A Convenient Synthesis of 5-Trichloromethyl-5-hydroxy-3-heteroalkyl-4,5-dihydroisoxazoles

Abstract

A synthetic strategy to obtain a series of 3-heteroalkyl-4,5-dihydroisoxazoles, which is based on the cyclocondensation reaction of 5-heteroalkyl-1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones 1a-g, 2a-g with hydroxylamine has been developed. The preparation of 1,1,1-trichloro-5-heteroalkyl-4-methoxy-3-penten[hexen]-2-ones in good yields is also described.Isoxazole derivatives possess very interesting pharmacological properties, especially some heteroalkylisoxazoles such as semi-synthetic penicillins and cephalosporins that were prepared from 2-(3-chloroisoxazole-5-il)acetic acid, 1 muscimol an analog of g-aminobutiric acid (GABA), 2 the 3-aminomethylisoxazole and the furtetronium (2-trimethylamonium methylfurane) a GABA A receptor. 3As part of our research program, we have developed general synthesis of 1,1,1-trihalo-4-methoxy-3-alken-2-ones 4,5 and demonstrated their usefulness in the preparation of heterocycles. 4,6-8 In general, the presence of a trihalomethyl group in the precursor is a determining factor to establish the regiochemistry of the heterocyclic ring 5-8 and increases its biological activity. 9-12 The transformation of the trichloromethyl group under mild conditions 8 into carboxylic groups prompted us to devote special attention to these substrates. Despite extensive studies on the applications of 1,1,1-trihalo-4-alkoxy-3-alken-2-ones in heterocyclic chemistry 4,6-8,13-16 , the strategy to synthesize 5-heteroalkyl substituted 1,1,1-trihalo-4-alkoxy-3-alken-2-ones and their usefulness in the synthesis of heterocycles has not yet been developed. These compounds are highly functionalized intermediates, which may be useful for further synthetic conversions.In this paper we report a new and efficient synthetic approach for the preparation of a series 5-heteroalkyl-1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-one intermediates. 1-3 In a second step, we show a cyclocondensation reaction of 5-heteroalkyl-1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones with hydroxylamine to obtain the related 3-heteroalkyl-4,5-dihydroisoxazoles (Scheme 1).The compounds 1a, 2a were obtained from the reaction of 1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones with bromine in the presence of pyridine. The 1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones were synthesized from the reaction of the enol ethers or acetals with trichloroacetyl chloride. 4,5The allyl nucleophilic substitution reaction for the synthesis of 1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones 1b, 1f, 1g, 2b, 2f and 2g were carried out in acetone at 25°C for 2-96 h (Table 1). In the case of 1c and 2c, under the same conditions, we obtained only starting materials. To obtain compounds 1c and 2c it was necessary to use potassium carbonate (1 equiv) in acetone under reflux for 10-16 h.Compounds 1d, 1e, 2d and 2e were obtained by the reaction of 1a and 2a, respectively, with the appropriate nucleophile in benzene and triethylamine (1 equiv) at 25°C for 2 h. Table 1 shows the reaction conditions used for the synthesis of compounds 1b-g and 2b-g. Scheme 1 i)...

Antinociceptive effect of novel pyrazolines in mice

“…3-Ethoxymethyl-5-ethoxycarbonyl-1H-pyrazole (Pz 1), and its corresponding 1-substituted methyl (Pz 2) and phenyl (Pz 3) analogues were obtained from the cyclocondensation reaction of 5-bromo-1,1,1-trichloro-4-methoxy-3-penten-2-one (15,16) with hydrazine (methyl hydrazine or phenyl hydrazine) using ethanol as a solvent. 3-(1-Ethoxyethyl)-5-ethoxycarbonyl-1H-pyrazole (Pz 4) and its corresponding 1-substituted methyl (Pz 5) and phenyl (Pz 6) analogues were obtained from the cyclo-condensation reaction of 5-bromo-1,1,1-trichloro-4-methoxy-3-hexen-2-one (15,16) with methyl hydrazine or phenyl hydrazine using ethanol as a solvent.…”

Regiospecific synthesis of new fatty N-acyl trihalomethylated pyrazoline derivatives from fatty acid methyl esters (FAMEs)

“…21,22,[25][26][27] Also, the presence of a trihalomethylated group at the vinyl ketone and the chain derived from the fatty acid at the dinucleophile were crucial for the regiochemistry of the reactions, which produced only the 5-trihalomethylated isomers. The suggested pathway to the cyclocondensation reaction is shown in Scheme 2.…”

Synthesis of novel quinolines using TsOH/ionic liquid under microwave

“…Products were characterized by 1 H, 13 C NMR spectroscopy, mass spectrometry and melting points for solid products. Quinolines 3a-f, 8a-11a showed a set of 1 H and 13 C NMR data that corresponded to the proposed structures.…”

“…Products were characterized by 1 H, 13 C NMR spectroscopy, mass spectrometry and melting points for solid products. Quinolines 3a-f, 8a-11a showed a set of 1 H and 13 C NMR data that corresponded to the proposed structures. Compounds 3a-f, 9a, 10a and 11b showed 1 H NMR chemical shifts of the methyl protons (CH 3, H9) as a singlet at d 2.61, and compound 8a showed a shift of the methyl protons (CH 3 , H9) as singlet at d 2.81.…”

“…[13][14][15][16][17][18][19][20] In 2008, our group described the synthesis of a set of trifluoromethyl-cycloalka [b]quinolines from reactions of mono-substituted anilines and 2-trifluoroacetyl-1-methoxycycloalkenes using poly-phosphoric acid (PPA). 21 In this synthesis, it was explored the well-known reactivity of 1,3-dielectrophilic of 4-alkoxyvinyl ketones.…”