Reactions at the Methylene Group

The direct preparation of e.p. [ CJglycidic acids/esters has been made possible by the development of a closely related diastereoselective procedure . According to this 

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Otherwise, the main reactions at the methylene group are the dialkylation with alkyl haUdes (77), the acetylation with acetyl chloride which yields acetylma1 ononitrile [1187-11-7] (78), the Knoevenagel condensation, as well as the condensation with triethyl orthoformate, gives... 

Reactions of diphenylmethane are similar to those of biphenyl, since the benzyl group, C H CH, is also ortholpara directing, although bromi-nation results in reaction at the methylene group. 

Reactions of the methylene group Reactions at the methylene group of the molecule yield dicyanomethylene compounds in many cases. These will be discussed in Section III. A. 3 in detail. Some compounds have been reported, which result from reactions at the methylene group of 10 but are no classical dicyanomethylene compounds. So, for example, nitrosation with nitrous acid in the presence of nucleophilic catalysts yielded the corresponding oxime product (NC)2C=N0H42. 

Thiophene-1-oxides Thiophene-1,1 -dioxides. 2.1 Reaction with nucleophiles. 2.2 Cycloaddition reactions. 2.3 Other reactions Thiophene S,N-ylides and S,C-ylides. 3.1 Cycloaddition reactions of S,N-ylides and S,C-ylides. 3.2 Cyclopropanation reactions of S,C-ylides. 3.3 Thermal transformations of thiophene S,N- and S,C-ylides Oxothiophenes Tautomeric with Hydroxythiophenes. 4.1 Tautomerism. 4.2 Alkylation and acylation. 4.3 Condensation reactions at the methylene group. 4.4 Halogenation. 4.5 Oxidative coupling. 4.6 Cycloaddition. 4.7 2,3-Diones 4 Sulfoxides and sulfones. 4.9 Photochemistry. 4.10 Macrocyclic polyethers... 

Preparation of Carbon-14-Labeled Compounds 359 6.5.1 Reactions at the Methylene Group... 

The large sulfur atom is a preferred reaction site in synthetic intermediates to introduce chirality into a carbon compound. Thermal equilibrations of chiral sulfoxides are slow, and parbanions with lithium or sodium as counterions on a chiral carbon atom adjacent to a sulfoxide group maintain their chirality. The benzylic proton of chiral sulfoxides is removed stereoselectively by strong bases. The largest groups prefer the anti conformation, e.g. phenyl and oxygen in the first example, phenyl and rert-butyl in the second. Deprotonation occurs at the methylene group on the least hindered site adjacent to the unshared electron pair of the sulfur atom (R.R. Fraser, 1972 F. Montanari, 1975). 

Reactions. Heating an aqueous solution of malonic acid above 70°C results in its decomposition to acetic acid and carbon dioxide. Malonic acid is a useful tool for synthesizing a-unsaturated carboxyUc acids because of its abiUty to undergo decarboxylation and condensation with aldehydes or ketones at the methylene group. Cinnamic acids are formed from the reaction of malonic acid and benzaldehyde derivatives (1). If aUphatic aldehydes are used acryhc acids result (2). Similarly this facile decarboxylation combined with the condensation with an activated double bond yields a-substituted acetic acid derivatives. For example, 4-thiazohdine acetic acids (2) are readily prepared from 2,5-dihydro-l,3-thiazoles (3). A further feature of malonic acid is that it does not form an anhydride when heated with phosphorous pentoxide [1314-56-3] but rather carbon suboxide [504-64-3] [0=C=C=0], a toxic gas that reacts with water to reform malonic acid. 

Only moderate induced diastereoselectivity is achieved in the addition reactions of lithium enolates of the following a-silyloxy ketones43 and carbohydrate-derived ketones44, deproto-nated in each case at the methylene group in a regioselective manner to benzaldehyde. 

In the presence of a sufficiently strong base, such as an alkyllithium, sodium or potassium hydride, sodium or potassium amide, or LDA, 1,3-dicarbonyl compounds can be converted to their dianions by two sequential deprotonations.41 42 For example, reaction of benzoylacetone with sodium amide leads first to the enolate generated by deprotonation at the methylene group between the two carbonyl groups. A second equivalent of base deprotonates the benzyl methylene group to give a diendiolate. 

The results indicate that the product ratio is determined by the competition between the various reaction steps. Under base-catalyzed conditions, 2-butanone reacts with benzaldehyde at the methyl group to give l-phenylpent-l-en-3-one. Under acid-catalyzed conditions, the product is the result of condensation at the methylene group, namely, 3-methyl-4-phenylbut-3-en-2-one. Under the reaction conditions used, it is not possible to isolate the intermediate ketols, because the addition step is rate-limiting. These intermediates can be... 

The metallation of 3-methyl-4//-5,6-dihydro-l,2-oxazine has been shown to take place at the methyl group with hindered bases and at the methylene group with unhindered bases (81JA5916). Deprotonation of (753) with lithium dimethylamide at -65 °C followed by reaction with benzyl bromide gave (754) in 85% yield. This product was converted to enone (755) by reaction first with triethyloxonium tetrafluoroborate to produce an oxoiminium salt. The salt was stirred with trimethylamine and the resulting a,/3-unsaturated imine hydrolyzed with wet silica gel to the enone (Scheme 174). The lithiated derivative of (753) serves as a synthon for the unknown a-anion of methyl vinyl ketone. 

In a solution of sodium sulfite at pH 5, thiamin is cleaved by what appears to be a nucleophilic displacement reaction on the methylene group to give the free thiazole and a sulfonic acid. 

Reactions. Malonie acid is a useful tool lor synthesizing a-unsaturaled carboxylic acids because of its ability lo undergo decarboxylation and condensation with aldehydes or ketones at the methylene group. Cinnamic... 

This reaction has been indepoidently reinvestigated by Lauer and Schmid. Rearrangement of (1), bearing a C label at the distal carbon of the allylic moiety (starred), gives phenol (4) with 84% of the label at the terminal carbon of the side chain and 16% at the methylene group. This result demonstrates that the reaction proceeds principally through a double transposition of the allylic residue the labeling pattern is maintained independent of the pathway to phenol (4). 

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