Dual Ligand-Enabled Nondirected C-H Cyanation of Arenes

Article abstract of DOI:10.1021/acscatal.8b04639

Aromatic nitriles are key structural units in organic chemistry and, therefore, highly attractive targets for C-H activation. Herein, the development of an arene-limited, nondirected C-H cyanation based on the use of two cooperatively acting commercially available ligands is reported. The reaction enables the cyanation of arenes by C-H activation in the absence of directing groups and is therefore complementary to established approaches.

Full text of DOI:10.1021/acscatal.8b04639

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Letter
Dual Ligand-Enabled Nondirected C–H Cyanation of Arenes
Hao Chen, Arup Mondal, Philipp Wedi, and Manuel van Gemmeren
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ACS Catalysis
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Dual Ligand-Enabled Nondirected C–H Cyanation of Arenes
Hao Chen,† Arup Mondal,† Philipp Wedi,† Manuel van Gemmeren*†,‡
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† Max Planck Institute for Chemical Energy Conversion, Stiftstraße 34-36, 45470 Mülheim an der Ruhr (Germany)
‡ Organisch-Chemisches Institut Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster (Germany)
ABSTRACT: Aromatic nitriles are key structural units in organic chemistry and thus highly attractive targets for C–H activation.
Herein the development of an arene-limited, nondirected C–H cyanation based on the use of two complementary commercially
available ligands is reported. The reaction enables the cyanation of arenes by C–H activation in the absence of directing groups and
is thus complementary to established approaches.
KEYWORDS: C–H activation; Cyanation; Dual-ligand catalysis; Palladium catalysis; Nitriles
BR2/Hal
Aromatic nitriles are highly useful synthetic intermediates as
A
Approach 1: indirect synthesis
R
well as important motifs in natural products and
pharmacologically active compounds. Thus, it is not surprising
that a variety of approaches have been pursued for their
• Several steps required
• Selectivity dictated by prefunctionalization method
synthesis.1
Besides
traditional
functional
group
H
CN
This work: non-directed C–H
interconversions, such as benzamide to benzonitrile
dehydrations, methods starting from non-functionalized arenes
and building upon a C–H functionalization or activation are
particularly attractive, due to their potential to introduce
molecular complexity and utilize more easily available starting
materials. Several approaches towards this goal are depicted in
Scheme 1A. Firstly, it is not surprising that established
methods for the introduction of other functional groups, such
as boronic esters or halides, can be combined with the
conversion of the respective functionality into a nitrile, e.g. by
the Rosenmund-von Braun reaction in the case of aryl
bromides (Approach 1).2 While this approach is suited to
deliver a variety of aromatic nitriles, it faces the inherent
disadvantage of requiring several steps and relying on another
C–H functionalization as a source of the required reactivity
and selectivity. It should be noted however, that in some cases
the preceding functionalization step and the cyanation have
elegantly been combined into one-pot procedures, for example
by Hartwig and co-workers, who developed a sequence of Ir-
catalyzed borylation and subsequent Cu-mediated conversion
of the resulting boronate esters to nitriles.3 Alternatively, arene
C–H cyanations via radical pathways have been developed
which, given that the substrate is suitably substituted to
stabilize the radical intermediate, can deliver the desired
benzonitrile derivatives (Approach 2).4 Two recent variants of
these radical-involving processes are particularly noteworthy.
McManus and Nicewicz have described a synthetically highly
useful method based on photoredox catalysis, which allowed
for the cyanation of a wide range of substrates, the
regioselectivity being determined by the distribution of partial
charges in a radical cation preceding radical formation, thus
giving predominantly cyanation in the para- and ortho-
positions relative to the strongest donor substituent.4d
R
R
activation/cyanation
• No directing groups (DGs)
• Selectivity controlled by
sterics/electronics
• Ar–H as limiting reagent
H
CN
Approach 2: via radical reactions
R
R
•
• Scope limited by need for radical stabilization
• Selectivity controlled by radical stability
DG
CN
Approach 3: directing groups (DGs)
• Scope limited by requirement for DG
• Selectivity controlled by properties of DG
B
Proposed mode
of action
Pd-source
Pyridine ligand
Ac-Gly-OH
R
O
H
EWG
O
N
R
R
R
R
Pd
olefin
N
O
H
Scheme 1. Established approaches for the C–H cyanation
of arenes (A) and our proof of concept for the dual ligand-
enabled nondirected C–H activation of arenes (B).
