric hindrance, such as substitution in the
2-position of pyridine, was required. As such, the quinoxaline appears to strike the
right balance between being electron-poor enough to render the Pd catalyst
electrophilic for metalation, and sufficiently bulky to prevent coordination and deac-
tivation by cyanide.64,81,82
MPAA ligands have been shown to be effective in Pd-catalyzed C–H functionaliza-
tion.62–68 Previous reports have shown that the displacement of acetate in Pd(II)
complexes by MPAA is facile.66,68 Considering the fact that Pd(II) and quinoxaline
or Pd(II) and amino acid alone could not effect cyanation, it is plausible to assume
that the active Pd catalyst in the cyanation reaction features a bidentate amino
acid ligand and a monodentate quinoxaline ligand.45 Consistent with this assump-
tion, we have observed Pd(quinoxaline)2(Ac-Ile-OH)2 by in situ mass spectrometry
(see also Figure S1). We speculate that the N-acetyl group of the amino acid ligand
could serve as an internal base to shuttle the hydrogen to an external base for the
Pd-mediated C–H cleavage step, thus lowering the barrier of C–H metala-
tion.45,62–68 The N-acetyl group is crucial for the electrophilicity of Pd and the proton
affinity,62–68 as N-Boc (tert-butyloxycarbonyl)-protected amino acid significantly
decreased the yield compared with the N-acetyl-protected amino acid (see also Ta-
ble S6). During catalysis, after an initiation period, during which the active Pd(II) cata-
lyst may form from Pd carboxylate and ligands, we observed a reaction order of zero,
with constant reaction rate until conversions up to 70% (see also Figures S2–S5). In
addition, we measured the absence of a primary kinetic isotope effect (kH/kD = 1)
when comparing the two independent reaction rates for cyanation of C6H6 and
C6D6 (see also Tables S9 and S10; Figure S6). Moreover, we observed that isotope
scrambling in the starting arene (cyanation of C6D6 in proteo-HFIP) occurs faster than
product formation, but at a comparable rate, because C6HnD(5Àn)CN were observed
for all n = {1, 2, 3, 4, 5} (see also Figures S7–S11). The reaction is heterogeneous due
to low solubility of the cyanide source in the reaction solvent, so the order in cyanide
6
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Table 3. Late-Stage C–H Cyanation
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Table 3. Continued
MPAA, mono-N-protected amino acid; HFIP, hexafluoroisopropanol; Ac-Ala-OH, N-acetyl-L-alanine; Ac-Ile-OH, N-acetyl-L-isoleucine. See also
Figures S59–S134.
aReaction conditions II: arene (1.0 equiv), K3Fe(CN)6 (0.20 equiv), Pd(OAc)2 (15 mol %), quinoxaline (45 mol %), Ac-Ile-OH (30 mol %), KTFA (1.0 equiv), Ag2CO3
(2.0 equiv) in 1.0 mL of HFIP, at 80ꢀC for 24 hr.
b6-(Trifluoromethyl)quinoxaline (45 mol %) instead of quinoxaline, CsTFA (2.0 equiv) instead of KTFA.
cReaction conditions I: arene (1.0 equiv), K3Fe(CN)6 (0.17 equiv), Pd(OPiv)2 (10 mol %), Ac-Ala-OH (20 mol %), quinoxaline (30 mol %), KTFA (1.0 equiv), Cu(OAc)2
(2.0 equiv) in 0.65 mL of HFIP, at 85ꢀC for 24 hr.
source could not be probed kinetically (see Supplemental Information for all mech-
anism experiments). Taken together, both MPAA and quinoxaline are responsible
for accessing a catalyst sufficiently active for C–H metalation, while the cyanide
source provides cyanide fast enough for reaction with the Pd(II) aryl complex formed
in situ for benzonitrile reductive elimination, but slow enough to not poison the cata-
lyst. All these data are in agreement with rate-limiting transmetalation arising from
slow release of cyanide from K3Fe(CN)6 but, because the exact species from which
reductive elimination occurs is elusive, we cannot exclude rate-limiting reductive
elimination. The required fine balance and importance of ancillary ligands and
cyanide source is consistent with the mechanism proposal discussed above and
shown in Scheme 2.
