Zn(OTf)2 - Catalyzed direct cyanation of benzylic alcohols - A novel synthesis of α-aryl nitriles

Article abstract of DOI:10.1016/j.tetlet.2012.08.021

This work demonstrates an efficient method to prepare α-aryl nitriles by direct cyanation of benzylic alcohol with TMSCN in the presence of a catalytic amount of Zn(OTf)₂ under heating condition. A variety of benzylic alcohols can be converted into the corresponding α-aryl nitriles in good to excellent yields. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.08.021

Tetrahedron Letters 53 (2012) 5535–5538
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Zn(OTf) —catalyzed direct cyanation of benzylic alcohols—a novel synthesis of
2
a-aryl nitriles
⇑
Palani Theerthagiri, Appaswami Lalitha
Department of Chemistry, Periyar University, Salem 636 011, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This work demonstrates an efficient method to prepare
alcohol with TMSCN in the presence of a catalytic amount of Zn(OTf)
of benzylic alcohols can be converted into the corresponding
a
-aryl nitriles by direct cyanation of benzylic
under heating condition. A variety
Received 25 June 2012
Revised 2 August 2012
Accepted 4 August 2012
Available online 10 August 2012
2
a
-aryl nitriles in good to excellent yields.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzylic alcohols
Zinc triflate
a-Aryl nitriles
Trimethylsilyl cyanide
Cyanation
In continuation of our earlier work in the synthesis of amides
from nitriles using iodine as a catalyst, we were interested to ex-
plore the direct cyanation of benzylic alcohols. A careful literature
survey revealed that there is no precedent for the triflate-catalyzed
cyanation of alcohols to prepare a-aryl nitriles. Nitriles are versa-
tile intermediates with extensive biological activities and utility
in the synthesis of compounds like verapamil,2 that is used clini-
cally for the treatment of chronic obstructive pulmonary disease.
Although direct cyanation of alcohols constitutes an attractive
synthetic route to nitriles in terms of both starting material
accessibility and economy concerns, unfortunately many of these
reported methods suffered from drawbacks such as harsh reac-
tion conditions (or) tedious work-up procedure, unsatisfactory
yields, prolonged reaction times, and often-expensive catalysts.
Therefore, development of a more practical and economical
method for direct cyanation of alcohols using TMSCN as cyanat-
ing agent may be highly desirable. In recent years, more atten-
tion has been paid to new synthetic methods using triflates
due to their unique chemical and physical properties, such as
excellent chemical and thermal stability with ease of reuse.
Triflates have emerged as powerful Lewis acid catalysts in the
performance of many useful organic transformations under mild
reaction conditions. Metal triflates are easily prepared in 50%
1
As synthetic intermediates,
a-aryl nitriles are potentially valuable
precursors for the synthesis of well known drugs, such as indopro-
fen, cicloprofen, and naproxen.4 Furthermore,
3
a
-aryl nitriles are
important building blocks for constructing the corresponding
5
amides, aldehydes, ketones, primary amines, and heterocycles.
Commonly, aryl nitriles are synthesized from aryl halides using a
stoichiometric amount of copper(I)cyanide.6 Nitriles are also pre-
7
pared by dehydration of amides and aldoximes, acylations of silyl
TfOH aqueous media. Unlike other Lewis acids like SnCl
4
and
ketene imines, displacement of aryl triflate9 and hydrocyanation
8
AlCl , triflates are stable in air and also act as Lewis acids even
3
1
0
14
of olefins. When alcohol is used as the starting material for the
synthesis of the corresponding nitrile, usually the hydroxy group
is first converted into halides and sulfonates. However, there are
only a few reports on direct cyanation of alcohols into nitriles in
in the presence of water. Seeking to broaden the scope of
Lewis acid catalysts for the cyanation of alcohols with TMSCN,
we are interested in establishing a method using Zn(OTf)
2
as a
reusable catalyst. Herein, we report the use of Zn(OTf) as a ver-
2
1
1
a one-pot procedure.
satile catalyst for the direct cyanation of secondary benzylic
alcohols with TMSCN, allowing the easy preparation of useful
synthetic intermediates for various applications and representing
the first example of triflate-catalyzed direct cyanation of
alcohols.
1
2
3
InBr ,
with TMSCN in dichloroethane, has been reported as a
convenient system for cyanation of secondary alcohols. Very
1
3
recently B(C
6
F
5
)
3
has also been reported to catalyze these reac-
tions efficiently.
As the first attempt, the reaction of benzhydrol (1) with tri-
methylsilyl cyanide (1a) in the presence of 15 mol % Zn(OTf)
2
⇑
Corresponding author. Tel.: +91 427 2345271; fax: +91 427 2345766.
E-mail address: lalitha2531@yahoo.co.in (A. Lalitha).
was selected as a prototype reaction to develop the optimum reac-
tion conditions (Scheme 1).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.021