Recently, Gooßen and coworkers have disclosed an
electrochemical method for the cyanation of arenes, which
likewise proceeds through a sequence of first radical cation
and then radical formation and features regioselectivity
patterns analogous to the ones reported using photoredox
catalysis.4e Thus, a complementary method based on a C–H
activation remains highly desirable. However, to date methods
based on a C–H activation have remained limited to substrates
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bearing suitable directing groups (DGs) to enable the desired
CF3
H
CN
Conditions A or B
reactivity (Approach 3).5,6
1
2
3
4
5
6
7
8
R
R
N
We have recently developed a novel strategy for the Pd-
catalyzed nondirected activation of aromatic C–H bonds that is
based on the use of two complementary ligands and have
applied it to the arene-limited nondirected olefination of
arenes (Scheme 1B).7 Herein we report the development of an
arene-limited nondirected C–H cyanation of arenes based on
this dual ligand approach.8
1
2
L1
Mono-substituted arenes:
CO2Me
a
2a
2b
2c
, 48%
,
,
Starting from the conditions reported in our study on the
olefination of arenes, we could, through the introduction of
suitable cyanide sources and an extensive optimization of the
reaction conditions, develop two complementary sets of
reaction conditions for the cyanation of arenes using copper(I)
cyanide and zinc cyanide respectively. As can be seen from
the results obtained for products 2a and 2b, Conditions A are
particularly suited for alkyl-substituted arenes, while
Conditions B deliver better results for functionalized arenes
(Scheme 2). Having established reaction conditions that enable
the nondirected arene-limited cyanation of arenes, we
proceeded to explore the scope of our method. It should be
noted that for both sets of reaction conditions, the mass
balance is mostly accounted for by remaining starting
material, although some non-specific decomposition was also
observed, as can be seen from the difference between
conversion and yield observed during the optimization studies
(see the Supporting Information for details).
9
58%a, o:m:p = 6:52:42
38% (GC)b, o:m:p = 6:52:42
31% (GC)a , o:m:p = 12:53:35
71%b, o:m:p = 12:48:40
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i-Pr
t-Bu
NPhth
, 66%b,d (47%b)
a
a
a
2g
2d
, 67%
2e
2f
, 66%
, 69%
o:m:p = 7:53:40
o:m:p = 4:54:42
m:p = 58:42
m:p = 59:41
SiMe3
NHAc
CO2Me
NPhth
b,e
b
a
2h
, 51%
2j
, 51%
2i
, 37%
m:p = 60:40
o:m:p = 9:48:43
o:m:p = 2:63:35
O
Cl
F
b
, 53%c,f (37%c)
o:p = 33:67
, 47%
, 58%b,g (45%)b
m:p = 41:59
2k
2l
2m
o:m:p = 46:22:32
We were pleased to find that benzene can be cyanated to give
benzonitrile (2c) in a synthetically useful yield. The products
derived of mono-alkyl substituted arenes (2a, 2d-f) were
obtained in good yields. The decrease of ortho product from
6% in the toluene-derived product 2a to no detectable ortho-
product formation in the iso-propyl and tert-butyl substituted
products 2e and 2f clearly highlights the influence of steric
factors on the regioselectivity of the process. The
hydrocinnamic acid-derived product 2b and phenethylamine-
derived products 2g and 2h could be obtained analogously, as
well as the product 2i derived from protected phenyl alanine.
We next examined the influence of non-alkyl substituents on
the arene. A trimethylsilyl-substituent was tolerated by the
reaction conditions to give the respective product 2j. The low
amount of ortho product observed in this case is in good
agreement with the steric demand of this substituent. The
anisole-derived product 2k could be obtained under slightly
modified reaction conditions and was formed as a mixture of
ortho and para regioisomers, thus highlighting the influence of
electronic effects on the regioselectivity of the reported
method. As expected due to the analogy with our previous
study on the olefination of arenes,7 a chloro substituent had an
ortho-directing effect and the product 2l derived of
chlorobenzene was obtained in an o:m:p-ratio of 46:22:32. We
furthermore found that our protocol is suitable for the
cyanation of electron-deficient substrates, as highlighted
through the cyanation of fluorobenzene, giving 2m in good
yield.
