Stable nitrile oxides

The diazepine 26 reacts with the stable nitrile oxide 27 to yield the cycloadduct 28, accompanied by a trace of the rearranged adduct 29.102... 

A positive feature of the reaction is that nitrile oxides are more regioselective, in cycloadditions to methylenecyclopropanes, compared to nitrones. Only traces (up to 5%) of the 4-spirocyclopropane regioisomers are generally observed with methylenecyclopropanes unsubstituted on the exocyclic double bond. The yields are only moderate, but higher with more stable nitrile oxides (Table 27, entries 5, 6, 10-12). 

Evidently, stable nitrile oxides can be investigated by spectral and X-ray methods using ordinary procedures. As examples, X-ray diffraction studies of o-sulfamoylbenzonitrile oxides (20), 5-methyl-2-(methylsulfonyl)-3-thiophene-carbonitrile oxide (21), (),( >-diphenylacrylonitrile oxide (22), and (dimorpholino-phosphoryl) carbonitrile oxide (23) can be cited. It should be underlined that structures of the latter compounds differ from those of classical stable 0,0 -disubstituted arylcarbonitrile oxides and tert-alkylcarbonitrile oxides. Therefore, not only purely steric shielding of the CNO group but also electrostatic or donor-acceptor interactions between the atoms of the latter and adjacent polar substituents (21, 23) and also electron delocalization in it-systems (20, 22) enhance the stability of nitrile oxide. 

In this section, generation means formation, usually succeeded by in situ transformation of an unstable nitrile oxide, while preparation relates to stable nitrile oxides, which can be isolated and stored for a long time. A review including data on formation of nitrile oxides was published recently (25). 

Different procedures of this dehydrogenation are thoroughly discussed in the monograph (4). It is only necessary to note here that the process is carried out mainly as halogenation-dehydrohalogenation. The intermediate hydroximoyl halide is frequently not isolated (Scheme 1.3). The reaction is convenient for both the generation of unstable nitrile oxides (in the presence of a dipolarophile) and the preparation of stable nitrile oxides. It is usually carried out in a two-phase water-organic solvent system with methylene dichloride as the preferred solvent. 

The latter procedure was used in syntheses of stable nitrile oxides such as P,P-diphenylacrylonitrile oxide and 2,6-diphenylbenzonitrile oxide (22), a series of functionally substituted 2,6-dimethylbenzonitrile oxides (29), as well as 2,4,6-triethylbenzene-l,3-dicarbonitrile oxide (29), stable bis(nitrile oxides) of a novel structure 6, in which two benzene rings, bearing hindered fulmido groups are connected with a bridge (30), tetrachloroisophthalo- and terephthalonitrile oxides (31). Stable o-sullamoylbenzonitrile oxides with only one shielding substituent were also prepared using NaOCl/NaOH in a two-phase system (20, 32). 

Thermal dehydrochlorination of hydroximoyl chlorides affords nitrile oxides (50-52). O-Ethoxycarbonylbenzohydroximoyl chloride, generating benzonitrile oxide, was used as a stable nitrile oxide precursor, which was efficiently used in... 

Lysenko Z, Wessling RA, Rose GD. Formulations containing stable nitrile oxide reagents and their use in coatings, composites, and moldings, PCT Int. Appl. WO 9703142 [Chem. Abstr. 1997 126 200214],... 

Parker DK. Synthesis of stable nitrile oxide compounds, Eur. Pat. Appl. 903338 1999 [Chem. Abstr. 1999 130 268404],... 

Dipolar cycloadditions of nitrile oxides 216 onto 1 gave much poorer yields of cycloadducts 217 than those of nitrones 205. The cycloadditions of 216 to 1 require higher temperatures and unfavorably compete with their dimerization to furoxanes. However, stable nitrile oxides 216 with bulky substituents R that hamper dimerization, can be used. The thermal rearrangements of 5-spirocyclopropane-annelated isoxazolines 217 always required higher temperatures than the isoxazolidine counterparts. Under these conditions the second cyclopropane ring was also cleaved to give furopyridines 218 (Scheme 48) [136, 137]. 

In a recent paper, Kim and Ryu have demonstrated that the reaction of some stable nitrile oxides with uracil nucleosides cleanly gave products of 1,3 addition (Scheme 34). The 5-aroylpyrimidine nucleoside oximes 57-64 were prepared in moderate to good yield by the reaction of hydroximoyl chlorides 55a-e with the corresponding pyrimidine nucleosides 56a-d. 

