3.4.5- Trisubstituted isoxazoles

Spectroscopic methods have been successfully applied to the elucidation of some details of the fine structure of isoxazole derivatives. Thus IR spectra revealed steric hindrance in the case of some 3,4,5-trisubstituted isoxazoles for phenylisoxazoles this results in the nonplanarity of the benzene and isoxazole rings and decreasing mutual interaction. 

Denmark SE, Kallemeyn JM (2005) Synthesis of 3,4,5-trisubstituted isoxazoles via sequential [3+2] cycloaddition/silicon-based cross-coupling reactions. J Org Chem 70 2839-2842... 

Trisubstituted isoxazoles 14 with ferrocenyl groups in 4- and 5-position can be synthesized utilizing acid chlorides 4, terminal alkynes 5, and hydroximinoyl chlorides 13 in a sequence consisting of modified Sonoga-shira cross-coupling I and cyclocondensation. Hydroximinoyl chlorides 13 are employed as synthetic equivalents of the corresponding aromatic nitrile... 

Especially useful are the 4-iodo compounds 21 (E = I) due to their potentiality of undergoing various PdcoupHng reactions to yield 3,4,5-trisubstituted isoxazoles. 

Disubstituted and trisubstituted isoxazoles are generally stable to alcoholic and aqueous alkali. Such stability of the ring is characteristic both of alkyl-substituted compounds and of the esters, nitriles, etc., of isoxazole carboxylic acids,for example (127 ->128). 

The cleavage proceeds under extremely mild conditions in aqueous solution at room temperature and can therefore be used for complicated syntheses. The mechanism of this reaction proved to be very complicated and has been elucidated only recently. The ring opening of quaternary salts of trisubstituted isoxazoles by nucleophiles proceeds under similar conditions, and the mechanism of this reaction was extensively studied by Kohler et The authors... 

Disubstituted and trisubstituted isoxazoles are in general comparatively resistant to nucleophilic attack, and many of the reported examples involve rearrangement of the isoxazole before reaction with the nucleophile (see Section III,C). However, if electron-withdrawing substituents are present, reaction is facilitated.1 In compounds with 3-acyl substituents, reaction probably occurs via attack at the carbonyl group (Scheme 8). Such reactions can occur even in the absence of a 5-substituent. In other cases, a mechanism... 

The first FGI is needed to introduce acetyl as the amino protecting group. Disconnection of the N-S bond in the sulfonamido group of TM 7.2a leads to maximal simplification and results in trisubstituted isoxazole TM 7.2b and para-acetylaminobenzensulfonyl chloride TM 7.2c, a commodity product of the chemical industry. Particularly instmctive is the disconnection of the C-O bond in TM 7.2b as rctro-cyclization with participation of the NH2 group (Scheme 7.3). 

In a similar approach, aromatic oximes 66 were oxidized to nitrile oxides 67 in tire presence of a mild trivalent iodine reagent, HTIB (Koser s reagent). Subsequently, the reactive 1,3-dipolar nitrile oxide 67 was treated with various alkynes 68 to afford trisubstituted isoxazoles 69 in good yields (Scheme 12) [28]. 

Disubstituted and trisubstituted 3-isonitrosopyrroles rearrange to 3-acylisoxazoles under the influence of hot, dilute mineral acids. For example, isonitrosotriphenylpyrrole (436), when treated with boiling alcoholic mineral acid, is converted into 3-benzoyl-4,5-diphenyl-isoxazole (437) (62HC(17)1, p. 34). 

Imidazole nitrones 127 reacted with dimethyl acetylenedicarboxylate to yield imidazo[l,5-fc]isoxazoles 128, which in the presence of base afforded imidazoles 129 <00TL5407>. Chiral imidazoline nitrone 130 participated in a [3+2] cycloaddition reaction with various dienophiles to furnish imidazoisoxazoles 131 <00SL967>. A convenient synthesis of AyvyV -trisubstituted ethylenediamine derivatives from 2-methyl-2-imidazoline has been reported <00SC3307>. Dehydrogenation of 1,3-di- and 1,2,3-trisubstituted imidazolidines afforded l//-4,5-dihydroimidazolium salts <00SC3369>... 

When both the 3- and the 5-positions of isoxazole are substituted, stable metalated derivatives can be obtained via direct lithiation at C-4, with subsequent reaction giving rise to a variety of 3,4,5-trisubstituted in very good yields (Scheme 71) (70CJC1371). 

The use of nitro aromatics as dipolarophiles in cycloaddition reactions has shown great utility in heterocyclic synthesis. The reaction of 3-substituted-4-nitroisoxazoles (299) with trisubstituted oxazolium 5-oxides (300) affords an intermediate adduct (301) which eliminates carbon dioxide and nitrous acid to afford 3,4,6-trisubstituted pyrrolo[3,4-r/]isoxazoles (302) (Scheme 56) <93G633>. 

A small library of alkyl, sulfone, and carboxamide-functionalized pyrazoles and isoxazoles has been developed via a rapid sequential condensation of various R-acylketene dithioacetals with hydrazine hydrate or hydroxylamine hydrochloride, followed by oxidation of sulfide to sulfone using water as the reaction medium [3] (Scheme 8.3). An efficient and safe oxidation of sulfides to the corresponding sul-fones using sodium per borate system in aqueous medium has also been reported. The concise and two-step synthesis of trisubstituted pyrazoles and isoxazoles was investigated under a variety of reaction conditions. The newly developed methodology has the advantage of excellent yield and chemical purity with short reaction time using water as a solvent. 

Savant MM, Pansuriya AM, Bhuva CV, Kapuriya N, Patel AS, Audichya VB, Pipaliya PV, NaliparaN (2010) Water mediated construction of trisubstituted pyrazoles/isoxazoles library using ketene dithioacetals. J Comb Chem 12(1) 176-180... 

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