Di- and tri-substituted arenes:


a
a
a
a
2n
2o
2p
2q
, 70%
, 52%
, 64%
, 71%
: = 79:21
 as sole
product

: = 65:35
: = 91:9



,


O
NTs
NAc
'
'
'
Cl
'
'
2u
b,e
b
, 51%b,d (41%b)
:, = 50:50
, 50%b,e (44%b)
'(') =
43:42:15
, 53%
2r
2s
2t
, 47%
' = 50:50
'' =
54:43:3


F
Cl
'
F
'
b
a
b
b
2v
2w
2x
2y
, 63%
, 52%
, 67%
, 59%
'' =
41:39:16:4
: > 95:5
3 mmol scale
: = 84:16
: = 86:14
: 59%,
OMe
Br
CO2Me
OMe
MeO
OMe
b
b,g
c
, 61%b,g (50%b)
2ac
2z
2aa
2ab
, 65%
: = 79:21
, 29%
: = 65:35
, 69%
: = 82:18
Scheme 2. Scope of the dual ligand-enabled nondirected
C–H cyanation of arenes.
In light of the particular attractiveness of arene-limited
methods for the functionalization of multiply substituted
starting materials, we proceeded to evaluate the performance
of our method with di- and tri-substituted substrates. Both
meta- and ortho-xylene were suitable substrates giving the
products 2n and 2o respectively. The observation that 2n was
obtained as a 79:21 ratio of regioisomers, while 2o was
The reactions in this table were carried out on a 0.2 mmol scale. a
Conditions A: Pd(OAc)2 (10 mol%), L1 (20 mol%), N-acetyl
glycine (30 mol%), AgF (4 equiv), CuCN (2 equiv), HFIP (2 mL),
90 °C, 18 h. b Conditions B: Pd(OAc)2 (10 mol%), L1 (20 mol%),
N-acetyl glycine (30 mol%), AgF (3 equiv), Zn(CN)2 (2 equiv),
HFIP (2 mL), 80 °C, 18 h. c Conditions B were used with 2-
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ACS Catalysis
methyl-5-nitropyridine instead of L1, due to the formation of
the Pd-source led to no product formation (Entry 5). During
the optimization of the reaction conditions, product formation
was observed in the absence of a Ag-source (see Supporting
Information, Scheme S1) and it was confirmed that an
identical reaction outcome is obtained when the reaction is
conducted in the dark (see Supporting Information, Scheme
S6). Together with the fact that different cyanide sources with
different metal cations can be used, these observations indicate
that palladium is the catalytically active metal, since it is the
only metal, which is found to be entirely essential for the
reaction to occur. Together with the observed influence of
both ligands, we thus propose a complex of palladium bearing
both ligands as the active species. In this complex, the N-
acetyl glycine would, in analogy to previous studies utilizing
N-acylated amino acids as ligands,11 act as internal base in the
key concerted metalation-deprotonation step. Due to the
bidentate nature of the amino acid-derived ligand, L1 would
necessarily be coordinated cis to the site of C–H activation,
which is in good agreement with the strong influence of this
ligand on the o:m:p-ratio. The pyridine-derived ligand would
furthermore help to prevent catalyst decomposition and assist
speciation as has been proposed for such ligands in preceding,
non-arene-limited protocols.12 Based on this hypothesis, a
comparable result would be expected, if the Pd-source and the
two ligands were employed in a 1:1:1-ratio. Indeed, when we
conducted this experiment, we observed the same o:m:p-ratio
as in the reference reaction, albeit with a reduced yield. This
suggests that the excess of these ligands employed under the
optimized reaction conditions, while not altering the active
species, helps to stabilize it or to increase its concentration
under the reaction conditions (Entry 6). Although cases of
Ag/Pd co-catalysis have been reported,13 the formation of
product in the absence of silver indicates that the role of AgF
in our reaction system is likely the re-oxidation of the
palladium-based active species from Pd(0) to Pd(II) after the
product forming step. Finally, we attribute the role of
CuCN/Zn(CN)2 as the best reagents for this reaction to the
need for control the precise quantity of cyanide anions in
solution, which could otherwise act as a highly potent catalyst
poison.14,2b,2c,5a,5v
1
2
3
4
5
6
7
8
inseparable mixtures between the product and L1. d 13 mol% of
catalyst were used. e 15 mol% of catalyst were used. f 20 mol% of
catalyst and 6 equiv AgF were used. g 20 mol% of catalyst were
used.
