5- isoxazolines, preparations

Fig. 15.46. Isoxazolines (preparation Figure 15.45) are synthetic equivalents for y-amino alcohols and /J-hydroxyketones.

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>. 

Bromomethyl)isoxazolines, prepared from a nitrile oxide and an allyl bromide, may be reductively ring opened to y-enoximes XIV) XIV may be reduced in aqueous THF with Al(Hg) to the homoallylamine (XV), as in Eq. (6) [98] ... 

In the reaction of dimethylfoimamide chloride with the imidoyl cyanide (299 equation 160) the amidine (300) is formed. Isoxazolines, prepared from amide chlorides and hydroxylamine, rearrange on heating or irradiation to give 2-aminoazirine (301 Scheme 46). Azirines (302) can also be prepared by treating chloroenamines with base and sodium azide. ... 

An interesting new route to %5-unsaturated a-amino-acids involves ring cleavage of 2-isoxazolines prepared from allyl bromides and nitrile oxides (Scheme 51). The prospects of extending this process to other substrates seem to be good. 

Diacetates of 1,4-butenediol derivatives are useful for double allylation to give cyclic compounds. l,4-Diacetoxy-2-butene (126) reacts with the cyclohexanone enamine 125 to give bicyclo[4.3.1]decenone (127) and vinylbicy-clo[3.2.1]octanone (128)[85,86]. The reaction of the 3-ketoglutarate 130 with cij-cyclopentene-3,5-diacetate (129) affords the furan derivative 131 [87]. The C- and 0-allylations of ambident lithium [(phenylsulfonyl)methylene]nitronate (132) with 129 give isoxazoline-2-oxide 133, which is converted into c -3-hydroxy-4-cyanocyclopentene (134)[S8]. Similarly, chiral m-3-amino-4-hyd-roxycyclopentene was prepared by the cyclization of yV-tosylcarbamate[89]. 

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. 

The two major methods of preparation are the cycloaddition of nitrile oxides to alkenes and the reaction of a,/3-unsaturated ketones with hydroxylamines. Additional methods include reaction of /3-haloketones and hydroxylamine, the reaction of ylides with nitrile oxides by activation of alkyl nitro compounds from isoxazoline AT-oxides (methoxides, etc.) and miscellaneous syntheses (62HC(i7)i). 

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>. 

Amino-2-isoxazolines were prepared by the condensation of acrylonitriles with N-hydroxyurea (73BSF1138) or of urea and acetophenones, as shown in Scheme 127 (78ZOR2000). 

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). 

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). 

This series of compounds was also discussed briefly by Quilico in 1962 and only a limited number of new representatives have been reported 62HC(17)l,p. 3). The pressure reaction of ethylene and nitric acid in the presence of Ni, Zn or Cu produced 3,3 -bis(isoxazoline) 70FRP94493), and the isoxazoline IV-oxide (515) was prepared by the reaction of /3-dimethylaminoacrylaldehyde and methyl nitroacetate (74IZV845). 

Isoxazolidinones have been prepared by the cyclization of ethyl 3-O-hydroxyl-aminopropionate and by the cyclization of a-chloropropionhydroxamic acid (62HQ17)1, p. 7). 3-Isoxazolidinones can also be prepared by the hydrolysis of 3-alkoxy- or 3-amino-2-isoxazolines or 2-isoxazolinium salts (Scheme 159) (74BSF1651, 62G501). 

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 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. 

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. 

The stability of the heterocyclic ring toward oxidation by permanganate depends on the experimental conditions. In acid media the ring is not cleaved, and acetylisoxazoles are readily prepared from isopropenyl derivatives.2-Isoxazolines are dehydrogenated into isoxazoles (cf. 192 193). The stability of the heterocyclic ring is also observed when this oxidation is carried out in acetone solution. It is of interest that this method allows the preparation both of... 

Hydrogenolytic cleavage of isoxazolines has also proved useful in preparation of -dihydroxy ketones and -hydroxy carboxylic acids (47). The isoxazolines were prepared by a [3 -1- 2] cycloaddition. 

The concept of the use of dilithio reagents for the preparation of heterocyclic systems has been extended to the synthesis of 2-isoxazolin--5-ones10 by carboxylation of a dilithio oxime, followed by eyolin-zation, and the synthesis of pyrazoles from dilithiophenylhydrazones and trilithiothiohydrazones.11 12... 

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. 

The regioisomer 18 of isoxazoline 14 was also synthesized by an INOC reaction (Eq. 2). Homoallylamine 16 prepared by displacement of 4-bromo-l-butene... 

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. 

Primary nitro compounds are good precursors for preparing nitriles and nitrile oxides (Eq. 6.31). The conversion of nitro compounds into nitrile oxides affords an important tool for the synthesis of complex natural products. Nitrile oxides are reactive 1,3-dipoles that form isoxazolines or isoxazoles by the reaction with alkenes or alky nes, respectively. The products are also important precursors for various substrates such as P-amino alcohols, P-hydroxy ketones, P-hydroxy nitriles, and P-hydroxy acids (Scheme 6.3). Many good reviews concerning nitrile oxides in organic synthesis exist some of them are listed here.50-56 Applications of organic synthesis using nitrile oxides are discussed in Section 8.2.2. 

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... 

Isoxazolines are good precursors of a,(3-unsaturated ketones.63,94 This transformation is useful for synthesis of polyenes. For example, nitrile oxide cycloaddition chemistry is used to prepare 4-oxo-2-alkenylphosphonates, which are useful to synthesize a long polyethylenic unit via Woodworth-Emmons olefination (Eq. 8.66).101... 

The present tandem nitro aldol-cyclization process is used for the preparation of the enantiomerically pure 4-hydroxy-2-isoxazoline-2-ones. They are prepared starting from chiral a-mesyloxy aldehydes and ethyl nitroacetate under mild reaction conditions (Eq. 8.85).136... 

New applications of nitrile oxide 1,3-DC have been reported. Soluble, single-wall carbon nanotubes (SWNT) 32 functionalized with pentyl esters at the tips and pyridyl isoxazoline rings along the walls were prepared using pentyl ester-SWNT as dipolarophile. The complex... 

Polymeric isoxazolines were prepared by cycloaddition of nitrile oxides to norbomadiene followed by ring-opening metathesis polymerization (ROMP) <06PLM3292 06MM3147>. 

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>. 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

A promising combination of sequential multicomponent Ugi reaction and INOC has been carried out for the preparation of fused isoxazoles and isoxazolines (413). The coupling of these two reactions (Scheme 1.38) provide access to the heterocyclic ring systems in two steps, from easily available starting materials (e.g., R = Ph, R/=PhCH2), in moderate to good overall yields (the yields of Ugi reaction products 354 were 50%-70%, those of the INOC products 355 were 27%-64%). 

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