Metal-Free Regioselective Monocyanation of Hydroxy-, Alkoxy-, and Benzyloxyarenes by Potassium Thiocyanate and Silica Sulfuric Acid as a Cyanating Agent

Article abstract of DOI:10.1021/acs.joc.8b02191

A novel and efficient metal- and solvent-free regioselective para-C-H cyanation of hydroxy-, alkoxy-, and benzyloxyarene derivatives has been introduced, using nontoxic potassium thiocyanate as a cyanating reagent in the presence of silica sulfuric acid (SSA). The desired products are obtained in good to high yields without any toxic byproducts.

Full text of DOI:10.1021/acs.joc.8b02191

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Article
Metal-free Regioselective Mono Cyanation of Hydroxy-,
Alkoxy- and Benzyloxyarenes by Potassium Thiocyanate
and Silica Sulfuric Acid as a Cyanating Agent
Ali Reza Sardarian, Iman Dindarloo Inaloo, Ali Reza Modarresi-Alam, Erich Kleinpeter, and Uwe Schilde
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02191 • Publication Date (Web): 09 Jan 2019
Downloaded from http://pubs.acs.org on January 9, 2019
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Metal-free Regioselective Mono Cyanation of Hydroxy-,
Alkoxy- and Benzyloxyarenes by Potassium Thiocyanate
and Silica Sulfuric Acid as a Cyanating Agent
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Ali Reza Sardarian,*a Iman Dindarloo Inaloo,a Ali Reza Modarresi-Alam,b Erich Kleinpeterc and
Uwe Schildec
a Chemistry Department, College of Sciences, Shiraz University, Shiraz 71946 84795, Iran
b Chemistry Department, College of Sciences, University of Sistan and Baluchestan, Zahedan, Iran
c University of Potsdam, Institute of Chemistry, Karl-Liebknecht-Strasse 24-25, D-14476 Potsdam, Germany
E-mail address: sardarian@shirazu.ac.ir
KS CN
OR
OR
CN
X
X
R= H, Alkyl, Benzyl
SSA
19 entries
67-86 %
Solvent-free
100 oC, 12h
Abstract
A novel and efficient metal- and solvent-free regioselective para C-H cyanation of hydroxy-,
alkoxy- and benzyloxyarene derivatives have been introduced with using non-toxic potassium
thiocyanate as a cyanating reagent in the presence of silica sulfuric acid (SSA). The desired
products are obtained in good to high yields without any toxic byproducts.
Keywords: Cyanation, C-H functionalization, Silica sulfuric acid(SSA), Potassium thiocyanate
(KSCN), Metal-free.
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Introduction
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Benzonitriles (cyanoarenes) constitute key components of various commercial compounds such as
versatile building blocks in the synthesis of natural products,1 polymers,2 pharmaceuticals,3
herbicides,4 pesticides5 and dyes.6 These nitrile-containing bioactive molecules have been shown
to treat a broad spectrum of ailments, such as depression, breast cancer, anti-HIV, and Parkinson’s
disease.7 For instance, etravirine, periciazine, fadrozole, letrozole and citalopram are well-known
drugs containing an aromatic nitrile scaffold.6b, 7 They have also served as the intermediates for
many synthetic targets and can be easily transformed into a various important functionalized
products, such as alcohols, amines, amides, imines, aldehydes, ketones, benzoic acid derivatives,
esters and heterocyclic compounds (tetrazoles, triazoles, oxazoles, thiazoles, etc).8 As a result,
much effort has been devoted to the development of various effective methods for the introduction
of a cyanide functionality into aromatic compounds.1-9
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Classical methods of introducing a cyano group into aromatic rings require pre-functionalized
arenes as precursors (Scheme 1), such as diazonium salts (Sandmeyer reaction),10 aryl halides
(Rosenmund-von Braun reaction),11 aldehydes (Schmidt reaction),12 toluenes (by
ammoxidations),13 and many others.14
These methods suffer some important disadvantages such as consuming uses an excessive amount
of hazardous cyanating reagents, limited substrate scope, elevated temperatures, high-pressure
conditions, multistep organic transformations and production of large amounts of heavy metal
waste.10-14
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NH2
1) diazotization
2) CuCN
CN
R
R
Sandmeyer reaction
CN
CN
CN
I
CuCN
R
R
R
Rosenmund-von Braun
reaction
R
R
R
150-250 o
C
CHO
HN3
Schmidt reaction
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H2SO4
Cat. NH3, O2
300-550 o
Ammoxidations
C
Scheme 1. Traditional methods for the synthesis of benzonitriles.
In the past decade, significant progress has been made in the development of methods to access
aryl nitriles directly by the transition-metal-catalyzed cross-coupling (Pd,15 Cu,16 Ni,17 Co,18 Ru,19
Rh,20 Zn and Ir ) of aryl-X compounds [X = I, Br, Cl, CH₃SO₃-, -CON(R)2, -OCONMe2, -
OCOt-Bu, -COOH, B(OH)2 and H].15-23 Although these reactions are reliable for the synthesis of
aryl nitriles by many cyanating agents, which are metal cyanides, such as CuCN,20c KCN,16d
NaCN,16c Zn(CN)2,15b, 15e, 17a K4[Fe(CN)6],15a and trimethylsilyl cyanide (TMSCN),15d aryl(cyano)-
iodonium Triflates.[24] but the generation of hazardous hydrogen cyanide gas and stoichiometric
amounts of metal-containing waste are serious limiting factors in their applications. Although
several practical methods for the synthesis of aryl nitriles with nonmetallic cyanating agents [N-
21
22
cyano-N-phenyl-ptoluene sulfonamide (NCTS),16a, 18, 19a, 20, 21 aminoacetonitriles,17b acetonitrile,16b
16e
acetone
cyanohydrin,15c
tert-butyl
isocyanide,20d
N,N-dimethylformamide,15d,
DMSO/NH4HCO3 15e and hexamethylenetetramine15d have been developed but cyanation reactions
that are employing organic cyanating agents remain in their infancy in synthetic chemistry.25
Nonetheless, general problems in these reactions are using expensive aryl halides, high catalyst
loading due to the cyanide poisoning, need to excess amounts of additives (generally metal salts),
and lack of generality and versatility.
