Cobalt-catalyzed C-H cyanation of (Hetero)arenes and 6-Arylpurines with N -cyanosuccinimide as a new cyanating agent

Article abstract of DOI:10.1021/ol503680d

A cobalt-catalyzed C-H cyanation reaction of arenes has been developed using N-cyanosuccinimide as a new electrophilic cyanating agent. The reaction proceeds with high selectivity to afford monocyanated products with excellent functional group tolerance. Substrate scope was found to be broad enough to include a wide range of heterocycles including 6-arylpurines.

Full text of DOI:10.1021/ol503680d

Letter
pubs.acs.org/OrgLett
Cobalt-Catalyzed C−H Cyanation of (Hetero)arenes and
6‑Arylpurines with N‑Cyanosuccinimide as a New Cyanating Agent
Amit B. Pawar†,‡ and Sukbok Chang*,†,‡
†Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305-701, Korea
‡Department of Chemistry, Korea Advanced Institute of Science & Technology (KAIST), Daejeon 305-701, Korea
S
* Supporting Information
ABSTRACT: A cobalt-catalyzed C−H cyanation reaction of arenes has been
developed using N-cyanosuccinimide as a new electrophilic cyanating agent. The
reaction proceeds with high selectivity to afford monocyanated products with
excellent functional group tolerance. Substrate scope was found to be broad
enough to include a wide range of heterocycles including 6-arylpurines.
uring the past decades, significant progress has been made
in the area of C−H bond functionalization,1 and this
Scheme 1. Co-Catalyzed C−H Cyanation with N-
D
Cyanosuccinimide
method now offers a straightforward synthetic tool in organic
synthesis as an alternative to the traditional cross-coupling
reactions requiring prefunctionalized starting materials. The
majority of the currently developed C−H activation methods
employ precious transition-metal catalysts such as Pd, Rh, Ru, or
Ir. Since the first-row transition metals are more abundant and
cheap compared to their 4d or 5d metal congeners, develop-
ments of efficient catalytic systems based on the first row metals
are of special interest.2 Among the first row metals, cobalt has
emerged especially as one of the most promising species for the
direct C−H functionalization, leading to synthetically useful and
cost-effective transformations.3 Benzonitriles, on the other hand,
represent an important structural motif frequently found in a
variety of natural products, pharmaceuticals, and agrochemicals.4
Although transition-metal-catalyzed/mediated cyanation of aryl
(pseudo)halides has been well established,5 direct introduction
of a cyano unit in arenes via C−H bond activation strategy would
be a more beneficial approach, thus avoiding the use of
prefunctionalized substrates.6
(3aa) was formed in 31% yield at 120 °C (entry 1). In this case, a
cationic cobalt catalyst was generated in situ upon treatment of
the cobalt precursor with a silver salt, which is the same system
employed by the Kanai and co-workers in the direct C−H
amidation of indoles with sulfonyl azides.13 In order to improve
the reaction efficiency, we examined additive effects to reveal that
product yield could be increased by the addition of silver acetate
(entries 2−4).1f At this stage, we decided to further examine
additional analogous electrophilic cyanating reagents. While
cyanation with N-cyanophthalimide substituted with 5-nitro
(2b) was sluggish (entry 5), an analogue (2c) bearing a methyl
group was more efficient (entry 6). More pleasingly, when N-
cyanosuccinimide (2d) was employed under otherwise identical
conditions, product (3aa) was obtained in 80% yield (entry 7). It
is noteworthy that this cyanating reagent (2d) displays such
attractive features such as easy preparation and being bench
stable, thus not requiring a special precaution for the cyanation
reaction. In addition, it generates a byproduct (succinimide) that
is easily removed by a simple basic workup, thus making the
purification process convenient. Solvents other than 1,2-
dicloroethane were less effective as shown in entries 8−10.
The cyanation did not take place in the absence of cobalt catalyst
or AgNTf2. In addition, the use of other cobalt species such as
In recent years, Rh-7 and Ru8-catalyzed electrophilic C−H
cyanation has been developed using N-cyano-N-phenyl-p-
toluenesulfonamide (NCTS). Since these procedures show
attractive features such as broad substrate scope and/or external
oxidant-free conditions, investigation of NCTS variants using
inexpensive first-row transition-metal catalysts is highly desir-
able.9 In continuation of our efforts in developing more efficient
and selective cyanation methods,10 described herein is the cobalt-
catalyzed C−H cyanation11 using N-cyanosuccinimide as a new
electrophilic cyanating reagent12 that is easy to prepare and
bench-stable (Scheme 1).
