4-Dimethylaminopyridine , nitrile oxide

Giacomelli et al. constructed 3-propylisoxazole-5-yl-methanol via a [3-1-2] cycioaddition (Fig. 15) [158]. Nitrobutane was converted to nitrile oxide in the presence of 4-(4,6-dimethoxy [1,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and catalytic 4-dimethylaminopyridine (DMAP). Trityl chloride resin-bound propargyl alcohol was employed as the dipolarophile to trap the nitrile oxide, forming the cyclo adduct isoxazole ring under unusually mild conditions (i.e., microwave irradiation at 80 °C for five times 1 min). Disappearance of the starting material was monitored by FT-IR. 

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). 

A literature survey of nitrile oxide [3+2] cycloaddition reactions with MW activation for the period 2002-2005 reveals that only a limited number of examples have been reported. Among these examples, nitroalkenes are converted in situ into nitrile oxides using 4-(4,6-dimethoxy[l,3,5]triazin-2-yl)-4-methylmorpholinium chloride (DMTMM) and 4-N,N-dimethylaminopyridine (DMAP) (Scheme 11.27) [38]. The generated 1,3-dipoles undergo cycloaddition to alkene 103 or alkyne 106 dipo-larophiles (5 equiv.), to furnish 4,5-dihydroisoxazoles 104 or isoxazoles 107, respectively. Open-vessel conditions were used and full conversions with very high yields of products were achieved within 3 min at 80 °C. 

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). 

Coupling Reactions. Dimerization of aromatic nitrile oxides can be catalyzed by pyridine, affording 3,6-diaryl-1,4,2,5-dioxadiazines in good yields (eq 20). Other nucleophiles such as 4-phenylpyridine, 4-methylpyridine, 4-dimethylaminopyridine, and N-methylimidazole are also suitable catalysts for the reaction. 

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