Alkylation ambident anion

Class (2) reactions are performed in the presence of dilute to concentrated aqueous sodium hydroxide, powdered potassium hydroxide, or, at elevated temperatures, soHd potassium carbonate, depending on the acidity of the substrate. Alkylations are possible in the presence of concentrated NaOH and a PT catalyst for substrates with conventional pX values up to - 23. This includes many C—H acidic compounds such as fiuorene, phenylacetylene, simple ketones, phenylacetonittile. Furthermore, alkylations of N—H, O—H, S—H, and P—H bonds, and ambident anions are weU known. Other basic phase-transfer reactions are hydrolyses, saponifications, isomerizations, H/D exchange, Michael-type additions, aldol, Darzens, and similar... 

Azolinones are protonated on oxygen in strongly acidic media. O-Alkylation of 2-azolinones can be effected with diazomethane thiazolinone (486) forms (487). Frequently O- and iV-alkylation occur together, especially in basic media where proton loss gives an ambident anion. 

A mechanism of this type permits substitution of certain aromatic and ahphatic nitro compounds by a variety of nucleophiles. These reactions were discovered as the result of efforts to explain the mechanistic basis for high-yield carbon alkylation of the 2-nitropropane anion by p-nitrobenzyl chloride. p-Nitrobenzyl bromide and iodide and benzyl halides that do not contain a nitro substituent give mainly the unstable oxygen alkylation product with this ambident anion ... 

For a monograph, see Reutov, O.A. Beletskaya, I.P. Kurts, A.L. Ambident Anions Plenum NY, 1983. For a review, see Black, T.H. Org. Prep. Proced. Int., 1989, 21, 179. Both cyanates and isocyanates have been isolated in treatment of secondary alkyl iodides with NCO Holm, A. Wentrup, C. Acta Chem. Scand., 1966, 20, 2123. 

Reactions of trident and ambident anions of hydroxy compounds with alkylating reagents were also studied.121 The ion-pair extraction method was found to be superior alkylating agents were methyl iodide (soft) and dimethyl sulfate (hard). Upon alkylation by ion-pair extraction the 5-methyl-substituted selenolene-2-one system gives mainly C-alkylation with the soft acid, methyl iodide, and mainly O-alkylation with the hard acid, dimethyl sulfate. 

Smith and Hanson, 1971). Upon addition of NaBPh4, the free anion was converted into the ion pair, and upon addition of dibenzo-18-crown-6 [11] the ion pair was converted into the free anion. The results (Table 26) show the free anion to be much more reactive than the ion pair towards both methyl iodide and methyl tosylate. The increase in rate is again mainly due to the enhanced reactivity of the hard oxygen centre. The ratio of the rates of alkylation at the two sites of the ambident anion (kN/k0) decreased from about 1.2 for the ion pair to 0.55 and almost zero for the free anion. Increased alkylation of the hard... 

Kornblum et al. (1963) demonstrated that O- vs. C-alkylation (24) of yS-naphthoxide ion (an ambident ion) is markedly solvent dependent. For example, the reaction with benzyl bromide conducted in dimethylformamide gave 97% O-alkylated product, whereas in water 81% C-alkylated product resulted. The difference is attributed to changes in the solvation of ambident anions. The course of the reaction is also influenced by water concentration in... 

The chemistry used to prepare the antischistosomal hydroxyquinolines provided the initial entry to this series. Thus, addition-elimination of aminopicoline (38-1) to EMME (38-2) gives the corresponding enamino ester (38-3). Thermal cyclization of that intermediate leads to the hydroxyquinoline (38-4). Reaction of the ambident anion from that compound leads to alkylation via the keto tautomer and thus the formation of the Al-alkylated derivative (38-5). Saponification of the ester then gives nalidixic acid (38-6) [44]. It has incidentally been shown that the presence of the strong Michael acceptor function in this series plays a little role in the mechanism of action in these compounds. 