We commenced our study by examining a series of N-
cyanoimides in a reaction with 2-phenylpyridine (1a) under the
perspective cobalt catalytic systems (Table 1).
When N-cyanophthalimide (2a) was subjected to conditions
Received: December 22, 2014
using Cp*Co(CO)I2 as a catalyst, the desired cyanated product
© XXXX American Chemical Society
A
DOI: 10.1021/ol503680d
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Arene Substrates
b,c
entry
“CN” source
additives
solvent
yield (%)
1
2
2a
2a
2a
2a
2b
2c
2d
2d
2d
2d
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,4-dioxane
THF
31
58
NaOAc
Cu(OAc)2
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
3
25
4
66
5
42
6
74
7
80 (74)
67
8
9
60
10
acetone
38
a
Reaction conditions: 1a (0.10 mmol), 2 (1.5 equiv), Cp*Co(CO)I2
(10 mol %), AgNTf2 (20 mol %), and additives (20 mol %) in 1,2-
b
1
DCE (0.5 mL) at 120 °C for 12 h. Yields are based on crude H
NMR (internal standard: 1,1,2,2 tetrachloroethane). Isolated yield in
c
parentheses.
Co(OAc)2 or Co(acac)3 was ineffective (see the Supporting
Information for details).
With the optimized conditions in hands, the scope of
substrates was next investigated (Scheme 2). As anticipated, 2-
phenylpyridine derivatives bearing a range of functional groups
were readily cyanated. While electron-donating groups led to
higher product yields in general, reaction of a substrate bearing
an amino group was also facile (3ae). Intriguingly, a sulfide group
did not deteriorate the cyanation (3af). A range of ethers such as
alkoxy, benzyloxy, and phenoxy was compatible with the present
conditions (3ba−bc). Synthetically versatile groups including
amide, ketone, and ester were also tolerated (3ca−cc). Note that
cyanation took place selectively at the C−H bonds ortho to the 2-
pyridyl moiety even in the presence of those carbonyl groups,
which were shown to work as effective directing groups in the Rh,
Ru, or Ir catalyst systems.14 Substrates bearing acetal and CF3
groups underwent the cyanation in moderate to good yields (3d
and 3e). Cinnamate was smoothly cyanated under the present
cobalt catalytic system (3f). Functional group compatibility of
the present cyanation conditions was additionally proven by
examining various hydroxyl-protecting groups such acetate, silyl,
methoxymethyl (MOM), and p-methoxybenzyl (PMB) (3ga−
gd). 2-(2-Naphthalenyl)pyridine was cyanated selectively at the
C-3 position in good yield (3h). Substrates bearing halides like F,
Cl, or Br also underwent the cyanation without difficulty (3ia−
ic), thus offering an opportunity for additional functionalizations.
In addition, cyanation of a substrate containing methanesulfonyl
group proceeded smoothly and the structure of product 3j was
confirmed by an X-ray crystallographic analysis. Compounds
containing meta-substituents were selectively cyanated at the
sterically less encumbered position irrespective of the electronic
property (3ka−kc).
a
aReaction conditions: 1 (0.10 mmol), 2d (1.5 equiv), Cp*Co(CO)l2
(10 mol %), AgNTf2 (20 mol %), and AgOAc (20 mol %) in 1,2-DCE
(0.5 mL) at 120 °C for 12 h; isolated yields are given.
change the reaction efficiency (3l) very much, their position was
found to be more important. For instance, whereas a methyl
group at the 4- or 5-position in pyridine did not affect the
reaction (3ma,mb), cyanation of 6-methyl-2-phenylpyridine did
not take place. N-Heterocycle derivatives such as pyrazole (3n)
and pyrimidine (3o) worked well as effective directing groups. In
addition, cyanation of benzo[h]quinoline was smooth (3p).
We also examined the feasibility of the Co catalyst system in
the cyanation of heterocyclic C−H bonds (Scheme 3). Since
heteroaryl nitriles play an important role in medicinal
chemistry,15 the successful cyanation of these substrates was
anticipated to be highly promising. Indeed, we were pleased to
observe that thiophenyl C−H bonds were selectively cyanated
(5a and 5ba). It should be noted that in the case of 5a, the
cyanation occurred exclusively at the 2-position of thienyl
moiety. Direct cyanation of furanyl (5bb) and pyrrolyl (5c) C−
H bonds was also facile when pyridyl and pyrimidyl were used as
directing groups, respectively. In addition, benzo- and dibenzo-
fused substrates were reacted without difficulty (5da−eb).
