alyst due to the high affinity of the cyanide ion towards Pd,
Ni, and Cu, which often results in fast deactivation of the
Results and Discussion
[12]
catalytic system. Although, a few palladium-catalyzed cy-
anations have been accomplished with low catalyst load-
During our search of efficient and less-toxic cyanation re-
agents, we became interested in N-cyano-N-phenyl-p-meth-
ylbenzenesulfonamide (2), which is stable, safe, and known
[11a]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ings,
the limited substrate scope and the toxicity often as-
[29]
sociated with nucleophilic cyanation sources, makes the de-
velopment of novel methodologies desirable. For example,
recently, interesting CÀH functionalizations with subsequent
to have fungicidal properties. Owing to the NÀCN group,
we estimated that this compound might behave as an elec-
trophilic cyanation reagent. Notably, compound 2 is readily
synthesized by the reaction of phenylurea 1 with p-toluene-
sulfonyl chloride in pyridine. After the initial dehydration of
urea, tosylation took place to give 2 in good yield
cyanation of the directing group containing arenes by palla-
dium catalysis and copper-mediated reactions have been re-
[13]
ported.
However, these reactions also suffer from the
[30]
high catalyst loading, use of excess of oxidant, and are re-
stricted to chelation-assisted substrates.
(Scheme 2).
On the other hand, the electrophilic cyanation of aryl hal-
ides is a complementary procedure to the transition-metal-
catalyzed nucleophilic cyanation of aryl halides. So far, elec-
trophilic cyanations of aryl nucleophiles (such as lithium,
magnesium, and zinc reagents) have been scarcely studied
[14]
compared to nucleophilic cyanations,
and there is only
Scheme 2. Synthesis of N-cyano-N-phenyl-p-methylbenzenesulfonamide.
one recent report on a more general methodology avail-
[15]
able.
Earlier examples using aromatic nucleophiles in-
clude electrophilic cyanations of aryl zinc reagents with
To evaluate the reactivity of 2, the electrophilic cyanation
of 4-bromotoluene (3) was investigated as a benchmark re-
action. Hence, 3 was converted into the corresponding aryl
Grignard 4 in presence of LiCl, according to the procedure
[16]
tosyl cyanide, directed lithiation of phenyl, 2-furyl, and 2-
thiophenyl derivatives followed by electrophilic cyanation
[17]
with phenyl cyanate, reaction of 3-pyridyllithium with N-
[18]
[31]
cyanoimidazole, reaction of aryl trimethylstannanes with
cyanogen chloride in the presence of aluminum(III) chlo-
and reaction of aryl lithium reagents with penta-
developed by Knochel and co-workers. Subsequent cyana-
A
H
U
G
R
N
U
G
tion of p-CH C H MgBr·LiCl (4) with 2 yielded 4-cyanoto-
3
6
4
[19]
ride,
chlorobenzonitrile.
agents, to date the nucleophilic displacement of p-toluene-
luene (5) (Scheme 3). Whereas cyanation of p-tolylmagnesi-
[20]
With respect to aryl Grignard re-
[
21]
sulfonyl cyanide with phenylmagnesium bromide, and cy-
[
22]
anation with 2-pyridyl cyanate have been investigated. In
addition, most recently aryl boronic acids were also em-
ployed as aryl nucleophiles in the palladium-catalyzed and
[
23]
Scheme 3. Electrophilic cyanation of p-bromotoluene by using a Grignard
reagent.
copper-mediated cyanation with benzylthiocyanate,
as
well as in the copper-promoted cyanation with zinc cyanide,
which is coupled with iridium-catalyzed borylation of
[24]
arenes. However, most of the electrophilic cyanation reac-
tions need highly toxic cyanogen halides, either as the direct
cyanation reagent or to prepare the cyanation reagent.
Therefore, the development of versatile and safer methodol-
ogies for the electrophilic cyanation of aryl nucleophiles is
of continuing interest in organic synthesis.
um bromide 4 with 2 at lower temperature (08C) was found
to be sluggish in different solvents, increasing the tempera-
ture to room temperature in THF improved the formation
of the desired product to give 4-cyanotoluene (5) in 82%
isolated yield (Scheme 3).
Recently, we began to investigate the use of functional-
Next, the scope and limitation of aryl bromides were ex-
amined in more detail. As shown in Table 1, a wide range of
aryl bromides is converted into the corresponding benzoni-
triles in good yield. Simple aryl bromides such as o-, m-, and
p-bromotoluenes underwent smooth cyanation to yield o-,
m-, and p-cyanotoluenes in excellent yield (Table 1, en-
tries 1–3). This result reveals that irrespective of the position
of substitution the present electrophilic cyanation can be ap-
plied at any place of the arene. Good to excellent yields are
obtained in the cyanation of sterically demanding (o-tolyl,
o-anisyl, mesityl), and also non-hindered (m-tolyl and 3,5-di-
methylphenyl) aryl bromides (Table 1, entries 2, 4, 9, 3 and
10). More stabilized electron-rich aryl bromides such as 2-
methoxy-, 2-thiomethyl-, and 3-diphenylamino-substituted
[25]
ized Grignard reagents
bond-formation reactions. As a result, an efficient electro-
philic fluorination and cyanation of aryl Grignard reagents
for challenging CÀF and CÀCN
[26]
with N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate,
[15]
and N-cyanobenzimidazole,
respectively, have been dis-
covered. Inspired by this and our long-standing interest in
[27]
the synthesis of benzonitriles, we envisioned the applica-
tion of N-cyano-N-phenyl-p-methylbenzenesulfonamide as a
[28]
novel and benign electrophilic cyanation reagent. Based
on this idea, herein, we disclose the most general and con-
venient electrophilic cyanation of various (hetero)aryl hal-
ides by in situ generated functionalized Grignard reagents.
4218
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 4217 – 4222