There is another correlation that seems to have validity in many situations, at least where kinetic control is dominant namely, the.freer (less associated) the ambident anion is from its cation, the more likely is the electrophile to attack the atom of the anion with the highest negative charge. Thus O-alkylation of the sodium enolate of 2-propanone is favored in aprotic solvents that are good at solvating cations [such as (CH3)2SO, Section 8-7F],... 

Stereochemical results for the alkylation of two anions by optically active a-ehloro-/Miitrophenylcthanc have been interpreted in terms of competition between SrnI and, S N2 mechanisms.103 The ambident anion of 2-nitropropane gives C-alkylation with complete racemization by iS KN 1 and 0-alkylation by, S N2. The other anion studied was diethyldithiocarbamate. 

Le Noble, W. J. Conditions for the alkylation of ambident anions. Synthesis 1970, 1-6. 

Komblum, N. Berrigan, P. J. Le Noble, W. J. Chemical effects arising from selective solvation selective solvation as a factor in the alkylation of ambident anions. /. Am. Chem. Soc. 1960, 82, 1257-1258. 

The requisite 2-aryl-2-oxazolin-4-ones can be synthesized using the procedure briefly described by Gordon for the preparation of 2-phenyl-2-oxazolin-4-one (65a)53K The method utilizes an intramolecular O-alkylation of an imide ambident anion. 

Komblum, in his investigations of the factors that control the course of ambident anion alkylation reactions [64, 65], found a new type of radical chain substitution reaction that involves anion-radicals and free radical intermediates. When... 

The synthesis of the allyl ethers in nitrogen heterocyclic systems presents an element of complication in that the allylation could occur on the oxygen atom or the basic nitrogen atom. This is a feature of alkylation of ambident anions.3 However, this applies only when the allylation is effected by reacting the oxo or hydroxy derivative of the compound with an allyl halide in the presence of a base.3 The alternative method is to react the appropriate halo derivative with sodium allyloxide in allyl alcohol. The latter approach provides not only better yields of the allyl ethers but also certainty of the constitution of the ethers obtained. A diagnostic tool in deciding between the 1-allyl derivative and the O-allyl compound that has commonly been employed is the infrared absorption of the amide carbonyl in the case of the former which is clearly absent in the latter. 

To summarize, it can be stated that the freer the ambident anion in every respect, the larger the 0/C-alkylation ratio in the case of 1,3-dicarbonyl compounds [365]. Thus, if 0-alkylation products are desired in the alkylation of enolates, dipolar non-HBD and dissociating solvents such as A, A -dimethylformamide, dimethyl sulfoxide, or, especially, hexamethylphosphoric triamide should be used. If C-alkylation is desired, protic solvents like water, fluorinated alcohols, or, in the case of phenols, the parent phenol will be the best choice [365]. 

Pyridazinones have been reported to undergo a number of reactions with substitution on oxygen or nitrogen of the amide group. They can react as ambident anions in alkylations, but in view of the complexity of some such reactions this theory seems not to be so simply explainable when applied to pyridazinones. 

The mono-anion of ascorbic acid is an ambident anion that can display nucleophilicity at the C2 as well as 03 positions. This ambident character was first observed by Jackson and Jones (4) in the synthesis of 3-0-benzylascorbic acid by alkylation of sodium ascorbate with benzyl chloride. In strongly cation solvating solvents, such as dimethyl sulfoxide (DMSO), exclusive 03 alkylation was observed. In water, a mixture of the expected 03 alkylated 13 and C2 benzylated product 14 was produced. 

The selectivity for reaction at carbon rather than at oxygen must be favorable since ambident anions may react at either terminus of the enolate system depending on choice of solvent, counterion, and alkyl halide. 

Of particular preparative value is the observation that ambident anion alkylations, by appropriate choice of reaction conditions, may be manipulated to operate preferentially in one direction. The results of Guillemard s classical work in this area have been reviewed by Kurtz. Although most of the modem investigations do not deal in particular with the nitrile/isonitrile problem, the following rules can be summarized. 

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