Indole was cyanated at the C-2 position when pyridyl or
pyrimidyl groups were employed as directing groups (5fa and
5fb, respectively). An indolone derivative was cyanated
exclusively at the C-2 position in high yield, and the structure
of its product (5g) was confirmed by an X-ray crystallographic
analysis.
We subsequently examined the scope of pyridine and
additional directing groups under the present cobalt catalytic
system. While the electronic nature of substituents did not
B
DOI: 10.1021/ol503680d
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
structure of 7b was confirmed by an X-ray diffraction analysis.
Cyanation with a removable N9-substituent (e.g., benzyl) was
also facile (7d). Electronic effects of the aryl side were examined
to reveal that electron-donating groups facilitated the cyanation
more efficiently (7e−g). It was interesting to observe that a
purinyl analogue devoid of N7-nitrogen was cyanated in good
yield (7h), implying that the N5-nitrogen atom rather than N7 in
purine works as a directing group.17d
Scheme 3. Scope of Heteroarenes
To gain mechanistic insights, preliminary experiments were
briefly carried out (Scheme 5). A substrate 1ba was found to
Scheme 5. Preliminary Mechanistic Experiments
a
aReaction conditions: 4 (0.10 mmol), 2d (1.5 equiv), Cp*Co(CO)l2
(10 mol %), AgNTf2 (20 mol %), and AgOAc (20 mol %) in 1,2-DCE
(0.5 mL) at 120 °C for 12 h; isolated yields are given.
6-Arylpurines represent a unique class of heterocyclic
compounds displaying a wide range of biological activities.16 In
this regard, a selective installation of useful functional groups in
6-arylpurines is important. However, only a few examples of
direct C−H functionalization of 6-arylpurines17 have been
reported, including our own.17d In this regard, we prepared a
series of 6-arylpurine derivatives to test our working hypothesis
of utilizing a purinyl moiety as a directing group for the direct C−
H cyanation at the aryl pendant.
To our delight, 6-arylpurines were selectively cyanated under
the present cobalt catalyst system (Scheme 4). The N9-
substituents did not significantly change the reaction efficiency.
In fact, 6-phenylpurines bearing N9-phenyl, ethyl, and butyl
groups were all smoothly cyanated leading to the desired
products (7a−c) in moderate to good yields, and the solid
undergo a notable H/D exchange by the cobalt catalyst system in
the presence of CD3OD (Scheme 5a), implying that the C−H
activation step would be reversible. Additionally, the observed
low values of intermolecular kinetic isotope effect in parallel
reactions in separate vessels (kH/kD ≈ 1.1) and competitive
experiment (kH/kD ≈ 1.2) suggests that the C−H bond cleavage
may not be involved in the rate-limiting step although it is not
conclusive at the present stage (Scheme 5b).
A plausible mechanism of the present Co-catalyzed cyanation
is proposed in Scheme 6 based on the preliminary experiments
and the relevant Rh- or Ru-catalyzed reactions.7,8 First, a cationic
Co(III) species A generated in situ from Cp*Co(CO)I2 and
AgNTf2 in the presence of AgOAc reacts reversibly with 2-
phenylpyridine (1a) to form a cobaltacycle B. Coordination of a
a
Scheme 4. Scope of 6-Arylpurines
Scheme 6. Proposed Mechanism
a
aReaction conditions: 6 (0.10 mmol), 2d (1.5 equiv), Cp*Co(CO)l2
(10 mol %), AgNTf2 (20 mol %), and AgOAc (20 mol %) in 1,2-DCE
(0.5 mL) at 120 °C for 12 h; isolated yields are given.
C
DOI: 10.1021/ol503680d
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) For Cu- and Pd-catalyzed/mediated C−H cyanation, see:
(a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790. (b) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett.
2009, 11, 4716. (c) Jia, X.; Yang, D.; Wang, W.; Luo, F.; Cheng, J. J. Org.
Chem. 2009, 74, 9470. (d) Yan, G.; Kuang, C.; Zhang, Y.; Wang, J. Org.