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Therefore, the development of new, safe and more environmentally friendly cyanation methods
(metal-free methods) with less toxic cyanide sources on a broad substrate scope remains an
extremely attractive but challenging task for organic chemists. In 2011, Jianbo Wang has
demonstrated the successful direct cyanation of indoles and pyrroles with NCTS as the non-metal
cyanation reagent in the presence of BF3-OEt2 as Lewis acid (Scheme 2, reaction 1) 26 and also, in
2017 Nicewicz introduced a new method for the direct C-H cyanation of arenes via organic
photoredox catalysis reaction and TMSCN as a cyanide source (Scheme 2, reaction 2).27 Moreover,
as a safe cyanide source, potassium thiocyanate was applied for the oxidative α-cyanation of
tertiary amines (Scheme 2, reaction 3) 28 and also cyanation of aryl halides in the presence of Pd
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and Cu as catalyst (Scheme 2, reaction 4).29
a) Previous work
CN
H
BF3.OEt2
NCTS, 80 oC, 12 h
R1
R1
1)
N
N
R3
R3
R2
R2
CN
Organic Photoredox Catalysis
TMSCN, 455 nm LEDs, O2, 24 h
R
2)
3)
R
R3
CH2
R1
N
R2
R3
CH
CN
R1
N
R2
KSCN. tBuOOH
H2O, 20-80 oC, 3 h
X
CN
PdCl2(dppe), CuI, KSCN
H, HCOONa, DMSO/H2O
100 oC, 48 h
4)
R
R
X= I,Br,BX2
OR
OR
b) This work
5)
KSCN, SSA
solvent-free, 100 oC, 12h
CN
R= H, Alkyl, Benzyl
Scheme 2. Different approaches to the synthesis of cyano-arene Derivatives.
After the successful efforts in the employs thiocyanate salts as the green and affordable cyanide
sources in recent years,28-30 herein, we wish to report a novel and efficient regioselective para C-
H cyanation of hydroxy-, alkoxy- and benzyloxy of arene derivatives with potassium thiocyanate,
as nontoxic cyanide source, and silica sulfuric acid (SSA) as a novel cyanating agent under a metal-
free condition (Scheme 2, reaction 5).
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Results and discussion
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Initially, for finding of the optimized parameters of cyanation reaction, the reaction of m-cresol
with potassium thiocyanate in the presence of silica sulfuric acid was chosen as a model reaction
and then the effect of solvent, temperature, and molar ratio SSA: m-cresol: KSCN were studied,
which their results are summarized in Table 1. According to these data, using 2:1:2 molar ratios
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o
of SSA, m-cresol and potassium thiocyanate under a solvent-free condition at 100 C gives the
highest yield of 4-hydroxy-2-methylbenzonitrile after 12 h (Table 1, entry 7). Performing the
reaction in a longer reaction time (Table 1, entry 10), higher temperature (Table 1, entry 9) and
using the higher amount of potassium thiocyanate and SSA in related to KSCN (Table 1, entry 8)
does not show any improvement in the efficiency of model reaction. As it is clear from Table 1,
the reaction is not preceded efficiently in any type of solvents studied (Table 1, entries 15-19).
Table 1. Optimization of the reaction parameters of m-cresol with potassium thiocyanate in the
presence of SSA.
Entry
Molar ratio
SSA:m-Cresol :KSCN
Solvent
T
(oC)
rt
t
Yield
(%)a
0
(h)
12
12
12
12
12
12
12
12
12
24
12
12
12
12
12
12
12
12
12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1:1:1
1:1:1
1:1:1
1.5:1:1.5
1:1:1.5
1.5:1:1
2:1:2
3:1:3
2:1:2
2:1:2
2:1:2
2:1:2
2:1:2
2:1:2
2:1:2
2:1:2
2:1:2
--
--
--
--
--
--
--
--
--
60
51
63
68
62
61
84
83
77
78
40
43
38
36
37
0
100
100
100
100
100
100
130
100
Reflux
--
CH3CN
CH3CO2Et Reflux
CHCl3
CH2Cl2
CH3Cl
Toluene
PEG200
DMSO
DMF
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
17
18
19
41
0
0
2:1:2
2:1:2
[a] Isolated yield.
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A closer look to the model reaction mixture under the optimized conditions by gas chromatography
(GC) technique appeared also the formation of 2-hydroxy-4-methylbenzonitrile (B) as a by-
product in only 3% yield (Scheme 3).
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OH
OH
NC
OH
CN
A(84%)
B(3%)
OH
SiO2-OSO3H
KS CN
+
Solvent-Free,
100 oC, 12h
OH
CN
NC
D(0%)
C(0%)
Scheme 3. Selective cyanation of m-cresol.
The crystal structure of 4-hydroxy-2-methylbenzonitrile (A) was further determined by X-ray
crystallography. This compound is crystallized in the monoclinic crystal system C2/c space group.
The molecular structure, shown in Figure 1, confirms that the C-N group is located in the para
position in relation to phenyl O-H group. The intermolecular hydrogen bonding interaction (O···N
2.849(2) Å) stabilizes the molecular conformation. All the crystallographic data for the molecule,
hydrogen-bond geometry, containing bond distances, angles and torsion angles are listed in the
supporting information.
Figure 1. Molecular structure for 4-hydroxy-2-methylbenzonitrile.
