Aldoximes alkylation

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

In an alternative approach, the isomeric unsaturated pyrrolidine or piperidine aldoximes 245 a and 245b were prepared and subjected to lOOC reaction affording 246a and 246b, respectively (Eq. 28). Esterification of 240 followed by N-tert-BOC protection and DIBALH reduction provided aldehyde 244 (X = 0) which was subjected to Wittig olefination. Introduction of a two carbon aldoxime chain on N in 244 (X = CH2) was carried out by alkylation with Et a-bromoacetate after deprotection of the N atom in 244. Reduction and oxima-tion led to 245. 

On the other hand, 3-phenylpropionitrile was synthesized from Z-3-phenyl-propionaldoxime (0.75 M) in a quantitative yield (98gP ) by the use of cells of E. coli JM 109/pOxD-9OF, a transformant harboring a gene for a new enzyme, phenylacetaldoxime dehydratase, from Bacillus sp. strain OxB-1. Other arylalkyl- and alkyl-nitriles were also synthesized in high yields from the corresponding aldoximes. Moreover, 3-phenylpropionitrile was successfully synthesized by the recombinant cells in 70 and 100% yields from 0.1 M unpurified P/Z-3-phenylpropionaldoxime, which is spontaneously formed from 3-phenylpropionaldehyde and hydroxylamine in a butyl acetate/water biphasic system and aqueous phase, respectively. 

Aliphatic aldoximes and ketoximes undergo palladium-catalyzed O- and N-alkylation by butadiene in reactions that presumably occur via jr-allyl... 

Functionalized isoxazoles were obtained in good yields from activated acetylenes and alkyl 2-nitroethanoates in the presence of triphenylphosphine <06TL1627>. The use of PPI13/DDQ offers a neutral and highly efficient method for the conversion of 2-hydroxyaryl aldoximes and ketoximes to 1,2-benzisoxazoles in excellent yields at room temperature <06TL8247>. 

In the presence of Lewis acids (Znl2 and BF3 OEt2), aldoximes react with u,l )-unsaturated carbonyl compounds (129) at room temperature affording good yields of /V-alkyl nitrones (130) (Scheme 2.47) (299). 

Alkylation of Z-aldoximes (144) and (145) with bromo esters (146) and (147) provides good yields of high purity DEEPN and EPPyON nitrones (Scheme 2.52) (306). 

Intramolecular addition of trialkylboranes to imines and related compounds have been reported and the main results are part of review articles [94, 95]. Addition of ethyl radicals generated from Et3B to aldimines affords the desired addition product in fair to good yield but low diaster control (Scheme 40, Eq. 40a) [96]. Similar reactions with aldoxime ethers [97], aldehyde hydrazones [97], and N-sulfonylaldimines [98] are reported. Radical addition to ketimines has been recently reported (Eq. 40b) [99]. Addition of triethylborane to 2H-azirine-3-carboxylate derivatives is reported [100]. Very recently, Somfai has extended this reaction to the addition of different alkyl radicals generated from trialkylboranes to a chiral ester of 2ff-azirine-3-carboxylate under Lewis acid activation with CuCl (Eq. 40c) [101]. 

These nitrones are identical with the N-ethers of the aldoximes and are also formed—when an alkyl group occupies the place of C6H6—by the action of alkyl halides on the stereoisomeric /3-aldoximes ... 

Subsequently, Kato and Goto have reported the synthesis of 2- and 4-pyridinecarbox-aldoximes from 2- and 4-picoline with potassium amide and amyl nitrite in liquid ammonia at — 33°C, although they failed to obtain either of these oximes when the reaction was carried ont with sodium amide in liquid ammonia at room temperature in a sealed tube. Finally, in 1964, aUcyl-substituted heteroaromatic compounds and allyl-substituted benzenes were oximated in liquid ammonia at —33 °C with sodamide and an alkyl nitrite . 

It is usually an oxime, either isolated or prepared in situ. The a-groups of the oxime may be alkyl, aryl, heteroaryl (ketoxime) and one may be hydrogen (aldoxime). 

The kinetic scheme for the reactivation of OP-inhibited AChE is depicted in equation 20 for pyridinium-based aldoximes, where R = CH3 or an alkoxy group, and = alkyl or aryl. The nerve agents that generate the covalent OP-AChE conjugates are those with R = CH3 and R = ethyl(VX), isopropyl (sarin), cyclohexyl (cyclosarin) and pinacolyl (soman). For tabun-inhibited AChE, R = Af,A-dimethylamido and R = ethyl. 

Another methodology for the in situ preparation of nitrile oxide is the dehydro-halogenation of hydroxymoyl chlorides vrith triethylamine. Hydroxymoyl chlorides are accessible by the reaction of aldoximes vrith chlorinating agents such as NCS (N-chlorosuccinimide). Isoxazolines of C50 and C70 [293-295] with R = Ph, alkyl, 4-C5H4OCH3 4-C5H4CHO, amino acid [305], dialkoxyphosphoryl [296, 297] or ferrocene [298] have been synthesized in ca. 20 0% yields. The latter reaction is slower than the dehydration of nitroalkanes and requires one equivalent of hydroxymoyl chloride whereas excess nitroalkane is necessary for an optimum reaction [293]. 

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... 

A convenient one-step conversion of moderately activated nitroarenes to phenols was achieved in DMSO via nucleophilic nitrite displacement by the anion of an aldoxime.153 TTie resulting O-arylaldox-ime is rapidly cleaved to the phenol derivative under the reaction conditions. The reaction is also applicable to activated fluorides and even to 2-chloropyridine which, at 110 °C, is converted to 2-pyridone in 72% yield.153 A somewhat related process concerns the synthesis, in 82-92% yield, of 4-alkoxybenzoni-triles (45 R = Me, CH2-oxirane, CHrfh, CHMeCTfcMe from O-alkyl-4-nitrobenzaldoximes (44) via hydride-induced elimination of the alkoxide followed by alkoxy denitration (Scheme 17).154... 

Oxime formation can occur by various mechanisms. One possibility is the direct oxygenation of imino groups. The stoichiometry of this process is given in equation 4, where R2 = H (or alkyl) to yield either aldoximes or ketoximes. 

Alkyl-substituted 4-quinolinecarboxylic acids 197 were synthesized by the condensation of isatin 7 with the aldoximes 198 [176],... 

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