In conclusion, we have presented the first Pd-catalyzed late-stage aromatic C–H
cyanation reaction employing commercially available ligands and a safe cyanating
reagent. Although the cyanation method reported herein exhibits low regioselectiv-
ity, it affords aromatic nitriles with a substrate scope that includes electron-rich and
electron-poor arenes. The reaction is expected to serve for the late-stage modifica-
tion in drug development as it can give quick access to structural diversity for
molecular discovery.
EXPERIMENTAL PROCEDURES
Representative Procedure I for Cyanation of Arenes
Under an atmosphere of argon, a 4-mL vial was charged with a stirring bar, Pd(OPiv)2
(10 mol %), Ac-Ala-OH (20 mol %), and quinoxaline (30 mol %). HFIP (c = 0.77 M) was
added via syringe, and the mixture was stirred at 23ꢀC for 30 min. The resulting
reaction mixture was then transferred via syringe to another 4-mL vial containing a stir-
ring bar, arene (1.00 equiv), K3Fe(CN)6 (0.170 equiv), KTFA (1.00 equiv), and Cu(OAc)2
(2.00 equiv). The vial was sealed with a Teflon cap and placed in a preheated metal heat-
ing block (85ꢀC). The reaction mixture was then stirred at 85ꢀC for 24 hr. After cooling to
23ꢀC, the reaction mixture was filtered through a short plug of silica gel eluting with
approximately25mLofdichloromethaneorethylacetate. Thefiltrate wasconcentrated,
and the residue was purified by chromatography on silica gel. Where necessary, further
purification was accomplished by preparative HPLC.
Representative Procedure II for Cyanation of Arenes
Under an atmosphere of argon, a 4-mL vial was charged with a stirring bar, Pd(OAc)2
(15 mol %), Ac-Ile-OH (30 mol %), and quinoxaline (45 mol %). HFIP (c = 0.50 M)
was added via syringe, and the mixture was stirred at 23ꢀC for 30 min. The
resulting reaction mixture was then transferred via syringe to another 4-mL vial con-
taining a stirring bar, arene (1.00 equiv), K3Fe(CN)6 (0.200 equiv), KTFA (1.00 equiv),
and Ag2CO3 (2.00 equiv). The vial was sealed with a Teflon cap and placed in a
preheated metal heating block (80ꢀC). The reaction mixture was then stirred at
80ꢀC for 24 hr. After cooling to 23ꢀC, the reaction mixture was filtered through a
short plug of silica gel eluting with approximately 25 mL of dichloromethane or ethyl
acetate. The filtrate was concentrated, and the residue was purified by
8
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oxidant [CuII or AgI]
H
CN
II
[LPd0]
R
+
[LPd ]
O
N
R
O
N
R'
Me
N
C–H activation via
reductive
elimination
PdII
O
H
R
[LPdII]CN
[LPdII]
R
R
TS
R' = Me or sec-Butyl
II
I
K3Fe(CN)6
transmetalation
L = MPAA & quinoxaline
Scheme 2. Proposed Catalytic Cycle
chromatography on silica gel. Where necessary, further purification was accom-
plished by preparative HPLC.
SUPPLEMENTAL INFORMATION
Supplemental Information includes Supplemental Experimental Procedures, 134
figures, and 10 tables and can be found with this article online at https://doi.org/
10.1016/j.chempr.2018.09.027.
ACKNOWLEDGMENTS
We thank the Max-Planck-Institut fur Kohlenforschung for funding. We thank the
¨
HPLC, MS, and NMR departments of the Max-Planck-Institut fur Kohlenforschung
¨
for technical assistance. We thank Gregory B. Boursalian (Max-Planck-Institut fur
¨
Kohlenforschung) for helpful discussions.
AUTHOR CONTRIBUTIONS
Methodology, D.Z.; Investigation, D.Z. and P.X.; Writing – Review & Editing, D.Z.,
P.X., and T.R.; Supervision, T.R.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: August 1, 2018
Revised: September 27, 2018
Accepted: September 28, 2018
Published: November 1, 2018
REFERENCES AND NOTES
1. Fatiadi, A. (1983). Preparation and synthetic
application of cyano compounds. In
Triple-Bonded Functional Groups, P. Patai
and Z. Rappaport, eds. (Wiley),
pp. 1057–1303.
and fine chemical industries. Adv. Synth. Catal.
