Oximes, Hydrazones and Related Species

2-Alkyn-l-one O-methyl oximes (21) undergo electrophilic cyclization with a range of reagents, E-X (e.g. I2, Br2, IC1, PhSeBr), to give substituted isoxazoles (22)87 

Base-catalysed nitrosation of acetone by t-butyl nitrite to give l-hydroxyimino-2-oxopropane [H3C-C(=0)-CH=N0H] has been studied by ab initio methods.89 Using a sodium enolate route, the cation participates to give Z-isomer, whereas a naked enolate calculation results in the -product being favoured. 

Under the relatively mild conditions of chlorosulfonic acid in toluene, ketoximes undergo Beckmann rearrangement, whereas aldoximes dehydrate to nitriles.90 

Hydrolysis of cyclohexane-1,2,3-trione-l,3-dioxime (23, X = O) and its 2-imine (X = NH) has been studied in perchloric acid solution.91 The mechanism is proposed to involve a protonation pre-equilibrium, followed by slow water addition to protonated and non-protonated forms. Oxime protonation pXas have been calculated. 

Using a BINOL auxiliary with allylindium and indium metal, hydrazones have been allylated enantioselectively,92 to give homoallylic amines in up to 97% ee. 

A statistical study for prediction of values of substituted benzaldoximes has been based on quantum chemical methods. 

The kinetics of oxidative deoximation (in AcOH) ofiV-methyl-2,6-diphenyl piperidin-4-one oximes by acid dichromate and of 3,5-dimethyl-2,6-diaryl piperidin-4-one oximes by pyridinium chlorochromate have been detennined and are found to be consistent with polar mechanisms, first order in each reactant and subject to acid catalysis. 

Biodegradable imidazolium-based ionic liquid solvents have been applied effectively to cyanuric-chloride-catalysed Beckmann rearrangement of ketoximes. Conflicting views of the mechanism of aldoxime to amide rearrangements catalysed by metals have been reviewed and whether or not a universal mechanism applies has been discussed in the light of new evidence.  

The mechanism of addition of oxime derivatives to alkynyl Fischer carbene complexes has been studied experimentally and by DFT methods.  

Conjugate addition of donor-acceptor hydrazones (EDG-NH-N=CH-EWG) to a,P-unsaturated aldehydes, catalysed by a proline derivative through a formal diaza-ene reaction, gives access to 1,4-dicarbonyl compounds with up to 99% 

The Beckmann rearrangement of cyclohexanone oxime has been modelled kinetically, focusing on simulation of industrial conditions, and taking into account self-catalysis and the role of polymorphs.86 

Chiral 1,2-oxazines (33) have been prepared from achiral ketones, R -CO-CfT-R2, via an a-oximation step (with a tetrazolylpyrrolidine organocatalyst), followed by a Wittig reaction.87 Subsequent N—O cleavage yields enantiopure ds-allylic alcohols bearing a pendant amine. 

Aryl alkyl ketoxime ethers, Ar-C(R1)=N-OR2, have been reduced with borane-THF at ca 0 °C to give amines, Ar- CH(R )-NH2 88 A chiral BINAP with an O3BN (ee) framework gives up to 98% ee. 

The kinetics of oxidative deoximation of aldo- and keto-oximes by 2,2/-bipyridinium chlorochromate (back to the parent carbonyl compounds) have been studied in DMSO, where the reaction is found to be first order in both oxime and oxidant.89 The aldoximes proved more reactive, and rates correlated well with the Pavelich-Taft dual substituent equation. Following extension of the study to hindered cases, and to 18 other solvents (analysed by Taft and Swain multi-parametrics), a cyclic intermediate is proposed for the rate-determining step. The same reaction order behaviour is found using the pyridinium version, and again electronic, steric, and solvent effects were examined.90 

Electroanalytical techniques indicate the formation of two carbinolamine intermediates and one monohydrazone in the reaction of terephthalaldehyde with hydrazine at pH 7.3.91 

A range of benzaldehydes and acetophenones (28) with a, jS-unsaturated amides in the (3rt/to-position have been converted into their oximes (29). ° Two major cyclization routes are then available  

The reaction of hydroxylamine with (28) has been investigated for a variety of substituent patterns, and the combinations which produce (29), (30), or (31) as major product have been characterized. Substituent has a significant electronic effect, while and R, together with buttressing substituents placed ortho to both amide and carbonyl, have major steric influences on the outcome. 

The pKi, values of a series of para- and meffl-substituted benzaldoximes and phenyl methyl ketoximes, ArCR=NOH (R=H, Me), have been measured in DMSO. The aldoximes exhibit pK. = 20.05 + 3.21ap. The homolytic bond dissociation energy of the O-H bond has been estimated as 88.3 (aldoximes) and 89.2kcal mol (ketoximes) by relating the pK to the oxidation potential of the conjugate base (i.e. ox for ArCR=NO- ArCR=NO ). 

3-Hydroxyaminobenzo-furan and -thiophene (32a X = O, S) are the unstable enam-ine tautomers of the corresponding oximes (32b). Kinetics of the tautomeric interconversions have been measured, yielding tautomeric constants the latter have been compared with the corresponding keto-enol constants. The enamines are ca 40 times less stable, relative to the oximes, than are the enols, relative to the ketones. The minor tautomers are ca 100 times more stable (relative to the major) for the benzothiophene system. 

