Ketones nitrone 1,3-dipolar cycloadditions, reaction

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

Scheme 1.64). The Ag(I)-mediated cyclization afforded dipole 306 for 1,3-dipolar cycloaddition with methyl vinyl ketone to yield adducts 307 and the C(2) epimer as a 1 1 mixture (48%). Hydrogenolytic N—O cleavage and simultaneous intramolecular reductive amination of the pendant ketone of the former dipolarophile afforded a mixture of alcohol 308 and the C(6) epimer. Oxidation to a single ketone was followed by carbonyl removal by conversion to the dithiolane and desulfurization with Raney nickel to afford the target compound 305 (299). By this methodology, a seven-membered nitrone (309) was prepared for a dipolar cycloaddition reaction with Al-methyl maleimide or styrene (301). 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Sneider et al. (27,28) applied a familiar nitrone for the synthesis the immunosuppressant (—)-FR901483 (14) in a recent study (Scheme 12.7). The nitrone 12 is generated in situ from ketone 10 and the optically pure hydroxylamine 11 at 25 °C. The resultant nitrone 12 underwent a 1,3-dipolar cycloaddition reaction with ethyl acrylate in refluxing toluene to give the diastereomer 13 with 71 % diastereomeric excess (de). In 22 synthetic steps including the 1,3-dipolar cycloaddition, the target molecule 14 was obtained. 

Tethering the alkene to the carbon atom of the nitrone allows the preparation of cw-l,2-disubstituted cycloalkanes such as 212. Examples in which the alkene is tethered to the nitrogen atom of the nitrone are also common. Thus, addition of formaldehyde to the hydroxylamine 213 promoted formation of the intermediate nitrone and hence the cycloadduct 214 (3.140). " Subsequent transformations led to the alkaloid luciduline. This synthesis illustrates a useful feature of the 1,3-dipolar cycloaddition reaction of nitrones, in that it provides an alternative to the Mannich reaction as a route to (3-amino-ketones, via reductive cleavage of the N-0 bond in the isoxazolidine and oxidation of the 1,3-amino-alcohol product. In another example of such an intramolecular cycloaddition reaction, the bridged bicyclic product 217, used in a synthesis of indolizidine 209B, was formed by addition of an aldehyde to the hydroxylamine 215, followed by heating the intermediate nitrone 216 (3.141).142... 

The nitrone arising from reaction between (Z)-19-nor-5,10-secosteroidal ketone 260 a and M-methylhydroxylamine hydrochloride undergoes transannu-lar 1,3-dipolar cycloaddition to give isoxazolidines 261 and 262 and an aromatic derivative 263 originating from 261 (Scheme 28). Corresponding reaction of 260b produces two types of structurally different isoxazolidines 264 and 265 as well as the dienone 266. 

The 1,3-dipolar cycloaddition of nitrones to alkenes is a useful route to isoxazolidine derivatives, the reductive cleavage of which furnishes a range of compounds such as fi-hydroxy ketones, /S-amino alcohols, etc. [29]. Although Lewis acids are known to promote the cycloaddition [29,30], some nitrones, especially aliphatic nitrones, are unstable under these conditions and lower yields are sometimes obtained. The three-component coupling reaction of benzaldehyde, A/-benzylhydroxylamine, and A-phe-nylmaleimide proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3, to afford the corresponding isoxazolidine derivative in a good yield with high diaster-eoselectivity (Eq. 12) [31]. 

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds —activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Man-nich-type reaction of A-(a-aminoalkyl)benzotriazoles with silyl enol ethers, the 1,3-dipolar cycloaddition of nitrones to alkenes, the 1,2-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24], These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky s diene to give the dihydropyridones (Eq. 14) [25,26], The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tet-rahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thio-esters reacted with N-(a-aminoalkyl)benzotriazoles to give the /5-amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazoli-dines (Eq. 17) [28]. Addition of diazoesters to imines afforded CK-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot. 

