LETTER
2025
Simple and Efficient One-Step Conversion of Benzonitrile into Methylarene
under Mild Conditions
C
É
onversion of
B
t
enzonitrile in
e
to Methylar
n
ene ne Ouellet, Donald Poirier*
Laboratory of Medicinal Chemistry, CHUQ (CHUL) – Research Center and Laval University, 2705 Laurier Blvd, Quebec,
QC, G1V 4G2, Canada
Fax +1(418)6542761; E-mail: donald.poirier@crchul.ulaval.ca
Received 16 June 2011
form additional experiments to explore and define the
Abstract: A very simple and efficient method has been developed
scope of this reaction.
for the synthesis of various methylarenes from the corresponding
benzonitriles under mild conditions. The protocol uses Pearlman’s Hydroxybenzonitriles (Table 1, entries 2–5) were selected
catalyst to achieve the transformation under an atmosphere of gas-
eous hydrogen and proceeds smoothly in many common solvents.
A series of methylarenes were thus obtained in high yields and pu-
conversion for meta vs. 100% for para). Investigating the
rities.
as starting point. We can already notice that a meta sub-
stituent seems to diminish the reactivity (41% and 0% of
effect of a carbonyl group to the reactivity, we observed
Key words: reduction, nitriles, palladium, methylarene, Pearlman’s
the smooth reduction of both aldehyde and nitrile
catalyst
(
Table 1, entry 6). Furthermore, 6-cyano-2-naphthol was
found to be reactive as well (Table 1, entry 7). However,
these mild conditions are limited to the reduction of con-
jugated nitriles (aromatic nitriles), since the reduction of
The cyano group is widely used in organic synthesis as it
can lead to various functional groups. It can also be used
1
4
-hydroxybenzyl cyanide (Table 1, entry 8) yielded a
indirectly to stabilize carbanion or to orientate aromatic
substitution. Thus, it is important to have a broad variety
of reactions to functionalize the cyano group. The reduc-
tion of this functionality into a methyl group has been the
mixture of starting material and the corresponding prima-
ry amine (11%).
Knowing the extent of the reaction, we then explored the
reactivity as a function of time for a given substrate. Six
reactions were started in parallel and stopped after differ-
ent reaction times (Figure 1). The results show that 18
hours are needed to achieve complete conversion of 0.15
mmol of starting material for the given conditions, when
2
object of very few publications. In fact, the methods re-
3
ported in literature often use special apparatus, demand
4
high-pressure hydrogen, or require particular manipula-
5
tions. Reported procedures work well, but are limited to
very specific substrates and require extensive purification.
During the course of our studies on the synthesis of steroid
derivatives as inhibitors of steroidogenic enzymes, such
using 20 mg (19 mol%) of Pd(OH) /C (Pearlman’s cata-
2
lyst) and THF as solvent. We found that the reaction time
was long, so we tried to reduce it by doubling the quantity
of Pearlman’s catalyst (38 mol%). Interestingly, complete
conversion of starting material to the desired compound
took place in about one third of the time needed previous-
ly. At that point, total conversion of starting material
could be observed in 6 hours.
6
–8
as 17b-hydroxysteroid dehydrogenase type 1, we found
that methylarenes could be easily obtained from benzoni-
triles. This procedure can be done in usual glassware, does
not require high-pressure hydrogen, and the reaction gives
9
the desired products in high yields and purities. We now
report the scope and optimization of this very simple, ef-
ficient, and mild method to achieve the transformation of We next investigated the effect of various common sol-
a nitrile into a methyl.
vents on the reaction rate with the previous conditions [20
mg of Pearlman’s catalyst (19 mol%), 0.15 mmol of start-
ing material and 4 h of reaction time, Table 2]. It is note-
worthy that the reaction can be performed in various
solvents, depending on the solubility of the substrate, but
protic solvents provided a faster conversion rate. Indeed,
methanol and ethanol gave the best results (100%),
whereas acetone gave a good result (60%). EtOAc,
CH Cl , and THF all gave lower yields (11–14%). Select-
ing methanol, we showed (Figure 1) that 100% conver-
sion could be achieved in only 3 hours. These conditions
were found satisfactory since we were able to reduce re-
action time without increasing the quantity of Pearlman’s
catalyst.
The methyl formation from a benzonitrile was first ob-
served while attempting the hydrogenolysis of a benzylic
alcohol (Table 1, entry 1). TLC analysis showed complete
conversion of starting material to a less-polar product. Af-
1
ter H NMR spectroscopy analysis, we were surprised to
still see the signals of the alcohol and the presence of a
singulet at d = 2.3 ppm, which is roughly the same signal
as for the methyl of toluene. The transformation of the cy-
ano into a methyl group was then confirmed by IR and C
NMR spectroscopy. This observation prompted us to per-
2
2
13
SYNLETT 2011, No. 14, pp 2025–2028
x
x
.x
x
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0
1
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Advanced online publication: 10.08.2011
DOI: 10.1055/s-0030-1261164; Art ID: S05611ST
With optimal conditions determined, we wanted to see if
the conversion of less reactive substrates could be im-
©
Georg Thieme Verlag Stuttgart · New York