Hydroximoyl chloride

The first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes was reported by Ukaji et al. [76, 77]. Upon treatment of allyl alcohol 45 with diethylzinc and (l ,J )-diisopropyltartrate, followed by the addition of diethylzinc and substituted hydroximoyl chlorides 46, the isoxazolidines 47 are formed with impressive enantioselectivities of up to 96% ee (Scheme 6.33) [76]. 

The reaction of hydroximoyl chlorides with the chiral, nonracemic hydrazones 313 (Equation 58) in the presence of TEA gave the 4,5-dihydro-l,2,4-oxadiazoles 314 as single diastereomers from which the chiral auxiliary was easily removed to furnish the corresponding 4-unsubstituted 4,5-dihydro-l,2,4-oxadiazoles with high ee s <1999H(50)995>. 

Aziridinylbenzaldoxime 340, formed from the reaction of a hydroximoyl chloride with aziridine 339 (Scheme 56), reacts with HG1 to form the chloroalkyl-substituted amidoxime 341. Reaction with sodium hydride affects ring closure to give the 3-aryl-4,5-dihydro-5-isopropyl-l,2,4-oxadiazoles 343. This latter reaction is proposed to proceed... 

The reaction of hydroximoyl chlorides 403 with amidoximes 402 in the presence of TEA leads to 1,2,4-oxadiazole 4-oxides 404 via 1,3-dipolar cycloaddition and elimination of an amine (Equation 77) <1997T1787, 2005JC0887>. 

Diazotization of 4-amino-l,2,5-oxadiazole-3-carbohydroximoyl chloride 132 gives 4-[chloro(hydroxyimino)-methyl]-l,2,5-oxadiazole-3-diazonium salt 133 (Scheme 35). Treatment of the latter with NaN3 afforded 4-azido-l,2,5-oxadiazole-3-carbohydroximoyl chloride 134 and the reaction with NaN02 yielded 2-cyano-2-hydro-xyiminoaceto-hydroximoyl chloride 135. By oxidation of 4-amino-l,2,5-oxadiazole-3-carbohydroximoyl azide 136... 

Di-(2,3,4,6-tetra-0-acetyl-a-D-mannopyranosyl)-l,2,5-oxadiazole 2-oxide 306 was synthesized from D-mannose 305 by a route involving dimerization of mannopyranosyl nitrile oxide as the key step. Three methods were used for the generation of the nitrile oxide isocyanate-mediated dehydration of nitromethylmannose derivatives, treatment of aldoxime with aqueous hypochlorite, and base-induced dehydrochlorination of hydroximoyl chloride (Scheme 76) <2001TL4065, 2002T8505>. 

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... 

Microwave irradiation promotes the 1,3-dipolar activity of nitrile oxides generated from hydroximoyl chlorides. They interacted in situ over alumina with alkenes and alkynes (150). The effect was demonstrated in reactions of... 

The intramolecular cycloaddition reactions of the nitrile oxides 357 (n = 1, 2, 3, 9), obtained in situ from the 2,5-difunctional furan hydroximoyl chlorides or nitro compounds (415) has specific features because of the 2,5-arrangement of two open chains bearing acetylenic and fulminic moieties. Only with 357 (n = 3) is the expected furanoisoxazolophane 358 formed, in acceptable yield. Compound 357 ( =9) gives a complex product mixture whereas 357 ( = 1, 2) gives rise to the exclusive reaction of the dipole with a double bond of the furan system. 

Optically active 3-arylisoxazoline-5-carboxylic acid derivatives 403 or 404 have been, prepared by the reaction of (S)- or (/ )-3-acryloyl-4-benzyl-5,5-dimethyloxazolidin-2-one (405 or 406) with nitrile oxides, obtained from benzo-hydroximoyl chloride and its substituted derivatives in the presence of a catalytic amount of metal salt, for example, Yb(OTf)3 (445). This procedure improves the diastereoselectivity of compounds 403 or 404, which are industrially useful as intermediates for various drugs and agrochemicals. It also enables the amount... 

Modification of crs-poly(butadiene) and cA-poly(isoprene) has been attained on heating in boiling toluene, in the presence of mononitrile oxides 35%-55% of C=C bonds have been replaced by isoxazoline fragments. The process also demands the presence of a base because the nitrile oxides have been generated from hydroximoyl chlorides (505). 

It is evident that reactions of unsaturated polymers with bisnitrile oxides lead to cross-linking. Such a procedure has been patented for curing poly(butadiene), butadiene-styrene copolymer, as well as some unsaturated polyethers and polyesters (512-514). Bisnitrile oxides are usually generated in the presence of unsaturated polymers by dehydrochlorination of hydroximoyl chlorides. Cross-linking of ethylene-propylene-diene co-polymers with stable bisnitrile oxides has been studied (515, 516). The rate of the process has been shown to reduce in record with the sequence 2-chloroterephthalonitrile oxide > terephthalonitrile oxide > 2,5-dimethylterephthalonitrile oxide > 2,3,5,6-tetramethylterephthalo-nitrile oxide > anthracene-9,10-dicarbonitrile oxide (515). 

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. 

