Mononuclear Heterocyclic Rearrangement of 5-Arylisoxazole-3-hydroxamic Acids into 3,4-Substituted 1,2,5-Oxadiazoles

Abstract

By a series of successive transformations, 5-arylisoxazole-3-carboxylic acids (aryl = phenyl, p-tolyl, 2,5-dimethylphenyl) have been converted into 5-arylisoxazole-3-hydroxamic acids, which undergo rearrangement by the action of aqueous KOH to form 3,4-substituted 1,2,5-oxadiazoles. The structure of one of them, 1-(2,5-dimethylphenyl)-2-(4-hydroxy-1,2,5-oxadiazol-3-yl)ethanone, has been confirmed by single crystal X-ray analysis.The chemistry of 1,2,5-oxadiazole (trivial name furazan) is of great interest, because a large number of compounds incorporating furazan cycle possess a wide spectrum of biological activity. 1 Moreover, they attract great attention as energetic materials, 2 dyes, and precursors for organic synthesis of useful products. 3 There are different methods available for the synthesis of furazans. One of them is based on the mononuclear heterocyclic rearrangement of the isoxazoles bearing an oxime group in the 3 position of the heterocycle. 4 Hydroxamic acids can be considered as synthetic equivalents of oximes as they can exist in two tautomeric forms, keto or enol (Scheme 1). 5 The latter is produced in low percentage, is less stable, and contains the oxime moiety. Scheme 1 Tautomeric forms of hydoxamic acidsThe transformation of isoxazolylhydroxamic acids and their derivatives into furazans is not described up till now. We intended to synthesize the 5-arylisoxazole-3-hydroxamic acids (aryl = Ph, 3-MeC 6 H 4 , 2,5-Me 2 C 6 H 3 ) 1-3 and their O-acetyl derivatives 4-6, and to study the possibility of their use in obtaining substituted 1,2,5-oxadiazoles via mononuclear heterocyclic rearrangement. The 5-arylisoxazole-3-carboxylic acids 7-9 were taken as starting compounds. Recently, we have reported their synthesis from the corresponding available 5-arylisoxazole-3-carbaldehyde oximes. 6 Two approaches were tested for the synthesis of arylisoxazole-3-hydroxamic acids 1-3. One of them included the amidation of methyl 5-arylisoxazole-3-carboxylates 10-12 by reaction with hydroxylamine. Another path consisted in acylation of hydroxylamine by the action of 5-arylisoxazole-3-carbonyl chlorides 13-15, easily obtained by the reaction of acids 7-9 with thionyl chloride. The former approach was found to be more preferable, as it allows to obtain the target hydroxamic acids 1-3 in higher yields (75-88% instead of 51-60% in the latter approach) and with higher purity. Thus, the first approach was used in practice. Acetylation of hydroxamic acids proceeded selectively on the hydroxy group and led to the corresponding acetyl derivatives 4-6 in 83-96% yields (Scheme 2).At first it was planned to convert the O-acetylhydroxamic acids 4-6 into 3-amino-5-arylisoxazoles by heating with aqueous alkali. The conversion of O-acylhydroxamic acids to isocyanates and further to amines or ureas is well known as Lossen rearrangement. 7 However, the process proceeded quite differently and led to 1-aryl-2-(4-hydroxy-1,2,5-oxadiazol-3-yl)ethanones 16-18, that is, substituted furazans (Scheme 2). The hydrolysis of acylated fragme...

