Nitrile Oxides and Nitriles

The 4-hydroxyheptadecan-7-one, isolated from the root of Chiococca alba, is simply prepared using hydroxy-functionalized nitroalkenes, as shown in Eq. 6.29 

The Henry reaction of ketones with nitroalkanes in the presence of ethylenediamine gives allylic nitro compounds, which give a,P-unsaturated carbonyl compounds via the Nef reaction (Eq. 6.30).49 

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). 

The reaction of nitroalkenes or nitroalkanes with TiCl4 and Me3SiN3 gives a-azido functionalized hydroxamoyl chlorides, which act as precursors of nitrile oxides (Eq. 6.34).59 

A new route to nitrile oxides based on the reaction of primary alkyl bromides with NaN02 in the presence of acetic acid, is also reported (Eq. 6.35).60 This reaction is used for the direct 

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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. 

Dipolar cycloadditions of nitrile oxides " and nitrile imines " " with dehydroamino acid derivatives have also been described. 

In oxadiazoles, 1,3-retroaddition (Section 4.21.7.2.1) of the nitrile oxide and nitrile (split a + b in 92 Scheme 15) does not compete well with the break at c, the weakest bond, followed by the break at d, except when X is NH2 <76AC(R)57,77AC(R)37i, 77AC(R)62i, 80OMS573). 

Dipolar Cycloadditions of Nitrile Oxides and Nitrile Mines... 

Dipolar cycloadditions of nitrile oxides and nitrile imines... 

Dihydro-l,4-diazepines will perform 1,3-dipolar cycloaddition reactions with nitrile oxides and nitrile imines but it is only the imine bonds in the diazepine that react. Thus, 2,3-dihydro-5,7-diphenyl-1-methyl-17/-1,4-diazepine (64 R = Me) only gave mono adducts (65) with arylnitrile... 

The first report of the reaction of 2//-l-benzopyran (139) with various 1,3-dipoles has appeared/ Good yields of single cycloaddition products (140) were obtained upon reaction with nitrile-imines, whereas nitrile oxides gave 1 1 mixtures of the regioisomers (141) and (142), The reactions with diazomethane gave rather inconclusive results, and phenyl azide and diphenyl nitrone failed to react. Similar types of reactions have been carried out using a variety of enones in which the overall conclusion appears to be that simple aliphatic or alicyclic enones produce mixtures of regioisomers upon reaction with nitrile oxides and nitrile imines whereas enones of the chalcone type show only one product. Experts in FMO theory will probably declare these results... 

SCHEME 9.12 Calculated energy correlations between nitrile oxides and nitriles. 

Stannous fluoride probably was first prepared by Scheele in 1771 and was described by Gay-Lussac and Thenard in 1809. Commercial production of stannous fluoride is by the reaction of stannous oxide and aqueous hydrofluoric acid, or metallic tin and anhydrous hydrogen fluoride (5,6). Snp2 is also produced by the reaction of tin metal, HP, and a halogen in the presence of a nitrile (7). 

Nitrile A-oxides, under reaction conditions used for the synthesis of isoxazoles, display four types of reactivity 1,3-cycloaddition 1,3-addition nucleophilic addition and dimerization. The first can give isoxazolines and isoxazoles directly. The second involves the nucleophilic addition of substrates to nitrile A-oxides and can give isoxazolines and isoxazoles indirectly. The third is the nucleophilic addition of undesirable nucleophiles to nitrile A-oxides and can be minimized or even eliminated by the proper selection of substrates and reaction conditions. The fourth is an undesirable side reaction which can often be avoided by generating the nitrile A-oxide in situ and by keeping its concentration low and by using a reactive acceptor (70E1169). 

Hi) Preparation of isoxazoles from nitrile N-oxides The reaction between a nitrile //-oxide and an alkyne is so facile that it is usually sufficient to leave an ether solution of the reactants at room temperature to obtain the desired isoxazole in good yield. The reaction is in general sensitive to the size of the substituent on the alkyne but not on the nitrile -oxide. In the case of poorly reactive alkynes, the difficulty may be overcome by generating the nitrile -oxide in situ and keeping its concentration low. 

Table 13 Isoxazoles from Nitrile iV-Oxides and Alkynes...

Table 14 Isoxazoles from Nitrile N-Oxides and C=C Dipolarophiles...

Both 4,5-dimethylisoxazole and 3,4-dimethylisoxazole are formed on treatment of the sodium derivative of a-methylacetaldehyde with hydroxylamine hydrochloride. The two isomers can be separated by fractional distillation <62HC(17)1, p. 54). 4,5-Dialkylisoxazole or 3,4-dialkylisoxazole can be obtained as the sole reaction product from an appropriate nitrile iV-oxide and an appropriate vinyl acetate. 

The reaction of alkyl nitro compounds with acetyl chloride in the presence of an alkenic compound produced a 2-isoxazoline. The mechanism is believed to proceed via a nitrile oxide and is illustrated in Scheme 112 (B-79MI41613). 

Generalized methods of preparation include the reaction of /3-keto esters (or amides) with hydroxylamine, a-alkynic and a,/3-unsaturated esters (or amides) with hydroxylamine (real or generated in situ), hydroxylamine and nitrile oxides, and /3-keto and a-alkynic nitriles with hydroxylamine (62HC(l7)l, pp. 3,7). 

For example, the most reactive of the allenes, 1,1 -difluoroallene, reacts at room temperature with nitrones, nitrile oxides, and diazoalkanes to give cycloadducts in high yield [22, 23, 24, 25] (equation 15)... 

