Synthesis of nitriles containing 3-phenoxyphenyl fragment

Article abstract of DOI:10.1134/S107036321004016X

Reactions of the aldol-crotonic condensation, acylation of acetonitrile, and addition of amine to the activated double bond of acrylonitrile in the series of diphenyl oxide derivatives are studied. Effective procedures for preparing the nitriles containin

Full text of DOI:10.1134/S107036321004016X

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 4, pp. 776–780. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © Yu.V. Popov, T.G. Korchagina, V.S. Kamaletdinova, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 4, pp. 614–
618.
Synthesis of Nitriles Containing 3-Phenoxyphenyl Fragment
Yu. V. Popov, T. G. Korchagina, and V. S. Kamaletdinova
Volgograd State Technical University, pr. Lenina 28, Volgograd, 400131 Russia
e-mail: viktori_2008@bk.ru
Received June 16, 2009
Abstract—Reactions of the aldol-crotonic condensation, acylation of acetonitrile, and addition of amine to the
activated double bond of acrylonitrile in the series of diphenyl oxide derivatives are studied. Effective
procedures for preparing the nitriles containing diphenyl oxide fragment like 3-(3-phenoxyphenyl)-
propenonitrile, 3-(3-phenoxyphenyl)-2-butenonitrile, 3-phenoxybenzoylacetonitrile, 3-(3-phenoxyphenyl)-
propionitrile, and 3-phenoxybenzylamino)propionitrile are developed.
DOI: 10.1134/S107036321004016X
Diphenyl oxide derivatives containing various
functional groups present significant practical interest.
These compounds were used for the first time for the
introduction of diphenyl oxide fragment in the
molecule of cyclopropanecarboxylic acid derivatives
to improve photochemical stability of synthetic
insecticides (pyrethroids) which are the analogs of
natural insecticides, pyrethrins. It occurred however
that pyrethroids exhibit also the physiological activity.
For example, permethrin, (3-phenoxyphenyl)methyl-3-
(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecar-
boxylate, a mixture of cis- and trans-isomers (3:1), and
phenothrin, (3-phenoxyphenyl)methyl-2,2-dimethyl-3-
(2-methyl-1-propenyl)cyclopropanecarboxylate, are
used as medicines exhibiting antiparasite, anti-
pedicular, insecticide, and ovocide pharmacological
activity [1].
Great interest in the series of functionalized
diphenyl oxide derivatives present the nitriles contain-
ing another functional groups in the side chain. These
compound exhibit various types of biological activity
and may serve also as the starting substances for the
synthesis of derivatives possessing medico-biological
activity.
Recently synthetic procedure for preparing 3-
phenoxybenzonitrile was developed [3], and on its
basis the corresponding nitro- and bromoderivatives
were prepared [4].
Diphenyl oxide-based nitriles containing the un-
saturated bond in the side chain present great interest
in the organic synthesis because they may take part in
the reactions proceeding by the nitrile group as well as
by the double bond.
Such compounds are 3-(3-phenoxyphenyl)-2-acrylo-
nitrile III and 3-(3-phenoxyphenyl)-2-butenonitrile IV
which we prepared by the reaction of 3-phenoxy-
benzaldehyde I or 3-phenoxyphenyl methyl ketone II
with acetonitrile according to the following scheme.
It is known also that phenoxyphenylacetylenes
prepared on the basis of 1-(2-methyl-4-phenoxy-
phenyl)ethanone and 1-(3-phenoxyphenyl)ethanone
are used as antithrombic, antiseptic, antipyretic, and
analgetic drugs [1].
O
C=CH_CN
O
O
C
KOH
R
R
+
CH3CN
_H2O
III, IV
I, II
R = H, CH3.
776

SYNTHESIS OF NITRILES
777
Reaction was carried out in acetonitrile in the
presence of potassium hydroxide at 80–82°C at the
carbonyl compound, acetonitrile, and potassium
hydroxide molar ratio 1:(20–22):1.