The addition of ZnBr2 to the tandem 1,3-azaprotio cyclotransfer-cycloaddition of a ketoxime with divinyl ketone results in rate enhancement and the exclusive formation of l-aza-7-oxabicyclo[3.2.1]octan-3-ones7 The 1,3-dipolar cycloaddition of 1-aza-l-cyclooctene 1-oxide with alkenes produces the corresponding isoxazolidines in high yields with a minimum of polymeric material. The cycloaddition of thiophene-2-carhaldehyde oxime with acetonitrile and methyl acrylate produces the 1,3-dipolar adduct, suhstituted isoxazolidines, and not the previously reported 4 - - 2-adducts. Density functional theory and semi-empirical methods have been used to investigate the 3 + 2-cycloaddition of azoxides with alkenes to produce 1,2,3-oxadiazolidines. The 3 -h 2-cycloaddition of a-nitrosostyrenes (62) with 1,3-diazabuta-1,3-dienes (63) and imines produces functionalized cyclic nitrones (64) regioselectively (Scheme 22). The first imequivocal 1,3-dipolar cycloaddition of sulfines involves the reaction of 2,2,4,4-tetramethyl-3-thioxocyclobutanone S-oxide with diaryl thioketones to produce... 

Dipolar cycloaddition of nitrone 917 to methylenecyclopropane 918 was marginally stereoselective, and gave a 1 1.2 mixture of isoxazolidine adducts 919 and 920 in 80% yield (599). Thermal rearrangement of the mixture afforded the separable ketones 921 (26%) and 922 (38%). Conversion of these into lasubines I and II, respectively, had been reported some years previously (600). The second route, also not very stereoselective, used a Wittig reaction between acetyl-methylenetriphenylphosphorane and A -protected piperidin-2-ol 923 to m e pelletierine (924), Mannich condensation of which with veratraldehyde gave a 1 2.8 ratio of the ketones 921 and 922 (60%) (601). 

Nitrogen can be incorporated as an oxime into a different kind of ene reaction that has been explored by Grigg and his group. The ene component now bears no resemblance to a diene one pair of electrons comes from the lone pair on nitrogen and the other from the OH bond of the oxime 140. The enophile is a more conventional enone and the initial product is a nitrone 141. No nitrogen heterocycle is formed in this step, but, if the enophile contains a second alkene, a 1,3-dipolar cycloaddition gives a bicyclic structure. The simplest reagent for this job is the rather unstable divinyl ketone (penta-l,4-dien-3-one, 143). Fortunately this can be released from the dichloroketone 142 with base and distilled with the solvent THF into the reaction mixture.24... 

The cyclic a,/ -unsattirated ketone cyclohex-2-en-l-one (50) was used as building block in the one-pot domino cycloaddition of enol ether 14 and nitrostyrene 15a. At 15 kbar and 50 "C, nitroso acetal 51 was formed in 67 % yield, whereas nitroso acetal 54a was formed as a side product (Scheme 9.18). This result indicated that the 1,3-dipolar cycloaddition is still faster with the electron-poor substituted cyclohexenone 50 than with the electron-rich mono-substituted enol ether 14. The one-pot reaction of 52 with enol ether 14 and nitrostyrene 15a merely resulted in formation of nitroso acetal 54a instead of nitroso acetal 53. The unwanted side reaction was not observed in the one-pot three-component reaction with 14 and methyl-substituted nitrostyrene 15b and 52 (Scheme 9.19). The large difference in reactivity between the three components in both the Diels-Alder and the [3 + 2] cycloaddition resulted in the formation of 55 as the main product. The side reaction of 16b with 14 to form 54b was prevented, since 14 was completely consumed in the reaction with 15b to give nitronate 16b (15 kbar, 50 °C, 16 h). However, heating (50 °C) the reaction mixture for 76 h at 15 kbar was necessary to produce nitroso acetal 55, which was formed as a mixture of two major diastereomers (ratio 3 1) in 69 % yield. 

Scheme 18.14). Upon treatment of ketones or aldehydes with 62, condensation reactions lead to the formation of nitrones including 63 [71, 72]. Such nitrones were observed to participate in dipolar cycloadditions with olefin 64 and to furnish the corresponding isoxazolidines (cf. 65) in a diastereoselective manner. Facile removal of the chiral carbohydrate-derived auxiliary was effected upon exposure of the adduct to acidic hydrolysis, providing the chiral isoxazolidine 66 (> 90% ee). 

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