Synthesis of 2-(3-phenoxyphenyl)-substituted benzoxazoles, based on nitriles containing the diphenyl oxide fragment

Article abstract of DOI:10.1007/s10593-011-0822-0

A method is proposed for the preparation of 2-(3-phenoxyphenyl)-substituted benzoxazoles, which are of interest as structural blocks for the synthesis of compounds possessing potential biological activity.

Full text of DOI:10.1007/s10593-011-0822-0

Chemistry of Heterocyclic Compounds, Vol. 47, No. 6, September 2011 (Russian original Vol. 47, No. 6, June, 2011)
SYNTHESIS OF 2-(3-PHENOXYPHENYL)-
SUBSTITUTED BENZOXAZOLES,
BASED ON NITRILES CONTAINING
THE DIPHENYL OXIDE FRAGMENT
Yu. V. Popov1*, T. K. Korchagina1, and V. S. Lobasenko1
A method is proposed for the preparation of 2-(3-phenoxyphenyl)-substituted benzoxazoles, which are of
interest as structural blocks for the synthesis of compounds possessing potential biological activity.
Key words: o-aminophenol, benzoxazole, diphenyloxide, nitrile, 3-phenoxyphenyl fragment.
Substituted benzoxazoles possess high biological activity. It is known that benzoxazole is produced by
plants to protect themselves against diseases and pests. On the market there are insectoacaricides with contact
and intestinal action – Zolon, based on a natural benzoxazole [1] and 2-aryl-substituted benzoxazoles may be
used as herbicides [2]. Some derivatives of benzoxazoles are effective for treatment of diabetes, migraine, and
display neuroleptic properties [3]. The preparations Rispolept, and Risperidone are derivatives of benzoxazole
which have antipsychotic effects and are effective against schizophrenia [4, 5].
From the literature analysis it may be concluded that the practical value of benzoxazoles in the first
place is determined by the substituent nature in a heterocyclic ring. In this connection there has been
considerable interest in the introduction of the 3-phenoxyphenyl fragment in the benzoxazole ring since the
combination of different pharmacophores in a molecule permits the broadening of the range of biological
activity or its strengthening as a synergism result. For example, such derivatives of diphenyl oxide as Permethrin
[(3-phenoxyphenyl)methyl ester of 3-(2,3-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid] and Phe-
nothrin [(3-phenoxyphenyl)methyl ester of 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylic acid]
are used as medicines possessing antiparasitic, anti-louse, insecticidal, ovicidal pharmacological effects. There
are examples of the use of phenoxyphenylacetylenes, obtained on the basis of 1-(2-methyl-4-phenoxyphenyl)-
ethanone and 1-(3-phenoxyphenyl)ethanone, as antithrombotic, anti-inflammatory, antipyretic agents, and
analgesics [6].
In the present work we suggested the possibility of preparing 2-(3-phenoxyphenyl)-substituted benzoxa-
zoles 3a–i on the basis of the nitriles 1a–i, which contain the diphenyl oxide fragment, and o-aminophenol hyd-
rochloride 2 [7].
_______________
*To whom correspondence should be addressed, e-mail: viktori_2008@bk.ru.
1Volgograd State Technical University, 28 Lenin Pr., Volgograd 400131, Russia
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 849–851, June, 2011. Original article
submitted March 16, 2011.
0009-3122/11/4706-0700©2011 Springer Science+Business Media, Inc.
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During the course of the study, it was established that the reaction occurred at 190–200°C without sol-
vent, with yields of 32–80% after recrystallization from ethanol. The low yield of compound 3i is a result of
steric hindrance arising from the complex structure of the nitrile 1i which contains two diphenyl oxide frag-
ments. A period of 7–10 h was required for the synthesis of the 2-(3-phenoxyphenyl)-substituted benzoxazoles
3a–i. Hydroquinone was added to the reaction mixture for the successful synthesis of benzoxazoles 3c,d,i
avoiding polymerization of the unsaturated nitriles 1c,d,i at the high reaction temperature.
N
.
O
X
O
X
N
NH2 HCl
ꢀ
O
+
– NH4Cl
OH
1a–i
2
3a–i
1, 3 a X is absent, b X= –CH2–, c X= –CH=CH–, d X= –(Me)C=CH–, e X= –(CH2)2,
f X = CH NH(CH ) –,
g X= –CH O(CH ) –, h X= –(C=O)OC(Me) –,
i X= –CH=C–C6H4OC6H5
2
2 2
2
2 2
2
Compounds 3a–i are dark-colored crystalline substances, soluble in DMF, DMSO, CCl4, benzene, and
