Isoxazolidines, isoxazolines

Isoxazolidines, Isoxazolines, Oxazolines, and Oxazines isoxazoiidines, easily obtained by cycloaddition of nitrones to olefins, are reduced to 1,3-amino alcohols by reaction with LAH in ether media. The synthesis of racemic sedridine from 3.256 is illustrative [TA2] (Figure 3.100). 

SOLID-PHASE SYNTHESIS OF ISOXAZOLIDINES, ISOXAZOLINES, AND ISOXAZOLES... 

Isoxazoles, isoxazolines, isoxazolidines and benzisoxazoles are all thermally stable, distilling without decomposition, but the stability of the system depends on the substitution pattern. For example, aminoisoxazoles distill unchanged but the isoxazole carboxylic acids usually decompose at or above their melting points without giving the corresponding isoxazole. 

Sodium borohydride and 3-isoxazolium salts with a 3-unsubstituted position also give isoxazolines, as do the 3-substituted 5-unsubstituted derivatives. With the latter group, further reduction occurs to the isoxazolidines (74CPB70). 

Nitrones or aci-nitro esters react with alkenes to give in some cases A/-substituted isoxazolidines and in others 2-isoxazolines. When the intermediate isoxazolidines were observed, a number of procedures transformed them into the 2-isoxazolines. Acrylonitrile and phenyl rzcf-nitrone esters produced an A/-methoxyisoxazolidine. Treatment with acid generated a 2-isoxazole while treatment with base generated an oxazine (Scheme 118) (68ZOR236). When an ethoxycarbonyl nitrone ester was reacted with alkenes, no intermediate isoxazolidine was observed, only A -isoxazolines. Other aci-mtro methyl esters used are shown in Scheme 118 and these generate IV-methoxyisoxazolidines or A -isoxazolines which can be further transformed (72MI41605). 

The trimethylsilyl group has been used to prepare stable aci-nitro esters and these react with alkenes to produce intermediate isoxazolidines which were readily converted into 2-isoxazolines (Scheme 119) (73ZOB1715, 74DOK109, 78ACS(B)ll8>. 

This small class of compounds is characterized by an N-alkyl moiety, and they are synthesized from isoxazolium salts by isomerization or by the dehydration of 2-alkyl-isoxazolidin-3-ols (Scheme 128) (74BSF1025). The reaction of isoxazolium salts that are unsubstituted in the 5-position with phenylmagnesium halides was reported to give 3-isoxazolines by 1,4-conjugate addition, and this reaction is also shown in Scheme 128 (74CPB70). 

The reduction of 3,5-diphenylisoxazoline with sodium cyanoborohydride produced a mixture of isomeric 3,5-diphenylisoxazolidines. The H and NMR spectra were utilized to distinguish the isomers SOLAIOI). Sodium borohydride reductions likewise reduce isoxazolines to isoxazolidines (equation 56) (80JA4265). 

Previous reviews on the chemistry of isoxazole dealt primarily with the synthetic routes and the nucleophilic cleavage of isoxazole derivatives. The first part of the present review is concerned with new investigations in the synthetic field, but the main attention is devoted to a study of the properties of isoxazoles. The review covers studies undertaken during this decade though some earlier works are mentioned when necessary. No complete coverage of the chemistry of partly or fully reduced isoxazoles and their oxo derivatives is attempted, but those aspects of the chemistry of isoxazolines and isoxazolidines that are closely related to the problems under discussion are also mentioned. 

The investigation of UV and IR spectra of isoxazolines has shown them to be the A -isomers. The IR spectra of isoxazolidin-3-ones were investigated in connection with the chemistry of cycloserine. ... 

As already mentioned, on passing from the aromatic system of isoxazoles to the nonaromatic ones of isoxazolines and isoxazolidines, the N—O bond becomes more labile. In these compounds the ring is extremely readily cleaved. Many such reactions are useful to determine the structure of reduced isoxazole derivatives and are also of preparative value. 

Nitronates derived from primary nitroalkanes can be regarded as a synthetic equivalent of nitrile oxides since the elimination of an alcohol molecule from nitronates adds one higher oxidation level leading to nitrile oxides. This direct / -elimination of nitronates is known to be facilitated in the presence of a Lewis acid or a base catalyst [66, 72, 73]. On the other hand, cycloaddition reactions of nitronates to alkene dipolarophiles produce N-alkoxy-substituted isoxazolidines as cycloadducts. Under acid-catalyzed conditions, these isoxazolidines can be transformed into 2-isoxazolines through a ready / -elimination, and 2-isoxazolines correspond to the cycloadducts of nitrile oxide cycloadditions to alkenes [74]. 

