Synthesis of biphenyl-2-carbonitrile derivatives via a palladium-catalyzed sp2 C-H bond activation using cyano as a directing group

Article abstract of DOI:10.1021/ol103075n

Pd^II-catalyzed aromatic C-H bond activation using cyano as a directing group was carried out in TFA medium. Biphenyl-2-carbonitrile derivatives were therefore synthesized from aryl nitriles and aryl halides in moderate to good yields.

Full text of DOI:10.1021/ol103075n

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1286–1289
Synthesis of Biphenyl-2-carbonitrile
Derivatives via a Palladium-Catalyzed sp2
C-H Bond Activation Using Cyano as a
Directing Group
Wu Li, Zhipeng Xu, Peipei Sun,* Xiaoqing Jiang, and Min Fang
Jiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and Materials
Science, Nanjing Normal University, Nanjing, 210097, China
sunpeipei@njnu.edu.cn
Received December 20, 2010
ABSTRACT
PdII-catalyzed aromatic C-H bond activation using cyano as a directing group was carried out in TFA medium. Biphenyl-2-carbonitrile derivatives
were therefore synthesized from aryl nitriles and aryl halides in moderate to good yields.
Aromatic nitriles possess versatile utilities and are indis-
pensible not only in organic synthesis but also in the chemical
industry.1 In fact, the nitrile group is an important precursor
for various functional groups such as aldehydes, amines,
amidines, tetrazoles, amides, and their carboxyl derivatives.2
In addition, biphenyls represent a key structural motif in a
large number of compounds used as pharmaceuticals, agro-
chemicals, dyes, chiral ligands for metal catalysts, liquid
crystals, organic semiconductors, and materials for molecu-
lar recognition devices. Furthermore, the biaryl subunit is
present in an extensive range of natural products.3 Consider-
ing the importance of the compounds with these structural
units, the development of an efficient approach for the
synthesis of biphenyl nitriles is therefore desirable.
otherwise unreactive C-H bonds into carbon-carbon or
carbon-heteroatom bonds.4 In particular, C-H arylation
has become an attractive alternative to traditional C-C
cross-coupling reactions due to the minimization of stoi-
chiometric metallic waste and the costs associated with the
preparation of starting materials,5 and many reactions
(4) (a) Handbook of C-H Transformations; Dyker, G., Ed.; Wiley-
VCH: Weinheim, 2005. (b) Arndtsen, B. A.; Bergman, R. G.; Mobley, T. A.;
Peterson, T. H. Acc. Chem. Res. 1995, 28, 154. (c) Shilov, A. E.; Shul’pin,
G. B. Chem. Rev. 1997, 97, 2879. (d) Dyker, G. Angew. Chem., Int. Ed.
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Kakiuchi, F.; Chatani, N. Adv. Synth. Catal. 2003, 345, 1077. (g) Dick,
A. R.; Sanford, M. S. Tetrahedron2006, 62, 2439. (h) Godula, K.; Sames,
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C.; Kefalidis, C. E.; Clot, E.; Fagnou, K.; Baudoin, O. J. Am. Chem. Soc.
2010, 132, 10706.
In recent years, transition-metal-catalyzed C-H func-
tionalization has emerged as a powerful tool to transform
(5) (a) Robin B. Bedford, R. B.; Limmert, M. E. J. Org. Chem. 2003,
68, 8669. (b) Goj, L. A.; Gunnoe, T. B. Curr. Org. Chem. 2005, 9, 671. (c)
Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (d) Stuart,
D. R.; Fagnou, K. Science 2007, 316, 1172. (e) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174. (f) Seregin, I. V.; Gevorgyan, V.
Chem. Soc. Rev. 2007, 36, 1173. (g) Thirunavukkarasu, V. S.; Parthasarathy,
K.Cheng, C. H. Angew. Chem., Int. Ed. 2008, 47, 9462. (h) Caron, L.;
Campeau, L. C.; Fagnou, K. Org. Lett. 2008, 10, 4533. (i) Daugulis, O.;
Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (j) Chen, X.;
Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem., Int. Ed. 2009, 48,
5094. (k) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38,
2447. (l) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269. (m) Ack-
ermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48,
9792. (n) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (o)
Thirunavukkarasu, V. S.; Parthasarathy, K.; Cheng, C. H. Chem.;Eur.
J. 2010, 16, 1436. (p) Gandeepan, P.; Parthasarathy, K.; Cheng, C. H.
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(1) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceu-
tical Substances: Syntheses, Patents, Applications, 4th ed.; Georg Thieme:
Stuttgart, Germany, 2001.
(2) (a) Rappoport, Z. The Chemistry of the Cyano Group; Interscience
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New York, 1989.
(3) (a) Torssell, K. G. B. Natural Product Chemistry; Wiley: Chichester,
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ꢀ
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r
10.1021/ol103075n
Published on Web 02/21/2011
2011 American Chemical Society