351, 3027–3043.
7. Sandmeyer, T. (1884). Ueber die ersetzung der
amidgruppe durch chlor in den aromatischen
substanzen. Ber. Dtsch. Chem. Ges. 17,
1633–1635.
4. Jones, L.H., Summerhill, N.W., Swain, N.A., and
Mills, J.E. (2010). Aromatic chloride to nitrile
transformation: medicinal and synthetic
8. Sandmeyer, T. (1884). Ueber die ersetzung der
amid-gruppe durch chlor, brom und cyan in
den aromatischen substanzen. Chem. Ber. 17,
2650–2653.
chemistry. Med. Chem. Commun. 1, 309–318.
2. Kleemann, A., Engel, J., Kutscher, B., and
Reichart, D. (2001). Pharmaceutical Substances:
Syntheses, Patents, Applications (Thieme).
5. Larock, R.C. (1999). Comprehensive Organic
Transformations: A Guide to Functional Group
Preparations (Wiley-VCH).
3. Torborg, C., and Beller, M. (2009). Recent
applications of palladium-catalyzed coupling
reactions in the pharmaceutical, agrochemical,
9. Rosenmund, K.W., and Struck, E. (1919). Das
am ringkohlenstoff gebundene halogen und
sein ersatz durch andere substituenten. I.
6. Rappoport, Z. (1970). Chemistry of the Cyano
Group (John Wiley & Sons).
Chem 5, 1–11, January 10, 2019
9

Please cite this article in press as: Zhao et al., Palladium-Catalyzed Late-Stage Direct Arene Cyanation, Chem (2018), https://doi.org/10.1016/
j.chempr.2018.09.027
Mitteilung: ersatz des halogens durch die
carboxylgruppe. Ber. Dtsch. Chem. Ges. 52,
1749–1756.
25. Bag, S., Jayarajan, R., Dutta, U., Chowdhury, R.,
Mondal, R., and Maiti, D. (2017). Remote meta-
C-H cyanation of arenes enabled by a
pyrimidine-based auxiliary. Angew. Chem. Int.
Ed. 56, 12538–12542.
cyanation of arenes with aryl (cyano) iodonium
triflates. Angew. Chem. Int. Ed. 53, 2186–2189.
40. McManus, J.B., and Nicewicz, D.A. (2017).
Direct C-H cyanation of arenes via organic
photoredox catalysis. J. Am. Chem. Soc. 139,
2880–2883.
10. Ellis, G.P., and Romney-Alexander, T.M. (1987).
Cyanation of aromatic halides. Chem. Rev. 87,
779–794.
26. Yan, Y., Yuan, Y., and Jiao, N. (2014). Cu-
mediated C-H cyanation of arenes using N,N-
dimethylformamide (DMF) as the ‘‘CN’’ source.
Org. Chem. Front. 1, 1176–1179.
11. Anbarasan, P., Schareina, T., and Beller, M.
(2011). Recent developments and perspectives
in palladium-catalyzed cyanation of aryl
halides: synthesis of benzonitriles. Chem. Soc.
Rev. 40, 5049–5067.
41. Sono, M., Toyoda, N., Shizuri, Y., and Tori, M.
(1994). Functionalisation including fluorination
of caffeine, guanosine tetraacetate, and
uridine triacetate using electrochemical
27. Ding, S., and Jiao, N. (2011). Direct
transformation of N,N-dimethylformamide to
CN: Pd-catalyzed cyanation of heteroarenes
via C-H functionalization. J. Am. Chem. Soc.
133, 12374–12377.
oxidation. Tetrahedron Lett. 35, 9237–9238.
12. Yan, G., Zhang, Y., and Wang, J. (2017). Recent
advances in the synthesis of aryl nitrile
42. Liskey, C.W., Liao, X., and Hartwig, J.F. (2010).
Cyanation of arenes via Iridium-catalyzed
borylation. J. Am. Chem. Soc. 132, 11389–
11391.
compounds. Adv. Synth. Catal. 359, 4068–4105.
28. Hartwig, J.F., and Larsen, M.A. (2016).
Undirected, homogeneous C-H bond
functionalization: challenges and
13. Wen, Q., Jin, J., Zhang, L., Luo, Y., Lu, P., and
Wang, Y. (2014). Copper-mediated cyanation
reactions. Tetrahedron Lett. 55, 1271–1280.