formed as a single isomer can be rationalized by the
competition between electronic and steric effects in the former
case, while these effects work in the same direction in the
latter case. We next explored fused bicyclic-substrates, leading
to the formation of products 2p-t. The products 2p and 2q
derived of indane and tetraline respectively were both obtained
in good yields and with regioselectivities in favor of the less
hindered position, albeit with a lower selectivity than for 2o,
which reflects the reduction of steric demand in these
substrates. Isochromane and protected tetrahydroisoquinoline
could both be converted, giving 2r-t in moderate yield. Di-
substituted substrates bearing halide substituents were also
found to be tolerated, giving access to the products 2u and 2v
with a chloride and fluoride substituent respectively. The tri-
substituted product 2w was obtained in good yield and
regioselectivity. Importantly, the synthesis of this product was
shown to be scalable to a synthetically useful scale, giving a
similar result on a 3 mmol scale. The electron deficient halide-
bearing products 2x-z were all obtained smoothly, while an
even stronger electron-withdrawing ester functionality led to a
moderate yield (2aa). The reduced reactivity of very electron-
poor substrates also explains the perfect selectivity for mono-
cyanation observed in all cases (benzonitrile itself was found
to be unreactive as substrate). Finally, the methoxy-substituted
products 2ab and 2ac were obtained in good yields.
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Overall, the studies on the scope of the developed protocol
show its applicability to a wide range of substitution patterns
as well as a functional group tolerance ranging from a strongly
electron-donating methoxy group to moderately electron-
withdrawing halide substituents. We could demonstrate that
the reaction proceeds under a combined steric and electronic
control that enables a high degree of predictability regarding
the regioselectivity in future applications of this reaction.
Although mixtures of regioisomers were obtained in most
cases, high regioselectivity is possible in multiply substituted
substrates. Additionally, in the context of late-stage
diversification, the generation of mixtures including otherwise
challenging to access regioisomers can in fact be an
advantage, since it allows the rapid generation of samples that
can be used for preliminary evaluation, for example with
respect to their pharmacological activity. In this context it is
remarkable that for mono-substituted substrates the meta-
product was often observed as the major component, which
renders the reaction complementary to the existing methods
based on directing groups or radical cation intermediates
discussed above.9
Table 1. Mechanistically relevant control experiments.a
L1
Pd(OAc)2 (10 mol%),
(20 mol%)
CN
N-Acetyl glycine (30 mol%)
Me
AgF (4 equiv), CuCN (2 equiv)
HFIP (2 mL), 90 °C, 18 h
1a
2a
GC-
Entry Deviation
o:m:pb
Yieldb
57%
-
1
2
3
4
5
None
7:52:41
No Ac-Gly-OH
No L1
-
Having studied the scope of this transformation, we became
interested in further understanding the underlying mechanism,
in particular the role of the two complementary ligands and the
metal species involved. Towards this goal, we carried out a set
of control experiments (Table 1).10 First, we confirmed that
both ligands are essential for a satisfying reaction outcome
(Entries 1-3). While in absence of N-acetyl glycine, no
reaction occurred at all, the omission of L1 led to a drastically
reduced yield and worsened o:m:p-selectivity. The use of
quinoline instead of L1 still delivered a low yield, but restored
the selectivity partially (Entry 4). Importantly, the omission of
23%
19%
-
32:31:37
14:49:37
-
Quinoline instead of L1
No Pd(OAc)2
L1 (10 mol%),
6
7
17%
-
6:59:35
-
N-acetyl glycine (10 mol%)
Addition of KCN (20 mol%)
a The reactions in this table were carried out on a 0.1 mmol
scale. b GC-yields and o:m:p ratios were determined by GC-FID
analysis using 1,3,5-trimethoxy-benzene as an internal standard.
