Alkenes nitroalkanes, cycloaddition

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]. 

One obvious synthetic route to isoxazoles and dihydroisoxazoles is by [3+2] cycloadditions of nitrile oxides with alkynes and alkenes, respectively. In the example elaborated by Giacomelli and coworkers shown in Scheme 6.206, nitroalkanes were converted in situ to nitrile oxides with 1.25 equivalents of the reagent 4-(4,6-di-methoxy[l,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 10 mol% of N,N-dimethylaminopyridine (DMAP) as catalyst [373], In the presence of an alkene or alkyne dipolarophile (5.0 equivalents), the generated nitrile oxide 1,3-dipoles undergo cycloaddition with the double or triple bond, respectively, thereby furnishing 4,5-dihydroisoxazoles or isoxazoles. For these reactions, open-vessel microwave conditions were chosen and full conversion with very high isolated yields of products was achieved within 3 min at 80 °C. The reactions could also be carried out utilizing a resin-bound alkyne [373]. For a related example, see [477]. 

Nitrile oxides, which are formed by dehydration of nitroalkanes or by oxidation of oximes with hypochlorite,87 88 are also useful 1,3-dipoles. They are highly reactive and must be generated in situ.ss They react with both alkenes and alkynes. Entry 5 in Scheme 6.5 is an example in which the cycloaddition product (an isoxazole) was eventually converted to a prostaglandin derivative. 

Cyclic alkyl nitronates may be used in tandem [4+2]/[3+2] cycloadditions of nitroalkanes, and this reaction has been extensively studied by Denmark et al. (64,333-335). In recent work, they developed the silicon-tethered heterodiene-alkene 219 (Scheme 12.63). Steric hindrance and the fact that both the nitroalkene and the a,p-unsaturated ester in 219 are electron deficient renders the possibility of self-condensation. Instead, 219 reacts with the electron-rich chiral vinyl ether 220 in the presence of the catalyst 224 to form the intermediate chiral nitronate 221. The tandem reaction proceeds from 221 with an intramolecular 1,3-dipolar cycloaddition to form 222 with 93% de. Further synthetic steps led to the formation of ( )-detoxinine 223 (333). A similar type of tandem reaction has also been applied by Chattopadhyaya and co-workers (336), using 2, 3 -dideoxy-3 -nitro-2, 3 -didehydrothymidine as the starting material (336). 

Isoxazoles and their partially or fully saturated analogs have mainly been prepared, both in solution and on insoluble supports, by 1,3-dipolar cycloadditions of nitrile oxides or nitrones to alkenes or alkynes (Figure 15.10). Nitrile oxides can be generated in situ on insoluble supports by dehydration of nitroalkanes with isocyanates, or by conversion of aldehyde-derived oximes into a-chlorooximes and dehydrohalogenation of the latter. Nitrile oxides react smoothly with a wide variety of alkenes and alkynes to yield the corresponding isoxazoles. A less convergent approach to isoxazoles is the cyclocondensation of hydroxylamine with 1,3-dicarbonyl compounds or a,[3-unsatu-rated ketones. 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

Alkene-functionalized 1,3-diene complexes undergo regio-and stereoselechve 1,3-dipolar cycloaddition reactions with nitrile A-oxides. Related cycloaddihons of nitroalkanes in the presence of triethyl amine and phenylisocyanate afford dihydroisoxazoles. This type of cycloaddition was used in a synthesis toward macrolactin A (Scheme 163). 

To each row in a deep-well microtiter plate were added a 1.5 m solution (0.4 mL for each well) of each nitroalkane, a 1.5 m solution (0.4 mL for each well) of phenyl isocyanate, and a 0.0225 m solution (0.4 mL for each well) of EtsN in dioxane. Alkene-functionalized pins (213) secured in a pin holder block were put into each deep-well microtiter plate containing the above solution, and the assembled set (pin holder plus deep-well plate) was placed in a stainless steel container with the lid tightly sealed, where the reaction mixture was incubated overnight at 60 °C. The pins, secured in a pin holder block, were washed with dioxane and DMF in a chemically resistant polypropylene bath and dried. The [2 -i- 3]-cycloaddition reaction was repeated twice more (as above but for 6 h). Finally, pins in a pin holder block were washed with dioxane, DMSO (60 °C), DMF, THF, and DCM (250 mL for each solvent) in a chemically resistant polypropylene bath and dried to give isoxazoline-functionalized pins (214). 

The addition of nitronates to alkenes opens up a route to isoxazolidines, useful precursors for the synthesis of 2-isoxazolines. Tandem [4+2]/[3+2] cycloaddition reactions of nitroalkanes involving cyclic alkyl nitronates have been reported by Denmark et al. ... 

Among the dipoles used for the construction of the isoxazoline ring, nitrile oxides have a prominent place in the Uterature owing to the convenient generation of this intermediate from diverse precursors such as oximes, a-halooximes and nitroalkanes (see Section 2.1). Cycloaddition of nitrile oxides with multiple bonds, especially alkenes, has been extensively investigated in recent years both from the theoretical and synthetic perspectives. 

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