Synthesis of new derivatives of diphenyl oxide

Article abstract of DOI:10.1134/S1070363210030163

Studying of chemical properties of nitriles containing diphenyl oxide fragment in their structure opens wide prospects for obtaining new compounds possessing various chemical and pharmacological properties. They can be used as biologically active substances and ingredients of rubber mixtures of polyfunctional action. Effective synthetic approaches to imidate hydrochlorides, N-substituted imidates, and amidines containing 3-phenoxyphenyl fragment were developed from the corresponding nitriles like 3-(3-phenoxyphenyl)-2- propenylnitrile, 3-(3-phenoxyphenyl)-2-betenylnitrile, and 2-methyl-2-(3- phenoxybenzyloxy) propionitrile.

Full text of DOI:10.1134/S1070363210030163

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 3, pp. 468–471. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © Yu.V. Popov, T.K. Korchagina, V.S. Kamaletdinova, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 3, pp. 445–
448.
Synthesis of New Derivatives of Diphenyl Oxide
Yu. V. Popov, T. K. Korchagina, and V. S. Kamaletdinova
Volgograd State Technical University, pr. Lenina 28, Volgograd, 400131 Russia
е-mail: viktori_2008@bk.ru
Received June 16, 2009
Abstract―Studying of chemical properties of nitriles containing diphenyl oxide fragment in their structure
opens wide prospects for obtaining new compounds possessing various chemical and pharmacological proper-
ties. They can be used as biologically active substances and ingredients of rubber mixtures of polyfunctional
action. Effective synthetic approaches to imidate hydrochlorides, N-substituted imidates, and amidines
containing 3-phenoxyphenyl fragment were developed from the corresponding nitriles like 3-(3-
phenoxyphenyl)-2-propenylnitrile, 3-(3-phenoxyphenyl)-2-betenylnitrile, and 2-methyl-2-(3-phenoxybenzyl-
oxy)propionitrile.
DOI: 10.1134/S1070363210030163
At present versatile types of pharmacological
activity of the diphenyl oxide functional derivatives
are well known. Thus, permethrin [(3-phenoxyphenyl)-
methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopro-
pionate, a mixture of cis- and trans-isomers (3:1)] and
phenothrin [(3-phenoxyphenyl)methyl 2,2-dimethyl-3-
(2-methyl-1-propenyl)cyclopropionate] are used as
drugs which possess antiparasitic, antipediculosis,
insecticidal and ovicidal pharmacological actions [1, 2].
It is presumable that the elaboration of synthesis
methods of imidate hydrochlorides containing 3-
phenoxyphenyl fragment, N-substituted imidates and
amidines would allow to obtain the new structures with
various chemical and pharmacological properties.
Synthesis of ethylimidates hydrochlorides by the
Pinner reaction. It is known from literature [4] that
aliphatic, aromatic and heterocyclic nitriles react with
alcohols and hydrogen chloride by Pinner reaction to
give imidate hydrochlorides. The practical significance
of imidate hydrochlorides is due to their solubility in
water, an important property for using the biologically
active compounds in practice. Nitriles containing
diphenyl oxide fragment were found to react readily
with ethanol and hydrogen chloride by Pinner reaction.
We carried out hydrochlorination of nitriles by Pinner
reaction to form the corresponding imidate hydro-
chlorides containing diphenyl oxide fragment:
The use of phenoxyphenylacetylenes obtained on
the base of 1-(2-methyl-4-phenoxyphenyl)ethanone and
1-(3-phenoxyphenyl)ethanone as antithrombotic, anti-
inflammatory, antipyretic agents and analgesics is
known [1].
Nitriles, imidate hydrochlorides, imidates, and
amidines containing 3-phenoxyphenyl fragment are
promising compounds for the synthesis of new psycho-
tropic medicines and drugs acting on the protozoa
organisms, viruses and atypical (tumorous) cells [3].
NH HCl
O
X
CN
O
X
C
+ C2H5OH + HCl
OC2H5
I_III
IV_VI
O
C
CH3
(I, IV);
(III, VI).