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This excellent regioselectivity is in agreement with previous reports 27, 31, 32 where the bromination
of anisole and the cyanation of multi-substituted benzenes have been reported. Although the origin
of this regioselectivity is not clear at the moment, it seems the steric effect may be a reason.31b, 33
In the next step, the effect of Brønsted acids such as HCl, H2SO4, CCl3COOH, HClO4, CF3COOH,
SiO2-HClO4, ClSO3H, p-TSA, polyphosphoric acid (PPA) and 4-dodecylbenzenesulfonic acid
(DBSA) were also explored on the model reaction. On the basis of the results, which are presented
in Table 2, the desired product is not produced in the presence of HCl, H2SO4, CCl3COOH, HClO4,
SiO2-HClO4, p-TSA, PPA and DBSA but the model reaction provides the desired product to some
extent in the presence of CF3COOH and ClSO3H after 12 hours at 100 oC although not as well as
SSA. Also, employment of the other thiocyanate salts in the place of potassium thiocyanate dose
not resulted in higher efficiency of the cyanation reaction (Table 2, entries 12 and 13).
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Table 2. Comparison among efficiency of sodium and ammonium thiocyanates with potassium
thiocyanate and some Brönsted acids with SSA.a
Entry
Catalyst
HCl (37%)
H2SO4 (98%)
CCl3COOH
HClO4
Cyanate salt
KSCN
Yield (%)b
1
2
3
0
0
0
KSCN
KSCN
KSCN
4
0
5
6
SiO2-HClO4
DBSA
KSCN
KSCN
0
0
7
p-TSA
KSCN
0
8
PPA
KSCN
0
9
SiO2
KSCN
0
10
11
12
13
SiO2+CF3COOH
SSA
KSCN
KSCN
NaSCN
NH4SCN
39
84
74
70
SSA
SSA
a Reaction condition: m-cresol (1 mmol), MSCN (2 mmol), acid (2 mmol), 100 oC, 12 h.
b Isolated yields
With the optimized results in hand, various phenols and phenyl ether are treated with potassium
o
thiocyanate salt in the presence of SSA at 100 C to determine efficiency, scope, versatility and
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regioselectivity of the method for one pot and solvent-free synthesis of the related aryl cyanides,
which their results are shown in Table 3.
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Table 3. Cyanation of phenols and alkyl aryl ethers by potassium thiocyanate salt in the presence
of SSA.a
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OR1
OR1
SSA
R2
R2
+
KS CN
2a
Solvent-free, 100 oC
1a-z
CN
3a-z
R1= H, Alkyl, Benzyl
OH
OH
OH
NC
NC
NC
NC
NC
NC
3a, 0% b
3b, 0% b
3c, 0% b
3e, 0% b
3f, 84% b
3d, 0% b
OH
O
O
OH
OH
NC
NC
NC
NC
NC
3j, 0% b
3k, 85% b
3g, 80% b
3h, 83% b
3i, 77% b
O
O
O
O
Bn
O
Bn
NC
NC
NC
NC
NC
3l, 80% b
3m, 77% b
3o, 80% b
3n, 78% b
3p, 78% b
OH
CN
CN
O
CN
O
Bn
OH
O
NC
3t, 74% b
3q, 72% b
3s, 86% b
3u, 69% b
CN
3r, 0% b
HO
OH
CN
CN
CN
O
CN
OH
OH
OH
O
Bn
CN
3x, 76% b
3v, 67% b
3w, 71% b
OH
3y, 80% b
3z, 83% b
a Reaction conditions: Phenol or alkyl aryl ethers (1 mmol), KSCN(2 mmol), SSA (2 mmol, 0.8
g), 100 oC and 12 h.
b Isolated yields.
Cyanation of benzene (Table 3, entry 3a), toluene (Table 3, entry 3b), m-xylene (Table 3, entry
3c), phenol (Table 3, entry 3d), o-cresol (Table 3, entry 3e), and anisole (Table 3, entry 3j) are not
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proceeded under the optimized condition after 24 hours at 100 oC. But, when m-cresol is checked
against the cyanation reaction in the presence of potassium thiocyanate under the optimized
condition, the corresponding nitrile derivative is formed in 84% yield after 12 hours (Table 3, entry
3f).
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These results encourage us to check the other m-cresols against the cyanation reaction, the reaction
with KSCN in the presence of SSA at 100 oC under a solvent-free condition. These experiments
are conducted to the corresponding nitrile derivatives in 77-84% yields (Table 3, entries 3g-3i).
Although, anisole does not undergo the cyanation reaction m-methyl anisole and the other m-tolyl
alkyl ethers carry out this reaction under the optimized reaction conditions and the desired products
are produced in high yields after 12 hours (Table 3, entries 3k-3o). Conversely, cyanation of para-
methyl substituted phenol and alkyl aryl ethers, such as 1-((3,4-dimethylphenoxy) methyl)
benzene, 3,4-dimethylphenol and 4-methoxy toluene, are difficult to achieve and do not give the
desired products. The above-mentioned reactions appear that the presence of alkyl group in meta-
position of hydroxyl and alkoxy group is necessary for performing the cyanation reaction.
α-Naphthol, the same as phenol does not undergo the cyanation reaction but cyanation of
2-
naphthol is led to the desired nitrile product in 86% yield after 12 hours (Table 3, entries 3r-3s).
When the corresponding 2-alkoxynaphthalenes are treated with potassium thiocyanate in the
presence of SSA at 100 oC, it provides the related cyano product in 67-74% yields (Table 3, entries
3t-3w), which are lower than their alkoxybenzenes that might be because of the considerable steric
effect in ipso position of 2-alkoxynaphthalene. In addition, benzene-1,3-diol, naphthalene-2,3-diol
and naphthalene-1,3-diol were also employed and fortunately, the related cyanation reaction
proceeds as well as 2-naphthol and m-cresol (Table 3, entries 3x-3z).
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The cyanation of thiophenols and their thioether derivatives, such as 3-methylbenzenethiol and
methyl-m-tolyl sulfide, and also N, N-dimethylaniline, as an aniline derivative, do not occur at all.
Reactive heterocyclic aromatic compounds like furan, thiophene, N- methylpyrrole and N-
methylindole are also unreactive towards this reaction.
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In the next step, for showing monoselective ability of KSCN/SSA, two experiments are designed.