involving directing-group-assisted activation of sp2 C-H
bonds of ortho aromatic C-H bonds have been exten-
sively investigated. Many directing groups, such as acetyl,
acetamino, carboxylicacid, oxazolyl, pyridyl, nitro, hydro-
xyl, and imino moieties have been used for C-H bond
activation. Mechanistic studies indicated that aromatic
C-H bonds can be activated via five-membered
metallacycles.5,6 A few methods were used to obtain
biphenyl nitriles via a directed C-H functionalization,
for example, a magnesiation or zincation to arenes with
magnesium bis(amide) or zinc bis(amide) and then
Table 1. Optimization of the Reaction Conditionsa
entry
catalyst
solvent
NMP
additive
yield (%)b
7
quenching with aryl iodide, and a palladium-catalyzed
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2CO3
AgOAc
AgNO3
BQ
0
benzamide ortho-arylation that is then treated with
trifluoroacetic anhydride.8 To the best of our knowledge,
no benzonitrile ortho-arylation directed by a cyano group
has been reported. Herein, we wish to report a new
synthesis of biphenyl-2-carbonitrile derivatives from
aryl nitriles and aryl halides via a palladium-catalyzed
aromatic C-H bond activation using cyano as a directing
group.
2
DMF
Toluene
AcOH
AcOH/toluene
TFA
0
3
0
4
22
5
20
6
70 (58, 71)c
45
7
TFA
8
TFA
trace
36
9
TFA
10
11
12
13
14
15
16
TFA
trace
trace
trace
trace
trace
trace
trace
Initially, benzonitrile 1a and iodobenzene 2a were cho-
sen as model substrates for surveying the reaction param-
eters (Table 1). Pd(OAc)2 was selected as a catalyst for
the cross-coupling. We at first performed the reaction
under basic or neutral conditions. Unfortunately, no
desired cross-coupling product biphenyl-2-carbonitrile
3aa was observed. An acidic medium appeared possible
for this transformation. AcOH, AcOH/toluene (1:1), and
TFA were tested as the solvent. The result showed that
TFA was the best one in which 3aa was obtained in 70%
yield in 9 h. No reaction took place without a catalyst in
this acidic system. Pd(OAc)2 has the dual role of electro-
philic activation of the arene and intramolecular deproto-
nation, as reported previously. Other palladium species,
such as PdCl2, Pd(PPh3)4, Pd(dba)2, and Pd nanoparticles
(NPs), were substantially less effective (Table 1, entries
13-16). It was found that the nature of the additive plays a
critical role on the reaction efficiency. Several silver com-
pounds and oxidants as additive were tested; the best result
was obtained by the use of Ag2O (Table 1, entry 6), while
Ag2CO3, AgOAc, AgNO3, BQ, K2S2O8, and O2 showed
poor reactivity (Table 1, entries 7-12). Increasing reaction
temperature led to higher conversion (Table 1, entry 6).
When the reaction temperature was raised to 110 °C, it
reached the highest yield. Thus, the optimized reaction
proceeded using 10 mol % of Pd(OAc)2 as a catalyst with
Ag2O as an additive in TFA at 110 °C.
TFA
K2S2O8
O2
TFA
TFA
Ag2O
Ag2O
Ag2O
Ag2O
Pd(PPh3)4
Pd(dba)2
Pd NPs
TFA
TFA
TFA
a Reaction conditions: benzonitrile (1.0 mmol), iodobenzene (2.0
mmol), catalyst (10 mol %), additive (1.0 mmol), and solvent (2.0 mL)
at 110 °C for 9 h. b Isolated yields. c Reaction proceeded at 90 and 120 °C,
respectively.
electron-donating group. For example, benzonitrile reacted
smoothly with 1-iodo-4-nitrobenzene or 1-iodo-3-nitroben-
zene to give the ortho-arylated products in 91 and 93%
isolated yield, respectively (entries 3, 4), while it reacted with
iodobenzene or 3-iodo-toluene and gave the correspond-
ing products in 70 and 51% isolated yield, respectively
(entries 1, 2). Electron-withdrawing groups weaken C-I
bonds, which might explain the increased yields. The reaction
can finish in 9 h, and the extension of reaction time was not
beneficial for increasing the yield (entry 1).
The reactions of various arylnitrile and aryl iodide
derivatives were investigated as shown in Table 3. It can
be seen that a range of arylnitriles participate in this
reaction efficiently. We can also see that, with increasing
Hammett constant σm values (-0.07, 0.12, and 0.37 for
CH3, OCH3, and Cl, respectively)9 of para substituents of
the cyano group of arylnitriles (they are also at the meta
position of activated C-H), the yields of the products
decreased. Though the exact reason was not very clear, we
presume that it decreases the coordinating ability to palla-
dium with increasing inductive electron-withdrawing abil-
ities of those groups. This is different from the substituent
effect on aryl iodides. It is noticeable that the reaction has
evident compatibility to some functional groups. The
groups existed on the aromatic ring of the reactants with
a directing function; whether a group was present on
With identification of the optimal reaction conditions,
reactions of benzonitrile with various aryl iodides were
studied (Table 2). The experiment showed that aryl iodides
with an electron-withdrawing substituent gave higher
yields of ortho-arylated products than those with an
(6) (a) Jun, C.-H.; Moon, C. W.; Lee, D.-Y. Chem.;Eur. J. 2002, 8,
2422. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010,
110, 624.
(7) Rohbogner, C. J.; Wunderlich, S. H.; Clososki, G. C.; Knochel, P.
Eur. J. Org. Chem. 2009, 1781.
(8) Shabashov, D.; Maldonado, J. R. M.; Daugulis, O. J. Org. Chem.
2008, 73, 7818.
(9) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
Org. Lett., Vol. 13, No. 6, 2011
1287