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“…The synthesis of 4,5-diarylisoxazole-3-carboxylic acids 1 – 4 is outlined in Scheme 3. Methyl 5-phenylisoxazole-3-carboxylate 14 is well known 20,21 and was synthesized from acetophenone by a slight modification of literature procedures (see Experimental Methods). Following bromination of the methyl carboxylate 14 , Suzuki couplings of the bromoisoxazole 15 (22) with phenyl-, 3-methoxyphenyl-, and 3-hydroxyphenyl-boronic acids gave the 4,5-diarylisoxazole-3-carboxylates 16 , 23 17 , and 18 .…”

“…The white precipitate was filtered off, washed with water, and then dissolved in EtOAc. The solution was dried (MgSO 4 ) and concentrated under reduced pressure to give the title compound 14 as a white solid (18.4 g, 90.6 mmol, 88%); mp 81.8–82.5 °C (lit . 80–82 °C); TLC (Et 2 O:light petroleum, 10:90 v/v) R f = 0.2; 1 H NMR (300 MHz, DMSO- d 6 ) δ 7.98–7.92 (m, 2H), 7.57–7.52 (m, 3H), 7.51 (s, 1H), 3.92 (s, 3H); 13 C NMR (75 MHz, DMSO- d 6 ) δ171.1, 159.8, 156.6, 131.0, 129.3, 126.0, 125.8, 100.8, 52.8; IR (film) 3130, 2951, 1724, 1612, 1591, 1571, 1445, 1425, 1246, 1141, 1004, 946, 934, 920, 851, 837, 807, 781, 764 cm –1 .…”

“…Methyl 5-Phenylisoxazole-3-carboxylate (14). 20,21 Sodium methoxide (18.36 g, 340 mmol) in MeOH (80 mL) was added to acetophenone (20 mL, 161.92 mmol) and dimethyl oxalate (28.66 g, 242.9 mmol) in MeOH (450 mL) at rt, and the solution was stirred at rt for 2 h before being cooled to rt and poured into aqueous hydrogen chloride (2 M, 800 mL). The solid methyl 2,4-dioxo-4-phenylbutanoate was filtered off, washed with water, and used in the next step without further purification.…”

“…The solution was dried (MgSO 4 ) and concentrated under reduced pressure to give the title compound 14 as a white solid (18.4 g, 90.6 mmol, 88%); mp 81.8−82.5 °C (lit. 21 Methyl 4-Bromo-5-phenylisoxazole-3-carboxylate (15). 22 N-Bromosuccinimide (6.85 g, 38.47 mmol) was added to methyl 5phenylisoxazole-3-carboxylate 14 (7.1 g, 34.98 mmol) in trifluoroacetic acid (100 mL), and the solution was stirred under reflux for 48 h before being cooled to rt and poured onto ice.…”

Mechanochemistry Enabled Construction of Isoxazole Skeleton via CuO Nanoparticles Catalyzed Intermolecular Dehydrohalogenative Annulation

“…Ethyl 5-hexylisoxazole-3-carboxylate (3 g) [12g] Clear oil; Yield: 189 mg (84%); FT-IR (neat): υ = 1716, 1597, 1223 cm À 1 ; 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 6.33 (s, 1H), 4.36 (q, J = 7.5 Hz, 2H), 2.72 (t, J = 7.5 Hz, 2H), 1.66 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.5 Hz, 3H), 1.30-1.28 (m, 2H), 1.25-1.22 (m, 4H), 0.82-0.80 (m, 3H); 13 Methyl 5-phenylisoxazole-3-carboxylate (3 h) [44] White solid; Yield: 173 mg(85%); mp65-67 °C; FT-IR (neat): υ = 1722, 1648, 1235 cm À 1 ; 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 7.74-7.72 (m, 2H), 7.41-7.40 (m, 3H), 6.86 (s, 1H), 3.93 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ): δ (ppm) 171.8, 160.5, 156.7, 130.9, 129.2, 126.6, 125.9, 99.9, 52.9. [44] White solid; Yield: 193 mg(89%); mp128-130 °C; FT-IR (neat): υ = 1728, 1642, 1226 cm À 1 ; 1 H NMR (500 MHz, CDCl 3 ): δ (ppm) 7.70 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 6.88 (s, 1H), 4.01 (s, 3H), 2.42 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ): δ (ppm) 172.0, 160.5, 156.6, 141.3, 129.8, 125.9, 123.9, 99.3, 52.9, 21.5.…”