In the first experiment, 1 mmol of naphthalene-2,3-diol, which there are two same positions for
cyanation, are reacted with 4 mmol potassium thiocyanate under the optimized reaction condition
and only 2,3-dihydroxy-1-naphthonitrile are produced and the related 1,4-dicyano derivative of
2,3-dihtdroxynaphthalene is not detected in the reaction mixture by TLC monitoring. In the second
experiment, 1 mmol 2,3-dihydroxy-1-naphthonitrile was treated with 2 mmol potassium
thiocyanate and SSA under the optimized reaction condition for 12 h but 2,3-
dihydroxynaphthalene-1,4-dicarbonitrile is not detected in the reaction mixture (Scheme 4).
CN
OH
OH
OH
SSA(4 mmol)
Solvent-free, 100 o
+
OH
KS CN
C
1y
2a
(1mmol)
CN
(4mmol)
3y
, 82%
OH
OH
SSA(2 mmol)
Solvent-free, 100 o
No Reaction
KS CN
+
C
3y
(1mmol)
2a
(2mmol)
Scheme 4. Study of mono selective cyanation of naphthalene-2,3-diol.
To determine recyclability of SSA after completion of the cyanation of 3-methylphenol, SSA is
removed from the mixture by filtration. Then it is washed with hot toluene for 2 h in a Soxhlet
apparatus to remove the adsorbed unconsumed starting materials on the surface of SSA and then
dried in a vacuum oven at 100 oC. The recovered SSA is reused in the next run. According to the
results summarized in Figure 2, the efficiency of SSA remains over four runs without significant
loss of activity.
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Figure 2. Study of reusability SSA in cyanation of 3-methylphenol.
According to the color change of SSA from white to yellow after the first run (Figure 3) it was
decided to do CHNS analysis on the fresh SSA and the used SSA. These results, as shown in Table
4, reveal the existence of more sulfur content in the recovered catalyst.
Figure 3. The color of SSA before (A) and after the reaction (B) and after recovery process (C).
Table 4. CHNS analysis of SSA samples.
Type of SSA
SSA(Fresh)
SSA(First Used)
C(%)
0.0
0.0
H(%)
2.14
2.25
N(%)
0.0
0.0
S(%)
5.11
7.16
For looking deeply at the cyanation reaction, at the first, KSCN was treated with SSA. After
completion of the reaction, the product (thiocyanogen) was isolated and purified (Scheme 5,
reaction 1). Then, m-cresol was mixed with thiocyanogen in the presence of SSA at 100 oC under
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a solvent-free condition. After 12 h stirring and purification of the mixture, 4-hydroxy-2-
methylbenzonitrile was obtained (Scheme 5, reaction 2). The repetition of this reaction in the
absence of SSA has not resulted in 4-hydroxy-2-methylbenzonitrile after 12h (Scheme 5, reaction
3). These findings appear that the presence of simultaneous SSA and thiocyanogen is necessary
for carrying out the reaction.
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100 oC, 12h
1)
KS CN
2a
SSA
+
NC S S CN
Solvent-free
4
, 93%
OH
OH
SSA, 100 oC, 12h
Solvent-free
+
NC
NC
S
S
S
CN
CN
2)
4
1f
CN
, 86%
3f
OH
100 oC, 12h
Solvent-free
No Reaction
+
S
3)
4
1f
Scheme 5. Investigation of the reaction pathway.
Although for proposing a precise mechanism there is still more data to get, based on all of the
reported information in the literature 34 and the above-mentioned results, the following plausible
mechanism pathway can be suggested for the formation of benzonitriles derivatives (Scheme 6).
In the first step, isothiocyanic acid (5) will produce by the protonation of potassium thiocyanate
(2a) with SSA, which is in equilibrium with thiocyanic acid (6). A self-oxidative coupling of
thiocyanic acid (6) is led to thiocyanogen (4) under atmosphere condition. In the next step,
thiocyanogen undergoes the protonation reaction in the presence of SSA and forms 7 that is
converted to the desired products (3a-z) through an electrophilic aromatic substitution.
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SSA
HN
S
C S
5
NC SH
KS CN
6
2a
air
-H2
SSA
2
NC SH
NC
S
S
CN
S
H
H
NC
+
S
CN
6
7
4
OR
OR
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+
NC SH
+
+
NC
S
S
CN H
6
7
CN
1a-z
3a-z
Scheme 6. The suggested mechanism for the regioselective para-cyanation of hydroxy and
alkoxy arenes with potassium thiocyanate in the presence of silica sulfuric acid.
In summary, we have developed a novel and efficient metal-free regioselective para C-H
cyanation of electron-rich phenyl rings with employment of potassium thiocyanate and SSA as the
cyanating reagent. The use of inexpensive chemicals, less toxic cyanide source, mild reaction
conditions, high regioselectivity and good to high yield of products make this approach one of the
most attractive and practical methods for cyanation of hydroxy and alkoxyarenes.
Experimental:
General:
Chemicals were obtained from Sigma-Aldrich and Merck. Column chromatography was
performed using silica gel from Macherey-Nagel (60 M, 0.04–0.063 mm). The products were
characterized by comparison of their spectral and physical data such as NMR, FT-IR, MS, CHNS
and melting point with available literature data. 1H and 13C NMR data were recorded in DMSO on
a 250 MHz Bruker avance DPX 250MHz instrument with Me4Si or solvent resonance as the
internal standard, spectrometer at r.t. Chemical shifts are reported relative to residual DMSO (δ =
1
13
3.35 ppm H, δ =39.42 ppm for C). Fourier transforms infrared (FTIR) spectra were obtained
using a Shimadzu FT-IR 8300 spectrophotometer. The C, H, N and S elemental analyses were
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carried out by the using a Thermofinigan Flash EA-1112 CHNSO rapid elemental analyzer. The
mass spectra were recorded on a Shimadzu GC-MS QP 1000 EX instrument. Melting points were
recorded by Electrothermal 9100. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication nos.
