Isoxazoline formation, dipolar

Fig. 15.43. Isoxazoline formation by way of a 1,3-dipolar addition of an in situ generated nitrile oxide to trans-butene.

Phase-transfer addition (c/. Vol. 6, p. 31) of dibromocarbene to carvone and reduction to a monobromo-ketone by tributyltin hydride, or to a dibromo-alcohol with lithium aluminium hydride, is reported/ 1,3-Dipolar cycloaddition of acetonitrile oxide occurs exclusively at the exocyclic double bond in limonene to give (155 R = Me, X = Hi), whereas isoxazoline formation with carvone yields (155 R = Me, X —O) and the isomeric product from attack at the C-6 double bond benzonitrile oxide, however, only yields (155 R = Ph, X = 0 or NOH). A re-investigation of aqueous chlorination of a -terpineol indicates that the diequator-ial chlorohydrin (156) and the corresponding diaxial chlorohydrin are the major... 

Nitrile oxides are usually prepared via halogenation and dehydrohalogenation of aldoximes [11] or via dehydration of primary nitro alkanes (Scheme 1) [12]. However, it is important to note that nitrile oxides are relatively unstable and are prone to dimerization or polymerization, especially upon heating. 1,3-Dipolar cycioaddition of a nitrile oxide with a suitable olefin generates an isoxazoline ring which is a versatile synthetic intermediate in that it provides easy access to y-amino alcohols, )5-hydroxy ketones, -hydroxy nitriles, unsaturated oximes, and a host of other multifunctional molecules (Scheme 1) [5a]. Particularly for the formation of )5-hydroxy ketones, nitrile oxide-olefin cycioaddition serve as an alternative to the Aldol reaction. 

An interesting antibody-catalyzed intermolecular asymmetric 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide and N,N-dimethylacrylamide generating the corresponding 5-acylisoxazoline was observed (216). Reversed regioselectivity of nitrile oxide cycloaddition to a terminal alkene was reported in the reaction of 4-A rt-butylbenzonitrile oxide with 6A-acrylamido-6A-deoxy-p-cyclodextrin in aqueous solution, leading to the formation of the 4-substituted isoxazoline, in contrast to the predominance of the 5-substituted regioisomer from reactions of monosubstituted alkenes (217). 

Akiyama et al. (180) overcame this problem by employing ch/ro-inositol derivatives as chiral auxiliaries for the acrylic ester, which afforded dipolar cycloadducts with a high degree of stereoselectivity (Scheme 6.34). Formation of the major products [(55)-isoxazoline-5-esters] was suggested to arise from the s-cis conformer of acrylate 27, the minor product being derived from the s-trans conformer 28. The bulky protective group (in this case tert-butyldiphenylsilyl) would effectively shield the Re face of the olefinic double bond and destabilize the s-trans conformer 28. 

Another example of oligomer preparation by C-C bond formation is outlined in Figure 16.30. In this synthesis, nitroalkyl phenyl selenides are converted into nitrile oxides in the presence of support-bound terminal alkenes, forming isoxazolines. Oxidative elimination of the selenide yields a new alkene, which can then be subjected to further 1,3-dipolar cycloaddition with a new nitrile oxide. Although this synthesis is short and easy to perform, the cycloadditions proceed with low diastereoselectivity... 

The 3 + 2-cycloaddition of nitrile oxides to 2-crotyl-l,3-dithiane 1-oxides produces exclusively 5-acyldihydroisoxazoles.92 Lewis acid addition to 1,3-dipole cycloaddition reactions of mesityl nitrile oxide with a, /i-unsaturated 2-acyl-1,3-dithiane 1-oxides can reverse the sense of induced stereoselectivity.93 The 1,3-dipolar cycloaddition of 4-t-butylbenzonitrile oxide with 6A-acrylainido-6A-deoxy-/i-cyclodextrin (68) in aqueous solution favours the formation of the 4-substituted isoxazoline (69) rather than the 5-substituted regioisomer (Scheme 24).94 Tandem intramolecular cycloadditions of silyl nitronate, synthons of nitrile oxides, yield functionalized hydrofurans.95... 

Unstable 4-isoxazolines have also been indicated as intermediates in some reactions <2005TL657>. The dihy-droimidazolium nitrone 112 reacted with dimethyl acetylenedicarboxylate (DMAD) to give the dione 115. The formation of this bicyclic product can be rationalized by N-0 bond cleavage of the primary 1,3-dipolar cycloadduct... 

