Isoxazoline syntheses

New theoretical calculations of mechanisms of isoxazoline syntheses have been reported. 

In the following section we focus our attention on library analysis, and especially on libraries which are not related to oligomers. To demonstrate the possibilities and limits of this analysis, two typical compound libraries were chosen. The first group of libraries contains an aromatic scaffold, pyrroles, which were synthesized by the Hantzsch pyrrole synthesis. The second class of compounds are heterocyclic isoxazolines synthesized via a 1,3-dipolar cyclo-addition. In both cases the reaction conditions were first established on single compounds. Supporting mass spectrometric data are presented in Section 17.7 (Appendix). 

The selected examples by Studer et al. [159-161] reported the synthesis of two small discrete libraries of isoxazolines (eight compounds) and of amides derived from a Ugi 4CC reaction (ten compounds). The synthesis of the tagging silicon derivative and the scheme for isoxazoline synthesis are reported... 

FIGURE 7.20 Synthesis of tagging silicon derivative and scheme for isoxazoline synthesis. 

Table 10 2-Isoxazoline synthesis from benzonitrile oxide (223).

Figure 17.18. Isoxazoline synthesis via a 1,3-dipolar cyclo-addition.

The selected examples by Studer et al. [97-99] reported the synthesis of two small, discrete libraries of isoxazolines (eight compounds) and of amides derived from a Ugi 4CC reaction (10 compounds). The synthesis of the tagging silicon derivative and the scheme for isoxazoline synthesis are reported in Figure 16. A known silane [100] was coupled quantitatively with bromine in the fluorinated solvent FC-72 [101] and the tagging reagent was used to protect and label the allyl alcohols in THF. After the cycloaddition of the fluorinated dipolarophiles with the nitrile oxides, the protected isoxazolines were finally cleaved with HF/pyridine complex in ethyl ether. The scheme of the purification for each synthetic step is depicted in Figure 17. 

The commonly used reactive intermediates for isoxazoline synthesis are nitrile oxides, and two new ways of generating these... 

Fig. 14 Isoxazolines synthesis through 1,3-dipolar [3+2] cycloaddition reactions between ortho-quinone monoketals and benzonitrile oxides...

In theory, three isoxazolines are capable of existence 2-isoxazoline (2), 3-isoxazoline and 4-isoxazoline. The position of the double bond may also be designated by the use of the prefix A with an appropriate numerical superscript. Of these only the 2-isoxazolines have been investigated in any detail. The preparation of the first isoxazoline, 3,5-diphenyl-2-isoxazoline, from the reaction of )3-chloro-)3-phenylpropiophenone with hydroxylamine was reported in 1895 (1895CB957). Two major syntheses of 2-isoxazolines are the cycloaddition of nitrile A-oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamine. Since 2-isoxazolines are readily oxidized to isoxazoles and possess some of the unique properties of isoxazoles, they also serve as key intermediates for the synthesis of other heterocycles and natural products. 

In 1888 Claisen (1888CB1149) first recognized a general synthesis of isoxazoles (283) by the condensation-cyclization of 1,3-diketones (280) with hydroxylamine. It is now generally accepted that the monoxime (281) of the 1,3-diketone and the subsequent 5-hydroxy-isoxazoline (282) are the intermediate products of the reaction. The isolation of the monoxime (281) and 5-hydroxyisoxazoline (282), which were both readily converted into the isoxazole (283) by treatment with acid or base, has been reported (62HC(17)l). 

Nitrile A-oxides, under reaction conditions used for the synthesis of isoxazoles, display four types of reactivity 1,3-cycloaddition 1,3-addition nucleophilic addition and dimerization. The first can give isoxazolines and isoxazoles directly. The second involves the nucleophilic addition of substrates to nitrile A-oxides and can give isoxazolines and isoxazoles indirectly. The third is the nucleophilic addition of undesirable nucleophiles to nitrile A-oxides and can be minimized or even eliminated by the proper selection of substrates and reaction conditions. The fourth is an undesirable side reaction which can often be avoided by generating the nitrile A-oxide in situ and by keeping its concentration low and by using a reactive acceptor (70E1169). 

This class was first reported in 1924 and was formed 62HC(17)l) by cyclization of a-bromo-/3-aryl-y-nitroketones. The direct synthesis by oxygenation of 2-isoxazolines has not been reported. To date only 3-substituted derivatives have been prepared. Aryl-nitromethanes react with nitrostilbene to form isoxazoline A-oxide by a nitrile ion displacement (Scheme 138) <62HC(17)1, 68TL3375). 

Earlier reported syntheses have been shown to give isoxazolin-5-ones. Other isoxazolin-3-ones have been prepared by the reaction of methylacetoacetic esters and hydroxylamine. An additional synthesis was reported by the action at 0°C of hydroxylamine on ethyl -benzoylpropionate to produce an insoluble hydroxamic acid which cyclized on acid treatment. The hydroxamic acid acetal was similarly transformed into the isoxazolin-3-one (Scheme 149) (71BSF3664, 70BSF1978). 

Isoxazoli dino[2,3-6][A -l,2,5]oxadiazoline synthesis, 6, 997 Isoxazolidone, 5-hydroxy-synthesis, 6, 112 Isoxazoline, 5-hydroxy-synthesis, 6, 61 Isoxazoline, 3-nitro-/V-oxides... 

IsoxazoIine, 4,5-dichIoro-3-phenyI-synthesis, 6, 90 2-IsoxazoIine, 3,5-dimethyl-synthesis, 6, 91 2-Isoxazoline, 3,5-diphenyI-reactions... 

IsoxazoIine, 5-isocyanato-3-phenyI-pyrolysis, 6, 39 2-Isoxazoline, 4-methylene-synthesis, 6, 91... 

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