3- isoxazoles, precursor

Isoxazole-oxazole photoisomerization was studied by irradiation of matrix-isolated 3,5-dimethylisoxazole (18) at 222 nm. 2-Acetyl-3-methyl-2H-azirine (20) was obtained, likely through an acetyl vinyl nitrene intermediate 19 as primary photoproduct, while upon longer time UV irradiation, two additional photoproducts were identified as acetyl nitrile ylide 21 and 2,5-dimethyloxazole (22) (13JOC10657). Analogously, 3,5-diphenylisoxazole and 2-benzoyl-3-phenyl-2f/-azirine behaved as precursors to triplet vinyl nitrene (of type 19) through laser flash photolysis (13JOC11349). Reductive heterocycle—heterocycle transformations of (2-nitrophenyl)isoxazole precursors, such as 23 and 26, afforded 4-amino quinolines of type 24, quinolin-4(lfJ)-ones 25, and 3-acylindoles 27. Che-moselective heterocyclizations were observed from 3,4-,4,5-, and 3,4-bis(2-nitrophenyl)isoxazoles (13OL2062). 

Most reactions leading to isoxazoles must involve at some stage cyclization of an intermediate which contains all five atoms of the isoxazole ring. In some cases the acyclic intermediates are short-lived and unisolable, in others they are stable and able to be isolated. In this section we discuss reactions which involve an isolable acyclic precursor. These reactions mostly utilize (CCCNO) synthons although a few examples of (OCCCN), (CCCON) and (CONCC) synthons are encountered. We are unaware of examples involving (CNOCC) synthons. 

Although the unsaturated nitrile oxides 124 can be prepared via the aldoxime route (see Scheme 8), the older procedure suffers from the disadvantage that a tenfold excess of allyl alcohol and two additional steps are required when compared to Scheme 15. Therefore, unsaturated nitro ether 123 that can be prepared by condensation of an aldehyde 120 and a nitro alkane followed by Michael addition of alcohol 122, was a useful precursor to nitrile oxide 124 [381. The nitrile oxide 124 spontaneously cyclized to ether 125. This procedure is particularly suitable for the synthesis of tetrahydrofurans (125a-h) and tetrahydropyrans (125i-k) possessing Ar substituents in 72-95% yield (Table 12). The seven-membered ether 1251 was obtained only in 30% yield on high dilution. The acetylenic nitro ether 126 underwent INOC reaction to provide the isoxazole 127. 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

As discussed in Section 6.2, nitro compounds are good precursors of nitrile oxides, which are important dipoles in cycloadditions. The 1,3-dipolar cycloaddition of nitrile oxides with alkenes or alkynes provides a straightforward access to 2-isoxazolines or isoxazoles, respectively. A number of ring-cleaving procedures are applicable, such that various types of compounds may be obtained from the primary adducts (Scheme 8.18). There are many reports on synthetic applications of this reaction. The methods for generation of nitrile oxides and their reactions are discussed in Section 6.2. Recent synthetic applications and asymmetric synthesis using 1,3-dipolar cycloaddition of nitrile oxides are summarized in this section. 

Macrocycles containing isoxazoline or isoxazole ring systems, potential receptors in host—guest chemistry, have been prepared by multiple (double, triple or quadruple) 1,3-dipolar cycloadditions of nitrile oxides, (prepared in situ from hydroxamoyl chlorides) to bifunctional calixarenes, ethylene glycols, or silanes containing unsaturated ester or alkene moieties (453). This one-pot synthetic method has been readily extended to the preparation of different types of macrocycles such as cyclophanes, bis-calix[4]arenes and sila-macrocycles. The ring size of macrocycles can be controlled by appropriate choices of the nitrile oxide precursors and the bifunctional dipolarophiles. Multiple cycloadditive macrocy-clization is a potentially useful method for the synthesis of macrocycles. 

The synthesis of new 11-deoxyprostaglandin analogs with a cyclopentane fragment in the oo-chain, prostanoid 418, has been accomplished by a reaction sequence involving nitrile oxide generation from the nitromethyl derivative of 2-(oo-carbomethoxyhexyl)-2-cyclopenten-l-one, its 1,3-cycloaddition to cyclopenten-l-one and reductive transformations of these cycloadducts (459). Diastereoisomers of a new prostanoid precursor 419 with a 4,5,6,6a-tetrahydro-3aH-cyclopent[d isoxazole fragment in the oo-chain have been synthesized. Reduction of 419 gives novel 11-deoxyprostanoids with modified a- and oo-chains (460). 