Acetyl- and 3-benzoylisoxazoles 389 (and isoxazolines) have been prepared by one-pot reactions of alkynes (and alkenes) with ammonium cerium(iv) nitrate (CAN(lv)) or ammonium cerium(lll) nitrate tetrahydrate (CAN(m))-formic acid, in acetone or acetophenone. These processes probably involve 1,3-dipolar cycloaddition of nitrile oxides produced via nitration of the carbonyl compound by cerium salts. The existence of nitrile oxides as reaction intermediates was proved by the formation of the dimer furoxan 390 when the above reaction was carried out in absence of any dipolarophile (Scheme 95) <2004T1671>. An analogous improved procedure has been applied to alkynyl glycosides as dipolarophiles for the preparation of carbohydrate isoxazoles <2006SL1739>. 

An antibody-catalyzed 1,3-dipolar cycloaddition between 4-acetamidobenzonitrile oxide and A, A -dimethylacryl-amide has been described for the first time. The most efficient antibody, 29G12, catalyzed the formation of 5-substituted isoxazolines with high regioselectivity which afforded up to 98% ee <2000JA3244>. Further investigation detailed the substrate specificity and mechanistic parameters <2005JOC7810>. 

Michael addition of diethyl cyanomethylphosphonate to a-nitroalkenes in the presence of LDA (1 eq) followed by treatment with Mc,SiOI provides a one-pot synthesis of 2-isoxazoline derivatives. The reaction proceeds through a 1,3-dipolar cycloaddition of trimethylsilyl nitronate with an a-cyanovinylphosphonate. Similarly, the 1,4-addition of the sodium diethyl cyanomethylphosphonate to the azo-ene system of conjugated alkenes results in the formation of l,2-diamino-3-(dietlioxyphosphinyl)pyrroles in moderate to good yields via a hydrazonic intermediate. - In a route to phosphonylated pyrones, the sodium diethyl cyanomethylphosphonate reacts with 3-anilinometliylene derivatives of 4-hydroxycouinaiins in DMF with displacement of aniline. ... 

The first synthesis of this compound to be completed was the result of studies by Smith and co-workers in 1982. The readily available flavor constituent cyclotene (368) (Scheme 2.28) was reduced and isomerized to 2-methyl-2-cyclopenten-l-one (369) in 64% yield. Addition of dimethyl cuprate followed by isomerization and Baeyer-Villiger oxidation gave the racemic 8-lactone 370 (86%). Addition of allyl Grignard reagent followed by formation of the methyl ketal provided a 71% yield of 371, which possesses the expected axial methoxy group. Conversion of the terminal olefin into the functionalized isoxazoline 373 was accomplished in 68% by the 1,3 dipolar cycloaddition of nitrile oxide 372. 

To investigate further modifications of the resin-bound allylic alcohols, we synthesized isoxazolines [24] via a 1,3-dipolar cycloaddition of nitrile oxides. The nitrile oxides were created by using primary nitroalkanes, phenylisocyanate and triethylamine. Two different strategies were followed (Fig. 6.8). When the 3-hydroxy-2-methylidene propionic acids were treated with nitrile oxides, the hydroxy function reacted with phenylisocyanate under carbamate formation. This by-product formation was prevented by alkylating the hydroxy function with benzyl bromides prior to the 1,3-cycloaddition step. 

Dipolar cycloadditions. In the n oxides cocomplexation of the alcohol and dii course in the formation of 2-isoxazolines. Bi cycloadditions to the boron atom of a chiral gen atoms is important to determine the ir products. 

FORMATION OF ISOXAZOLINES AND ISOXAZOLES VIA DIPOLAR CYCLOADDITION BY CATALYTIC OXIDATION OF ALDOXIMES WITH HYDROGEN PEROXIDE AND W(VI) PEROXO COMPLEXES... 

Dipolar cycloadditions of nitrile oxides with alkenes or alkynes give isoxazolines or isoxazoles, respectively. Typically, nitrile oxides are generated in situ, and the cycloaddition reaction occurs smoothly at room temperature. Awide variety of nitrile oxide cycloadditions have been studied on solid support since Yedidia and Leznoff published their smdies in 1980. ° Dimerization of the nitrile oxides has limited the utility of nitrile oxide cycloadditions in solution. Solid-supported reactions enabled the formation of resin-bound nitrile oxide in situ and trapped the reactive 1,3-dipole with an excess of the dipolarophile in solution (Scheme 11.32). Trityl resin-bound cycloadducts were then cleaved with highly diluted trifluoroacetic acid and the products were obtained as phenols. 

Among the most synthetically useful 1,3-dipolar cycloaddition reactions are those involving nitrones. The nitrone shown in entry 4 is the condensation product of benzaldehyde and N-methylhydroxylamine. It reacts with alkenes to yield isoxazolines. Entry 6 shows an intramolecular cycloaddition proceeding via in situ formation of nitrone A. 

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