A convenient synthesis of benzonitriles via electrophilic cyanation with N-cyanobenzimidazole

Article abstract of DOI:10.1002/chem.201000086

(Chemical Equation Presented) Couplings: N-Cyanobenzimidazole has been used in the synthesis of aryl- and heteroarylnitriles from the corresponding Grignard reagents (see scheme). This electrophilic cyanation is further extended to the synthesis of 2-cyano1,1'-biaryls through a domino Grignard-coupling/ cyanation strategy.

Full text of DOI:10.1002/chem.201000086

COMMUNICATION
DOI: 10.1002/chem.201000086
A Convenient Synthesis of Benzonitriles via Electrophilic Cyanation
with N-Cyanobenzimidazole
Pazhamalai Anbarasan, Helfried Neumann, and Matthias Beller*[a]
Benzonitriles constitute an important part of dyes, herbi-
cides, agrochemicals, pharmaceuticals, and natural prod-
ucts.[1] In addition, the nitrile group serves as a valuable in-
termediate for a multitude of transformations into other
functional groups, such as benzoic acid derivatives, benzyl-
work and our long standing interest in the synthesis of ben-
zonitriles,[10,12] we got attracted by the idea to directly syn-
thesize benzonitriles from aryl Grignard reagents
(Scheme 1). We envisioned that in situ generation of func-
tionalized Grignard reagents[13,14] and the subsequent elec-
trophilic cyanation should result in the desired benzonitriles.
Such an approach is different from the known syntheses of
benzonitriles and makes use of an electrophilic cyanation re-
agent under mild conditions. Electrophilic cyanations have
been less studied compared to nucleophilic cyanations.[15]
Examples using aromatic nucleophiles include cyanations of
arylzinc reagents with tosyl cyanides,[16] directed lithiation
followed by electrophilic cyanation with phenyl cyanate or
p-toluenesulfonyl cyanide,[17] reaction of 3-pyridyllithium
with N-cyanoimidazole,[18] reaction of aryltrimethylstannanes
with cyanogen chloride in the presence of aluminum chlo-
ride,[19] and reaction of aryllithium compounds with penta-
chlorobenzonitrile.[20] With regard to aryl Grignard reagents
so far the nucleophilic displacement of p-toluenesulfonyl cy-
anide and phenylmagnesium bromide,[21] and cyanation with
2-pyridyl cyanate have been investigated.[22]
ACHTUNGTRENNUNG
merous ways. Ammoxidation is the method of choice in in-
dustry on ton-scale synthesis,[2] whereby toluene derivatives
are reacted with oxygen and ammonia at high temperature
(300–5508C) in the presence of a heterogeneous fixed-bed
catalyst. However, lack of functional group tolerance and
the harsh reaction conditions make this method not suitable
for the preparation of functionalized benzonitriles.
Direct cyanation is probably the most versatile route to
prepare functionalized benzonitriles. Traditional stoichio-
metric methods such as the Rosenmund–von Braun reaction
of aryl halides[3] and diazotization of anilines with subse-
quent Sandmeyer reaction[4] have been replaced in recent
years by transition-metal-catalyzed cyanations.[5] Hence, no-
table advancements for the catalytic cyanation of aryl hal-
ides using various cyanation reagents such as KCN,[6]
Zn(CN)2,[7] acetone cyanohydrin,[8] trimethylsilyl cyanide
(TMSCN),[9] and K4[Fe(CN)6][10] have been reported. How-
ever, a general problem in these reactions is the high affinity
of cyanide towards Pd-, Ni-, and Cu-based catalysts, which
often results in fast deactivation of the catalytic system.
Therefore, the development of new methods is of continuing
academic interest.
Scheme 1. Synthesis of benzonitriles via electrophilic cyanation.
At the beginning of our work we prepared different N-
cyano reagents, such as N-cyano-4-(N,N-dimethylamino)pyr-
idinium tetrafluoroborate (4), N-cyano-4-methoxypyridini-
um tetrafluoroborate (5), N-cyanophthalimide (6), and N-
cyanobenzimidazole (7),[23,24] either by treating the corre-
sponding pyridine derivative with cyanogen bromide in the
presence of silver tetrafluoroborate or by the reaction of the
corresponding amide and amine with cyanogen bromide and
triethylamine (for more details see Supporting Information).
Next, these reagents were tested in the Grignard–cyanation
sequence of 4-bromotoluene (1) to give 4-methylbenzoni-
trile (2) (Scheme 2).
Recently, we developed a convenient protocol for the
electrophilic fluorination of aryl and heteroaryl Grignard re-
agents applying pyridinium fluorides.[11] Inspired by this
[a] Dr. P. Anbarasan, Dr. H. Neumann, Prof. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-51113
E-mail: matthias.beller@catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000086.
Chem. Eur. J. 2010, 16, 4725 – 4728
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4725