Lett. 2010, 12, 1052. (e) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133,
12374. (f) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun. 2011,
6725. (g) Jin, J.; Wen, Q.; Lu, P.; Wang, Y. Chem. Commun. 2012, 9933.
(h) Xu, S.; Huang, X.; Hong, X.; Xu, B. Org. Lett. 2012, 14, 4614.
(i) Peng, J.; Zhao, J.; Hu, Z.; Liang, D.; Huang, J.; Zhu, Q. Org. Lett.
2012, 14, 4966. (j) Pan, C.; Jin, H.; Xu, P.; Liu, X.; Cheng, Y.; Zhu, C. J.
Org. Chem. 2013, 78, 9494. (k) Kou, X.; Zhao, M.; Qiao, X.; Zhu, Y.;
Tong, X.; Shen, Z. Chem.Eur. J. 2013, 19, 16880. (l) Yuen, O. Y.;
Choy, P. Y.; Chow, W. K.; Wong, W. T.; Kwong, F. Y. J. Org. Chem.
2013, 78, 3374. (m) Xu, H.; Liu, P.-T.; Li, Y.-H.; Han, F.-S. Org. Lett.
2013, 15, 3354. (n) Hong, X.; Wang, H.; Qian, G.; Tan, Q.; Xiu, B. J.
Org. Chem. 2014, 79, 3228. (o) Yan, Y.; Yuan, Y.; Jiao, N. Org. Chem.
Front. 2014, 1, 1176.
cyanating reagent (2d) to the cobalt center of B and subsequent
migratory insertion of cyano (CN) moiety into the metallacycle
would lead to a key imido intermediate D. A cyanated product
(3aa) will be liberated from D giving rise to a succinimido cobalt
complex (E) that is subsequently converted to a catalytically
active species A with the concomitant release of a byproduct
(succinimide, 8).
In conclusion, Co-catalyzed C−H cyanation of (hetero)arenes
has been developed by using N-cyanosuccinimide as a
convenient cyanating reagent that is easy to prepare, bench
stable, and gives succinimide as a readily removable byproduct.
The reaction proceeds efficiently over a broad range of
substrates, including various heterocycles, such as 6-arylpurines,
with excellent functional group tolerance.
ASSOCIATED CONTENT
■
(7) (a) Gong, T.-J.; Xiao, B.; Cheng, W.-M.; Su, W.; Xu, J.; Liu, Z.-J.;
Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 10630. (b) Chaitanya, M.;
Yadagiri, D.; Anbarasan, P. Org. Lett. 2013, 15, 4960. (c) Gu, L.-J.; Jin,
C.; Wang, R.; Ding, H.-Y. ChemCatChem. 2014, 6, 1225. (d) Han, J.;
Pan, C.; Jia, X.; Zhu, C. Org. Biomol. Chem. 2014, 12, 8603.
(8) Liu, W.; Ackermann, L. Chem. Commun. 2014, 1878.
S
* Supporting Information
Experimental procedure and characterization of new compounds
(1H, 13C NMR spectra). This material is available free of charge
via the Internet at http://pubs.acs.org.
(9) Very recently, Buchwald and co-workers reported the Cu-catalyzed
borylation/ortho C−H cyanation of vinyl arenes with NCTS: Yang, Y.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2014, 53, 8677.
AUTHOR INFORMATION
■
Corresponding Author
(10) (a) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272. (b) Kim,
J.; Kim, H.; Chang, S. Org. Lett. 2012, 14, 3924. (c) Kim, J.; Choi, J.;
Shin, K.; Chang, S. J. Am. Chem. Soc. 2012, 134, 2528. (d) Wang, Z.;
Chang, S. Org. Lett. 2013, 15, 1990. (e) Pawar, A. B.; Chang, S. Chem.
Commun. 2014, 448.
*E-mail: sbchang@kaist.ac.kr.
Notes
The authors declare no competing financial interest.
(11) During the preparation of this manuscript, Ackermann and
Glorius groups independently reported the Co-catalyzed C−H
cyanation of arenes by using NCTS: (a) Li, J.; Ackermann, L. Angew.
Chem., Int. Ed. 2014, DOI: 10.1002/anie.201409247. (b) Yu, D.-G.;
Gensch, T.; de Azambuja, F.; Vasquez-Cespedes, S.; Glorius, F. J. Am.
Chem. Soc. 2014, 136, 17722.