3-(3-phenoxyphenyl)-2-butenonitrile is due to the
lower reactivity of 3-phenoxyphenyl methyl ketone as
compared to 3-phenoxybenzaldehyde. Further increase
in the acetonitrile excess and in the reaction time does
not affect the yield of the target products III, IV and is
unnecessary.
The reaction was carried out under a large excess of
acetonitrile. Potassium hydroxide was dissolved in it
under nitrogen. Under the action of base the acetonitrile
was deprotonated to form carbanion which reacts with
the carbonyl compound added to the reaction mixture
by portions. The cyanhydrine formed eliminates the
molecule of water to give the unsaturated nitrile. The
formation of ester according to Tishchenko process
was not observed because under the above-described
reaction conditions the hydride ion transfer did not
take place.
3-(3-Phenoxyphenyl)-2-acrylonitrile and 3-(3-phen-
oxyphenyl)-2-butenonitrile were purified by vacuum
distillation with the addition of hydroquinone to avoid
polymerization. The nitriles are colorless liquids
obtained in 48–51% yield. Moderate yield of the target
products is caused by partial polymerization of un-
saturated nitriles in the course of vacuum distillation
under the action of high temperature.
Structure and composition of the nitriles syn-
1
Our studies showed that the optimum and techno-
logically feasible reaction procedure should take
10 min in the case of 3-phenoxybenzaldehyde 3 h in
the case of 3-phenoxyphenylmethylketone at the
indicated molar ratio of the carbonyl compound, aceto-
nitrile, and potassium hydroxide. Smaller acetonitrile
excess leads to some decrease in the yield of
unsaturated nitriles (40–42%) due to the incomplete
conversion of the carbonyl compound and the forma-
tion of a heterophase system because of the incomplete
dissolution of potassium hydroxide in acetonitrile.
Significant duration of the reaction in the synthesis of
thesized were confirmed by the IR and H NMR spec-
troscopy and elemental analysis.
The developed procedure permits the preparation of
unsaturated nitriles containing 3-phenoxyphenyl frag-
ment in one stage and in good yields. It is simple, and
the target products are easily isolated in a highly pure
form.
3-Phenoxybenzoylacetonitrile we prepared through
acylation of ethyl cyanoacetate with 3-phenoxybenzoyl
chloride. The reaction proceeded according to the
following scheme.
O
O
O
C
O
C
NaOH
NaCl
Cl
CH(CN)COOC2H5
+ CH2(CN)COOC2H5
Yield 94_95%
IV
V
O
O
C
O
C
O
150_153oC
_CO2
NaOH, HCl
_C2H5OH
C
CH(CN)COOH
CH2
C
N
Yield 86_87%
Yield 92%
VII
VI
In the first stage of the reaction ethyl 3-
phenoxybenzoylcyanoacetate V is formed. The acyla-
tion was carried out in presence of sodium hydroxide
in acetone over 2 h at the temperature not exceeding
20°C. The organic layer was separated and washed
with distilled water until neutral reaction. Ethyl 3-
phenoxybenzoylcyanoacetate V is an oily yellow
liquid. It was prepared in 94–95% yield.
The second stage of the reaction was the hydrolysis
of ethyl 3-phenoxybenzoylcyanoacetate V to the free
acid VI. No hydrolysis of the nitrile group was
observed. It can be probably ascribed to performing
the reaction in the alkaline medium at low temperature
and to the steric effect of the diphenyl oxide fragment.
3-Phenoxybenzoylcyanoacetic acid is the coarsely
dispersed powder, mp 150–152°C. Its structure and
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778
POPOV et al.
1
composition were confirmed by the IR and H NMR
spectroscopy and elemental analysis.
