Isoxazolines 5-substituted

The multipolymer enzymatic resolution of soluble polymer-supported alcohols 42 and 43 was achieved using an immobilised lipase from Candida Antarctica (Novozym 435). The R-alcohol was obtained in enantiomerically pure form (>99% ee) after its cleavage from the poly(ethylene) glycol (PEG) scaffold . The achiral hydantoin- and isoxazoline-substituted dispirocyclobutanoids 47 were produced using both solution and solid-phase synthesis <00JOC3520, OOCC1835>. 

Achiral hydantoin- and isoxazoline-substituted dispirocyclobutanoids 394 have been prepared by solid-phase synthesis (437). The facial and selective Boc-NH-mediated H-bond delivery of nitrile oxides afford dispirocyclobutanoids 394 (R = Bz, Et R1 =Ph, PI1CH2, Bu) as major compounds. 

Additional examples of libraries of isoxazolines prepared by 1,3-dipolar cycloaddition of Wang resin-<1998TL939> or chlorotrityl resin- <1998TL2447> supported dipolarophiles, generated in the presence of a variety of dipolarophiles, have been reported. The achiral hydantoin- and isoxazoline-substituted bis-spirocyclobutanoids 458 and 459 were produced using SPS (Scheme 105) <2000CC1835>. 

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. 

The photolysis of 4-substituted 2,3-dimethyl-3-isoxazolin-5-ones has been studied. Irradiation in methanol or ethanol with a 100 W high-pressure mercury lamp through a Pyrex filter of a 4-phenylthio compound produced a semithioacetal (Scheme 5). In contrast, an H, Cl or OPh moiety gave no reaction. The use of alkylthio substitution gave similar products. Cyclic compounds yielded cyclic products (Scheme 5), and the photolysis of (29) in benzene... 

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). 

The hydrogenation of fV-substituted isoxazolin-5-one ethyl esters produced amino-methylenemalonates (74G715), while hydrogenation of 4-benzoyl-3-phenylisoxazolin-5-one generated an a-aminomethylene-/3-keto acid (Scheme 64). 

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 chlorination of 3,5-dimethylisoxazole gave the 3,4-dichloro-4-isoxazoline (489) (77MIP41602). Additional 2-substituted 4-isoxazolines were prepared by the addition of nitrones to triple bonds (76AP1014, 77H(8)387, 70CB3196, 67AG(E)709, 69CB2346), as shown by the conversion of (490) into (491) (76AP1014). 

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). 

Cyclopropenones react with nitrosobenzene by an O-initiated attack at C-1 to produce isoxazolin-5-ones (75TL3283, 78USP4053481), and an isoxazolin-5-one was produced as a by-product in the photolysis of nitroethylene (78AJCU3). Substituted oxazolin-5-ones have... 

Bis(isoxazoline) decomposes to a number of products depending on the substitution (77H(6)1599) On photolysis using NiS04, two major products were formed. ESR spin trapping demonstrated the intermediacy of imino and 2-isoxazolinyl radicals (77TL4619). 

Isoxazolin-5-one, 2,3-dimethyl-4-substituted photolysis, 6, 14 Isoxazolinones synthesis, 5, 132 Isoxazolin-3-ones alkylation, 6, 43 synthesis, 6, 106, 129 Isoxazolin-4-ones synthesis, 6, 106-107 Isoxazolin-5-ones alkylation, 6, 39 4,4-dialkyl substituted... 

The condensation of P-keto esters with hydroxylamine can occur in two directions to give either isoxazolin-3-ones [which exist predominately as 3-hydroxyisoxazoles (2)] or isoxazolin-5-ones (3). Early work by Claisen, Hantzch, and others showed that the products from 2-unsubstituted P-keto esters were isoxazolin-5-ones. In the early 1960 s, Katritzky found that 2-substituted analogues give 3-hydroxyisozaoles. Jacquier later showed that both types of products could be produced from both types of keto esters depending on the precise pH variation during the reaction workup. ... 

For the isoxazolines 284 substituted at position 3, ring-chain tautomerism is depicted by the equilibrium 284 and 285-287 (Scheme 103). In general the cyclic tautomers 284 are strongly preferred. The ring-opened forms exist in equilibrium with 284 in rare cases [95ZOB705 96AHC(66)1, p. 21]. The equilibrium of the oxazolidinones 288 [78MI1, p. 107] is affected by the nature of the solvent. 

