Unsaturated oximes

The catalytic reduction of 2-methyl-3-phenyl-3-isoxazoline (159) produced /3-hydroxypropiophenone (160) (74CPB70). Ring fission also occurred on base treatment of the 3,5-diaryl-3-isoxazoline (161) to give the a,/3-unsaturated oxime (162) (70CI(L)624). 

Jurd reported the isolation of a 2//-3-isoxazoline by the reaction of the flavylium salt (488) with hydroxylamine. Gentle heating of the material caused isomerization to the more stable 2-isoxazoline. Treatment with base generated an a,/3-unsaturated oxime which on photolysis regenerated the starting flavylium salt (Scheme 129) (70CI(L)624). 

Unsaturated oximes are attractive substrates for aziridine synthesis. Treatment of oxime 77 with Red-Al yielded vinylaziridines 78, 79, and 80, in various ratios depending on the E/Z ratio of the starting oxime 77 (Scheme 2.22) [38]. This reaction should proceed through abstraction of HA, Hb, or He in the intermediate 81, followed by hydride reduction of the resulting 2H-azirines 82-84. 

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 unsaturated oximes 224 (see Table 21) were readily prepared by AT-alkyl-ation of allyl amines with a-bromoketones or O-silyl-a-bromoaldoximes. Heating the oximes 224 in toluene under an argon atm at 110 -180 °C smoothly led to isoxazolidines 225 in good yields with cis ring junction stereochemistry. Even when three stereocenters were generated, as in 225 g-1, a single stereoisomer... 

Isoxazole derivatives have also been synthesized in variable yield by the palladium-catalyzed intramolecular oxidative cyclization of a,/i-unsaturated oximes (Scheme 110).174 Reactions of this type are reminiscent of procedures... 

In a recent study, classical heating, microwave radiation and gamma radiation have been compared as energy sources to perform 1,3-dipolar reactions between unsaturated oximes and conventional dipolarophiles. On using gamma radiation the reactions were clean and yields obtained were similar to those for the thermal reactions. However, microwave radiation reactions were extremely clean, occurred more rapidly and gave higher yields [102],... 

Bromocyclization of y,S-unsaturated oximes (98) and (99) affords the corresponding bromomethylpyrroline-iV-oxides (100) and (101). Depending on the structural characteristics, the yields vary from 23% to 87% (Scheme 2.40). 

Similar INAC reactions of oximes with olefin moieties proceed in the presence of Lewis acids (729) and also under microwave irradiation of unsaturated oximes, placed on the surface of silica gel (730). 

Tandem processes mediated by triethylborane involving conjugate addition to enones followed by aldol reaction are reported (Scheme 52, Eq. 52a). More recently, a tandem process involving addition of an isopropyl radical to an o ,/3-unsaturated oxime ether afforded an azaenolate intermediate that reacts with benzaldehyde in the presence of trimethylaluminum. The aldol product cyclizes to afford an isopropyl substituted y-bulyroloaclonc in 61% overall yield (Scheme 52) [116]. In these reactions, triethylborane is acting as a chain transfer reagent that delivers a boron enolate or azaenolate necessary for the aldolization process. 

Acyclic /ky-unsaturated oxime ethers are found to undergo both cis-trans isomerization and N—O bond fission130,132 (equations 74 and 75). 

The tautomerism of 1-nitroprop-l-enyl sugars into a,p-unsaturated oximes is catalysed by potassium fluoride in the presence of tetra-n-butylammonium hydrogensulphate, providing a route to 1,3-dicarbonyl sugar derivatives [7],... 

The synthesis of compounds 39, 41, and 43 by the ODPM rearrangement opens a novel photochemical route to chrysanthemic acid and other cyclopropane carboxylic acids present in pyrethrins and pyrethroids [52]. In fact, aldehyde 43 can be transformed to tran -chrysanthemic acid by simple oxidation. This new synthetic route to ecologically benign insecticides competes with the one previously described by us using the 1-ADPM rearrangement of p,y-unsaturated oxime acetates [30,53]. 

In qualitative terms, the rearrangement reaction is considerably more efficient for the oxime acetate 107b than for the oxime ether 107a. As a result, the photochemical reactivity of the oxime acetates 109 and 110 was probed. Irradiation of 109 for 3 hr, under the same conditions used for 107, affords the cyclopropane 111 (25%) as a 1 2 mixture of Z.E isomers. Likewise, DCA-sensitized irradiation of 110 for 1 hr yields the cyclopropane derivative 112 (16%) and the dihydroisoxazole 113 (18%). It is unclear at this point how 113 arises in the SET-sensitized reaction of 110. However, this cyclization process is similar to that observed in our studies of the DCA-sensitized reaction of the 7,8-unsaturated oximes 114, which affords the 5,6-dihydro-4//-l,2-oxazines 115 [68]. A possible mechanism to justify the formation of 113 could involve intramolecular electrophilic addition to the alkene unit in 116 of the oxygen from the oxime localized radical-cation, followed by transfer of an acyl cation to any of the radical-anions present in the reaction medium. 