Aminolysis of 0-aryloximes shows a third-order term for both pyrrolidine and piperidine bases temperature effects on different routes are reported and explained. Hydrolysis of a-hydroxy-a-phenylbenzeneacetic acid salicylidenehydrazide (33) in aqueous ethanol proceeds via fast protonation, followed by rate-determining attack of water the results are compared with several related molecules. 

Neighbouring halogen participation effects have been investigated for pm-chloro- and pcn-bromo-substituted 0-tosyl oximes under acid-catalysed Beckmann rearrangement conditions. Evidence for stabilization of a nitrogen cation by nearby halogen is presented, including diversion of expected pathways. 

A DFT study of organo-mediated Beckmann rearrangements recharacterizes the species as initiators, rather than tme catalysts. A self-propagating mechanism has been identified and shown to be energetically more favourable than previous proposals involving Meisenheimer complexes. 

The oxime derived from the triterpenoid, oleanohc acid, has been studied under Beckmann rearrangement conditions.  

A [3+3]-type condensation of O-acetyl ketoximes and a, -unsaturated aldehydes yields pyridines for example, Ph-(Me)C=N-OAc and trans-cinnamaldehyde (trans-Ph-CH=CH-CHO) give 2,4-diphenylpyridine (54) using copper(I) iodide as catalyst and a salt of a secondary amine only a trace of the 2,6-product is observed. A synergistic copper/iminium catalysis is proposed the oxime reacts with the copper iodide to give an iminyl copper species, Ph-(Me)C=N-Cu-X (i.e., N-O reduction), which tautomerizes to a copper(II) enamide, Ph-C(=CH2)-NH-CuX, which then acts as a nucleophile towards the iminium ion (formed from the aldehyde and 2° amine). 

Oximes (56) and a, 0-unsaturated aldehydes (57) undergo a redox esterification to oxime esters (58) catalysed by a triazolium salt. A wide variety of oxime and enal types are tolerated. 

Diethylaminosulfur trifluoride (DAST, Et2NSF3) a-cleaves cyclic ketoximes to give fluorinated carbonitriles,47 e.g. (27)— (28). Two mechanisms are proposed, one for substrates with substituents that can stabilize an a-carbocation, and an iminium cation route for ketoximes without such groups. 

Three O-substituted benzophenone oximes (29 X = OMe, F, Cl) have been subjected to aminolysis by pyrrolidine and piperidine, in benzene solution.483 Kinetics were third order in amine, and involved two routes one accelerates with a rise in temperature, the other decelerates. Of the many mechanisms proposed for this reaction in non-polar media, the results support Hirst s mechanism of electrophilic catalysis48b in this instance. 

4-Benzoquinone oximes (30) exhibit sidedness the structures exhibit anomalous 1H-NMR coupling constants (J21 can exceed by 0.6 Hz), and its additions show a syn selectivity.49 The apparent stereoelectronic effect is concluded to be primarily steric in origin. 

Synthesis of a-substituted and a, /i-disubstitutcd amines with high stereoselectivity has been achieved by addition of alkyllithiums to chiral hydrazones.50 

Kinetics of reactions of cyclic secondary amines with benzohydrazonyl halides (31) have been measured in benzene51 at 30 °C. The products result from nucleophilic substitution at the halo-carbon via an associative addition-elimination mechanism. For X = Cl or Br, the rate equation has significant terms that are both first and second order in amine, whereas two amine molecules are essential for the fluoro compounds to react. 

Kinetics of the synthesis and aminolysis of 2,4-dinitrophenyl and 5-nitropyridine N-hydroxy oxime derivatives have been studied spectrophotometrically in acetonitrile. The reaction of several cholesterol-related oximes with 2-chloroethylamine in the presence of methoxide ion gives the corresponding oxime ethers DFT calculations indicate an oximate anion intermediate.  

Benzyl phenyl ketone oxime reacts with acetylene in superbase (DMSO/KOH/ 130 °C) to give Ai-benzyl benzamide and AT-vinyl-2,3-diphenylpyrrole, plus benzoic acid, via azirines and aziridine intermediates.  

Beckmann rearrangement of oximes to amides can deviate to fragmentation to form nitriles and carbocations, if the latter possess reasonable stability. Both 1-substituted-phenyl-2-propanones and 3-substituted-phenyl-2-butanones in aqueous solvents give both products, and calculations have been used to probe the mechanisms. In borderline cases, a dynamic path bifurcation from a single transition state is claimed. 

Kinetic evidence for such a dynamic path bifurcation in the mechanism of the Beckmann rearrangement has also been presented for reactions of oxime sulfonates (43, R /R = H/Me). In addition to the rearrangement product (amide), these substrates can also fragment (to alcohols), with the bifurcation in the mechanism apparently occurring after the rate-determining transition state. 

Propylphosphonic anhydride (44, T3P ) catalyses Beckmann rearrangements ketoximes give amides (84-95% yield) and aldoximes give nitriles (87-99%).  

---

For more references to Asymmetric Oxidation, see sections titled Reactions of Glucosides , Oximes, Hydrazones, and Related Species , and a-Halogenation, a-Alkylation, and Other -Substitutions . 

---