Table 2. Reaction Results of Benzonitrile with Aryl Iodidesa
Table 3. Reaction Results of Arylnitrile with Aryl Iodidesa
a Unless otherwise mentioned, all the reactions were carried out using
nitrile 1a (1.0 mmol), aryl iodide 2 (2.0 mmol), Pd(OAc)2 (10 mol %),
and Ag2O (1.0 mmol) in TFA (2.0 mL) at 110 °C for 9 h. b Isolated yields.
c The reaction time was 6 and 12 h, respectively.
arylnitriles, such as methoxyl, or on aryl iodides, such as
the acetyl, nitro, and ester group, the directing effect of the
cyano group was not overridden. That is to say, no side
products were produced in which the substituent on the
ortho position of these groups were found, which revealed
that the cyano group was more effective in the activation to
the ortho C-H bond than the above groups under these
reaction conditions.
To account for the present catalytic reaction, a possible
mechanism is proposed (Scheme 1). It is different from
other directing groups such as acetyl, acetamino, and
carboxylic acid assisted activation of sp2 C-H bonds in
which oxygen acts as a coordinating atom; in arylnitriles,
the cyano group has a linear configuration, so it will be
difficult to form general five-membered metallacycles. For
minimizing the ring strain, the coordination of a π-electron
between carbon and nitrogen to palladium is possible.
Thus, the first step likely involves coordination of arylni-
triles to the Pd(II) species followed by ortho C-H activa-
tion, in which trifluoroacetate presumably participates in
aromatic proton abstraction to form an aryl palladium
intermediate. Oxidative addition of aryl iodide to this
a The reaction conditions were as above. b Isolated yields.
1288
Org. Lett., Vol. 13, No. 6, 2011

that decompose via reductive elimination pathways.12
Recently, Cheng et al. obtained an aryl palladium inter-
mediate in which C-Pd formed at the ortho position of the
directing group.5o,p These findings may be relevant to the
mechanism of this arylation procedure. Whereas the role
of silver oxide in the catalytic reaction is not entirely clear,
it likely acts as a halide scavenger to remove iodide and
serves to regenerate the Pd catalyst.5p,13
Scheme 1. Proposed Reaction Mechanism
In conclusion, we have successfully developed a new
method for the synthesis of biphenyl-2-carbonitrile deri-
vatives via a palladium-catalyzed C-H bond activation
using cyano as the directing group. To the best of our
knowledge, the present reaction is the first example of
transition-metal-catalyzed direct arylation of aryl nitrile.
Further studies of transition-metal-catalyzed C-H func-
tionalization in the presence of directing groups and
detailed mechanistic investigations are in progress in our
laboratory.
intermediate to give a Pd(IV) intermediate followed by
reductive elimination affords the product.5g,j,o,p,10 In fact,
as early as 1984, Tremont et al. found that Pd(II) can be
oxidized to Pd(IV) by RX.11 Canty and co-workers
showed that diaryliodonium triflates can transfer Phþ to
Pd(II), leading to the formation of unstable Pd(IV) species
Acknowledgment. This work was supported by the
National Natural Science Foundation of China (Projects
20972068, 20771060) and the Leading Academic Disci-
pline Program, 211 Project for Nanjing Normal University
(the third phase).
(10) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010, 12, 1972.
(11) Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106,
5759.
(12) Canty, A. J.; Patel, J.; Rodemann, T.; Ryan, J. H.; Skelton,
B. W.; White, A. H. Organometallics 2004, 23, 3466.
(13) Wang, G. W.; Yuan, T. T.; Li, D. D. Angew. Chem., Int. Ed.
2011, 50, 1380.
Supporting Information Available. Experimental pro-
cedures and full characterization for all compounds;
1
copies of H and 13C NMR for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 6, 2011
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