In this reaction, isoxazole (173) rather than the corresponding aziridine was isolated in good yield. It was stated (223) that acyl nitronate (172) rather than the corresponding nitrile oxide is a precursor of isoxazole (173). This interpretation is supported by the fact that the corresponding nitrile oxide dimer (furoxan (174))... 

Isoxazolines are partially unsaturated isoxazoles. In most cases these compounds are precursors to the isoxazoles, and as a result, the synthesis can also be found in Sect. 3.2.1b. Kaffy et al., used a 1,3-dipolar cycloaddition of a nitrile oxide (186) with the respective styrene (201a or b) to generate isoxazolines (202a or b, respectively). Depending on the substitution of the vinyl portion of the styrene molecule, either 3- or 4-substituted isoxazolines could be formed (Scheme 55) [94], Simoni et al. employed similar chemistry to produce isoxazolines [60]. Kidwai and Misra emplyed microwave technology to treat chalcones with hydroxylamine and basic alumina [99]. The isoxazoles synthesized by Simoni et al. possess anti-proliferative and apoptotic activity in the micromolar range [60]. 

Intramolecular [3+2] dipolar cycloadditions have also been employed as a post-Ugi transformation to generate heterobicyclic structures, namely fused isoxazolines [130], isoxazoles [130] and triazoles [131] (Fig. 31). Isoxazoles were obtained through intramolecular nitrile oxide cycloaddition. The precursor of the nitrile oxide (a nitro group) was introduced into the carboxylic component, while a triple bond was positioned in the starting amine. Treatment of 152 with POCl3/Et3N gave the intermediate nitrile oxide, which spontaneously cyclized to isoxazoles 153. 

Inhibits the enzymes alanine racemase and D-alanyl-D-alanyl synthetase that are responsible for producing the dipeptide D-alanyl-D-alanine, a precursor of the pentapeptide chain in cell wall formation. It is believed that the rigid structure of the isoxazole ring gives the drug a better chance of binding to the enzyme than the more flexible structure of D-alanine. 

Fused ring systems can be prepared either from an azine precursor or from an isoxazole or isothiazole precursor. In the sections on synthesis of these compounds the former method is grouped under Azine approach , the latter under Azole approach . 

Also, the rigidification of the galactose ring was not sufficient to block the elimination of the 2-azido substituent of 17 even using the low-temperature reagent (Fig. 5). Another failure occurred with the isoxazole sulfone 19. Here, the heterocycle did not survive base treatment. The isoxazole sulfide precursor was also unstable to base (Fig. 6). 

The kinetics of hydrolysis of energetic material precursors - mono- and dinitro derivatives of pyrazole, imidazole, 1,2,4-triazole, and isoxazole has been studied by the polarographic and photometric methods [647], The alkaline hydrolysis rate constants experimentally determined depend on the nature of the heterocycle. A possible mechanism for hydrolytic transformations of nitroazoles is proposed on the basis of the calculated thermodynamic parameters of the reaction. 

Very many syntheses of isoxazoles from other heterocyclic compounds have been reported. The subject of ring transformations of heterocycles has been well reviewed35-37 and since many of the reactions are covered by the categories already discussed (the starting heterocycle serving merely as precursor of the appropriate intermediate), only a brief summary, with... 

To access substitution pattern of azuidinomitosene A, 116 the use of the isoxazole ring as a precursor of an azomethine ylide proved useful. Treatment of compound 117 with silver triflate and a cyanide salt afforded compound 118 <07JOC8506>. 

In order to adapt this strategy to the synthesis of lamellarin O dimethyl ether, a 3-unsubstituted keto-enamine 4 was prepared by hydrogenolysis of precursor isoxazole 3. 

Isoxazoles can be easily prepared from isoxazoline precursors through dehydrogenation or elimination processes. This aspect (see Section 4.03.6.2) is not discussed in detail in this section. 

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