(II, V);
X =
CH CH
C
CH
O
C
CH3
CH3
468

469
SYNTHESIS OF NEW DERIVATIVES OF DIPHENYL OXIDE
In all instances the reaction was carried out in the
spectroscopy and elemental analysis data.
reagents bulk at 0–5°С at the equimolar ratio of nitrile,
alcohol, and hydrogen chloride. The reaction
completion was attested by the added weight of the
reaction mixture. Gaseous hydrogen chloride for the
synthesis of imidate hydrochlorides was obtained using
sodium chloride of chemically pure grade, hydrochloric
and sulfuric acids. Hydrogen chloride was dried by
bubbling through concentrated sulfuric acid [4]. The
structure and composition of the obtained imidate
Synthesis of N-benzoyl-substituted ethylimidates
containing diphenyl oxide fragment. N-Benzoyl-
substituted imidates possessing hypoglycaemic, neuro-
leptic, tuberculostatic and fungicidal activities are very
promising substances which may be used for the
synthesis of the corresponding amidines.
We carried out reaction of imidate hydrochlorides
containing diphenyl oxide fragment with benzoyl
chloride according to the scheme:
1
hydrochlorides were proved by the IR and Н NMR
O
C
NH HCl
O
X
C
+
+ 2(C2H5)3N
Cl
OC2H5
IV_VI
O
C
N
O
X
C
+ 2(C2H5)3N Cl
CH3
OC2H5
VII_IX
(IV, VII);
O
C
(VI, IX).
(V, VIII);
X =
CH CH
C
CH
O
C
CH3
CH3
Triethylamine was used as an acceptor of hydrogen
chloride. This reaction was carried out at the equimolar
ratio of reagents and twofold triethylamine excess in
the anhydrous 1,4-dioxane at 60–65°С for 2 h. The
product yields were 95–99%.
benzoyl-substituted imidates were proved by the IR
and 1Н NMR spectroscopy.
Synthesis of amidines containing diphenyl oxide
fragment. The obtained N-benzoyl-substituted ethyl-
imidates were involved into the reaction with p-bromo-
The structure and composition of the obtained N-
anilines:
O
N
NH2
C
O
X
C
+
OC2H5
O
C
VII_IX
Br
N
O
X
C
NH
Br + C2H5OH
X_XII
O
C
CH3
(IX, XII).
CH3
(VII, X);
(VIII, XI);
X =
CH CH
C
CH
O
C
CH3
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470
POPOV et al.
The reactions were performed at 75–80°С in
Hydrochloride of ethylimidate of 2-methyl-2-(3-
phenoxybenzoyloxy)propenic acid (VI) was prepared
similarly. IR spectrum, ν, cm–1: 1654 (С=N); 2938
[ν(СH)]; 1287 [δ(СН3)]; 1732 (C=O). 1Н NMR
spectrum, δ, ppm: 1.8 s (6Н, СН3); 1.2 t (3Н, СН3); 4.2
m (2Н, СН2); 6.9–7.8 m (9Н, С6Н5ОС6Н4); 9.0 m (1Н,
NH). Found, %: C 67.26, 67.24; H 5.90, 5.98; N 4.67,
4.70; Сl 11.71; 11.72. Calculated, %: C 67.22; H 5.93;
N 4.61; Сl 11.7.
benzene over 2 h. The isolation of the N-substituted
amidines by means of vacuum distillation leads to the
target products in low yields. This process is accom-
panied with amidine decomposition. Under these
conditions the yields do not exceeded 50%. Aiming to
find more favorable method for the purification of the
synthesized amidines, we performed TLC using the
“Sorbfil” plates. As a result the conditions for products
purifying by the column chromatography were found.
The products yields amount to 95–99%. The structure
and composition of the obtained N-benzoyl-substituted
amidines were proved by the IR and 1Н NMR
spectroscopy.