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General procedure for preparation of silica sulfuric acid (SSA):35
At the first step for drying the silica gel (60-120 mesh), it was placed in the oven at 400 oC for 6
hours. Then, dry Silica gel (60.0 g) was taken in two necked round bottom flask. Chloro sulfonic
acid (23.3 g, 0.2 mol) was added dropwise and gradually during 60 minutes. Rapidly generated
HCl gas was neutralized by NaOH solution. Once the addition was over, the reaction mixture was
shaken for another 30 minutes to provide silica sulfuric acid (76.0 g) as a white solid. The amount
of chlorosulfonic loaded on silica gel was determined by acid-base titration method. For this
purpose, 0.1 g of silica sulfuric acid was added to 10mL of deionized water and stirred for 30 min
at room temperature. Then, this mixture was titrated by 25.0 mL of NaOH (0.01 M). Therefore,
the amount of chlorosulfonic acid loaded in 0.1g of silica sulfuric acid is equal to 2.5mmol (or
25mmol in 1g of SSA).
General procedure for regioselective para-cyanation of hydroxy-, alkoxy- and benzyloxy
arenes (3f-3z):
To a mixture of potassium thiocyanate (1.0 mmol) and a hydroxy-or alkoxy arene (1.0 mmol) was
o
added SiO2-OSO3H (0.8 g, 20 mmol). Then, the mixture was heated and stirred at 100 C in oil
bath under solvent-free solid-state conditions for 12 h. The reaction was monitored by TLC. After
completion of reaction, ethyl acetate (3 × 10 mL) was added and the mixture was filtered. The
solvent (EtOAc) was removed under reduced pressure and the product was purified by column
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chromatography on silica gel (petroleum ether and ethyl acetate, 8:2) and characterized. The
isolated pure products were obtained in excellent to moderate yields.
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4-Hydroxy-2-methylbenzonitrile (3f): Brown crystals (0.1119 gr, 84% yield), mp = 139-140 oC.
IR (KBr), ῦ(cm-1): 3305, 3194, 2914, 2226, 1624, 1304, 1233, 881. 1H NMR (250 MHz, 298K,
DMSO-d6),  (ppm): 2.34, (s, 3H), 6.67-6.75 (m, 2H), 7.51 (d, J = 7.5 Hz, 1H), 10.45 (s, 1H. OH).
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13C{1H} NMR (63 MHz, 298K, DMSO-d6),  (ppm): 19.9 (CH3), 101.6 (C), 113.8 (CH), 117.0
(CH), 118.6 (C), 134.3 (CH), 143.6 (C), 161.3 (C). Anal. Calcd for C8H7NO: C, 72.16; H, 5.30;
N, 10.52%. Found: C, 72.12; H, 5.31; N, 10.57%.
2-Ethyl-4-hydroxybenzonitrile (3g): Brown crystals (0.1176 gr, 80% yield), mp = 74-75 oC. IR
(KBr), ῦ(cm-1): 3260, 3191, 2926, 2230, 1599, 1591, 1293, 888, 823, 654. 1H NMR (250 MHz,
298K, DMSO-d6),  (ppm): 1.15 (t, J = 7.5 Hz, 3H), 2.65 (q, J = 7.5 Hz, 2H), 6.69-6.78 (m, 2H),
7.53 (d, J = 7.5 Hz, 1H), 10.53 (s, 1H. OH). 13C{1H} NMR (63 MHz, 298K, DMSO-d6),  (ppm):
14.8 (CH3), 27.0 (CH2), 100.7 (C), 114.0 (CH), 115.6 (CH), 118.5 (C), 134.6 (CH), 149.6 (C),
161.6 (C). Anal. Calcd for C9H9NO: C, 73.45; H, 6.16; N, 9.52%. Found: C, 73.41; H, 6.11; N,
9.57%.
4-Hydroxy-2,3-dimethylbenzonitrile (3h): Yellow crystals (0.1220 gr, 83% yield), mp = 132-
o
134 C. IR (KBr), ῦ(cm-1): 3274, 3164, 2928, 2230, 1598, 1585, 1291, 824, 789, 653. 1H NMR
(250 MHz, 298K, DMSO-d6),  (ppm): 2.05, (s, 3H), 2.33, (s, 3H), 6.76 (d, J = 8.25 Hz, 1H), 7.38
(d, J = 8.25 Hz, 1H), 10.40 (s, 1H. OH). 13C{1H} NMR (63 MHz, 298K, DMSO-d6),  (ppm): 11.5
(CH3), 17.9 (CH3), 102.0 (C), 113.1 (CH), 119.4 (C), 124.1 (C), 131.1(CH), 141.4 (C), 159.2 (C).
Anal. Calcd for C9H9NO: C, 73.45; H, 6.16; N, 9.52%. Found: C, 73.42; H, 6.11; N, 9.57%.
4-Hydroxy-2,6-dimethylbenzonitrile (3i): Yellow crystals (0.1114 gr, 77% yield), mp = 175-177
oC. IR (KBr), ῦ(cm-1): 3267, 3158, 2929, 2230, 1598, 1584, 1292, 824, 790, 654. 1H NMR (250
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MHz, 298K, DMSO-d6),  (ppm): 2.05 (s, 6H), 7.39 (s, 2H), 10.47 (s, 1H, OH). 13C{1H} NMR (63
5
6
7
8
MHz, 298K, DMSO-d6),  (ppm): 19.6 (CH3), 102.0 (C), 113.1 (CH), 119.4 (C), 141.4 (C), 159.16
(C). Anal. Calcd for C9H9NO: C, 73.45; H, 6.16; N, 9.52%. Found: C, 73.40; H, 6.12; N, 9.59%.
4-Methoxy-2-methylbenzonitrile (3k): Yellow crystals (0.1250 gr, 85% yield), mp = 51-52 oC.