Keywords Diels-Alder reactions of isoxazoles, isoxazolines, isoxazolidines, oxazoles and oxazolines... 

Because of the relative instabihty of many trimethylsilyl nitronates 1036, 1037, they should be reacted in situ with olefins 1053 [103-105] or acetylenes [127] to generate the isooxazolidines 1054 [103-105, 107-117, 119-133] or isoxazoles [127] (Scheme 7.37) The isoxazolidines 1054 with R2=H readily ehminate trimethylsilanol 4 in the presence of acids such as TsOH to form the isoxazolines 1055 in high yields [104, 105] (Scheme 7.37 cf. also the cycloadditions with acrylonitrile in Scheme 7.42). 

Nitrones, reactive 1,3-dipoles, react with alkenes and alkynes to form isoxazolidines and isoxazolines, respectively. With monosubstituted olefinic dipolarophiles, 5-substituted isoxazolidines are generally formed predominantly however, with olefins bearing strongly electron-withdrawing groups, 4-substituted derivatives may also be formed.631... 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

The impulse to the study of these cycloadditions came from the discovery that 5-spirocyclopropane isoxazolidines (or isoxazolines) undergo a thermal rearrangement resulting in the production of selectively substituted tetrahydro-(or dihydro) pyrid-4-ones (Scheme 42) [64], In particular, cyclic nitrones gave ultimately N-bridgehead bicyclic ketones, molecular skeleton of many alkaloid families [65]. 

Compound 384 derived from the reaction of two molecules of benzonitrile oxide (341) with one of BCP (3). Its formation can be explained with the cycloaddition of a second molecule of 341 to the isoxazoline Ml to give the isoxazolidine M5, which undergoes a thermal rearrangement to 384 (Scheme 54). 

Isoxazole (as well as isoxazoline, and isoxazolidine) analogues of C-nucleosides related to pseudouridines 25 and 27 have been regioselectively synthesized by 1,3-dipolar cycloaddition (1,3-DC) of nitrile oxides (and nitrones) derived from uracyl-5-carbaldehyde 24 and 2,4-dimethoxypyrimidine-5-carbaldehyde 26 respectively <06T1494>. 

Nitroisoxazolines were prepared from ALalkoxy-3,3-dinitroisoxazolidines by thermally induced P-elimination. For example, isoxazolidines 42 synthesized by a three-component reaction of tetranitromethane with two equivalents of alkenes 41, were converted into isoxazolines 43 by heating in boiling chlorobenzene <06S706>. 

High diastereomeric ratios were observed in the 1,3-DC of various nitrile oxides to the chiral acryloylhydrazide 38. For example benzonitrile oxide afforded the isoxazoline 40 in 98% de <00TL1453>. The levels of facial selectivity obtained in the same 1,3-DC with the chiral 3-acryloyl-2-oxazolidinone 39 was very low (dr 43 57), but in the presence of MgBr2 (1 equiv) the reaction proceeded with high diastereoselectivity to give preferentially the isoxazolidine 41 in 92% de <00TL3131>. 

Dipolar cycloadditions of ( -phenyl-/V-methylnitrone (585) to Baylis-Hillman adducts such as ( 3-hydroxy-a-methylene esters) (608-610) proceed with complete regioselectivity in good yields to afford the corresponding diastere-omeric 3,5,5-trisubstituted isoxazolines (611-613) (Scheme 2.269). Attack by the dipole in (585) from the less sterically hindered side of dipolarophiles (608-610) affords C-3/C-5 cis isoxazolidines (611a,b-613a,b) as the major products (780). 

By the action of protons and some other electrophilic agents, these isoxazolidines eliminate the corresponding silanol to give isoxazolines (224). At the same time, nucleophiles can cause elimination of the trialkylsilyl group to form oximino alcohols (225). 

At the same time, the reactions of isoxazolidines (239) with soft acids and retain LA (157, 341, 398, 399) resemble an analogous process considered above for iV-siloxynitroso acetals, which also affords isoxazolines (240). Methanol can be eliminated from nitroso acetals (239) also upon heating (341). 

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