N-Benzoyl-substituted ethylimidate of 3-(3-phen-
oxyphenyl)-2-propenic acid (VII). To a solution of
5.9 g (0.021 mol) of compound IV in anhydrous 1,4-
dioxane were added dropwise in succession solutions
of 4.25 g (0.042 mol) of triethylamine and 3 g
(0.021 mol) of benzoyl chloride in 1,4-dioxane under
stirring and cooling with ice bath. Then the reaction
mixture was stirred for 30 min at room temperature
and kept for 2 h at 60–65°С. The precipitated triethyl-
amine hydrochloride was filtered off. The solvent was
evaporated. Yield 6.8 g (0.02 mol, 95%). IR spectrum,
ν, cm–1: 1576 (С=С); 2900–3300 (С–Н); 1695 (С=О);
1678 (С=N); 1240–1070 (С–О–С). 1Н NMR spectrum,
δ, ppm: 1.203 t (3Н,СН3); 4.207 m (2Н, СН2); 6.839–
7.657 m (9Н, С6Н5ОС6Н3); 5.62-5.67 d (1H, CH–CN).
Found, %: C 77.46, 77.60; H 5.60, 5.70; N 3.76, 3.80.
Calculated, %: C 77.63; H 5.66; N 3.77.
EXPERIMENTAL
The IR spectra were recorded in mineral oil using
NaCl or KBr prisms on a Specord M-82 spectro-
photometer. The 1Н NMR spectra were registered on a
Varian Mercury 300BB instrument in DMSO-d6,
internal reference HMDS.
Hydrochloride of ethylimidate of 3-(3-phenoxy-
phenyl)-2-propenic acid (IV). A solution of 5.03 g
(0.026 mol) of 3-(3-phenoxyphenyl)-2-propenylnitrile
I and 1.26 g (0.027 mol) of anhydrous ethanol was
placed into the weighed reactor. The reaction mixture
was saturated with dry hydrogen chloride on cooling.
The reaction completing is attested by increase in the
reaction mass weight and its crystallization. Then the
reaction mixture was kept overnight at 0–5°С, there-
after the hydrogen chloride excess was removed by
evacuation. Yield 6.8 g (0.024 mol, 94%).
N-Benzoyl-substituted ethylimidate of 3-(3-phen-
oxyphenyl)-2-butenic acid (VIII) was prepared sim-
ilarly. IR spectrum, ν, cm–1: 1672 (С=С); 2930–3070
(С– Н); 1678(С=О); 1678 (С=N); 970–1126 (С–О–С).
1Н NMR spectrum, δ, ppm: 1.150 t (3Н, СН3); 2.67 m
(2Н, СН2); 6.622–7.657 m (9Н, С6Н5ОС6Н3); 7.442–
7.467 d (1H, CH-CN). Found, %: C 77.91, 77.92; H
5.93, 5.98; N 3.63, 3.68. Calculated, %: C 77.92; H
5.97; N 3.67.
IR spectrum, ν, cm–1: 1676 (С=С); 3064 (С–Н);
1
1509 (NH+); 1630 (С=N); 1240–1070 (С–О–С). Н
NMR spectrum, δ, ppm: 1.154 t (3Н,СН3); 4.207 m
(2Н, СН2); 6.935–7.657 m (9Н, С6Н5ОС6Н3); 7.914 m
(1Н, NH); 7.46–7.48 d (1H, Ar-CH); 5.62–5.67 d (1H,
CH–CN). Found, %: C 67.26, 67.24; H 5.90, 5.98; N
4.67, 4.70; Сl 11.71; 11.72. Calculated, %: C 67.22; H
5.93; N 4.61; Сl 11.7.
N-Benzoyl-substituted ethylimidate of 2-methyl-
2-(3-phenoxybenzoyloxy)propionic acid (IX) was
prepared similarly. IR spectrum, ν, cm–1: 1654 (С=N);