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Accordingly, when we conducted a reaction in the presence of
ASSOCIATED CONTENT
1
2
3
4
5
6
7
8
a catalytic amount of well-soluble KCN under otherwise
optimized conditions, no product formation was observed,
which highlights that catalyst poisoning is indeed possible
under our reaction conditions, when cyanide concentrations
become too high (Entry 7).15 At present, we can not fully
rationalize the observation that different cyanide sources are
best depending on the substrate class, but the sensitivity of the
catalytic system to poisoning suggests that the choice of the
cyanide source could serve to fine-tune the cyanide
concentration.16 Finally, we conducted measurements of the
kinetic isotope effect, which indicated that the C–H activation
step is rate limiting (Scheme 3). Based on these findings, we
propose the catalytic cycle shown in Scheme 3. Accordingly,
the catalytically active complex I, consisting of palladium and
both ligands employed, would engage in the rate-limiting C–H
activation step, leading to an aryl-palladium species II, which
would subsequently engage in a ligand exchange to give
intermediate III. A subsequent reductive elimination would
deliver the product and generate a Pd(0)-species IV, which
would then be re-oxidized by the silver source as terminal
oxidant, leading to the regeneration of the catalytically active
species I.
Supporting Information. Optimization of reaction conditions,
experimental procedures, and analytical data for the compounds
described. This material is available free of charge via the Internet
at http://pubs.acs.org.
ACKNOWLEDGMENT
We thank the members of our NMR and MS departments for their
excellent service. We thank Sabine Bognar and Kiron Kumar
Ghosh for proof reading this manuscript. Furthermore, we are
indebted to Prof. F. Glorius for his generous support.
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ABBREVIATIONS
HFIP, 1,1,1,3,3,3-hexafluoro-2-propanol.
REFERENCES
(1)
(a)
Larock,
R.
C.
Comprehensive
Organic
Transformations: A guide to Functional Group Preparations; 2nd ed.;
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Nitration of Toluene with Cyanamide and Nitramide through
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Fluorination of Aromatics with Fluorodiazonium Ion. J. Org. Chem.
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Nitriles via Highly Efficient Nitrogenation Strategy through C–H or
C–C Bond Cleavage. Acc. Chem. Res. 2014, 47, 1137-1145.
KIE
Competition experiment:
2 Ag0
Ar–H
PdIILn
kH/kD = 3.6
(2)
(a) Ellis, G. P.; Romney-Alexander, T. M. Cyanation of
I
aromatic halides, Chem. Rev. 1987, 87, 779-794; (b) Sundermeier,
M.; Zapf, A.; Beller, M. Palladium-Catalyzed Cyanation of Aryl
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Rizwan, S.; Ashfaq, M.; Shaheen, S.; Waseem, A. An Overview on
the Progress and Development on Metals/Non-Metal Catalyzed
Cyanation Reactions, Inorg. Chim. Acta 2018, 469, 408-423.
Separate experiments:
2 AgI
oxidation rate-limiting
C–H activation
kH/kD = 2.5
Pd0Ln
IV
PdIILn
II
C–H Activation via
R
CF3
reductive
elimination
ligand
exchange
O
O
Pd
N
Product
CN–
N
N
O
PdIILn
III
(3)
(a) Liskey, C. W.; Liao, X.; Hartwig, J. F. Cyanation of
R
H
R
Arenes via Iridium-Catalyzed Borylation, J. Am. Chem. Soc. 2010,
132, 11389-11391; (b) Ren, Y.; Yan, M.; Zhao, S.; Wang, J.; Ma, J.;
Tian, X.; Yin, W. Selective para-Cyanation of Alkoxy- and
Benzyloxy-Substituted Benzenes with Potassium Ferricyanide
Promoted by Copper(II) Nitrate and Iodine, Adv. Synth. Catal. 2012,
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Scheme 3. Preliminary mechanistic data and proposed
catalytic cycle.