After having identified suitable reaction conditions, we
were interested in the scope and limitations of the proce-
dure using different aryl Grignard reagents. As seen in
Table 2, the cyanation of aryl Grignard reagents has substan-
tial scope. Simple aromatic substrates, such as 4-methyl- and
4-methoxyphenylmagnesium bromides react smoothly to
provide the corresponding benzonitriles in high yields
(Table 2, entries 1 and 3). Notably, both electron-rich and
electron-poor substrates were efficiently cyanated leading to
the products in good isolated yield (Table 2, entries 3, 4, 10
and 11). Likewise, sterically demanding as well as non-hin-
dered benzonitriles are readily accessible in good yield from
the corresponding arylmagnesium bromides (Table 2, en-
tries 8, 6, 5, 2 and 3, 9, 7, 1). Moderate to high yields were
obtained in the cyanation of functionalized- (vinyl) and
hetero- (pyridine, benzothiophene) arylmagnesium bromides
(Table 2, entries 12–14). Notably, in case of the pyridyl sub-
strate the arylmagnesium species was prepared by halogen–
magnesium exchange.
Scheme 2. Cyanation of 4-MeC6H4MgBr·LiCl using various cyanation re-
agents: 3 (0.5 mmol), CN+ source (0.75 mmol), heptane (2 mL), 08C,
1.5 h. Yields are determined by GC with hexadecane as internal standard
and yield of toluene is given in parenthesis.
In our model reaction we converted 1 into the corre-
sponding aryl Grignard 3 in presence of LiCl, according to
the procedure developed by Knochel and co-workers.[25]
Based on our previous experience in electrophilic fluorina-
tions, the cyanation was performed in heptane at 08C. As
shown in Scheme 2, reaction of 3 with 4 and 5 gave 2 only in
poor yield of 8 and 2%, respectively. As major product tolu-
ene was obtained. No cyanation product at all was observed
in the reaction with 6. However, cyanation with 7 resulted in
the formation of 2 in 31% yield. To the best of our knowl-
edge 7 has not been applied for the synthesis of benzoni-
triles via electrophilic cyanations.
Finally, we were interested in the possibility to apply this
novel electrophilic cyanation procedure in
Grignard-coupling–cyanation sequence. Such
a
a
domino
reaction
would allow for the straightforward access of 2-biaryl- and
2-heteroarylarylnitriles.
The most prominent derivative of this class of compounds
is 2-(4-tolyl)benzonitrile, which is the central intermediate
for several angiotensin II antagonists.[26]
In order to further improve the results, the influence of
critical reaction parameters (temperature, solvent) were in-
vestigated in more detail, utilizing 4 and 7 as cyanation re-
agents. Selected results are shown in Table 1. Cyanation
with 4 at elevated temperature in heptane gave the product
in 43% yield and a similar trend was observed with 7
(Table 1, entries 1 and 4). In addition, changing the solvent
from heptane to THF showed a significant positive influence
on the cyanation. Thus, cyanation of 3 with 4 or 7 in THF at
08C provided 2 in 37 and 86% yield, respectively, and good
selectivity (Table 1, entries 2 and 5). Notably, compared to
metal-catalyzed cyanations the reaction is carried out at
mild conditions (Table 1, entries 3–4).
To our delight the coupling of 4-tolylmagnesium bromide
with benzyne, generated from 2-chloro-1-bromobenzene and
magnesium, followed by cyanation with N-cyanobenzimid-
AHCTUNGTREGaNNUN zole gave the desired product in 71% isolated yield
(Scheme 3). As shown in Scheme 4, similar coupling reac-
Table 1. Variation of temperature and solvents in the cyanation of 4-
MeC6H4MgBr·LiCl.[a]
Scheme 3. Synthesis of 2-(4-tolyl)benzonitrile via domino Grignard-cou-
pling–cyanation sequence.
Entry
CN+ Source
T [8C]
Solvent
Yield[b] 2 [%]
tions can be performed with various Grignard reagents. All
reactions proceeded smoothly in good yield to the corre-
sponding 2-cyanobiaryls. To the best of our knowledge these
transformations constitute the first examples of domino
Grignard-coupling–cyanation reactions.
In summary, an electrophilic cyanation of aryl and hetero-
aryl Grignard reagents applying N-cyanobenzimidazole has
been developed. This methodology could be further applied
1
2
3
4
5
4
4
4
7
7
0!RT[c]
heptane
THF
THF
heptane
THF
43
37
38
72
0
0!RT[c]
0!RT[c]
0
86 (77)[d]
[a] Reaction conditions: 3 (0.5 mmol), CN+ source (0.75 mmol), solvent
(2 mL), 1.5 h. [b] Determined by GC with hexadecane as internal stan-
dard. [c] Grignard reagent 3 was added at 08C and warmed up to RT and
stirred for 1.5 h. [d] Isolated yield is given in parenthesis.
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Chem. Eur. J. 2010, 16, 4725 – 4728

Synthesis of Benzonitriles
COMMUNICATION
Table 2. Scope and limitations of the cyanation of ArMgBr·LiCl with 7.[a]
Entry
1
ArMgBr·LiCl
Product
Yield[b] [%]
77
2
3
4
68
82
86
Scheme 4. Domino Grignard-coupling–cyanation for the synthesis of 2-
cyano-1,1’-biaryls. [a] 4 was used as cyanation reagent at 508C.
5
81
Keywords: arenes · benzimidazole · cyanides · electrophilic
cyanation · Grignard reaction
6
7
8
79
83
80
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Received: January 13, 2010
Published online: March 22, 2010
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