Reaction was carried out in the presence of copper
acetate monohydrate, the most effective cyanoethyla-
tion catalyst for amines [5], at 95°C over 3 h without a
solvent. The nitrile obtained was a viscous yellow
liquid which was purified by vacuum distillation, bp
172–175°C (2 mm Hg). Yield of the product after
vacuum distillation was 40%. Comparatively low yield
of the target product is caused by a partial
polymerization of acrylonitrile in the course of the
reaction. The structure and composition of the product
Heating of 3-phenoxybenzoylcyanoacetic acid above
its melting point caused decarboxylation to 3-phen-
oxybenzoylacetonitrile VII in 86–87% yield.
3-Phenoxybenzoylacetonitrile is a finely dispersed
powder, mp 140–142°C.
Its structure and composition were confirmed by
the IR and H NMR spectroscopy and elemental
1
1
were confirmed by the IR and H NMR spectroscopy
and elemental analysis.
analysis.
The alkylation of acetonitrile with 3-phenoxybenzyl
chloride VIII lead to the formation of 3-(3-phen-
oxyphenyl)propionitrile IX according to the scheme:
EXPERIMENTAL
IR spectra were measured on a Specord M-82
spectrometer in mineral oil, NaCl and KBr prisms
were used. H NMR spectra were taken on a Varian
CH2Cl
O
1
CH3C
N
+
Mercury 300BB spectrometer in DMSO-d6 against
internal HMDS. GLC was carried out on a Sigma-300
chromatograph equipped with a 2 m column filled with
15% of SKTF-50 on Inerton N–AV, evaporator
temperature 270°C, oven temperature 80–240°C,
β = 3 mm min–1, programming rate 5°C/min.
VIII
_
_
CH2 CH2 C
N
O
+ NaH
_NaCl, _H2
IX
3-(3-Phenoxyphenyl)-2-acrylonitrile (III). Potas-
sium hydroxide, 3 g, and 40 ml of acetonitrile were
placed in the reactor equipped with a mechanic stirrer,
a reflux condenser with a calcium chloride tube, a
thermometer, and a dropping funnel. The mixture was
heated to boiling and kept under nitrogen until the
complete dissolution of potassium hydroxide. After
that a solution of 10 g of 3-phenoxybenzaldehyde in
20 ml of acetonitrile was added dropwise in the course
of 1–2 min. After the addition was complete the
reaction mixture was stirred for 10 min, and the hot
solution was poured in 100 g of crashed ice. The two-
phase system formed, and the organic layer was
separated, the water layer was extracted 2 times with
50 ml of diethyl ether. Combined organic phases were
washed with distilled water. 3-(3-Phenoxyphenyl)-2-
acrylonitrile was isolated by vacuum distillation with
the addition of hydroquinone. Yield 5.3 g (48%), bp
194–196°C (4 mm Hg), purity 98.5% (GLC data). IR
spectrum, ν, cm–1: 2218 (C≡N), 1696 (C=C), 3064
The alkylation was carried out for 2 h under
nitrogen in anhydrous benzene at 80–82°C and
1:1.2:1.2 3-phenoxybenzyl chloride : acetonitrile :
sodium hydride molar ratio. Lithium amide and
sodium hydride were used for metallation of
acetonitrile, but in the first case 3-(3-phenoxyphenyl)
propionitrile was obtained in 22% yield. Using sodium
hydride permitted to achieve 60% yield of the target
product. The nitrile obtained is a viscous oily yellow
liquid which was purified by vacuum distillation, bp
172–175°C (2 mm Hg). The structure and composition
1
of the product were confirmed by the IR and H NMR
spectroscopy and elemental analysis.
3-(3-Phenoxybenzylamino)propionitrile XI was
obtained by cyanoethylation of 3-phenoxybenzylamine
X with acrylonitrile according to the scheme:
_
O
CH2 NH2
+ CH2=CH_C
N
1
(C–H). H NMR spectrum, δ, ppm: 6.84–7.2 m (9H,
X
Cu(OAc)2·H2O
C6H5OC6H4), 7.44–7.46 d (Ar–CH), 5.62–5.67 d (1H,
CH–CN). Found.%: C 81.46, 81.42; H 4.98, 5.00; N
6.28, 6.30. C15H11NO. Calculated, %: C 81.45; H 4.98,
N 6.33.
