Nitrones ketone-derived

The versatility of 5-nitrosopyrimidines in pteridine syntheses was noticed by Pachter (64MI21603) during modification of the Timmis condensation between (262) and benzyl methyl ketone simple condensation leads to 4-amino-7-methyl-2,6-diphenylpteridine (264) but in the presence of cyanide ion 4,7-diamino-2,6-diphenylpteridine (265) is formed (equation 90). The mechanism of this reaction is still uncertain (63JOC1187) it may involve an oxidation of an intermediate hydroxylamine derivative, nitrone formation similar to the Krohnke reaction, or nucleophilic addition of the cyanide ion to the Schiff s base function (266) followed by cyclization to a 7-amino-5,6-dihydropteridine derivative (267), oxidation to a quinonoid-type product (268) and loss of the acyl group (equation 91). Extension of these principles to a-aryl- and a-alkyl-acetoacetonitriles omits the oxidation step and gives higher yields, and forms 6-alkyl-7-aminopteridines, which cannot be obtained directly from simple aliphatic ketones. 

The isoxazolidines (47) and (48) were obtained by cyclization of the corresponding ketone-derived exocyclic nitrones (Scheme 11).22 Such reactions have been used for natural product sysnthesis, as in the conversion of isoxazolidine (49) to ( )-hirsutene. Methylation and catalytic hydrogenolysis provided a y-dimethylamino alcohol, which underwent Cope elimination to provide an alkenyl alcohol in a key step. A related synthesis of ( )-7,12-sechoishwaran-12-ol is also reported. 

In addition to tin and silicon, carbon-nitrogen double bonds as hydrazones, oximes, and nitrones can be treated with ozone to form carbonyl compounds (eq 53)7 While the transformation can be accomplished on several types of substrates, ketone-derived starting materials (e.g., ketoximes) perform better in the reaction, as the aldehyde-derived starting materials have the potential for overoxidation to the corresponding carboxylic acid product. 

Thus, the interaction of a-haloalkylnitrones 64a,b with amines and hydrazine leads to products that contain no iV-oxide oxygen atom. This allows aldehyde and ketone derivatives of 3-imidazoline nitroxide to be synthesized the latter are of interest as spin labels for biological systems (Schlude, 1973). The interaction of the same compounds (64a,b) with nitrogenous nucleophiles, which contain a more electronegative nitrogen atom than that in amines or hydrazine, as well as the interaction with C-, S-, and O-nucleophiles, proceeds with the preservation of the nitrone group and leads to nucleophilic substitution products. Dehydrobromination of 4-bromoalkyl derivatives leads to reactive a,j8-unsaturated nitrones... 

In the presence of a catalytic amount of tetrabutylammonium fluoride, either freshly dried over molecular sieves22 or as the trihydrate16, silylnitronates 2 derived from primary nitroalkanes react readily at — 78 C or below, via their in situ generated nitronates. with aromatic and aliphatic aldehydes to give the silyl-protected (/J, S )-nitroaldol adducts 3 in excellent yield4,22-24-26,27. Silylnitronates, derived from secondary nitroalkanes. afford the adducts in 30 40% overall yield24. In contrast to the classical Henry reaction (vide supra), the addition of silylnitronates to aldehydes is irreversible. Ketones are unreaetive under such conditions. 

The nitrone arising from reaction between (Z)-19-nor-5,10-secosteroidal ketone 260 a and M-methylhydroxylamine hydrochloride undergoes transannu-lar 1,3-dipolar cycloaddition to give isoxazolidines 261 and 262 and an aromatic derivative 263 originating from 261 (Scheme 28). Corresponding reaction of 260b produces two types of structurally different isoxazolidines 264 and 265 as well as the dienone 266. 

Chiral cyclic nitrones (185) were synthesized in the reaction of isonitroso-derivatives of Meldmm s acid (183) with ketones in boiling toluene (338—344). The reaction is likely to proceed, as in the case of the cycloaddition of a-nitrosostyrenes, by [3 + 2] cycloaddition of ketones to nitrosoketone (184), resulting from thermolysis of (183) (Scheme 2.65) (345). 

Metalated cyclic aldo-nitrones are characterized by high reactivity toward electrophilic reagents. Reactions with aldehydes and ketones afford satisfactory yields of a-hydroxymethyl substituted derivatives of nitrones (551). The reactions were also carried out with a number of aliphatic, aromatic, and hetero-aromatic aldehydes and ketones (Schemes 2.124 and 2.125). 

The reactions of a-bromoalkyl nitrones (298) with secondary amines lead initially to a-dialkylamino derivatives (432), which on heating, give aldehydes and ketones (75a,b) in high yield (Scheme 2.205) (540). 

The chemistry of acyl nitronates derived from secondary AN has received much more attention. Yoshikoshi and coworkers (226-228) developed a reliable procedure for the synthesis of these derivatives from readily available precursors (ketones and a-nitroalkenes), they demonstrated that the resulting acyl nitronates (123) are convenient reagents for the preparation of various heterocyclic and acyclic derivatives (226) (Scheme 3.104). 

The chlorodifluoromethylated ketone 130 proved to be a valuable substrate for promoting SrnI subtitution reaction with sodium phenylthiolate and to generate a new a-(phenylthio)-a,a-difluoroacetophenone derivative 131 (Equation 57) <2001TL3459>. Upon treatment with nitronate anions under classical SrnI reaction conditions or MW irradiation, 6-chloromethyl-5-nitro-imidazo[2,l- ]thiazole 132 yielded 5-nitroimidazothiazoles bearing a trisubstituted ethylenic double bond at the 6-position (Equation 58) <2001SC1257>. 

Nef reaction.4 Nitro compounds, primary or secondary, are converted to tri-alkylsilyl nitronates in greater than 90% yield by reaction with a trialkylsilyl chloride and DBU in CH2C12. The silyl nitronates derived from secondary nitro compounds are oxidized by C1QH4C03H at 25° to ketones in high yield. This sequence is not useful for conversion of primary nitro compounds to aldehydes. 

In general, copper-zinc compounds, unlike organolithium-derived organocopper reagents, undergo clean addition reactions to nitroolefins. After Michael addition, the resulting zinc nitronates can be oxidatively converted into polyfunctional ketones, such as 117 (Scheme 2.45) [96]. 

Decarboxylation of 1,3-dimethylorotic acid in the presence of benzyl bromide yields 6-benzyl-1,3-dimethyluracil and presumably involves a C(6) centered nucleophilic intermediate which could nonetheless have either a carbene or ylide structure. Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry has been used to explore the gas-phase reactions of methyl nitrate with anions from active methylene compounds anions of aliphatic ketones and nitriles react by the 5n2 mechanism and Fco reactions yielding N02 ions are also observed nitronate ions are formed on reaction with the carbanions derived from toluenes and methylpyridines. 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

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