1
2938 [ν(СH)]; 1287 [δ(СН3)]; 1732 (C=O). Н NMR
spectrum, δ, ppm: 1.8 s (6Н, СН3); 1.2 t (3Н, СН3); 4.2
m (2Н, СН2); 6.9–7.8 m (9Н, С6Н5ОС6Н4); 9.0 m (1Н,
NH). Found, %: C 72.36, 72.38; H 5.80, 5.86; N 3.22,
3.30. Calculated, %: C 72.39; H 5.80; N 3.25.
Hydrochloride of ethylimidate of 3-(3-phenoxy-
phenyl)-2-butenic acid (V) was prepared similarly. IR
spectrum, ν, cm–1: 1672 (С=С); 2930–3070 (С–Н);
1
1486 (NH+); 1638 (С=N); 970–1126 (С–О–С). Н
N-Benzoyl-substituted amidine of 3-(3-phenoxy-
phenyl)-2-propenic acid (X). To a solution of 4.8 g
(0.014 mol) of compound VII in anhydrous benzene
was added 1.23 g (0.017 mol) of p-bromoaniline under
stirring and cooling with water bath. Then the reaction
mixture was kept at 55–60°С for 2 h. The product was
NMR, δ, ppm: 1.150 t (3Н, СН3); 2.67 m (2Н, СН2);
6.622–7.657 m (9Н, С6Н5ОС6Н3); 7.64 m (1Н,NH);
7.442–7.467 d (1H, CH–CN). Found, %: C 67.96,
68.04; H 6.29, 6.48; N 4.37, 4.40; Сl 11.17; 11.18.
Calculated, %: C 68.03; H 6.30; N 4.41; Сl 11.18.
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471
SYNTHESIS OF NEW DERIVATIVES OF DIPHENYL OXIDE
isolated and purified by column chromatography
eluting with a mixture diethyl ether : hexane (2:1).
Yield 98% (0.137 mol), bp 252–254°С (4 mm Hg). IR
spectrum, ν, cm–1: 3320-3450 (С–N, N–H); 1740 (N–
H); 1695 (С=О); 1678 (С=N); 1240-1070 (С-О-С). 1Н
NMR spectrum, δ, ppm: 6.839–7.657 m (9Н,
С6Н5ОС6Н3); 3.55 s (1H, NH); 7.44-7.46 d (1Н, Ar-
CH); 5.62–5.67 d (1Н, СH–CN). Found, %: C 68.15,
68.22; H 4.18, 4.26; N 4.85, 4.88; Br 16.20, 16.24.
Calculated, %: C 68.15; H 4.26; N 4.87; Br 16.23.
prepared similarly, bp 258–260°С (4 mm Hg). IR
spectrum, ν, cm–1: 1654 (С=N); 2938 [ν(СH)]; 1287 [δ
(СН3)]; 1732 (C=O). 1Н NMR spectrum, δ, ppm: 1.8 s
(6Н, СН3); 6.9–7.8 m (9Н, С6Н5ОС6Н4); 3.45 s (1Н,
NH). Found, %: C 65.06, 65.22; H 4.48, 4.53; N 5.00,
5.10; Br 14.41, 14, 45. Calculated, %: C 65.10; H 4.52;
N 5.10; Br 14.47.
REFERENCES
1. Abdel-Rahman, A., Dechkovskaia, A., Goldstein, L.,
Bullman, S., and Khan, W., J. of Toxicology and
Environmental Health, Part A, vol. 67, 2004, p. 331.
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Application), Moscow: Khimiya, 1987.
3. Khimicheskaya entsyklopediya (Chemical Encyclo-
pedy), Knunyants, I.L., Ed., Moscow: Bol’shaya
Rossiiskaya Entsyklopediya, vol. 3, 1992.
N-Benzoyl-substituted amidine of 3-(3-phenoxy-
phenyl)-2-butenic acid (XI) was prepared similarly,
bp 260–262°С (4 mm Hg). IR spectrum, ν, cm–1:
3350–3500 (С–N, N–H); 1755 (N–H); 1708(С=О);
1
1672 (С=N); 970–1126 (С–О–С). Н NMR spectrum,
δ, ppm: 6.622–7.657 m (9Н, С6Н5ОС6Н3); 7.442–
7.467 s (1H, CH-CN); 3.55 s (1H, NH); 2.22–2.35 s
(3Н, CH3). Found, %: C 68.61, 81.42; H 4.98, 5.00; N
6.28, 6.30; Br 15.78, 15, 81. Calculated, %: C 68.64; H
4.54; N 4.73; Br 15.78.
4. Smirnova, M.V., Candidate Sci. (Chem.) Dissertation,
Volgograd, 2008.
5. Zil’berman, E.N., Reaktsii nitrilov (Nitriles Reactions),
N-Benzoyl-substituted amidine of 2-methyl-2-(3-
phenoxyenzoyloxy)propionic acid (XII) was
Moscow: 1972, p. 449.
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