43. Wang, P., Verma, P., Xia, G., Shi, J., Qiao, J.X.,
Tao, S., Cheng, P.T.W., Poss, M.A., Farmer,
M.E., Yeung, K.S., and Yu, J.Q. (2017). Ligand-
accelerated non-directed C-H functionalization
of arenes. Nature 551, 489–493.
opportunities. ACS Cent. Sci. 2, 281–292.
29. Neufeldt, S.R., and Sanford, M.S. (2012).
Controlling site selectivity in palladium-
catalyzed C-H bond functionalization. Acc.
Chem. Res. 45, 936–946.
14. Kim, J., Kim, H.J., and Chang, S. (2012).
Synthesis of aromatic nitriles using nonmetallic
cyano-group sources. Angew. Chem. Int. Ed.
51, 11948–11959.
44. Vora, H.U., Silvestri, A.P., Engelin, C.J., and Yu,
J.-Q. (2014). Rhodium (II)-catalyzed
30. Kuhl, N., Hopkinson, M.N., Wencel-Delord, J.,
and Glorius, F. (2012). Beyond directing
groups: transition-metal-catalyzed C-H
activation of simple arenes. Angew. Chem. Int.
Ed. 51, 10236–10254.
15. Ping, Y., Ding, Q., and Peng, Y. (2016).
Advances in C-CN bond formation via C-H
bond activation. ACS Catal. 6, 5989–6005.
nondirected oxidative alkenylation of arenes:
arene loading at one equivalent. Angew.
Chem. Int. Ed. 53, 2683–2686.
16. Kim, J., and Chang, S. (2010). A new combined
source of ‘‘CN’’ from N,N-dimethylformamide
and ammonia in the palladium-catalyzed
cyanation of aryl C-H bonds. J. Am. Chem. Soc.
132, 10272–10274.
45. Chen, H., Wedi, P., Meyer, T., Tavakoli, G., and
van Gemmeren, M. (2018). Dual ligand-
31. Mkhalid, I.A.I., Barnard, J.H., Marder, T.B.,
Murphy, J.M., and Hartwig, J.F. (2010). C-H
activation for the construction of C-B bonds.
Chem. Rev. 110, 890–931.
enabled non-directed C-H olefination of
arenes. Angew. Chem. Int. Ed. 57, 2497–2501.
46. Naksomboon, K., Valderas, C., Go´ mez-
17. Gong, T.-J., Xiao, B., Cheng, W.-M., Su, W., Xu,
J., Liu, Z.-J., Liu, L., and Fu, Y. (2013). Rhodium-
catalyzed directed C-H cyanation of arenes
with N-cyano-N-phenyl-p-toluenesulfonamide.
J. Am. Chem. Soc. 135, 10630–10633.
´
32. Cho, J.-Y., Tse, M.K., Holmes, D., Maleczka,
R.E., Jr., and Smith, M.R., III (2002). Remarkably
selective iridium catalysts for the elaboration of
aromatic CH bonds. Science 295, 305–308.
Martı´nez, M., Alvarez-Casao, Y., and
´
Ferna´ndez-Iba´n˜ ez, M.A. (2017). S, O-Ligand-
promoted palladium-catalyzed C-H
functionalization reactions of nondirected
arenes. ACS Catal. 7, 6342–6346.
33. Schorgenhumer, J., and Waser, M. (2016). New
¨
18. Pan, C., Jin, H., Xu, P., Liu, X., Cheng, Y., and
Zhu, C. (2013). Copper-mediated direct C2-
cyanation of indoles using acetonitrile as the
cyanide source. J. Org. Chem. 78, 9494–9498.
strategies and applications using electrophilic
cyanide-transfer reagents under transition-
metal-free conditions. Org. Chem. Front. 3,
1535–1540.
47. Cheng, C., and Hartwig, J.F. (2015). Catalytic
silylation of unactivated C-H bonds. Chem.
Rev. 115, 8946–8975.
48. Ackermann, L. (2011). Carboxylate-assisted
transition-metal-catalyzed C-H bond
functionalizations: mechanism and scope.
Chem. Rev. 111, 1315–1345.