5
536
P. Theerthagiri, A. Lalitha / Tetrahedron Letters 53 (2012) 5535–5538
CN
Table 2
OH
a
Reaction of benzhydrol and TMSCN with different catalysts
1
5 mol % Zn(OTf)2
CH3NO2, 100 o
Yieldb (%)
+
(CH3)3SiCN
Entry
Catalyst
Catalyst loading (mol %)
Time (h)
C
1
b
1
2
3
4
5
6
7
Sc(OTf)
Sc(OTf)
3
3
10
15
10
15
10
15
20
8.0
6.0
8.0
6.0
8.0
6.0
8.0
50
70
55
90
55
75
20
1
1a
Zn(OTf)
Zn(OTf)
2
2
Scheme 1. Zn(OTf)
2
-catalyzed direct cyanation of benzhydrol with TMSCN.
TMSOTf
TMSOTf
FeCl
3
a
Reaction condition: benzhydrol (1 mmol), TMSCN (1.2 mmol), nitromethane
Table 1
Optimizing the reaction conditions for the direct cyanation of benzylic alcohols
(
10 volume) at 100 °C in sealed tube.
Isolated yield after column chromatography.
a
b
OH
Ph
CN
Ph
Zn(OTf)2
solvent
+
(CH ) SiCN
3 3
Ph
Ph
The effect of solvent was also investigated and the yield was ob-
served to be highly dependent on the nature of the solvent. The
reaction did not proceed at all in coordinating solvents (Table 1,
entries 1, 7 and 8) like, tetrahydrofuran and dioxane, as well as
in dimethylformamide. However, 40% of the product was obtained
in acetonitrile (Table 1, entry 2). Hydrocarbon solvents such as tol-
uene gave a mixture of products and the desired product was ob-
tained in trace amount (Table 1, entry 3). Dichloromethane gave
only 50% of the desired product. Among the various solvents stud-
ied, nitromethane was the most effective, and afforded the desired
product in higher yield (Table 1, entry 6).
Entry
Solvent
DMF
T (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
100
80
100
45
25
100
70
24
8
—
CH
3
CN
40
25
50
30
90
—
Toluene
24
12
24
6.0
24
24
CH
CH
CH
2
3
3
Cl
2
NO
NO
2
2
THF
Dioxane
100
—
a
All reactions were performed with benzylic alcohol (1 mmol), TMSCN
1.2 mmol), and 15 mol % of Zn(OTf) in the indicated solvent (10 volume).
Isolated yield after flash column chromatography.
(
2
When the two reactants were mixed with zinc triflate in nitro-
methane at room temperature, only a trace amount of product was
b
Table 3
Zn(OTf)
-catalyzed direct cyanation of benzylic alcohols under the optimized conditionsa
2
OH
CN
Zn(OTf)2
+
(CH ) SiCN
3 3
R1
R2
R1
R2
CH NO ,100 °C
3
2
Entryb (%)
Alcohol
Time (h)
Product
Yield
9013
OH
CN
1
5.5
1b
OH Cl
OH
CN Cl
2
3
6.0
6.0
8216
2b
CN
9117
Me
3b
CN
Me
OH
4
5
6
6.0
6.0
6.0
80
4
b
F
F
OH
OH
CN
Br
Br
83
5
CN
b
8817
6b
Br
Br
OH
CN
7
6.0
7817
7b
OMe
OMe

