Synthesis of Isoxazole Derivatives

For the preparation of compounds with an aromatic isoxazole system, two synthetic paths are of high importance first the condensation to form the 1—5 and the 2—3 bonds of the isoxazole ring (I— 2) and second that to form the 1—5 and 3—4 bonds of this 

Syntheses of Isoxazoles Which Involve Formation of the 1—5 and 2—3 Bonds of the Isoxazole Ring 

The isoxazole ring is synthesized through the long known and extensively elaborated method of condensing j8-diketones or their derivatives with hydroxylamine. 

A number of recent papers have described the use of new types of /3-diketone derivatives to synthesize isoxazoles. We must first mention 1,1,3,3-tetraalkoxypropanes which are now manufactured on a large scale. Condensation of these derivatives with hydroxylamine has made readily available the parent compound, unsubstituted isoxazole itself (4). This type of reaction using tetraalkoxypropane 

Some polyketones have been used to synthesize diisoxazolyl alkanes, e.g., 1,4-di- (5 -phenyl-3 -isoxazoly 1) butane.  

Quilico, Atti accad. nail. Lincei, Rend. Classe sci. fis. mat. e nat. 15, 357 (1953). 

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In a unique approach to the synthesis of isoxazole derivatives, a-isonitroso ketone... 

Concluding this review of recent work on the synthesis of isoxazole derivatives, one should mention an interesting reaction, although at present it is of no preparative value. This reaction cannot, strictly speaking, be included in either of the two groups discussed in the foregoing because its mechanism is not yet known. It is a reaction of esters of a, -unsaturated-a-nitroacids (43) with butylamine resulting in isoxazole-3,5-dicarboxylic amides (44)." There is some indication... 

The 3,4-bis(4-fluorophenyl)-l,2,5-oxadiazole 2-oxide 324 was found as a side product in the synthesis of isoxazole derivatives (Scheme 82, method A) <2006AXEo4827>. Dimerization of 3- and 4-nitrobenzonitrile A-oxides gave corresponding 1,2,5-oxadiazole A-oxides (Scheme 82, method B) <1999MI111>. 

The [2 + 3] cycloaddition reaction of nitrile oxides, easily accessible from corresponding aldoximes, with different alkenes is known as an excellent route to isoxazohne derivatives . The reactions of asymmetric addition ° or addition of unsaturated ger-manes and stannanes to nitrile oxides were reviewed in recent years. In this subsection only the main directions of the synthesis of isoxazole derivatives are briefly reported. 

By means of a synthesis of isoxazol derivs with fulminic acid, it was establish that the structure of the acid reported in Ref a is incorrect. It should be 3-isoxazole carboxylic acidl... 

Bharate et al. (2013) applied montmorillonite clay Cu(ll)/NaN3 as a heterogeneous catalytic system for the four-component synthesis of isoxazole derivatives in water. The desired 3,5-disubstituted isoxazoles were obtained in moderate to good yields using the domino reactions of aldehydes, hydroxylamine, Af-chlorosuccinimide (NCS), and acetylenes (Scheme 4.61) the catalytic system could be efficiently recycled. 

Benzylamine added to a mixture of benzylidenebenzylamine and ethyl nitro-acetate, refluxed 2 hrs. 4-phenyl-3,5-bis (benzylcarbamyl) isoxazole. Y 84%.— This is a new synthesis of isoxazole derivatives. F. e. s. S. Umezawa and S. Zen, Bull. Ghem. Soc. Japan 36, 1150, 1146 (1963). 

No mechanism is reported for the synthesis of isoxazole derivatives from various primary nitro compounds by... 

A particular case of the synthesis of isoxazoles via -diketone derivatives is the preparation of 3-halogenoisoxazoles (11) from -nitroketones (9) treated with hydrogen halides. This inter-... 

As shown by the Italian school, the formation of isoxazole derivatives by the action of nitric acid or nitrogen oxides on acetylene derivatives and related reactions proceeds through intermediate nitrile oxides and must, therefore, be included with this type of synthesis. 

Scheme 29 Synthesis of isoxazole-3-hydroxamic acid derivatives...

The chemistry of nitrile oxides, in particular their application in organic synthesis, has been continuously developed over the past two decades and represents the main theme of this chapter. The parent compound, fulminic acid (formonitrile oxide), has been known for two centuries, and many derivatives of this dipole have been prepared since that time. Several simple and convenient methods for the preparation of nitrile oxides have evolved over the years. Dehydrochlorination of hydroximoyl chlorides was first introduced by Werner and Buss in 1894 (1). A convenient synthesis of isoxazoles was reported by Quilico et al. (2 ), and then the discovery of nitrile oxide cycloadditions to alkenes was subsequently noted by the same group (5). 