IR (KBr), ῦ(cm-1): 3058, 3027, 2918, 2219, 1605, 1250, 852, 821. 1H NMR (250 MHz, 298K,
DMSO-d6),  (ppm): 2.37, (s, 3H), 3.76, (s, 3H), 6.84 (d, J = 7.50 Hz, 1H), 6.92 (s, 1H), 7.59 (d, J
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= 7.50 Hz, 1H).13C{1H} NMR (63 MHz, 298K, DMSO-d6),  (ppm): 19.9 (CH3), 55.4 (CH3), 103.3
(C), 112.4 (CH), 115.6 (CH), 118.3 (C), 134.19 (CH), 143.6 (C), 162.4 (C). Anal. Calcd for
C9H9NO: C, 73.45; H, 6.16; N, 9.52%. Found: C, 73.41; H, 6.11; N, 9.57%.
4-Butoxy-2-methylbenzonitrile (3l): Yellow liquid (0.1512 gr, 80% yield), mp = 137-138 oC. IR
(KBr), ῦ(cm-1): 3090, 3077, 2961, 2221, 1605, 1251, 1113, 869, 821. 1H NMR (250 MHz, 298K,
DMSO-d6),  (ppm): 0.86 (t, J = 7.5 Hz, 3H), 1.28 (m, 2H), 1.47 (m, 2H), 2.20 (s, 3H), 3.87 (t, J
= 5.0 Hz, 2H), 6.84 (d, J = 7.50 Hz, 1H), 7.00 (s, 1H), 7.59 (d, J = 7.50 Hz, 1H). 13C{1H} NMR (63
MHz, 298K, DMSO-d6),  (ppm): 13.5 (CH3), 18.5 (CH3), 26.4 (CH2), 30.7 (CH2), 62.9 (CH2),
103.2 (C), 112.2 (CH), 115.8 (CH), 118.3 (C), 134.0 (CH), 143.6 (C), 162.6 (C). Anal. Calcd for
C12H15NO: C, 76.16; H, 7.99; N, 7.40%. Found: C, 76.11; H, 7.96; N, 7.44%.
4-sec-Butoxy-2-methylbenzonitrile (3m): White crystals (0.1455 gr, 77% yield), mp = 137-138
oC. IR (KBr), ῦ(cm-1):3253, 3185, 2968, 2219, 1604, 1498, 1251, 869. 1H NMR (250 MHz, 298K,
DMSO-d6),  (ppm): 0.56 (t, J = 7.5 Hz, 3H), 0.82 (d, J = 6.3 Hz, 3H), 1.10-1.28 (m, 2H), 2.09, (s,
3H), 4.24, (sex, J = 6.3 Hz, 1H), 6.59 (d, J = 7.50 Hz, 1H), 6.65 (s, 1H), 7.41 (d, J = 7.50 Hz, 1H).
13C{1H} NMR (63 MHz, 298K, DMSO-d6),  (ppm): 9.5 (CH3), 19.6 (CH3), 25.9 (CH2), 28.5
(CH3), 70.5 (CH), 100.9 (C), 114.2 (CH), 115.8 (CH), 118.8 (C), 134.8 (CH), 149.9 (C), 161.8
(C). Anal. Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40%. Found: C, 76.10; H, 7.94; N, 7.47%.
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4-iso-Propoxy-2-methylbenzonitrile (3n): White crystals (0.1365 gr, 78% yield), mp = 137-138
5
6
1
oC. IR (KBr), ῦ(cm-1): 3059, 3029, 2926, 2222, 1605, 1497, 1475, 1250, 869. H NMR (250 MHz,
7
8
9
298K, DMSO-d6),  (ppm): 1.24 (d, J = 6.3 Hz, 6H), 2.06 (s, 3H), 3.79 (hep, J = 7.50 Hz, 1H),
6.90 (d, J = 7.50 Hz, 1H), 7.00 (s, 1H), 7.65 (d, J = 7.50 Hz, 1H). 13C{1H} NMR (63 MHz, 298K,
DMSO-d6),  (ppm): 10.9 (CH3), 20.5 (CH3), 61.0 (CH), 103.8 (C), 113.0 (CH), 116.1 (CH), 118.8
(C), 134.6 (CH), 144.2 (C), 163.0 (C). Anal. Calcd for C11H13NO: C, 75.40; H, 7.48; N, 7.99%.
Found: C, 75.35; H, 7.72; N, 8.07%.
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4-(Benzyloxy)-2-methylbenzonitrile (3o): White crystals (0.1784 gr, 80% yield), mp = 137-138
oC. IR (KBr), ῦ(cm-1): 3026, 2917, 2228, 1602, 1589, 1494, , 1277, 728, 698. 1H NMR (250 MHz,
298K, DMSO-d6),  (ppm): 2.34 (s, 3H), 5.15 (s, 2H), 6.68 (d, J = 7.50 Hz, 1H), 6.75 (s, 1H), 7.22
(m, 5H), 7.51 (d, J = 7.50 Hz, 1H).13C{1H} NMR (63 MHz, 298K, DMSO-d6),  (ppm): 20.4 (CH3),
68.4 (CH2), 102.1 (C), 114.3 (CH), 117.5 (CH), 119.2 (C), 127.4 (CH), 128.1 (CH), 128.6 (CH),
134.8 (CH), 135.3 (C), 144.1 (C), 161.6 (C). Anal. Calcd for C15H13NO: C, 80.69; H, 5.87; N,
6.27%. Found: C, 80.64; H, 5.85; N, 6.32%.
4-(Benzyloxy)-2,3-dimethylbenzonitrile (3p): White crystals (0.1849 gr, 78% yield), mp = 137-
o
1
138 C. IR (KBr), ῦ(cm-1): 3167, 2957, 2231, 1598, 1584, 1291, 824, 790. H NMR (250 MHz,
298K, DMSO-d6),  (ppm): 2.05, (s, 3H), 2.33, (s, 3H), 5.29, (s, 2H), 6.76, (d, J = 7. 5 Hz, 1H),
7.09, (m, 5H), 7.37 (d, J = 7.5 Hz, 1H). 13C{1H} NMR (63 MHz, 298K, DMSO-d6),  (ppm): 11.5
(CH3), 17.9 (CH3), 71.0 (CH2), 102.0 (C), 113.10 (CH), 120.6 (C), 124.1 (CH), 125.6 (CH), 126.9
(CH), 129.2 (C), 131.1 (CH), 137.7 (C), 142.4 (C), 159.2 (C). Anal. Calcd for C16H15NO: C, 80.98;
H, 6.37; N, 5.90%. Found: C, 80.95; H, 6.34; N, 5.94%.