19. Chaitanya, M., Yadagiri, D., and Anbarasan, P.
(2013). Rhodium catalyzed cyanation of
chelation assisted C-H bonds. Org. Lett. 15,
4960–4963.
34. Okamoto, K., Watanabe, M., Murai, M.,
Hatano, R., and Ohe, K. (2012). Practical
synthesis of aromatic nitriles via gallium-
catalysed electrophilic cyanation of aromatic
C-H bonds. Chem. Commun. (Camb.) 48,
3127–3129.
49. Cho, S.H., Kim, J.Y., Kwak, J., and Chang, S.
(2011). Recent advances in the transition metal-
catalyzed twofold oxidative C-H bond
20. Gu, L., Jin, C., Wang, R., and Ding, H. (2014).
Rhodium catalyzed ortho-cyanation of
arylphosphates with N-cyano-N-phenyl-p-
toluenesulfonamide. ChemCatChem 6,
1225–1228.
35. Tamura, Y., Kawasaki, T., Adachi, M., Tanio, M.,
and Kita, Y. (1977). Thiocyanation and
cyanation Using a new combined reagent of
triphenylphosphine and thiocyanogen.
Tetrahedron Lett. 50, 4417–4720.
activation strategy for C-C and C-N bond
formation. Chem. Soc. Rev. 40, 5068–5083.
50. Yang, Y., Lan, J., and You, J. (2017). Oxidative
C-H/C-H coupling reactions between two
(hetero) arenes. Chem. Rev. 117, 8787–8863.
21. Yu, D.G., Gensch, T., de Azambuja, F.,
Vasquez-Cespedes, S., and Glorius, F. (2014).
Co(III)-catalyzed C-H activation/formal SN-type
reactions: selective and efficient cyanation,
halogenation, and allylation. J. Am. Chem. Soc.
136, 17722–17725.
¨
36. Graf, R. (1956). Uber die umsetzung von
chlorcyan mit schwefeltrioxyd. Chem. Ber. 89,
1071–1079.
51. Wedi, P., and van Gemmeren, M. (2018). The
arene-limited nondirected C-H activation of
arenes. Angew. Chem. Int. Ed. 57, 13016–
13027.
37. Smaliy, R.V., Chaikovskaya, A.A., Pinchuk, A.M.,
and Tolmachev, A.A. (2002).
22. Liu, W., and Ackermann, L. (2014). Versatile
ruthenium (II)-catalyzed C-H cyanations of
benzamides. Chem. Commun. (Camb.) 50,
1878–1881.
Isocyanatophosphoric acid dichloride: a novel
reagent for the introduction of a cyano group
into the molecules of electron-rich
heterocycles and enamines. Synthesis 16,
2416–2420.
52. Sundermeier, M., Zapf, A., Mutyala, S.,
Baumann, W., Sans, J., Weiss, S., and Beller, M.
(2003). Progress in the palladium-catalyzed
cyanation of aryl chlorides. Chem. Eur. J. 9,
1828–1836.
23. Li, J., and Ackermann, L. (2015). Cobalt-
catalyzed C-H cyanation of arenes and
heteroarenes. Angew. Chem. Int. Ed. 54,
3635–3638.
38. Dohi, T., Morimoto, K., Kiyono, Y., Tohma, H.,
and Kita, Y. (2005). Novel and direct oxidative
cyanation reactions of heteroaromatic
53. Erhardt, S., Grushin, V.V., Kilpatrick, A.H.,
Macgregor, S.A., Marshall, W.J., and Roe, D.C.
(2008). Mechanisms of catalyst poisoning in
palladium-catalyzed cyanation of haloarenes.
Remarkably facile C-N bond activation in the
[(Ph3P)4Pd]/[Bu4N]+ CN- system. J. Am. Chem.
Soc. 130, 4828–4845.