_
_
_
CH2 NH_CH2 CH2 C
N
O
3-(3-Phenoxyphenyl)-2-butenonitrile (IV). Potas-
sium hydroxide, 3 g, and 40 ml of acetinitrile were
XI
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SYNTHESIS OF NITRILES
779
placed in the reactor equipped with a mechanic stirrer,
a reflux condenser with calcium chloride tube, a
thermometer, and a dropping funnel. Potassium
hydroxide must be fresh. The reaction mixture was
heated to boiling and refluxed with stirring under
nitrogen until the complete dissolution of potassium
hydroxide. After that a solution of 10 g of 3-phen-
oxyphenylmethylketone in 20 ml of acetonitrile was
added dropwise in the course of 30–40 min, and the
resulting mixture was stirred for 3 h. The hot reaction
mixture was then poured on 100 g of crashed ice. After
cooling the two-phase mixture was formed. The
organic layer was separated, and water phase was
extracted with ether. Combined organic phases were
washed with distilled water and dried over sodium
sulfate. Ether was removed, and the residue was
distilled in a vacuum with the addition of hydro-
quinone to give 6 g (51%) of 3-(3-phenoxyphenyl)-2-
butenonitrile, bp 215–218°C (4 mm Hg), purity 97.2%
(GLC data).
(C=O). 2198 (C≡N), 2854 (OH). 1H NMR spectrum, δ,
ppm: 3.93 s (H, CH), 6.65–7.4 m (9H, C6H5OC6H4).
Decarboxylation of 3-phenoxybenzoylcyanoacetic
acid to 3-phenoxybenzoylacetonitrile was carried out
by heating the acid in the ceramic cup above its
melting point. After calcinations of 9,8 g of 3-
phenoxybenzoylcyanoacetic acid 9,2 g (90%) of 3-
phenoxybenzoylacetonitrile was obtained, mp 140–
143°C. IR spectrum, ν, cm–1: 1760 (C=O), 2248
(C≡N). 1H NMR spectrum, δ, ppm: 4.402 s (2H, CH2),
6.65–7.4 m (9H, C6H5OC6H4). Found, %: C 75.96.
75.99; H 5.96, 6.01; N 4.58, 4.61. C15H10NO2.
Calculated, %: C 75.95, H 5.91, N 4.64.
3-(3-Phenoxyphenyl)propionitrile (IX). A mix-
ture of 2.25 g of acetonitrile, 10 g of 3-phenoxybenzyl
chloride, and 20 ml of anhydrous benzene was placed
in a four-neck reactor equipped with a mechanical
stirrer, a reflux condenser, a thermometer, and a
dropping funnel, and heated to boiling. Sodium
hydride, 60% suspension, 2.2 g, was mixed with 30 ml
of anhydrous benzene and added with shaking in small
portions to a stirred reaction mixture. After the ad-
dition was complete the reaction mixture was refluxed
with stirring for 3 h. On cooling it was washed with
100 ml of water. The organic layer was separated, and
the water phase was extracted with benzene, 2×100 ml.
The combined organic phases were dried over sodium
sulfate, and the solvent was removed. The residue was
distilled in a vacuum to give 3-(3-phenoxyphenyl)
propionitrile, yield 60%, bp 172–165°C (3 mm Hg).
IR spectrum, ν, cm–1: 2218 (C≡N), 1672 (C=C),
1
2926–3034 (CH3). H NMR spectrum, δ, ppm: 6.84–
7.2 m (9H, C6H5OC6H4), 1.1–1.3 s (3H, CH3), 5.34–
5.37 s (1H, CH–CN). Found, %: C 81.60, 81.64; H
5.98, 6.00; N 5.49, 6.52. C16H13NO Calculated, %: C
81.70, H 5.96, N 5.53.