In summary, we have developed the first example of an arene-
limited non directed cyanation of arenes through a C–H
activation. The method is based on the use of a Pd(II) catalyst
with two complementary commercially available ligands, both
of which were shown to be essential for the success of the
reaction. The protocol described is applicable to a broad range
of substitution patterns and proceeds under a combination of
electronic and steric control. The possibility to cyanate
substrates bearing electron-donating as well as moderately
electron-withdrawing substituents, both of which can be used
as the limiting reagents, is expected to render this method
attractive in the context of late-stage modification.
(4)
(a) Eberson, L.; Nilsson, S.; Rietz, B. Direct Cyanation of
Aromatic Compounds. I. Diazotation of Cyanamide in the Presence of
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AUTHOR INFORMATION
Corresponding Author
* mvangemmeren@uni-muenster.de.
(5)
(a) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Chelation-
Assisted Palladium-Catalyzed Direct Cyanation of 2-Arylpyridine
C−H Bonds, Org. Lett. 2009, 11, 4716-4719; (b) Kim, J.; Chang, S. 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. 2010, 132, 10272-10274; (c) Ding, S.; Jiao, N.
Direct Transformation of N,N-Dimethylformamide to −CN: Pd-
Funding Sources
We gratefully acknowledge financial support from the Max
Planck Society (Otto Hahn Award to M.v.G.), FCI (Liebig
Fellowship to M.v.G.), and WWU Münster.
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ACS Catalysis
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For selected reviews on nondirected C–H activation, see:
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9
(9)
While we have isolated the mixtures of regioisomers during
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our scope studies, in order to obtain data on the overall yield and
unperturbed information on the regioselectivity, we could
demonstrate on selected examples (2d, 2e, 2p) that the separation of
the isomers is possible through chromatographic techniques. For
details, see the Supporting Information.
(10) Table 1 shows the results obtained using Conditions A.
Analogous results were obtained for the synthesis of 2b using
Conditions B. For details, see the Supporting Information.
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(6)
While this manuscript was under consideration for
publication, two contemporary studies on the nondirected cyanation
of arenes appeared online as accepted articles: (a) Zhao, D.; Xu, P.;
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(a) Chen, H.; Wedi, P.; Meyer, T.; Tavakoli, G.; van
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(13) (a) Politova, T. I.; Gal’vita, V. V.; Belyaev, V. D.;
Sobyanin, V. A. Non-Faradaic Catalysis: The Case of CO Oxidation
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Catalyzed C–H Activation: The Role of the Ag(I) Salt in Pd/Ag-
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& Sons Ltd. 2001; (b) Heaney, H. Zinc Cyanide, Encyclopedia of
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(16) The use of HFIP as solvent was found to be crucial in this
reaction. The unique suitability of this solvent for selective C–H
activation processes has been well documented. Multiple
rationalizations such as possible hydrogen bonds with the catalytically
active species or an ideal balance of solubilizing ability and polarity
offered by this solvent have been proposed, but no conclusive
statement can be made regarding the precise role of this solvent in
such reactions. For reviews on the role of HFIP in C–H activation,
see: (a) Wencel-Delord, J.; Colobert, F. A Remarkable Solvent Effect
of Fluorinated Alcohols on Transition Metal Catalysed C–H
Functionalizations, Org. Chem. Front. 2016, 3, 394-400; (b) Sinha, S.
K.; Bhattacharya, T.; Maiti, D. Role of hexafluoroisopropanol in C‒H
activation, React. Chem. Eng. 2019, advance article, DOI:
10.1039/C8RE00225H.
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Preferred TOC Graphic
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Pd(OAc)2, Ac-Gly-OH
CF3
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H
CN
N
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CN-source
Ag-salt
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• Arene as limiting reagent
• No need for directing groups
• Steric/electronic control
Alternative TOC:
Pd(OAc)2, Ac-Gly-OH
CF3
H
N
R
CN
R
CN-source
Ag-salt
• Arene as limiting reagent
• No need for directing groups
• Steric/electronic control
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