ACKNOWLEDGMENTS
■
This research was supported by the Institute for Basic Science
(IBS-R010-D1) in Korea. We thank Dr. Jeung Gon Kim (Center
for Catalytic Hydrocarbon Functionalizations, IBS, Korea) for
the valuable discussions.
(12) Beller and co-workers reported that N-cyanophthalimide was not
an efficient cyanating reagent with reaction of boronic acids and
Grignard reagents: (a) Anbarasan, P.; Neumann, H.; Beller, M. Angew.
Chem., Int. Ed. 2011, 50, 519. (b) Anbarasan, P.; Neumann, H.; Beller,
M. Chem.Eur. J. 2010, 16, 4725.
REFERENCES
■
(1) For recent reviews on C−H bond activation, see: (a) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (b) Mkhalid, I.
A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem.
Rev. 2010, 110, 890. (c) Lyons, T. W.; Sanford, M. Chem. Rev. 2010, 110,
(13) Sun, B.; Yoshino, T.; Matsunaga, S.; Kanai, M. Adv. Synth. Catal.
2014, 356, 1491.
1147. (d) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc.
̈
(14) Kim, J.; Chang, S. Angew. Chem., Int. Ed. 2014, 53, 2203 and
references therein.
(15) Fleming, F. F.; Yao, L.; Ravikumar, P. C.; Funk, L.; Shook, B. C. J.
Med. Chem. 2010, 53, 7902.
Rev. 2011, 40, 4740. (e) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem.
Soc. Rev. 2011, 40, 5068. (f) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(g) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 10236. (h) Engle, K. M.; Mei, T.-S.; Wasa, M.;
Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (i) Li, B.-J.; Shi, Z.-J. Chem. Soc.
Rev. 2012, 41, 5588. (j) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H.
Chem. Rev. 2012, 112, 5879. (k) Wencel-Delord, J.; Glorius, F. Nat.
Chem. 2013, 5, 369.
(16) (a) Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med. Chem.
2000, 43, 1817. (b) Gundersen, L.-L.; Nissen-Meyer, J.; Spilsberg, B. J.
Med. Chem. 2002, 45, 1383. (c) Bakkestuen, A. K.; Gundersen, L.-L.;
Utenova, B. T. J. Med. Chem. 2005, 48, 2710. (d) Hocek, M.; Naus, P.;
Pohl, R.; Votruba, I.; Furman, P. A.; Tharnish, P. M.; Otto, M. J. J. Med.
Chem. 2005, 48, 5869.
(17) For metal-catalyzed C−H activation using purine as a directing
group, see: (a) Lakshman, M. K.; Deb, A. C.; Chamala, R. R.; Pradhan,
P.; Pratap, R. Angew. Chem., Int. Ed. 2011, 50, 11400. (b) Guo, H.-M.;
Jiang, L.-L.; Niu, H.-Y.; Rao, W.-H.; Liang, L.; Mao, R.-Z.; Li, D.-Y.; Qu,
G.-R. Org. Lett. 2011, 13, 2008. (c) Chamala, R. R.; Parrish, D.; Pradhan,
P.; Lakshman, M. K. J. Org. Chem. 2013, 78, 7423. (d) Kim, H. J.; Ajitha,
M. J.; Lee, Y.; Ryu, J.; Kim, J.; Lee, Y.; Jung, Y.; Chang, S. J. Am. Chem.
Soc. 2014, 136, 113.
(2) Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087.
(3) For recent reviews on the Co-catalyzed C−H bond functionaliza-
tions, see: (a) Yoshikai, N. Synlett 2011, 1047. (b) Gao, K.; Yoshikai, N.
Acc. Chem. Res. 2014, 47, 1208. (c) Yoshikai, N. Bull. Chem. Soc. Jpn.
2014, 87, 843.
(4) (a) Larock, R. C. Comprehensive Organic Transformations: A Guide
to Functional Group Preparations; Wiley-VCH: New York, 1989; p 819.
(b) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substance: Synthesis, Patents, Applications, 4th ed.; Georg Thieme:
Stuttgart, 2001. (c) Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103,
2035.
(5) For reviews on transition-metal-catalyzed cyanations, see: (a) Ellis,
G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779.
(b) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev. 2011, 40,
5049. (c) Kim, J.; Kim, H. J.; Chang, S. Angew. Chem., Int. Ed. 2012, 51,
11948.
D
DOI: 10.1021/ol503680d
Org. Lett. XXXX, XXX, XXX−XXX