Few reactions of sulfonylfuroxans with olefins have been reported. Depending on the substituents at the furoxan ring, nature of dipolarophile, and temperature, different types of products may be obtained. It is relatively simple to cyclore-vert disulfonylfuroxans to a-sulfonyl nitrile oxides on thermolysis (81TL3371, 85T727). These nitrile oxides were trapped by dipolarophiles to yield sulfonyl-substituted isoxazole derivatives. For example, 3,4-bis(phenylsulfonyl)furoxan reacts with an excess of styrene in xylene under reflux to afford the corresponding isoxazoline 290 (Scheme 189). 

One of the most important routes to isoxazole and isoxazoline rings involving the formation of the 1—5 and 2—3 bonds involves the condensation of hydroxylamine with a,/8-unsaturated carbonyl compounds. This method was previously widely used, but it is now of no preparative value, though it has been recently applied to determine the configuration of oximes. " The only new modification of this synthesis is the use of the acetals (27) of a,/8-acetylenic aldehydes for preparation of 5-substituted isoxazoles (28)... 

The isoxazoline ring is also readily cleaved by such reducing agents as do not affect the isoxazole ring. Thus, for example, the treatment of isoxazolines (186) with LiAlHj proceeds with a smooth cleavage of the heterocyclic ring to form substituted 3-amino-propan->l-ols... 

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]. 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

The phenylsulfonyl group attached at the 3-position of isoxazolines (132) is readily substituted by a variety of nucleophiles (equation 101), as summarized in Table ll84. 

As we found that furan and thiophene substituted oximes can be used as substrates for the INOC reactions (Eq. 5) [29b] similarly, furan substituted nitro alkane 134 is also a good substrate for INOC reactions (Eq. 13) [40]. The furfuryl derivative 134, prepared via Michael addition of furfuryl alcohol to 4-methoxy- -nitrostyrene, was subsequently transformed without isolation of the intermediate nitrile oxide 135 to the triheterocyclic isoxazoline 136 as a 5 1 mixture of isomers in high yield. 

ISOC reaction was employed to synthesize substituted tetrahydrofurans 172 fused to isoxazolines (Scheme 21) [44b]. The silyl nitronates 170 resulted via the nitro ethers 169 from base-mediated Michael addition of allyl alcohols 168 to nitro olefins 167. Cycloaddition of 170 followed by elimination of silanol provided 172. Reactions were conducted in stepwise and one-pot tandem fashion (see Table 16). A terminal olefinic Me substituent increased the rate of cycloaddition (Entry 3), while an internal olefinic Me substituent decreased it (Entry 4). 

A strategy involving sequential 1,3-dipolar cycloadditions has been reported for the synthesis of novel bis-isoxazolo substituted piperidines 192a and 192b (Eqs. 18 and 19) [53]. It consists of the Michael addition of an unsaturated alkox-ide 185 to )3-nitrostyrene 184 followed by an INOC or ISOC reaction to provide isoxazolines 187-189 (Eq. 18 and Table 18). A polymer supported acyl chloride... 

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... 

Thus, isoxazolines are converted into y-amino alcohols and (3-hydroxy ketones stereoselec-tively. However, the intermolecular cycloaddition involving 1,2-unsymmetrically substituted alkenes such as trans-cinnamyl alcohol proceeds nonregioselectively to give a mixture of the two regioisomers (Eq. 8.63).98... 

The use of silylketals derived from allylic alcohols and 1-substituted nitroethanols for the stereocontrolled synthesis of 3,4,5-trisubstituted 2-isoxazolines via intramolecular 1,3-dipolar cycloaddition has been demonstrated. Here again, the use of silyl nitronates (ISOC) increases the level of selectivity compared to INOC (Eq. 8.92).145... 

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]. 

Halide substituted isoxazolines 371a-f gave bicyclic dihydropyridones 374 after rearrangement. Methoxycarbonyl substituted isoxazolines 371g-k gave the lactams 375, whereas carbonyl substituted isoxazolines 373a-e gave pyrroles 376 (Scheme 51). 

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