24. Liu, W., Richter, S.C., Mei, R., Feldt, M., and
Ackermann, L. (2016). Synergistic
compounds mediated by a hypervalent iodine
(III) reagent. Org. Lett. 7, 537–540.
heterobimetallic manifold for expedient
manganese (I)-catalyzed C-H cyanation. Chem. 39. Shu, Z., Ji, W., Wang, X., Zhou, Y., Zhang, Y.,
Eur. J. 22, 17958–17961.
and Wang, J. (2014). Iron (II)-catalyzed direct
10
Chem 5, 1–11, January 10, 2019

Please cite this article in press as: Zhao et al., Palladium-Catalyzed Late-Stage Direct Arene Cyanation, Chem (2018), https://doi.org/10.1016/
j.chempr.2018.09.027
54. Schareina, T., Zapf, A., and Beller, M. (2004).
Improving palladium-catalyzed cyanation of
aryl halides: development of a state-of-the-art
methodology using potassium
64. Yang, Y.-F., Hong, X., Yu, J.-Q., and Houk, K.N.
(2017). Experimental-computational synergy
for selective Pd(II)-catalyzed C-H activation of
aryl and alkyl groups. Acc. Chem. Res. 50,
2853–2860.
deficient arenes using 2,6-dialkylpyridine
ligands. J. Am. Chem. Soc. 131, 5072–5074.
74. Emmert, M.H., Cook, A.K., Xie, Y.J., and
Sanford, M.S. (2011). Remarkably high reactivity
of Pd(OAc)2/pyridine catalysts: nondirected C-
H oxygenation of arenes. Angew. Chem. Int.
Ed. 50, 9409–9412.
hexacyanoferrate (II) as cyanating agent.
J. Organomet. Chem. 689, 4576–4583.
65. Cheng, G.-J., Yang, Y.-F., Liu, P., Chen, P., Sun,
T.-Y., Li, G., Zhang, X., Houk, K.N., Yu, J.-Q.,
and Wu, Y.-D. (2014). Role of N-acyl amino acid
ligands in Pd(II)-catalyzed remote C-H
activation of tethered arenes. J. Am. Chem.
Soc. 136, 894–897.
55. Dobbs, K.D., Marshall, W.J., and Grushin, V.V.
(2007). Why excess cyanide can be detrimental
to Pd-catalyzed cyanation of haloarenes. Facile
formation and characterization of
75. Kubota, A., Emmert, M., and Sanford, M.S.
(2012). Pyridine ligands as promoters in PdII/0
-
[Pd(CN)3(H)]2- and [Pd(CN)3(Ph)]2-. J. Am.
Chem. Soc. 129, 30–31.
catalyzed C-H olefination reactions. Org. Lett.
14, 1760–1763.
66. Engle, K.M., Wang, D.-H., and Yu, J.-Q. (2010).
Ligand-accelerated C-H activation reactions:
evidence for a switch of mechanism. J. Am.
Chem. Soc. 132, 14137–14151.
76. Gary, J.B., Cook, A.K., and Sanford, M.S. (2013).
Palladium catalysts containing pyridinium-
substituted pyridine ligands for the C-H
oxygenation of benzene with K2S2O8. ACS
Catal. 3, 700–703.
56. Ushkov, A.V., and Grushin, V.V. (2011). Rational
catalysis design on the basis of mechanistic
understanding: highly efficient pd-catalyzed
cyanation of aryl bromides with NaCN in
recyclable solvents. J. Am. Chem. Soc. 133,
10999–11005.
67. Engle, K.M. (2016). The mechanism of
palladium (II)-mediated C-H cleavage with
mono-N-protected amino acid (MPAA)
ligands: origins of rate acceleration. Pure Appl.
Chem. 88, 119–138.
77. Cook, A.K., Emmert, M.H., and Sanford, M.S.
(2013). Steric control of site selectivity in the Pd-
catalyzed C-H acetoxylation of simple arenes.
Org. Lett. 15, 5428–5431.
57. Kou, X., Zhao, M., Qiao, X., Zhu, Y., Tong, X.,
and Shen, Z. (2013). Copper-catalyzed aromatic
C-H bond cyanation by C-CN bond cleavage of
inert acetonitrile. Chem. Eur. J. 19, 16880–
16886.
68. Gair, J.J., Haines, B.E., Filatov, A.S., Musaev,
D.G., and Lewis, J.C. (2017). Mono-N-
78. Izawa, Y., and Stahl, S.S. (2010). Aerobic
oxidative coupling of o-xylene: discovery of 2-
fluoropyridine as a ligand to support selective
Pd-catalyzed C-H functionalization. Adv. Synth.