ether, and on heating in ethanol and methanol. They are insoluble in water. The structures of compounds 3a–i
were confirmed by the absence of the nitrile stretching frequency from their IR spectra.
So previously unknown 2-(3-phenoxyphenyl)-substituted benzoxazoles have been synthesized, based on
nitriles containing the 3-phenoxyphenyl unit and o-aminophenol hydrochloride.
EXPERIMENTAL
IR spectra of nujol mulls were recorded at a Specord M-83 spectrometer. 1H NMR spectra of CCl4 solu-
tions (compounds 3a–c) and DMSO-d6 solutions (compounds 3d–i) with HMDS internal standard (ꢀ 0.05 ppm)
were recorded at a Varian Mercury 300B spectrometer (300 MHz). Mass spectra were recorded at a Varian
Saturn 2100T with an ionization energy of 70 eV.
Compounds 3a–i (General Method). A mixture of o-aminophenol hydrochloride 2 (0.012 mol) and
nitrile 1 (0.01 mol) was heated for 7–10 h in a sealed glass ampoule at 190–200°C. Hydroquinone (1–2 mg) was
added to the reaction mixture for the synthesis of benzoxazoles 3c,d,i . The reaction mixture was triturated with
ether, filtered, and washed with 4 N sodium hydroxide solution. The ether layer was filtered again, washed with
water, the solvent was evaporated, and the residue recrystallized from ethanol.
2-(3-Phenoxyphenyl)benzoxazole (3a). Yield 74%; mp 130–132°C. 1H NMR spectrum, ꢀ, ppm: 7.15–
7.75 (13H, m, H Ar). Mass spectrum, m/z (Irel, %): 287 [M]+ (100), 63 (16). Found, %: C 79.02; H 4.53; N 4.89.
C19H13NO2. Calculated, %: C 79.43; H 4.56; N 4.88.
2-(3-Phenoxybenzyl)benzoxazole (3b). Yield 80%; mp 137–140°C. 1H NMR spectrum, ꢀ, ppm: 7.10–
7.80 (13H, m, H Ar); 3.81 (2H, s, CH2). Mass spectrum, m/z (Irel, %): 301 [M]+ (64), 300 (100), 132 (25), 77
(17), 63 (11), 51 (13). Found, %: C 79.74; H 5.01; N 4.63. C20H15NO2. Calculated, %: C 79.72; H 5.02; N 4.65.
2-[(E)-2-(3-Phenoxyphenyl)vinyl]benzoxazole (3c). Yield 76%; mp 120–122°C. 1H NMR spectrum, ꢀ,
ppm (J, Hz): 7.10–7.65 (13H, m, H Ar); 7.44 (1H, d, J = 12.0, ArCH=CH); 5.25 (1H, d, J = 12.0, ArCH=CH).
Mass spectrum, m/z (Irel,%): 313 [M]+ (36), 312 (100). Found, %: C 80.48; H 4.78; N 4.48. C21H15NO2.
Calculated, %: C 80.49; H 4.82; N 4.47.
1
2-[2-(3-Phenoxyphenyl)propen-1-en-1-yl]benzoxazole (3d). Yield 64%; mp 140–142°C. H NMR
spectrum, ꢀ, ppm: 7.12–7.84 (13H, m, H Ar); 6.62 (1H, s, CH); 2.42 (3H, s, CH3). Mass spectrum, m/z (Irel,%):
327 [M]+ (100), 207 (13). Found, %: C 80.72; H 5.18; N 4.29. C22H17NO2. Calculated, %: C 80.71; H 5.23;
N 4.28.
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1
2-[2-(3-Phenoxyphenyl)ethyl]benzoxazole (3e). Yield 56%; mp 135–137°C. H NMR spectrum, ꢀ,
ppm (J, Hz): 7.10–7.70 (13H, m, H Ar); 2.82 (2H, t, J = 6.0, ArCH2CH2); 3.45 (2H, t, J = 6.0, ArCH2CH2).
Mass spectrum, m/z (Irel,%): 315 [M]+ (100), 207 (17). Found, %: C 80.00; H 5.41; N 4.44. C21H17NO2.
Calculated, %: C 79.98; H 5.43; N 4.44.
2-[2-(3-Phenoxybenzylamino)ethyl]benzoxazole (3f). Yield 80%; mp 127–130°C. 1H NMR spectrum,
ꢀ, ppm (J, Hz): 6.85–7.70 (13H, m, H Ar); 3.51 (1H, s, NH); 3.64 (2H, s, ArCH2N); 2.26 (2H, t, J = 6.0, NCH2);
2.69 (2H, t, J = 6.0, NCH2CH2). Mass spectrum, m/z (Irel,%): 344 [M]+ (100), 312 (24), 285 (14), 63 (25). Found,
%: C 76.69; H 5.85; N 8.09. C22H20N2O2. Calculated, %: C 76.72; H 5.85; N 8.13.
1
2-{2-[(3-Phenoxybenzyl)oxy]ethyl}benzoxazole (3g). Yield 51%; mp 143–145°C. H NMR spectrum,
ꢀ, ppm (J, Hz): 7.00–7.75 (13H, m, H Ar); 4.20 (2H, s, ArCH2O); 3.32 (2H, t, J = 6.0, OCH2CH2); 2.23 (2H, t,
J = 6.0, OCH2CH2). Mass spectrum, m/z (Irel,%): 345 [M]+ (100), 63 (12). Found, %: C 76.52; H 5.50; N 4.00.
C22H19NO3. Calculated, %: C 76.50; H 5.54; N 4.06.
1
1-(Benzoxazol-2-yl)-1-methylethyl-3-phenoxybenzoate (3h). Yield 62%; mp 160–162°. H NMR
spectrum, ꢀ, ppm: 6.80–7.20 (13H, m, Ar H); 1.80 (6H, s, 2CH3). Mass spectrum, m/z (Irel,%): 373 [M]+ (2),
289 (17), 287 (100). Found, %: C 74.02; H 5.18; N 3.73. C23H19NO4. Calculated, %: C 73.98; H 5.13; N 3.75.
1
2-[1,2-Bis(3-phenoxyphenyl)vinyl]benzoxazole (3i). Yield 32%; mp 180–182°C. H NMR spectrum,
ꢀ, ppm: 6.80–7.25 (23H, m, H Ar). Mass spectrum, m/z (Irel, %): 481 [M]+ (14), 480 (100), 352 (51), 281 (17),
207 (28), 77 (29), 51 (18). Found, %: C 82.32; H 4.88; N 2.89. C33H23NO3. Calculated, %: C 82.31; H 4.81;
N 2.91.
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