Oximes, as nucleophiles

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Scheme 9.36 Allylic substitutions with oximes as nucleophiles. In the lower row, Ar= Ph...

Regarding the hydroxylation of nitroolefins, the reaction is performed under hydrogen-bonding catalysis using quinine-derived thiourea 170 (5 mol%), ethyl glyoxylate oxime as nucleophile in toluene at -24°C [374], This process, which constitutes a valid alternative to the Henry reaction, yields the corresponding hydroxylated nitrocompounds in good yields (63-83%) and enantioselectivities (48-93% ee) from ahphatic electrophiles (styrene derivatives are prone to retio-Michael addition) and has been successfully employed in the synthesis of optically active P-amino alcohols (Scheme 2.132) [375]. 

Oximes as Nucleophiles in the Reaction with Acetylenes Literature Analysis... 

In many cases, the yields of these products are high. However, the use of /V-silylated triazoles as nucleophiles or the use of cyclic nitroso acetals (475) substituted at the C-3 atom leads to a noticeable decrease in the yield of the oximes. Therefore, steric hindrance in nitroso acetals and a decrease in nucleophilicity of A-centered nucleophiles result in an increase in the contribution of side reactions. It should be emphasized that C -nucleophiles, such as anions of nitro compounds, are not involved in coupling reactions with cyclic nitroso acetals (475). However, the products, which formally correspond to the C,C-coupling mechanism, can be prepared by the nucleophilic substitution of chlorine in compound (476 d) by a Sa/2 mechanism (Scheme 3.254, product (483c), the yield was 79%). 

Oxime reactivators (R-CH N0H) are weak acids that partly Ionize at biologic pH. This property allows them to function as nucleophiles and displace organophosphate moieties from inhibited acetylcholinesterase. It also makes them vulnerable to decomposition by other mechanisms in the body. 

A parallel situation appears to obtain for the mixed allyl nitrosyl complex Ru(NO)(C3H5)L2 prepared by Schoonover and Eisenberg (231). This complex which is coordinatively saturated (NO+ and rf -allyl), forms a CO adduct which is assigned a bent nitrosyl structure (231). Further reaction under CO leads to the formation of Ru(CO)3L2 with the possible elimination of acrolein oxime. The coupling of the allyl and nitrosyl ligands can be viewed in this case as nucleophilic attack of NO- on an f/3-allyl species. Unlike in reaction (110), both of the moieties to be coupled lie within the same coordination sphere. The significance of these results is that it lends viability to the notion embodied in (109) in which a migratory insertion of nitrosyl occurs as NO-. 

S)-proline-catalyzed reactions using unmodified aldehydes as nucleophiles retain the aldehyde group, and the aldehyde group of the products can be used for further transformations in the same reaction vessel. For example, one-pot Mannich-oxime formation [71b], Mannich-allylation [71c], and Mannich-cyanation [80] reactions have been demonstrated (Scheme 2.18). Mannich-type reaction products that possess an aldehyde functionality are easily epimerized during work-up and silica gel column purification. In the one-pot Mannich-cyanation reaction sequence, the cyanohydrin was obtained without epimerization at the a-position of the original aldehyde Mannich products. Thus, this one-pot sequence minimizes potential epimerization of the Mannich products. 

Although there is ample evidence for nucleophilic additions to benzyne la> and some other unstable angle strained cycloalkyne intermediates 15,27,31,205 207), only a few addition reactions to isolable angle strained cycloalkynes are known which can be classified as nucleophilic. Hydroxylamine and hydrazine add to (31) to yield the corresponding oxime and hydrazone, resp. 208). 

