Butyllithium reaction with oximes

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

The synthesis of FQ (Fig. 20) is simple and quite economical, which renders FQ attractive for the development of an antimalarial drug intended for use in areas, concerned by malaria, that are mostly overlaying with low-income countries. FQ was obtained starting from the commercially available AQV-dimethyl-1-ferrocenylmethanamine. The ferrocenic aldehyde results from a C-C bond formation, a two-step sequence involving metallation with tert/o-butyllithium and a reaction with DMF. This step has been previously studied and the 1,2 orientation of the two substituents of the cyclopentadienyl has been unambiguously established [125], The aldehyde is converted to the corresponding oxime, which is then reduced to the primary amine. The SNat reaction between the amine and 4,7-dichloroquinoline leads to the desired FQ [121]. 

Oximes are a useful source of carbanions in aldol-like condensations. Jung et al. showed that oxime 319 reacted with 2 equivalents of n-butyllithium to give the dianion, 320. Reaction with 1-bromopropane and treatment with water resulted in a 53% yield of 321. 2,193 O-Tetrahydropyranyl oximes such as 322 can also... 

Exposure of ketone oximes which have an o-hydrogen, to two mol equivalents of n-butyllithium leads to O- and C-lithiation (syn to the oxygen) reaction with dimethylformamide as electrophile then allows C-formylation and ring closure in situ... 

Much better results are achieved in the addition of butyllithium to oxime ethers 4a, 4b and 4c activated by boron trifluoride-diethyl ether complex (BF3 OEt2) at — 78 °C (above a reaction temperature of — 30 °C complex mixtures of products are obtained) using toluene as the solvent. Furthermore, the stereoselectivity depends on the E/Z ratio of the starting oxime ethers. The reaction appears to be highly stereoselective, with the diastereoselectivity of the... 

The initial reaction of butyllithium with the oxime is exothermic, and if the bath is not used, a slightly lower yield of colored product is obtained. 

Condensation of the 5-methyl group in (80) (R = Me, Et, Ph, SMe) with aromatic aldehydes leads to 5-styrylthiadiazoles (79). The action of carboxylic acid esters gives ethoxalyl derivatives (81) and that of isoamyl nitrite produces the oxime (82) (Scheme 20) <82AHC(32)285>. These reactions are restricted exclusively to the 5-methyl group in (80) (R = Me), reflecting the greater reactivity of substituents in the 5-position compared to the 3-position in 1,2,4-thiadiazoles. This point is further illustrated when (80) (R = Me) is selectively converted into the carboxylic acid (83) on treatment with n-butyllithium and carbon dioxide (Scheme 20) <84CHEC-I(6)463). 

Synthesis. Deoxybenzoin is converted to the corresponding oxime by treatment with hydroxylamine under basic conditions with sodium acetate in aqueous ethanol or in toluene in the presence of potassium hydroxide in absolute ethanol. Treatment of the oxime under nitrogen with two equivalents of butyllithium in tetrahydrofurane is followed by cyclization in ethyl acetate or acetic anhydride to the isoxazoline derivative. Finally, treatment of the isoxazoline with cold chlorosulfonic acid followed by reaction of the intermediate with aqueous ammonia affords the desired product. (Talley, 2000a Sorbera, 2001b). 

Treatment of benzaldehyde oxime ether (166) with butyllithium (pentane/-10 C) demonstrates the complexity of the reaction (Scheme 32) as the desired alkoxyamine (167 R = Bu) is accompanied by other oxime-derived side products" (entry 1, Table 12). Selectivity is reagent/solvent dependent as allyl Grignard (ether)," allylzinc bromide (THF)," and butyllithium (THF)" treatment produce predominantly amine (171 R = allyl) (the Beckmann rearrangement derived product), alkoxyamine (167 R = allyl) (the oxime addition product) and ketone (169 R = Bu) (the nitrile-derived pro ct), respectively (entries 2-4, Table 12). 

Deprotonation of Al,<9-bis(trimethylsilyl)hydroxylamine with n-butyllithium or potassium hydride at low temperature yields the nitrogen centered anion Al,<9-bis(trimethylsilyl)hydroxyl-amide. At higher temperatures the oxyanion Al,A -bis(tri-methylsilyl)hydroxylamide is formed by rearrangement. Each reacts with acyl chlorides chemospecifically by M-acylation and 0-acylation, respectively. The oxyanion also reacts with silyl halides, methyl iodide, and sulfonyl chlorides chemospecifically on oxygen. In a Peterson-type one-pot reaction, oximes and oxime derivatives can be prepared effectively from the N-anion of iV,0-bis(trimethylsilyl)hydroxylamine and an aldehyde or ketone (eq 5). Oximes of sterically hindered ketones can be formed in high yields by this procedure. 

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