Asymmetric cycloaddition of functionalized alkenes to nitrile oxides and nitrones 98YGK11. 

As shown by the Italian school, the formation of isoxazole derivatives by the action of nitric acid or nitrogen oxides on acetylene derivatives and related reactions proceeds through intermediate nitrile oxides and must, therefore, be included with this type of synthesis. 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

The mechanism is thought to be analogous to that suggested for the formation of 1,3,5-benzoxadiazepines from nitrile oxides and 2-phenylbenzazete (see Section 4.2.1.4.2.1.). 

Cycloadditions of the 1,3-dipolar nitrile oxides and diazoalkenes to acyclic vinyl sulfones are in general highly selective, the particular regioisomer formed depending on the substituents of both reactants213,214. Nitrones, on the other hand, tend to yield mixtures of the two possible isomers (see equation 78). 

In the course of this study, the authors determined /Lvalues for dibenzyl, methyl phenyl, methyl p-nitrophenyl, di-p-tolyl, di-isopropyl and tetramethylene sulphoxides and for diethyl, dipropyl and dibutyl sulphites. The /Lscales are applied to the various reactions or the spectral measurements. The /Lscales have been divided into either family-dependent (FD) types, which means two or more compounds can share the same /Lscale, family-independent (FI) types. Consequently, a variety of /Lscales are now available for various families of the bases, including 29 aldehydes and ketones, 17 carboxylic amides and ureas, 14 carboxylic acids esters, 4 acyl halides, 5 nitriles, 10 ethers, 16 phosphine oxides, 12 sulphinyl compounds, 15 pyridines and pyrimidines, 16 sp3 hybridized amines and 10 alcohols. The enthalpies of formation of the hydrogen bond of 4-fluorophenol with both sulphoxides and phosphine oxides and related derivatives fit the empirical equation 18, where the standard deviation is y = 0.983. Several averaged scales are shown in Table 1588. 

Chiral tricyclic fused pyrrolidines 29a-c and piperidines 29d-g have been synthesized starting from L-serine, L-threonine, and L-cysteine taking advantage of the INOC strategy (Scheme 4) [19]. L-Serine (23 a) and L-threonine (23 b) were protected as stable oxazolidin-2-ones 24a and 24b, respectively. Analogously, L-cysteine 23 c was converted to thiazolidin-2-one 24 c. Subsequent N-allylation or homoallylation, DIBALH reduction, and oximation afforded the ene-oximes, 27a-g. Conversion of ene-oximes 27a-g to the desired key intermediates, nitrile oxides 28 a-g, provided the isoxazolines 29 a-g. While fused pyrrolidines 29a-c were formed in poor yield (due to dimerization of nitrile oxides) and with moderate stereoselectivity (as a mixture of cis (major) and trans (minor) isomers), corresponding piperidines 29d-g were formed in good yield and excellent stereoselectivity (as exclusively trans isomers, see Table 3). 

Intramolecular nitrone cycloadditions often require higher temperatures as nitrones react more sluggishly with alkenes than do nitrile oxides and the products contain a substituent on nitrogen which may not be desirable. Conspicuously absent among various nitrones employed earlier have been NH nitrones, which are tautomers of the more stable oximes. However, Grigg et al. [58 a] and Padwa and Norman [58b] have demonstrated that under certain conditions oximes can undergo addition to electron deficient olefins as Michael acceptors, followed by cycloadditions to multiple bonds. We found that intramolecular oxime-olefin cycloaddition (lOOC) can occur thermally via an H-nitrone and lead to stereospecific introduction of two or more stereocenters. This is an excellent procedure for the stereoselective introduction of amino alcohol functionality via N-0 bond cleavage. 

Conventional conversion of amide, lactam, imide, and urea carbonyl groups into enaminones, enamino esters, or enamino nitriles requires prior activation of the carbonyl groups either by alkylation to imino ethers, followed by reaction with activated methylene groups, or by thiation, e.g. with P2S5, to thiocarbonyl groups followed by alkylation (and possibly also oxidation), and, again, subsequent reac-... 

A large range of stationary phases is available, and according to their polarity they can be divided into normal phase and reversed phase types. Silica gel, aluminium oxide, and a nitrile-bonded-phase are normal adsorbents used to separate carotenoids... 

Contrary to other Af-oxide containing heterocycles, Bfx and Fx are not formed by direct oxidation of the parents systems, benzofurazan (Bfz) and furazan (Fz), respectively. Even though each kind of heterocycle possesses individual synthetic procedures, some common approaches should be mentioned, i.e., thermo or photochemical intramolecular cychzation of 1,2-azidonitro derivatives and oxidative cychzation of 1,2-dioximes. Some other synthetic procedures, such as oxidation of o-nitroanUines to Bfx or dimerization of nitrile oxides and dehydration of a-nitrooximes to Fx, have been depicted. The following sections provide the most recent descriptions. 

The C(6)-C(15) segment was synthesized by Steps C-l and C-2. The stereoselectivity of the cycloaddition reaction between the nitrile oxide and allylic alcohol is the result of a chelated TS involving the Mg alkoxide.39... 

A large batch exploded violently (without flame) during vacuum distillation at 90-100°C/20-25 mbar. Since the distilled product contained up to 12% butyroni-trile, it was assumed that the the oxime had undergone the Beckman rearrangement to butyramide and then dehydrated to the nitrile. The release of water into a system at 120°C would generate excessive steam pressure which the process vessel could not withstand. The rearrangement may have been catalysed by metallic impurities [1]. This hypothesis was confirmed in a detailed study, which identified lead oxide and rust as active catalysts for the rearrangement and dehydration reactions [2],... 

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