3-Phenoxybenzoylacetonitrile (VII). 3-Phenoxy-
benzoyl chloride, 9.35 g, 5 g of ethyl cyanoacetate, and
40 ml of anhydrous acetonitrile were placed in the
three-neck reactor equipped with a mechanic stirrer, a
thermometer, and a dropping funnel. The solution
obtained was cooled with a mixture of ice and salt, and
40% sodium hydroxide solution was added dropwise
until the achievement of constant pH 8–9. The reaction
mixture was stirred at 20°C for 2 h and treated with
300 ml of ice water. Ethyl 3-phenoxybenzoyl-
cyanoacetate was precipitated with 10% hydrochloric
acid, and then separated. Yield 94–95%.
1
IR spectrum, ν, cm–1: 2250 (C≡N). H NMR
spectrum, δ, ppm: 2.2 d (2H, CH2), 2.7 d (2H, CH2),
6.8–7.2 m (9H, C6H5OC6H4). Found, %: C 80.64,
80.68; H 6.30, 6.33: N 5.81, 5.83. C15H13NO.
Calculated, %: C 80.72, H 6.28, N 5.83.
3-(3-Phenoxybenzylamino)propionitrile (XI). A
mixture of 10 g of 3-phenoxybenzylamine, 2.65 g of
acrylonitrile, and 0.4 g of copper acetate monohydrate
(4% to the mass of 3-phenoxybenzylamine) was placed
in a three-neck reactor equipped with a mechanic
stirrer, a reflux condenser, and a thermometer. The
mixture was heated to boiling with stirring and kept for
3 h at 95°C. After that excess acrylonitrile was
distilled off and 3-(3-phenoxybenzylamino)propio-
nitrile was purified by vacuum distillation through a
high Vigreux column. Yield 40%, bp 230°C (4 mm
Hg). IR spectrum, ν, cm–1: 2248 (C≡N), 3304 (N–H).
Ethyl 3-phenoxybenzoylcyanoacetate, 11.8 g, was
placed in a three-neck flask equipped with a mechanic
stirrer and a reflux condenser, 150 ml of 10%
potassium hydroxide solution was added, and the
reaction mixture was refluxed with stirring for 1–2 h
until the complete dissolution of ethyl 3-phenoxy-
benzoylcyanoacetate. The mixture obtained was cooled
and acidified with 100 ml of 5 N HCl. The crystals of
3-phenoxybenzoylcyanoacetic acid were formed. They
were filtered off and washed with distilled water. Yield
92 g, mp 150–152°C. IR spectrum, ν, cm–1: 1790
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POPOV et al.
1H NMR spectrum, δ, ppm: 8.2 br.s (N–H), 3.6 s (2H,
Ar–CH2–N), 2.2 d (2H, CH2), 2.7 d (2H, CH2), 6.8–7.2
m (C6H5OC6H4). Found, %: C 76.14, 76.16; H 11.06,
11.09: N 6.37, 6.37. C16H16N2O. Calculated, %: C
76.19, H 11.11, N 6.35.
2. Smirnova, M.V., Candidate Sci. (Chem.) Dissertation,
Volgograd, 2008.
3. Popov, Yu.V., Korchagina, T.K., and Smirnova, M.V.,
Izv. Volgograd. Gos. Tekh. Univ., Ser. Khim. i Tekh.
Elementoorg. Monomer. i Polimer. Material., 2007,
vol. 31, no. 5, p. 52.
4. Popov, Yu.V., Korchagina, T.K., Smirnova, M.V., and
Kamaletdinova, V.S., Izv. Volgograd. Gos. Tekh. Univ.,
Ser. Khim. i Tekh. Elementoorg. Monomer. i Polimer.
Material., 2008, vol. 39, no. 1, p. 87.
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