4-(Benzyloxy)-2,6-dimethylbenzonitrile (3q): White crystals (0.1706 gr, 72% yield), mp = 137-
1
138 oC. IR (KBr), ῦ(cm-1): 3060, 3026, 2917, 2228, 1599, 1581, 1291, 821, 792. H NMR (250
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MHz, 298K, DMSO-d6),  (ppm): 2.05, (s, 6H), 5.30, (s, 2H), 6.79, (s, 2H), 7.36, (m, 5H). 13C{1H}
5
6
7
8
NMR (63 MHz, 298K, DMSO-d6),  (ppm): 20.1 (CH3), 67.3 (CH2), 102.5 (C), 113.7 (CH), 119.9
(C), 127.5 (CH), 128.4 (CH), 129.8 (CH), 138.2 (C), 142.0 (C), 159.7 (C). Anal. Calcd for
C16H15NO: C, 80.98; H, 6.37; N, 5.90%. Found: C, 80.94; H, 6.35; N, 5.93%.
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2-Hydroxynaphthalene-1-carbonitrile (3s): Brown crystals (0.1453 gr, 86% yield), mp = 156-
o
158 C. IR (KBr), ῦ(cm-1): 3188, 2227, 1627, 1578, 1516, 1505, 1440, 1287, 968, 822, 776. 1H
NMR (250 MHz, 298K, DMSO-d6),  (ppm): 6.96, (d, J = 7. 5 Hz, 1H), 7.61, (m, 1H), 7.74, (m,
1H), 7.97, (m, 2H), 8.25 (d, J = 8.00 Hz, 1H), 11.48 (s, 1H. OH). 13C{1H} NMR (63 MHz, 298K,
DMSO-d6),  (ppm): 91.0 (C), 116.0 (C), 117.6 (CH), 122.6 (CH), 124.6 (CH), 126.9 (C), 128.8
(CH), 129.0 (CH), 132.9 (C), 135.1 (CH), 161.2 (C). Anal. Calcd for C11H7NO: C, 78.09; H, 4.17;
N, 8.28%. Found: C, 78.03; H, 4.12; N, 8.32%.
2-Butoxynaphthalene-1-carbonitrile (3t): White crystals (0.1665 gr, 74% yield), mp = 137-138
oC. IR (KBr), ῦ(cm-1):3163, 2943, 2147, 1617, 1595, 1504, 1460, 1440, 1334, 1271, 1234, 1060
1020, 826, 808, 773. 1H NMR (250 MHz, 298K, DMSO-d6),  (ppm): 0.63 (t, J = 7. 5 Hz, 3H),
1.06 (m, 2H), 1.35 (m, 2H), 4.01 (t, J = 7. 5 Hz, 2H), 6.97 (d, J = 8.00 Hz, 1H), 7.62 (m, 1H), 7.74
13
(m, 1H), 7.97 (t, J = 8.00 Hz, 2H), 8.25 (d, J = 8.00 Hz, 1H). C{1H} NMR (63 MHz, 298K,
DMSO-d6),  (ppm): 13.5 (CH3), 18.5 (CH2), 30.2 (CH2), 65.2 (CH2), 102.4 (C), 116.0 (CH), 117.6
(C), 122.6 (CH), 124.3 (CH), 126.9 (C), 128.8 (CH), 129.2 (CH), 132.9 (C), 135.1 (CH), 161.2
(C). Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22%. Found: C, 79.92; H, 6.67; N, 6.26%.
2-sec-Butoxynaphthalene-1-carbonitrile (3u): White crystals (0.1552 gr, 69% yield), mp = 137-
o
138 C. IR (KBr), ῦ(cm-1): 3066, 2958, 2920, 2146, 1621, 1594, 1505, 1460, 1273, 1238, 1059,
825, 808, 462. 1H NMR (250 MHz, 298K, DMSO-d6),  (ppm): 0.56 (t, J = 7. 5 Hz, 3H), 0.76 (d,
J = 7. 5 Hz, 3H), 1.06 (qun, J = 7. 5 Hz, 2H), 3.23 (sex, J = 7. 5 Hz, 1H), 6.95 (d, J = 7. 5 Hz, 1H),
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7.62 (m, 1H), 7.76 (m, 1H), 7.99 (m, 2H), 8.25 (d, J = 8.00 Hz, 1H). 13C{1H} NMR (63 MHz, 298K,
DMSO-d6),  (ppm): 9.7 (CH3), 19.0 (CH2), 28.2 (CH3), 70.6 (CH), 100.4(C), 115.2 (CH), 116.8
(CH), 121.8 (CH), 123.5 (C), 126.1 (C), 127.9 (CH), 128.2 (CH), 132.0 (C), 134.2 (CH), 160.4
(C). Anal. Calcd for C15H15NO: C, 79.97; H, 6.71; N, 6.22%. Found: C, 79.91; H, 6.66; N, 6.27%.
