1,4,2,5-Dioxadiazin

These routes are dimerization to furoxans 2 proceeding at ambient and lower temperatures for all nitrile oxides excluding those, in which the fulmido group is sterically shielded, isomerization to isocyanates 3, which proceeds at elevated temperature, is practically the only reaction of sterically stabilized nitrile oxides. Dimerizations to 1,2,4-oxadiazole 4-oxides 4 in the presence of trimethylamine (4) or BF3 (1 BF3 = 2 1) (24) and to 1,4,2,5-dioxadiazines 5 in excess BF3 (1, 24) or in the presence of pyridine (4) are of lesser importance. Strong reactivity of nitrile oxides is based mainly on their ability to add nucleophiles and particularly enter 1,3-dipolar cycloaddition reactions with various dipolarophiles (see Sections 1.3 and 1.4). 

Diphenylacrylonitrile oxide, exhibiting unexpected stability, presumably due to delocalization, dimerized to furoxan 20 or 1,4,2,5-dioxadiazine 21 (22). 

Dioxadiazine ring 377 was successfully obtained by dimerization of the corresponding hydroximoyl chloride 376 in the presence of EtsN (equation 164). ... 

While the parent compound remains unknown, several 3,6-disubstituted 1,4,2,5-dioxadiazines have been prepared. The ring formally possesses an 871-system, but the NMR and UV spectra of 3.6-dimethyl-1.4.2.5-dio adia/ine give little information on the electronic structure . 1.97... 

In a few cases, carbohydroximidoyl chlorides may be converted into 1,4,2,5-dioxadiazines without isolation of a nitrile oxide, e.g. treatment of trinuoroacelohydroximidoyl chloride with cesium fluoride in bis(2-methoxyethyl) ether (diglyme) at room temperature gives 3,6-bis(triflu-oromethyl)-l,4,2,5-dioxadiazine (1) in 34% yield.14... 

Treatment of 5-aminofurazan-4-carbohydroximidoyl chloride (4) with triethylamine in acetonitrile gives 3,6-bis(4-aminofurazan-3-yl)-1,4,2,5-dioxadiazine (5).16... 

The only route so far reported to unsymmetrically disubstituted 1,4,2,5-dioxadiazines 7 involves the reaction of carbohydroximidoyl chlorides with benzohydroximidamides 6.17... 

Schmitz s compound [( , )-3,6-diacetyl-1,4,2,5-dioxadiazine dioxime], obtained by the action of aqueous sodium hydrogen carbonate on dioxime 8, was only confirmed as 1,4,2,5-dioxadiazine 918 more than ninety years after its first preparation.19... 

A reinvestigation of a compound first described in 1893 from the reaction of (66) with aqueous sodium bicarbonate has shown it to be a 1,4,2,5-dioxadiazine (67). Further reaction of this product with nitrogen dioxide gives the bisdinitroethyl compound (68) (Scheme 13) <88Laioi7>. 

Other modes of dimerization of nitrile oxides have been observed. With Lewis acid catalysis 1,4,2,5-dioxadiazines (25) can be produced,161 and l,2,4-oxadiazole-4-oxides (26) may arise in the presence of a high alkali concentration.85 Fulminic acid (HCNO) forms a variety of oligomers, but no furoxan (24 R = H) is isolated,5 and phenylglyoxylonitrile oxide (PhCO CNO) forms a second product, reportedly a tetramer (see Section IV,A,2). But these are exceptional cases usually it is only dimerization to the furoxan that is observed. 

There are very little published data on the reactivity of 1,4,2,5-dioxadiazine derivatives, but some reactions of diamine 67 have been investigated (see Section 9.14.7). After heating compound 67 for 2h in 98% H2SO4, 93-94% of the compound can be recovered <2004RJ0884>. 

Dimerization of nitrile oxides is one of the most important methods of synthesis of 1,2,5-oxadiazole iV-oxides (furoxans). However, this process can also lead to formation of symmetrical 1,4,2,5-dioxadiazines. The dipyridyl dioxadiazine 20 was obtained in 59% yield by treatment of 2-pyridyl hydroximinoyl chloride hydrochloride with triethylamine and pyridine in ethanol <2003EJI405>. The coumarin nitrile oxide 196 was dimerized with pyridine in ethanol to give the dioxadiazine 197 in 66% yield (Scheme 34). When a chloroform solution of the nitrile oxide 196 was heated at reflux in the absence of base, the furoxan 198 was produced in 70% yield (Scheme 34). Attempted purification of 196 by recrystallization caused dimerization into furoxan 198 <1998JHC619>. 

Dioxadia%ines. Dimerization of aryl nitrile oxides (Scheme 34) - currently unclear how conditions (e.g., inclusion/exclusion of added base) influence which product (1,4,2,5-dioxadiazine or 1,2,5-oxadiazole A-oxide (fur-oxan)) is favored. 

The 1,4,2,5-dioxadiazines 67 and 157 have been patented in Russia as activators of the soluble form of guanylate cyclase, which plays a major regulatory role in the relaxation and contraction of blood vessel muscles and aggregation of thrombocytes <2003RUP2208438, 2003RUP2212409>. 

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