Alkylation at oxygen

Nitro Anions Remov of a proton from an aliphatic nitro compound gives a carbanion (R2C-NO2) that can be alkylated at oxygen or carbon. ... 

HSAB is particularly useful for assessing the reactivity of ambident nucleophiles or electrophiles, and numerous examples of chemoselective reactions given throughout this book can be explained with the HSAB principle. Hard electrophiles, for example alkyl triflates, alkyl sulfates, trialkyloxonium salts, electron-poor car-benes, or the intermediate alkoxyphosphonium salts formed from alcohols during the Mitsunobu reaction, tend to alkylate ambident nucleophiles at the hardest atom. Amides, enolates, or phenolates, for example, will often be alkylated at oxygen by hard electrophiles whereas softer electrophiles, such as alkyl iodides or electron-poor alkenes, will preferentially attack amides at nitrogen and enolates at carbon. 

The regioselectivity of the alkylation of enolates can also be controlled by the hardness of the alkylating agent [29]. As illustrated by the examples in Scheme 1.10, allyl, propargyl, or alkyl bromides or iodides mainly yield C-alkylated products, whereas the harder sulfonates preferentially alkylate at oxygen. 

Chapter 5 dealt with chemoselectivity how to react one functional group rather than another. Now we must face a more subtle and demanding problem how to react one specific part of a single functional group and no other. This is regioselectivity. We have already seen that anions of phenols 2 are alkylated at oxygen to give ethers 3 while enolate anions 5 are alkylated at carbon to form a new C-C bond 6. 

Secondary thioacetamides 4-Substituted thiobenzamides N-Phosphorylated thiobenzamides N-Toluenesulfonyloxymethylenethiobenzamide N-Benzoyithiobenzamide AA -Bis(thiobenzoyl)al lenediamines Five-member thiolactams Six-membered thiolactams Seven-membered thiolactams Eight-membered thiolactams Imidazolethiocaibonamides 2-Thiono-1 -azapenam derivatives Thioamide 5-oxides (alkylation at oxygen)... 

Cinnolines ° (see Sections V,B,3, D, and E). The greater reactivity of N-2 of cinnoline (26) can be reduced by introducing an alkyl group at the 3-position.More product resulting from quaternization of N-1 then results. A preference for alkylation at N-2 of the anion of 4(l.ff)-cinnolone (52) is also noted betaine 53 is favored 3 1 over cinnolone 54. Alkylation at oxygen is not observed. Again, the presence of a substituent at position 3 forces more reaction to occur at N-1. ... 

Compound 120 can be alkylated at oxygen or nitrogen, depending on the reaction conditions (Eq. 29).41 Usually, N-alkylation to 47 was observed when 120 was treated in the presence of base in DMF with alkyl halides such as propargyl chloride or allyl bromide.40 41 However, treating 120 in DMF with NaHC03 and n-propyl bromide produced a small amount of the O-alkyl compound 121 (R = n-propyl) as well as the /V-alkyl derivative (47 R = n-propyl).41... 

Pyridine iV-oxides protonate and are alkylated at oxygen stable salts can be isolated in some cases. 0-Alkylation with benzylic and allylic halides in the presence of silver oxide produces the corresponding aldehydes, the oxygen being derived from the iV-oxide. " ... 

The silver or alkali salts of MO-dibenzoyl derivatives are alkylated at oxygen 0-benzyl benzohydroxamate is derivatized at nitrogen in the presence of NaOMe (119). It is of interest to note that lengthening of the chain in the alkyl-ator leads to a gradual increase in 0-alkylation Mel (100 N), EtI (100 N), n-Prl (75 N, 25 O), -BuI (70 N, 30 O). Exclusive N-methylation also occurs with Mel, but the 0-methyl derivative is evident when Me2S04 is used. Diazomethane effects 0-methylation of 0-alkyl hydroxamates (120). 

On the other hand, enolates almost always form trialkyl enol ethers on reaction with the hard chlorosilanes (144). Ethylation of 4-/er/-butylcyclo-hexanone lithium enolate (145) with iodoethane leads solely to a-ethylated ketones. However, up to 17% enol ether is obtained when the Meerwein reagent is used. Acetophenone anion is alkylated at oxygen and carbon in the following ratios—0.1, 3.5, and 4.9—depending on whether the reagent is EtI, Me2S04, or EtjO BF respectively (146). Amylation of butyrophenone enolate in dimethyl sulfoxide (DMSO) with reference to halide variation has also been studied (147). The lesser amount of enol ether formed corresponds to the softer halide. 

Alkylation at Oxygen a Biological Example. The Use of a Sulfonium Salt. 

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