The use of isoxazole derivatives in organic synthesis is of great interest, but little has been done on the utilization of such compounds as a part of a diene system in [4 + 2]-cycloadditions. 3-Methyl-5-vinylisoxazole 236 gave cycloaddition reactions in a sealed tube in benzene solution at 120°C for 3 days. With the dienophiles acrolein and methyl acrylate, aromatiza-tion of the isoxazole ring via a 1,3-proton shift occurs readily under the reaction conditions, allowing the direct isolation of compounds 237, which are also detected in the mass spectrum of the raw reaction material. The reactions are regioselective (85H2019). 

The isoxazole-to-oxazole rearrangement has been also used in the synthesis of benzocondensed derivatives. The irradiation of benzisoxazoles 81 in water (high-pressure Hg lamp) produces almost quantitative yields of the corresponding ben-zoxazoles 82 (Scheme 12.24) [53]. Benzoxazolin-2-ones 83 are similarly obtained [54], Furthermore, oxazolo[5,4-b]pyridines 84 and oxazolo[5,4-b]quinoline 85 are obtained by preparative-scale photolysis in ether with a high-pressure Hg lamp of the corresponding isoxazolo[5,4-b]pyridines or isoxazolo[5,4-b]quinoline, respectively (Scheme 12.24) [55]. 

Gyclocondensation processes of 1,3-dicarbonyl derivatives or their analogues are widely employed for the synthesis of isoxazoles (see Section 4.03.9.1.1) but are less frequently reported for 4,5-dihydroisoxazoles. 

Although several methods have been reported, the synthesis of iV-monoalkylhydroxylamines from alkyl halides or sulfonates has remained difficult. Relating to this a new preparation of A -alkylhydroxyl-amines is based upon N-alkylation of isoxazole derivative (52). Besides 2-propyl iodide several primary alkyl halides have been described as the alkyladon agent in this procedure (equation 23). ... 

Substituted isoxazoles are of interest because they are versatile building blocks in organic synthesis and evince valuable pharmacological properties. The development of new methodologies for the synthesis and elaboration of isoxazole derivatives enhances more and more the appeal of these compounds. 

An efficient procedure for the synthesis of isoxazoles suitable for a multi-kilogram scale is shown in Scheme 1. An imine 1 is converted into its lithium derivative 2 by the action of lithium diisopropylamide, and an ester is added, The product 3 is treated with aqueous or methanolic hydroxylamine and the resulting oxime 4 (which exists largely as the hemiacetal 4a) is dehydrated to the isoxazole 5 with concentrated sulfuric acid. <97S439>. 5-Alkoxyisoxazoles and /VTV-disubstituted 5-isoxazolamines 6 (R = OMe, NMe2 or NMePh) rearrange to the azirines 7 in the presence of iron(II) chloride <97710911>. 

Pascuar developed a one-pot synthesis of 2-(alkylamino)-4-cyanooxazoles and 5-alkyl-2-(alkylamino)-4-cyanooxazoles by rearrangement of isoxazole-derived thioureas (Scheme 1.27). Reaction of an isoxazole isothiocyanate 94 with primary amines gave the thioureas 95, which were dehydrated to carbodiimides 97... 

High-temperature gas-phase pyrolysis of isoxazole derivatives 99MI27. Isoxazole derivatives in synthesis of prostanoids 99ZOR1749. 

In 1960 a new access to nitrile oxides was provided by dehydration of primary nitro compounds 4, achieved with 2 equiv of phenyl isocyanate, which is converted into diphenylurea, beside the substituted furoxan isoxazole derivatives are obtained in the presence of suitable dipolarophiles (Scheme 8.1) [6,7]. This method for the synthesis of isoxazoles has become popular in turn and both methods have been widely employed over the past 50 years the subject has been repeatedly reviewed [8-15]. 

Under the framework of green chemistry, an efficient and extremely fast procedure for the synthesis of quinazoline derivatives from 2-arylidenetetralin-l-one through a four-step procedure under microwave irradiation has been reported (Mehta et al, 2007). A considerable increase in the reaction rate has been observed with better yield. An efficient synthesis of quinazoline derivatives canying potential pharmacophores like thiazolidinone and isoxazole has also been carried out in an environmentally benign microwave protocol. The yields of the products formed under microwave irradiation were high (85%) in comparison to classical method (62%) and time required for completion of these reactions was also less. 

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