2-iso-Propoxynaphthalene-1-carbonitrile (3v): White crystals (0.1414 gr, 67% yield), mp =
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137-138 C. IR (KBr), ῦ(cm-1): 3064, 2968, 2957, 2146, 1621, 1594, 1505, 1459, 1269, 1249,
1059, 826, 808, 465. 1H NMR (250 MHz, 298K, DMSO-d6),  (ppm): 1.20 (d, J = 7. 5 Hz, 6H),
3.30 (hep, J = 7. 5 Hz, 1H), 6.96 (d, J = 7. 5 Hz, 1H), 7.54 (m, 1H), 7.84 (m, 1H), 7.97 (m, 2H),
8.30 (d, J = 8.00 Hz, 1H). 13C{1H} NMR (63 MHz, 298K, DMSO-d6),  (ppm): 21.7 (CH3), 72.8
(CH), 101.4 (C), 116.0 (C), 117.6 (CH), 122.6 (CH), 124.3 (CH), 126.9 (C), 128.8 (CH), 129.0
(CH), 132.9 (C), 135.1 (CH), 161.2 (C). Anal. Calcd for C14H13NO: C, 79.59; H, 6.20; N, 6.63%.
Found: C, 79.53; H, 6.15; N, 6.69%.
2-(Benzyloxy) naphthalene-1-carbonitrile (3w): White crystals (0.1839 gr, 71% yield), mp =
154-156 oC. IR (KBr), ῦ(cm-1): 3029, 2930, 2350, 1627, 1599, 1452, 1258, 1218, 1018, 839, 696.
1H NMR (250 MHz, 298K, DMSO-d6),  (ppm): 4.27, (s, 2H), 6.95, (d, J = 7. 5 Hz, 1H), 7.37, (m,
13
5H), 7.63, (m, 1H), 7.77, (m, 1H), 7.96, (m, 2H), 8.24 (d, J = 8.00 Hz, 1H). C{1H} NMR (63
MHz, 298K, DMSO-d6),  (ppm): 57.0 (CH2), 93.1 (C), 116.0 (C), 117.6 (CH), 118.8 (CH), 118.9
(CH), 121.6 (CH), 122.6 (CH), 124.3 (CH), 126.9 (C), 128.8 (CH), 129.0 (CH), 132.9 (C), 135.1
(CH), 144.0 (C), 161.2 (C). Anal. Calcd for C18H13NO: C, 83.37; H, 5.05; N, 5.40%. Found: C,
83.32; H, 5.01; N, 5.44%.
2,4-Dihydroxybenzonitrile (3x): White crystals (0.1026 gr, 76% yield), mp = 178-180 oC.
IR (KBr), ῦ(cm-1): 3029, 2930, 2350, 1627, 1599, 1452, 1258, 1218, 1018, 839, 819, 696. 1H NMR
(250 MHz, 298K, DMSO-d6),  (ppm): 6.78 (s, 1H), 6.84 (d, J = 7. 5 Hz, 1H), 7.54 (d, J = 7. 5 Hz,
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1H), 10.06 (s, 1H, OH), 10.40 (s, 1H, OH). 13C{1H} NMR (63 MHz, 298K, DMSO-d6),  (ppm):
92.4 (C), 101.6 (C), 109.7 (CH), 116.5 (CH), 129.5 (C), 135.4 (CH), 160.3 (C), 162.4 (C). Anal.
Calcd for C7H5NO2: C, 62.22; H, 3.73; N, 10.37%. Found: C, 62.20; H, 3.74; N, 10.42%.
2,3-Dihydroxy-1-naphthonitrile (3y): Brown crystals (0.1480 gr, 80% yield), mp = 164-165 oC.
IR (KBr), ῦ(cm-1): 3059, 3029, 2930, 2350, 1627, 1599, 1452, 1258, 1218, 1018, 839, 819, 696.
1H NMR (250 MHz, 298K, DMSO-d6),  (ppm): 6.52 (s, 1H), 7.80 (m, 1H), 7.96 (m, 1H), 8.20
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(d, J = 8.00 Hz, 1H), 8.62 (d, J = 8.00 Hz, 1H), 10.08 (s, 1H, OH), 10.41 (s, 1H, OH). C{1H}
NMR (63 MHz, 298K, DMSO-d6),  (ppm): 90.9 (C), 95.6 (C), 115.9 (CH), 117.8 (CH), 123.2
(CH), 124.4 (C), 128.6 (CH), 129.3 (CH), 142.9 (C), 160.3 (C), 162.2 (C). Anal. Calcd for
C11H7NO2: C, 71.35; H, 3.81; N, 7.56%. Found: C, 71.32; H, 3.78; N, 7.59%.
2,4-Dihydroxy-1-naphthonitrile (3z): Brown crystals (0.1536 gr, 83% yield), mp = 183-185 oC.
1
IR (KBr), ῦ(cm-1): 3059, 3029, 2930, 2350, 1627, 1599, 1452, 1258, 1218, 1018, 839, 725. H
NMR (250 MHz, 298K, DMSO-d6),  (ppm): 6.83 (s, 1H), 7.70 (m, 1H), 7.85 (m, 1H), 8.10 (d, J
= 8.00 Hz, 1H), 8.52 (d, J = 8.00 Hz, 1H), 10.05 (s, 1H, OH), 10.64 (s, 1H, OH). 13C{1H} NMR
(63 MHz, 298K, DMSO-d6),  (ppm): 90.4 (C), 99.7 (C), 108.5 (CH), 112.3 (CH), 119.2 (CH),
120.0 (CH), 127.2 (C), 133.1 (CH), 140.2 (C), 160.0 (C), 161.7 (C). Anal. Calcd for C11H7NO2:
C, 71.35; H, 3.81; N, 7.56%. Found: C, 71.30; H, 3.80; N, 7.60%.
o
Thiocyanogen: Yellow crystals, mp = 171-173 C. IR (KBr), ῦ(cm-1): 2050, 1021, 748, 485.
13C{1H} NMR (63 MHz, 298K, DMSO-d6), ppm; 129.6 (C). MS: Calcd m/z 116, Found 116.
Anal. Calcd for C2N2S2: C, 20.68; N, 24.12; S, 55.20%. Found: C, 20.67; N, 24.27; S, 55.06%.
Acknowledgements
Authors gratefully acknowledge the financial support of this work by the research council of Shiraz
University.
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Supporting Information:
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Copies of IR, H NMR, 13C NMR spectra and elemental analysis for all compounds 3a-3z,
Crystallographic data of compound 3f (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
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