On the other hand, conjugated nitroalkenes are very useful electron-poor alkenes, prone to act as nucleophilic acceptor, mainly in the Michael reaction (Berestovitaskaya et al., 1994) or in the Diels-Alder cycloaddition (Denmark and Thorarensen, 1996). Moreover, the nitro group can be easily turned into a respectable array of functional groups such as its reduction to a primary amine, replacement with hydrogen (Ballini et al., 1983 Ono, 2001), conversion into a carbonyl (Nef reaction) (Ballini and Petrini, 2004), and transformation into other important functionalities such as nitrile, nitrile oxide, oximes, hydroxylamines, and thiols (Colvin et al., 1979). 

It was found that La -catalysed methanolysis of hydroxy-p-nitrophenyl phosphate (HPNPP) (76) is a model for the RNA transestrification reaction (Scheme 16). The same authors proposed catalytic methanolysis promoted by La as a new method for controlled decomposition of paraoxon (74) (Scheme 17). They found that methanolysis of (74) promoted by La(OTf)3 (Tf=0S(0)2CF3) in a methanol medium is billion-fold accelerated. Investigation of the reaction of oximate ot-nucleophiles with diisopropylphosphoro-fluoridate (DFP) (77) and two model phosphonates (78) and (79) has been... 

Numerous biomimetic reactions catalyzed by CDs carrying catalytic or reactive functional groups, such as nucleophiles (imidazole, oxime, and amine), enzyme cofactors (pyridoxamine, thiazolium. nicotinamide, cobal-ainine, flavin), metal complexes, etc., were reported. " Typically, enzyme-like kinetics and improved performance of a catalytic group, as compared to a simple analog lacking CD. are observed. 

Melchiorre et al. accomplished the highly enantioselective otganocatalytic p-hydro)qrlation of a,p-unsaturated ketones by using oximes as the oxygen nucleophile. Catalyst salt, made by combining 9-amino-9-deoxy-epr-hydroquinine with d-AI-Boc phenylglycine, functions as an efficient catalyst, and optically active products are obtained with enantioselectivily up to 94%. 

Soon afterward, the 3-hydroxylation of enones was published by Melchiorre and co-workers [70]. The authors obtained 1,3-hydroxy ketones with moderate yields and good stereoselectivities using aromatic oximes as the oxygen nucleophile. The use of a catalytic primary amine salt in which both the cation and the anion are chiral was found to be crucial. 

The anilinium ion and its ring-substituted derivatives have been found to be considerably more effective as catalysts in semicarbazone and oxime formation than their pJC values would lead one to predict. Investigation showed that they are not functioning as classical general acid catalysts but as nucleophilic cabdysts, through the formation of reactive Schiff base intermediates . Similar Schiff base intermediates have been proposed to occur in the amine-catalyzed enoliza-tion of acetone . In reactions (39 and 40) the overall rate of... 

Sulfonamides are sufficiently reactive to serve as nucleophiles in the reaction with difluorostyrenes under basic conditions (Scheme 27) [100]. Imines and oximes have also been utilized as nucleophiles to provide 3-fluoroisoquinolines and their V-oxides, respectively (Scheme 28) [101]. When the isoquinoline V-oxide was treated with an isocyanate, the oxygen atom on the nitrogen was consequently eliminated after the 1,3-dipolar addition to afford a l-amino-3-fluoroisoquinoline (Scheme 28). 

Apparently, higher electron saturation and lower steric hindrance of the acetyl oxime group enable its easier (as compared to the benzoyl oxime fragment) nucleophilic addition to acetylene. 

SCHEME 1.190 Addition of acetophenone oxime as O-nucleophile to dimethyl acetylenedicarboxylate. 

Fluoropyridine is readily hydroly2ed to 2-pyridone in 60% yield by reflux in 6 Ai hydrochloric acid (383). It is quite reactive with nucleophiles. For example, the halogen mobiUty ratio from the comparative methoxydehalogenation of 2-fluoropyridine and 2-chloropyridine was 85.5/1 at 99.5°C (384). This labihty of fluorine has been utili2ed to prepare fluorine-free 0-2-pyridyl oximes of 3-oxo steroids from 2-fluoropyridine for possible use as antifertihty agents (385). 

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