Isoxazoline derivatives

Table 2 Melting Points (Boiling Points) of Various A -Isoxazoline Derivatives (62HC(i7)i, p. 95>...

The first synthesis of a 3,5-diarylisoxazole from aryl hydroxamic acid chlorides and sodium phenyl acetylides was that effected by Weygand and Bauer in 1927. Beginning in 1946, when Quilico and Speroni showed that acid chlorides of hydroxamic acids on treatment with alkalies readily yielded nitrile oxides,numerous isoxazole and especially A -isoxazoline derivatives have been prepared. 

New isoxazoline derivatives of a-tocopherol, the main component of vitamin E, have been synthesized in a facile, two-step sequence consisting of nitration followed by 1,3-dipolar cycloaddition. 5-Nitromethyl-a-tocopheryl acetate, obtained from a-tocopheryl acetate by direct nitration in one step, act as the nitrile oxide precursor in the reaction with various alkenes. The facile conversion proceeds in the presence of equimolar amounts of PhNCO and catalytic amounts of triethylamine to give isoxazolines, 446 (489). 

Methylene sugars are versatile starting compounds for the synthesis of aromatic and hydroxymethyl C-glycosyl compounds (71) and of double-ended C-glycosyl compounds (70). The double bond undergoes 1,3-dipolar cycloadditions to give isoxazoline derivatives (71), such as that used as a model for the synthesis of tunicamycin. Also, reaction with iodonium sym-... 

Zecchi and co-workers also reported 1,3-dipolar cycloadditions with nitrogen-substituted allenes. As illustrated in Scheme 8.75, the expected isoxazoline derivatives 285 were obtained by [3 + 2] cycloaddition reaction of aminoallenes 246 and nitrile oxide 284 [141, 142], Bis-adducts 286 became the major products when 2equiv. of nitrile oxide 284 were applied with prolonged reaction times. 

Isoxazoline derivatives of Cgo such as 250 (Scheme 4.40) are accessible by 1,3-dipolar cycloadditions of nitrile oxides to [6,6] double bonds of the fullerene [2, 278, 291-305]. The nitrile oxides 249 with R = methyl, ethyl, ethoxycarbonyl and anthryl are generated in situ from the corresponding nitroalkane, phenyl isocyanate and triethylamine. The isoxazoline derivative of Cgo 250 (with R = anthryl) crystallizes in black prisms out of a solvent mixture of CS2 and acetone (3 2) [292]. X-ray crystal structure analysis shows that addition of the nitrile oxide occurs on a [6,6] double bond of the fullerene framework. 

An intramolecular cycloaddition of the tetradecatrienyl nitroethyl ether 263 was used in the synthesis of the 14-membered bicyclic precursor 265 of crassin acetate 266, a cembrane lactone possessing antibiotic and antineoplastic activity (332). Nitro compound 263 was obtained from farnesyl acetate (262) in several steps and was then treated with phenyl isocyanate and triethylamine to give the tricyclic isoxazoline 264 (Scheme 6.98). Conversion to ketone 265 was accomplished by hydrogenation of the cycloadduct with Raney Ni and boric acid followed by acetylation (332). In this case, the isoxazoline derived from a 3-butenyl nitroethyl ether moiety served to produce a 3-methylenetetrahydropyran moiety (332). 

The isoxazoline derivative, (51), displays essentially no shift in reduction potentials with respect to those of C70, indicating a strong electron-withdrawing effect from the isoxazoline moiety [157]. 

Synthesis. Deoxybenzoin is converted to the corresponding oxime by treatment with hydroxylamine under basic conditions with sodium acetate in aqueous ethanol or in toluene in the presence of potassium hydroxide in absolute ethanol. Treatment of the oxime under nitrogen with two equivalents of butyllithium in tetrahydrofurane is followed by cyclization in ethyl acetate or acetic anhydride to the isoxazoline derivative. Finally, treatment of the isoxazoline with cold chlorosulfonic acid followed by reaction of the intermediate with aqueous ammonia affords the desired product. (Talley, 2000a Sorbera, 2001b). 

The formal total synthesis of the novel /3-lactam antibiotic thienamycin has been accomplished from an isoxazoline derivative generated by [3 + 2] dipolar cycloaddition <79H(l2)l 183). Reaction of the nitrile oxide derived from 3-nitropropanal dimethyl acetal with methyl crotonate gave the isoxazoline (477) regio- and stereo-selectively. The isoxazoline was converted to amino ester (478) by hydrogenation and then to /3-lactam (479) by ester saponification and ring closure with DCC. Treatment of (479) with p-nitrobenzyl chloroformate and reaction of the derived acetal (480) with excess N-p-nitrobenzyloxycar-bonylcysteamine gave thioacetal (481), a compound which has previously been converted into ( )-(8S )-thienamycin (Scheme 106). 

