Alkylation on oxygen

Monoanions derived from nitroalkanes are more prone to alkylate on oxygen rather than on carbon in reactions with alkyl halides, as discussed in Section 5.1. Methods to circumvent O-alkylation of nitro compounds are presented in Sections 5.1 and 5.4, in which alkylation of the a.a-dianions of primary nitro compounds and radial reactions are described. Palladium-catalyzed alkylation of nitro compounds offers another useful method for C-alkylation of nitro compounds. Tsuj i and Trost have developed the carbon-carbon bond forming reactions using 7t-allyl Pd complexes. Various nucleophiles such as the anions derived from diethyl malonate or ethyl acetoacetate are employed for this transformation, as shown in Scheme 5.7. This process is now one of the most important tools for synthesis of complex compounds.6811-1 Nitro compounds can participate in palladium-catalyzed alkylation, both as alkylating agents (see Section 7.1.2) and nucleophiles. This section summarizes the C-alkylation of nitro compounds using transition metals. 

From the above discussion it is evident that alkylation of 1,2,3-benzotriazin-4-one results almost entirely in substitution at Nj and/or Nj, and that alkylation on oxygen is at most a minor reaction. Alkylation of l,2,3-benzotriazine-4(3//)-thione (39, R = H), on the other hand, leads to predominant or exclusive substitution on sulfur, presumably as a result of the greater nucleophilicity of sulfur compared to oxygen. This difference in reactivity between the oxygen (10, R = H) and sulfur (39, R = H) compounds has been elegantly demonstrated by Murray and Vaughan. Treatment of the sodium salt of 10, R = H, with phenacyl bromide gives the Nj-substituted derivative 127, which, on... 

Pyridones are easy to prepare (see Chapter 44) and can be alkylated on oxygen as predicted by their structure. A more important reaction is the direct conversion to chloropyridines with POCI3. The reaction starts by attack of the oxygen atom at phosphorus to create a leaving group, followed by aromatic nucleophilic substitution. The overall effect is very similar to acyl chloride formation from a carboxylic acid. 

It is reported that alkylation of quinazolin-4(3//)-ones 2 almost invariably leads to 3-alkyl derivatives (cf. p 164), and that only occasionally, for reasons that are not clear, alkylation on oxygen occurs with the formation of quinazolin-4-yl ethers. However, with the Claisen method" using alkyl or aryl halides, or dialkyl sulfates and potassium carbonate in acetone or butanone, 0-alkyl derivatives 3 are obtained in good yields. " Selective... 

Alkylation on oxygen has been observed when either phenyl- or diphenylcyclopro-penone is treated with triethyloxonium tetrafluoroborate (equation 52). 

Normally, sodium enolates of ketones alkylate on oxygen. A superactive form of sodium hydride is formed whenbutylsodium is reduced with hydrogen superactive sodium hydride is an excellent base for essentially quantitative deprotonation of ketones, trapped as their silyl ethers. For example, cyclodode-canone is converted to its enol ether (containing a hyperstable double bond) in 92% yield (eq 15). 

Ambident Nucleophiles. Amides and related functional groups can be alkylated on oxygen or nitrogen and, as has been noted already, alkylation on carbonyl oxygen normally predominates. In the case of carbamates, 0-alkylation by Me0S02F can be faster, but W-alkylation predominates at equilibrium. It has been noted that methylation of secondary amides and thioamides occurs at the protonless heteroatom in the major tautomer. The ionic products of these reactions can be deprotonated to give synthetically useful products, e.g. imidates, but excess Me0S02F should be removed before treatment with base. ... 

The fourth item in the table, phenol (hydroxybenzene), is alkylated on oxygen, forming an ether, methoxybenzene (anisol), with the powerful alkylating agent trimethyloxonium tetrafluoroborate [(CH30)3 BFt]. Other alkoxonium tetrafluo-roborates are also commercially available and can be used to the same end with phenols, enols, and alcohols, forming aryl ethers, enol ethers, and dialkyl ethers, respectively. In contrast to dialkyl, diaryl, and aralkyl ethers, which are quite inert and are often used as solvents, enol ethers are capable of acid-catalyzed hydrolysis to produce ketones (or their equivalent enol) and the alcohol from which the enol ether is formed (Scheme 8.47). 

Scheme 10.32. Alkylation on oxygen. Benzamide (benzenecarboxamide) is alkylated by triethyloxonium tetrafluoroborate [(CH3CH2)30 BF4 ] on oxygen in chloroform (CHCI3) solution. Subsequently, the benzimidate tetrafluoroborate salt can be aminated by treatment with ethanolic ethanamine (ethylamine, CH3CH2NH2) to produce the corresponding amidine.

In the case of O-alkyl xanthates, the choice of the alkyl is cmcial. It is important that the alkyl on oxygen is a very poor homolytic leaving group with respect to the alkyl group on sulfur for cleavage of the S-R bond to be favored over cleat ge of the O-alkyl bond. For example, control (predicted Ad , low Af /Afn) can be obtained in RAFF polymerization with O-methyl, O-ethyl (170), O-isopropyl, and O-aryl xanthates but not with the O-tert-butyl xanthate. ... 

Details of the synthesis of metacycloprodigiosin (61) have been given cyciododecanone was converted (by a series of reactions) into the formyl derivative (58) and hence into the pyrrole (59), which was condensed with the known methoxy-bipyrrole aldehyde (60). 3-Hydroxy-pyrromethenes and 3-hydroxy-pyrroles can be alkylated on oxygen with trialkyloxonium tetrafluoroborate, whereas other reagents effect alkylation on nitrogen,and these reactions were... 

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