Catal. 352, 3223–3229.
protected amino acid ligands stabilize dimeric
palladium(II) complexes of importance to C-H
functionalization. Chem. Sci. 8, 5746–5756.
58. Chen, X., Hao, X.-S., Goodhue, C.E., and Yu,
J.-Q. (2006). Cu(II)-Catalyzed functionalizations
of aryl C-H bonds using O2 as an oxidant.
J. Am. Chem. Soc. 128, 6790–6791.
69. Jia, X.F., Yang, D.P., Wang, W.H., Luo, F., and
Cheng, J. (2009). Chelation-assisted palladium-
catalyzed cascade bromination/cyanation
reaction of 2-arylpyridine and 1-arylpyrazole
C-H bonds. J. Org. Chem. 74, 9470–9474.
79. Wang, C., Rakshit, S., and Glorius, F. (2010).
Palladium-catalyzed intermolecular
decarboxylative coupling of 2-phenylbenzoic
acids with alkynes via C-H and C-C bond
activation. J. Am. Chem. Soc. 132, 14006–
14008.
59. Xu, S., Huang, X., Hong, X., and Xu, B. (2012).
Palladium-assisted regioselective C-H
cyanation of heteroarenes using isonitrile as
cyanide source. Org. Lett. 14, 4614–4617.
70. Ren, Y., Yan, M., Zhao, S., Wang, J., Ma, J., Tian,
X., and Yin, W. (2012). Selective para-cyanation
of alkoxy- and benzyloxy-substituted benzenes
with potassium ferricyanide promoted by
copper (II) nitrate and iodine. Adv. Synth. Catal.
354, 2301–2308.
60. Peng, J., Zhao, J., Hu, Z., Liang, D., Huang, J.,
and Zhu, Q. (2012). Palladium-catalyzed C(sp2)-
H cyanation using tertiary amine derived
isocyanide as a cyano source. Org. Lett. 14,
4966–4969.
80. Cernak, T., Dykstra, K.D., Tyagarajan, S.,
Vachal, P., and Krska, S.W. (2016). The
medicinal chemist’s toolbox for late stage
functionalization of drug-like molecules. Chem.
Soc. Rev. 45, 546–576.
61. Hong, X., Wang, H., Qian, G., Tan, Q., and Xu,
B. (2014). Rhodium-catalyzed direct C-H bond
cyanation of arenes with isocyanide. J. Org.
Chem. 79, 3228–3237.
71. Kianmehr, E., Faghih, N., Tanbakouchian, A.,
and Mahdavi, M. (2016). Palladium-catalyzed
regioselective direct cyanation of acetanilide
derivatives with K4[Fe(CN)6] by C-H bond
activation. Eur. J. Org. Chem. 2016, 4269–4274.
81. Zhang, S., Shi, L., and Ding, Y. (2011).
Theoretical analysis of the mechanism of
palladium(II) acetate-catalyzed oxidative heck
coupling of electron-deficient arenes with
alkenes: effects of the pyridine-type ancillary
ligand and origins of the meta-
62. Wang, D.-H., Engle, K.M., Shi, B.-F., and Yu,
J.-Q. (2010). Ligand-enabled reactivity and
selectivity in a synthetically versatile aryl C-H
olefination. Science 327, 315–319.
72. Schareina, T., Zapf, A., and Beller, M. (2004).
Potassium hexacyanoferrate (II)—a new
cyanating agent for the palladium-catalyzed
cyanation of aryl halides. Chem. Commun.
(Camb.), 1388–1389.
regioselectivity. J. Am. Chem. Soc. 133,
20218–20229.
63. Shi, B.-F., Maugel, N., Zhang, Y.-H., and Yu,
J.-Q. (2008). PdII–catalyzed enantioselective
activation of C(sp2)-H and C(sp3)-H bonds
using monoprotected amino acids as chiral
ligands. Angew. Chem. Int. Ed. 47, 4882–4886.
82. Cook, A.K., and Sanford, M.S. (2015).
Mechanism of the palladium-catalyzed arene
C-H acetoxylation: a comparison of catalysts
and ligand effects. J. Am. Chem. Soc. 137,
3109–3118.
73. Zhang, Y.-H., Shi, B.-F., and Yu, J.-Q. (2009).
Pd(II)-catalyzed olefination of electron-
Chem 5, 1–11, January 10, 2019
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