Dihydro-1,2,4-oxadiazol-5-ones (74) cannot be 7V-acylated by either chlorocarbonyl isocyanate or trichloroacetyl chloride. However, preparation of 4-chlorocarbonyl compounds (73) can be achieved by cycloaddition of stable nitrile oxides to the C=N double bond of chlorocarbonyl isocyanate <888994, 90ZOR339). Compounds (73) decompose with ammonia, primary amines, or primary amides to isocyanates and (74) (Scheme 26). 

Nitrilium salts are more reactive 1,3-dipolarophiles than nitriles. With stable nitrile oxides, oxadiazolium salts (228) are obtained (Equation (38)). With unstable nitrile oxides the cycloaddition... 

The lactone 88 having an exo-cyclic double bond was applied in a 1,3-dipolar cycloaddition with nitrile oxides in recent work by Gallos et al. (Scheme 12.29) (133). The ip/ro-isoxazoline (89) was obtained as the sole diastereomer from the addition of the stable nitrile oxide 87. The resulting adduct 89 was further subjected to N—O bond cleavage by hydrogenolysis, followed by a spontaneous cyclization to give the carbocyclic product 90 in 64% yield. 

The first antibody-catalyzed asymmetric 1,3-dipolar cycloaddition was reported recently by Janda and co-workers (382). The reaction of the relatively stable nitrile oxide 280 and dimethyl acrylamide 281 was catalyzed by antibody 29G12 having turnover numbers >50, and the product 282 was obtained in up to >98% ee (Scheme 12.89). The antibody 29G12 was formed for hapten 283 and coupled to a carrier protein by standard protocols. The hapten 283 contains no chiral center and therefore the immune system elicited a stereochemical environment capable of stabilizing the enantiomeric transition state leading to 282. 

Thermal rearrangements of 5-spirocyclopropaneisoxazolines, 133, lead to dihydrofuro[2,3-f]pyridines (Scheme 42) <1996JOC1665>. Compound 133 is prepared from the reaction of bicyclopropyl idene, acting as a dipolarophile, with nitrile oxides. A one-pot variation of the reaction beginning with a stable nitrile oxide and bicyclopropyl idene affords higher yields of the furopyridines. 

Hydroxyindole-3-glyoxylic acid (113) with hydroxylamine hydrochloride yielded 3-cyano-l-hydroxyindole 115, presumably by the cyclic process indicated (114), but if sodium hydrogen carbonate was present, the presumably formed anion (116) underwent an alternative decomposition, yielding the remarkably stable nitrile oxide (117) [78JCS(P1)1117]. 

Reaction of [l,2,5]oxadiazolo[3,4- ]quinoxaline 1-oxides with stable nitrile oxides in refluxing dichloromethane affords l,2,4-triazino[5,6-/>]quinoxaline 1,2,4-trioxides 6 in good yield, which can be reduced by triphenylphosphane or sodium dithionite to the corresponding 5,10-dihydro derivatives 7. Oxidation of 7 with iodosobenzene bis(trifluoroacetate) yields 1,2,4-triazino-[5,6-6]quinoxalines 8.210... 

In contrast, Cu(I) catalysis makes possible the efficient synthesis of 3,5-disubstituted isoxazoles 57 from aromatic or aliphatic aldehydes and alkynes. Stable nitrile oxides can be isolated and subsequently submitted to the reaction... 

In contrast, Cu(I) catalysis makes possible the efficient synthesis of 3,5-disubsti-tuted isoxazoles 57 from aromatic or aliphatic aldehydes and alkynes. Stable nitrile oxides can be isolated and subsequently submitted to the reaction [21] in isolated form and submitted to the reaction in one-pot, three-step process [131]. Here, nitrile oxide intermediates 56 are generated in situ via the corresponding aldoxime and halogenation/deprotonation by Chloramine-T [132]. Capture of the intermediate nitrile oxide by copper(I) acetylides occurs presumably before dimerization. In this case, the Cu catalyst was obtained from copper metal and copper(II) sulfate, and the products were isolated by simple filtration or aqueous work-up. Trace amounts of toluenesulfonamide and unreacted acetylene are easily removed by recrystallization or by passing the product through a short plug of silica gel. 

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