Triphenyl- 1,2,4-butanetrione oxime in chloroform with hydrogen chloride cyclized in 70-75% yield to the purple 2,4,5-triphenyl-3f/-pyrrol-3-one 1-oxide (61) (30JA1590), along with an isoxazoline derivative. The pyrrlone was reduced by lithium aluminum hydride in ether [76JCS(P 1)2259] to l-hydroxy-2,3,5-triphenylpyrrole 62. 

Dihydropyridines containing at position 3 a carbonyl group similar to oc,(3-unsaturated ketones can be involved in cyclocondensation reactions with 1,2-binucleophiles. Dihydropyridine 376 treated with hydroxylamine yields isoxazoline derivatives 377 [363, 382, 383, 384, 385, 386] (Scheme 3.122). Dihydro-l,2,4-triazolo[l,5- ]pyrimidine 378 reacts with hydrazine and hydroxylamine in the same manner, giving the condensation products 379 [387]. 

Boron neutron capture therapy, isoxazoline deriv, 60, 297 Boroxine, aromaticity estimates/indices,... 

Most of the nonpeptide FXa inhibitors reported in the literature were compounds with two basic groups [74]. To date very few monobasic FXa inhibitors have been reported. Ellis and co-workers [74] have reported their effort on synthesizing a series of bisbenzamidine isoxazoline derivatives and a series of monobasic substituted biaryl isoxazoline derivatives (9-12). For these compounds, Eq. 9 was derived [72]. In Eq. 9, Ipyr was used to take values... 

In biaryl-substituted isoxazoline derivatives (13-14) [75], a biaryl moiety was designed to interact with the S4 aryl-binding domain of the FXa active site, hi this case, hydrophilicity was found to be the most important term (Eq. 10) [72]. 

The chiral isoxazoline derivatives 49 were prepared in a highly enantioenriched form by 1,3-DC of benzonitrile oxide and pivalonitrile oxide with acrylate 47 followed by reductive removal of the D-glucose-derived auxiliary R OH which was recovered in high yields <03SL1865>. 

Conti P, Dallanoce C, Amici MD (1998) Synthesis of new d -isoxazoline derivatives and their pharmacological characterization as /1-adrenergic receptor antagonists. Bioorg Med Chem 6 401 08... 

Dipolar cycloadditions between nitrones and alkenes to give isoxazolines are very important reactions in organic synthesis, because 1,3-amino alcohols can be synthesized from isoxazoline derivatives. Jprgensen and co-workers reported catalytic asymmetric... 

Several isoxazolidines such as 188 were prepared by Yb(OTf)3-catalyzed cycloaddition of polymer-supported nitrones and 3-(2-butenoyl)-l,3-oxazolidin-2-one. Oxidative cleavage from the resin with 2,3 dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) afforded 2-isoxazoline derivatives in good overall yields (Equation 21) <1998TL9211>. 

Enantioselective radical conjugate addition of an alkyl group to 587 was promoted by alkyltin hydride in the presence of chiral bis-isoxazoline derivatives <2002JA984>. 

Kano treated 3,4-dihydroisoquinoline N-oxides with two equivalents of ethyl propiolate in refluxing benzene and obtained dihydrobenzo[g]-indolizines 153 (82H2143). The supposed intermediates are the 4-isoxazoline-derived stable azomethine ylides 152 and the cycloadducts of 152 to the propiolate. 

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. ... 

Yuan, C., and Li, C., SIndies on organophosphorus compounds. Part 67. Reactions of a-nitroalkenes with compounds bearing active methylene groups. A novel and convenient synthesis of 2-isoxazoline derivatives, Phosphorus, Sulfur Silicon Relat. Elem., 78, 47, 1993. 

Bismuthonium 2-oxoalkylides react with dimedone, p-toluenesulfonic acid and benzenethiol to yield the corresponding a-substituted ketones and triphenylbismuthine. In the presence of a catalytic amount of copper iodide or nitrosobenzene, the ylides undergo reductive dimerization to form 1,2-diacy-lethenes. Aromatic nitrile oxide also catalyzes the dimerization but readily couples with the resulting olefin to give the corresponding isoxazoline derivative. 

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