A similar reaction gave dithiazole 139 (Scheme 70) with acyclic a,)S-unsaturated oxime 138. 

The 3-nitroisoxazoline has gas and liquid phase values available. Given the absence of knowledge about isoxazolines, we accept these data and use them in what follows. We are told that the dehydration reaction of 3-phenyl-A -isoxazoline-5-ol (an oxime ether) to form 3-phenylisoxazole (equation 42) is exothermic by 16 kJmol. The gas phase enthalpy of formation of the latter species is 139.5 6.2 kJmoG. (As the isoxazoles are nominally aromatic, they are not included here as unsaturated oxime ethers.)... 

Hydrogenated isoxazole derivatives were obtained by single electron transfer (SET) cyclization of /9,y-unsaturated oximes , by thermal [4- -2] cycloaddition of aldox-imes or ketoximes to conventional dienophiles or isomerization/cyclization of an ortho halogeno or nitro-substituted amidoximes. Preparation of 1,4-disubstituted 3-hydroximino-2-nitro-l-butenes and their oxidative cyclization to 4-nitroisoxazoles are reported " . Synthesis of fluorine-containing substituted isoxazolidines as well as isoxazoles by ultrasonic methods has been also described. 

The reaction of a,-unsaturated oximes with ethyl acetoacetate and related / -dicarbonyl compounds in the presence of FeCls or InCls leads to polysubstituted pyridines. Thus, oxime 295 in the system ethyl acetoacetate/FeCls (5 mol%) at 150-160 °C formed the pyridines 296 in 41-81% yield (equation 127). 

Metabolic activation of a,/ -unsaturated oximes, such as 46, leads to the conclusion that this class of unsaturated oximes are pro-haptens. They can undergo epoxidation that eventually produces reactive nitroso intermediates which act as strong contact sensitizers . Here, the oxime function plays a major role in the chemical activation that results in the reactive nitrosoaUcenes. It was further pointed by the authors that oximes can be hydrolyzed in vivo to the corresponding carbonyl compounds which are potential allergens. 

The reaction proceeds similarly with seven-membered cyclic oximes to give cyclohepta-1,2,3-dithiazoles (127) and (129) (Scheme 22) <93JCS(P1)769>. To effect chlorination up to 15 equivalents of S2CI2 are needed polychlorination is assisted by NCS. The noncyclic a,)S-unsaturated oxime (130)... 

Intramolecular cycloaddition of the nitrile oxide intermediate generated from the unsaturated oxime 221 was used for an evenmal synthesis of la,2p,25-trihydroxy-vitamin D3 (262) (Scheme 6.90). Oxime 221, prepared from tri-O-isopropyhdene-d-mannitol (220), was processed as usual to give isoxazoline 222 in good yield and with excellent stereoselectivity. Conversion of 222 to the aldol 223 proceeded in the normal manner and further elaboration gave the desired diene intermediate 224 (262). 

Metalation of 4,5-dihydro-3-phenylisoxazole occurs at position 4. Upon warming the anion solution to 25 °C, ring opening13 to the a,/i-unsaturated oximes 1 occurs, however, alkylation at — 78°C or below provides 4-substituted 4,5-dihydro-3-phenylisoxazoles 215. 

On the contrary, while working in the synthesis of the alkaloid ru-brolone, Bogerand Zhu (91TL7643) have found 0-alkyl a,/3-unsaturated oximes 98 to participate as effective 4ir components of an intramolecular Diels-Alder reaction with an electron-deficient dienophile. Thus, 98 was prepared from butane-1,4-diol and heated in triisopropylbenzene to furnish 2-pyrindine derivatives 99 by virtue of in situ elimination of alcohol (Scheme 25). 

Isoxazolines have been converted into unsaturated oximes, and thence into enones (76AG(E)50). Treatment of the isoxazoline (523), for example, with lithium diisopropylamide gave the ring cleavage product (524) which reacted with titanium(III) chloride to furnish enone (525 Scheme 115). Oxime formation has been shown to proceed via the anion (526) as revealed by deuteration studies. 

The negative contribution of a closely spaced nonbonding electron pair permits one to distinguish (E)- from (Z)-isomers of a, /J-unsaturated oximes and of azoxybenzenes [135]. 

Unsaturated oximes can be cyclized simply by heating.24b It has been suggested that nitrone intermediates are involved in this process. Thus, oxime (53) on heating at 180 °C cyclized to a pyrrolizidine in 60% yield presumably tautomerization to nitrone (54) first occurred followed by [3 + 2] cycloaddition (Scheme 14). Likewise, quinolizidine (55) was obtained in 69% yield from the corresponding oxime. 

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