The nitrile oxides were generated in situ from the corresponding hydroximoyl chlorides 55a-e. From these reactions, only the 1,3 addition products 57-64 were obtained. No products of cycloaddition could be isolated. 

Dihydro- and tetrahydrofuroisoxazoline rings were constructed by intramolecular cycloaddition of nitrile oxides or nitrones, generated from oximes . Thus, oxime 30 and sodium hypochlorite afforded furoisoxazolines 31 (equation 14). Similarly, furanyl or thienyl oximes 32 in the presence of NaOCl afforded tricyclic products 33 in 35-90% yields (equation 15). Nitrostyrenes (ArCH=CHN02) and various nucleophiles (for example, allyl mercaptan) also generated hydroximoyl chlorides which underwent similar cycloaddition leading to bicycUc tetrahydrothiophene and tetrahydrofuran derivatives ... 

Fluoride ion catalyzed 1,3-dipolar cycloaddition of bromo nitrile oxide, obtained in situ from dibromoformaldehyde oxime 184, to nonactivated alkynes provides a new approach to the synthesis of neuroactive isoxazoles. However, the regioselectivity of cycloaddition in this case is not high—products 185 and 186 are obtained in a 1 1 to 1 1.4 ratio (equation 80). Cycloaddition reaction of hydroximoyl chlorides and acetylene was snc-cessfully carried out also in the presence of NaHCOs as a base. For instance, a-keto oximes 187 were reacted with acetylene and NaHCOs to give isoxazoles 188 in good yields (equation 81). 

Oxadiazoles can be sucessfully obtained from amidoximes and diethyl carbonate/ f-BuOK °, triethyl orthoformate/BFs OEtg or by reaction of hydroximoyl chlorides with nitriles . ... 

Substituted 1,2,4-oxadiazoles were prepared by addition of nitrile oxides to imines or hydrazones. It has been reported that interaction of hydroximoyl chlorides 262 with chiral hydrazones 263 in the presence of EtsN leads to intermediates 264 with diastereoselectivity up to 97%. A subsequent N-N bond cleavage to remove chiral auxiliary by formic acid leads to 1,2,4-oxadiazolines 265 with ee up to 91% (equation 113). ... 

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

A derivative of the new heterocyclic ring system 4-benzyl-3-(2,6-dichlorophenyl)-6-ethoxy-4,5-dihydro-l,2,4,6-oxadiazaphosphinine 6-oxide (382) is prepared by the reaction of sterically hindered hydroximoyl chloride 381 with aminomethylphosphonate (equation... 

The first examples of furazan and furoxan nitrile oxides have been reported in the early 1990s. 4-Aminofurazan-3-carbonitrile oxide (65) was generated from the hydroximoyl chloride with base and its cycloaddition reactions investigated <92KGS687>, and the 4-phenyl analogue (66) is formed via the nitrolic acid derivative by treatment of the aldoxime with dinitrogen tetroxide <93LA44i>. Furazan-3-amidoximes react in the usual way with nitriles to yield 3-(furazan-3-yl)-1,2,4-oxadiazoles <9013941 >. 

Dipolar cycloaddition is one of the most important methods in assembling five-membered ring heterocycles. For the 1,4-(oxa/thia)-2-azole system, nitrile oxides, and nitrile sulfides have the correct sequence of atoms for the 47t 1,3-dipolar component and the 2n component can be a either a C=0 or a C=S heterodipolarophile (Scheme 41). Nitrile oxides, usually generated in situ from the corresponding hydroximoyl chlorides and a base, add to various types of (3=0 bond affording 1,4,2-dioxazole derivatives. 

The chemistry of nitrile oxides, in particular their application in organic synthesis, has been continuously developed over the past two decades and represents the main theme of this chapter. The parent compound, fulminic acid (formonitrile oxide), has been known for two centuries, and many derivatives of this dipole have been prepared since that time. Several simple and convenient methods for the preparation of nitrile oxides have evolved over the years. Dehydrochlorination of hydroximoyl chlorides was first introduced by Werner and Buss in 1894 (1). A convenient synthesis of isoxazoles was reported by Quilico et al. (2 ), and then the discovery of nitrile oxide cycloadditions to alkenes was subsequently noted by the same group (5). 

A method that avoids the conventional chlorination of aldoximes corresponds to the reaction of nitroalkanes or conjugate nitroalkenes with titanium tetrachloride (48) (Scheme 6.3). a-Chloro (a), alkyl (a, b, c), aryl (c), a-cyano (d), and a-azido (d) hydroximoyl chlorides have been prepared in good yield in this way (48). Concerning overall efficiency, however, this would necessitate that the nitro... 

Chloramine-T has also been employed, both as a halogenating reagent and base the reaction proceeds in good yield with aromatic as well as with aliphatic aldoximes (81). The role of chloramine-T probably involves an initial chlorination of the aldoxime to give the hydroximoyl chloride, followed by base-catalyzed hydrogen chloride elimination to afford the nitrile oxide (81). 

Examples of optically active aldehydes or nitroalkanes that have been used for the generation of nitrile oxides (mostly via hydroximoyl chlorides) and subsequent cycloadditions to olefins are collected in Table 6.9. 

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