P. Theerthagiri, A. Lalitha / Tetrahedron Letters 53 (2012) 5535–5538
5537
Table 3 (continued)
Entryb (%)
Alcohol
Time (h)
5.0
Product
MeO
F
Yield
OH
CN
8
9
9518
MeO
OMe
OMe
8b
OH
CN
9b
6.0
6.0
8613
F
F
F
OH
CN
Cl
Cl
Cl
Cl
1
0
89
10b
CN
OH
OH
11
12
13
14
15
5.0
8.0
8.0
6.0
8.0
85
1
1b
CN
4313
4813
5413
5213
1
2b
HO
NC
13b
Cl
Cl
OH
CN
14b
OH
CN
15b
MeO
MeO
OH
CN
1
6
6.0
77
16b
a
All reactions were performed with benzylic alcohol (1 mmol), TMSCN (1.2 mmol), and 15 mol % of Zn(OTf) in nitromethane (10 volume) at 100 °C in sealed tube.
Isolated yield after flash column chromatography.
b
observed even after 24 h (Table 1, entry 5). Elevating the reaction
temperature increased the yield considerably and the reaction pro-
ceeded with the highest efficiency at 100 °C in a sealed tube afford-
ing the product (1b) in 90% yield with shorter reaction time
As can be observed in Table 3, the reaction of TMSCN with ben-
zylic alcohols possessing various substituents on the aromatic ring
was examined in the presence of Zn(OTf) . Electron-rich benzylic
2
alcohols reacted with TMSCN to give 54–95% yield, and electron
deficient alcohols gave the desired product in 52–85% yield. Simi-
larly, the reactions of 1-phenylethanols with TMSCN proceeded
smoothly and afforded the corresponding products in moderate
yields (Table 3. entries 12–15).
(Table 1, entry 6).
In addition, the efficiency of similar other catalysts has also
been screened for the conversion of benzhydrol to the nitrile under
the same conditions (Table 2) and it was observed that the target
a
-aryl nitriles were formed in low yield (20%) with anhydrous
FeCl (20 mol %) in nitromethane at 100 °C (Table 2, entry 7).
The other catalysts employed [Sc(OTf) , TMSOTf] can also acti-
A possible mechanism may be discussed (Scheme 2) based on the
experimental observations. Mechanistic investigations revealed
3
3
vate benzylic alcohols, but in these cases, the desired product
was obtained in good to moderate yield (Table 2 entries 1, 2 and
R
(CH3)3SiCN
+ H2O
(CH3)3Si(OH)
Ar
R
5
, 6). We found that the reaction proceeded to give excellent yield
when 15 mol % of Zn(OTf) has been used whereas, the conversion
was very slow under similar condition when 5–10 mol % of
Zn(OTf) was used, revealing that 15 mol % of Zn(OTf) was the
optimum amount for this transformation.
Ar
Ar
OH
a
2
CN
Ar
d
c
2
2
OH
R
R
Using the optimized conditions, the present reaction was fur-
ther extended to a broad range of benzylic alcohols to evaluate
the scope and limitations of the method. The results are listed in
Table 3.
Ar
R
O
b
Ar
Scheme 2. Possible mechanism for the cyanation.

5
538
P. Theerthagiri, A. Lalitha / Tetrahedron Letters 53 (2012) 5535–5538
that the cyanation system soon attained equilibrium with alcohol,
symmetrical ether, and water via the benzylic carbocation. The ben-
zyliccationformedby theheterolyticcleavageoftheC–Obond ofthe
2. (a) Brogden, R. N.; Benfield, P. Drugs 1996, 51, 792–819; (b) Foot, E. A.; Leighton,
B. Diabetes 1994, 43, 73–79; (c) Holland, H. L.; Gu, J. X.; Orallo, F.; Camina, M.;
Fabeiro, P.; Willetts, A. J. Pharm. Res. 1999, 16, 281–287; (d) Prisant, L. M. Heart
Dis. 2001, 3, 55–62.
alcohols with the assistance of Lewis acidic Zn(OTf)
2
might have re-
3. Allegretti, M.; Bertini, R.; Cesta, M. C.; Bizzarri, C.; Di Bitondo, R.; Di Cioccio, V.;
Galliera, E.; Berdini, V.; Topai, A.; Zampella, G.; Russo, V.; Di Bello, N.; Nano, G.;
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product. The formation and stability of benzylic carbocations are
4
312–4331.
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006, 92, 1610–1615.
1
,15
well documented.
Moreover, support for this mechanism could
as catalyst
2
be observed in the reaction of substrate a with Zn(OTf)
2
5.
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in nitromethane at room temperature, where, dimerization giving
the symmetric ether b was observed. The formation of the ether
has been confirmed by its isolation in one of these experiments
and its characterization by NMR. In addition, reaction of isolated b
with trimethyl silylcyanide at 100 °C in the presence of a catalytic
amount of the zinc triflate under similar reaction conditions led to
the corresponding aryl nitrile in almost quantitative yield.
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In summary, we have developed a very simple and highly effi-
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TMSCN (trimethylsilyl cyanide) as cyanating agent catalyzed by
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2
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9
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Acknowledgment
1
2, 5954–5958.
We would like to thank Dr. P. N. Arunachalam for his encour-
agement and support.
1
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Supplementary data
3
566.
19. General procedure for the cyanation of secondary alcohols with TMSCN: A mixture
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.08.021.
of alcohol (1 mmol), trimethylsilyl cyanide (1.2 mmol), and zinc triflate
(
15 mol %) was placed in a 50 ml sealed tube and heated to 100 °C for the
appropriate time mentioned in Table 3. After completion of the reaction
monitored by TLC), the reaction mixture was diluted with 30 ml of water and
(
References and notes
extracted with dichloromethane (2 Â 50 ml). The organic layer was separated
and washed with water, brine and dried over sodium sulfate, concentrated to
furnish the desired
were purified by column chromatography (silica gel; petroleum ether/ethyl
acetate 8:2).
a-aryl nitriles. When necessary, the obtained nitriles
1
. (a) Theerthagiri, P.; Lalitha, A.; Arunachalam, P. N. Tetrahedron Lett. 2010, 51,
2
5
813–2819; (b) Theerthagiri, P.; Lalitha, A. Tetrahedron Lett. 2010, 51, 5454–
458.