Nitroalkanes 4-dimethylaminopyridine

Nitromethylation of aldehydes has been carried out in a one pot procedure consisting of the Henry reaction, acetylation, and reduction with sodium borohydride, which provides a good method for the preparation of l-nitroalkanes.16b 79 It has been improved by several modifications. The initial condensation reaction is accelerated by use of KF and 18-crown-6 in isopropanol. Acetylation is effected with acetic anhydride at 25 °C and 4-dimethylaminopyridine (DMAP) as a catalyst. These mild conditions are compatible with various functional groups which are often... 

For example, the reaction of nitroalkanes with di-tert-butyl dicarbonate, (B0C)20, and 4-dimethylaminopyridine (DMAP) as catalysts in the presence of dipolarophiles at room temperature affords cycloadducts in improved yields compared with the Mukaiyama-Hosino method.58 The conversion of Eq. 6.32 gives a 90% yield by this procedure, whereas the conventional method using PhNCO gives a 79% yield of the same product. An additional advantage of this new method is that the use of (B0C)20 allows the reaction to be carried out with substrates that contain NH or OH groups without prior protection. The cycloaddition leads directly to protected N- or (9-Boc products (see Eq. 6.33). 

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]. 

Dipolar cycloaddition of nitrile oxides to olefins and acetylenes is among the most widely exploited synthetic routes towards isoxazoles and isoxazolines. It is well-known that microwave irradiation in cycloaddition reactions considerably reduces reaction times. Indeed, the use of dielectric heating (microwave-heated reactions were performed in a flask with a reflux condenser mounted outside the apparatus) allowed for a remarkable reduction of the cycloaddition reaction time from 6-12 hours to merely 3 minutes [69]. Simple aqueous workup provided the target isoxazoles and isoxazolines. The requisite nitrile oxides for the cycloaddition reaction were generated in situ from the corresponding nitroalkanes, 4-(4,6-dimethoxy [1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 4-dimethylaminopyridine (DMAP) (Scheme 22). 

Nitrile oxides are conveniently generated from primary nitroalkanes RCH2NO2 (R = Me, Et, Ph, etc.) by the action of di-t-butyl dicarboiiate or ethyl chloroformate, catalysed by 4-dimethylaminopyridine. In the presence of olefins, isoxazolines are obtained in good yields <97S309>. 

The reagent DMTMM has been used also for the generation of nitrile oxides in situ from nitroalkanes under very mild conditions using microwave irradiation. The reaction requires the presence of 4-dimethylaminopyridine (DMAP) as catalyst (Scheme 66). 

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