Methylenation carboxylic acid derivatives

Step (a) preceding step (b) Preparation of carboxamide (III) requires the use of an active methylene carboxylic acid derivative due to subsequent step (b). So far, three routes have been used ... 

Methylene Carboxylic Acid Derivatives (Arndt-Eistert Reaction)... 

Conversion of Amides into Amines Reduction Like other carboxylic acid derivatives, amides can be reduced by LiAlH.4. The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction reaction is thus the conversion of the amide carbonyl group into a methylene group (C=0 —> CTbV This kind of reaction is specific for amides and does not occur with other carboxylic acid derivatives. 

Another titanium-based reagent for the methylenation of carbonyl compounds is that prepared from dibromomethane/zinc/titanium tetrachloride and related systems (Scheme 14.25) [48]. These systems transform a wide variety of carboxylic acid derivatives to terminal olefins in the same way as titanocene-methylidene does. 

The )V-(2,2-diethoxycarbonyl)vinyl derivative of cephalosporin C (34) was reacted with thiols in water at pH 6.5 at 60°C for 5-6 hr, or in boiling methylene chloride for 50 min, or in the absence of a solvent at 140°C for 15 min to give the mercapto derivatives (1584) (82EUP45717). When the mercapto derivatives (1584) first were reacted with dimethylaniline and dichlorodimethylsilane at 30°C for 10 min, the mixtures were then cooled to -10°C, and phosphorus pentachloride was added, followed by stirring at -5°C for 40 min, the 7-aminoceph-3-ene-4-carboxylic acid derivatives (1585) were obtained after work-up. 

J. Nishikawa, K. Tori, 3-Substituent Effect and 3-Methylene Substituent Effect on the Structure-Reactivity Relationship of 7 beta-(Acylamino)-3-cephem-4-carboxylic Acid Derivatives Studied by Carbon-13 and IR Spectroscopies , J. Med. Chem. 1984, 27, 1657-1663. 

The retrosynthesis involves the following transformations i) isomerisation of the endocyclic doble bond to the exo position ii) substitution of the terminal methylene group by a more stable carbonyl group (retro-Wittig reaction) iii) nucleophilic retro-Michael addition iv) reductive allylic rearrangement v) dealkylation of tertiary alcohol vi) homolytic cleavage and functionalisation vii) dehydroiodination viii) conversion of ethynyl ketone to carboxylic acid derivative ix) homolytic cleavage and functionalisation x) 3-bromo-debutylation xi) conversion of vinyl trimethylstannane to methyl 2-oxocyclopentanecarboxylate (67). 

Amides behave differently towards LAH than the other carboxylic acid derivatives, and the overall reaction observed is reduction of the carhonyl to a methylene group, with retention of the amino group. 

Alkylation of ll-mercaptopyrido[l,2-h]cinnolin-6-ium hydroxide inner salts (e.g., 41) with ethyl bromoacetate gave ll-(ethoxycarbonylmethyl(thio derivatives 64 (R = H), which could be hydrolyzed to the ll-(carboxy-methyl)thio derivative or back to the starting compound 41 (74JHC125). Hydrolysis of the ll-bis(methoxycarbonyl)methylene 66 (R = H), and 2-cyano derivatives of 17 (R = H) in boiling HCl afforded 11-methyl and 2-carboxylic acid derivatives, respectively (74JHC125). The 2-nitro derivative of 17 (R = H) was reduced to the 2-amino derivative over Pd/C with NaBH4 in aqueous methanol, and the 2-amino group was acylated with acetic anhydride at 100°C. 

Second, titanium-based reagents are suitable for methylenation or alkylidenation of carbonyl groups of carboxylic acid derivatives such as esters and amides (Equation (7)). ... 

The most common procedure is ozonolysis at -78 °C (P.S. Bailey, 1978) in methanol or methylene chloride in the presence of dimethyl sulfide or pyridine, which reduce the intermediate ozonides to aldehydes. Unsubstituted cydohexene derivatives give 1,6-dialdehydes, enol ethers or esters yield carboxylic acid derivatives. Oxygen-substituted C—C bonds in cyclohexene derivatives, which may also be obtained by Birch reduction of alkoxyarenes (see p. 103f.), are often more rapidly oxidized than non-substituted bonds (E.J. Corey, 1968 D G. Stork, 1968 A,B). Catechol derivatives may also be directly cleaved to afford conjugated hexa-dienedioic acid derivatives (R.B. Woodward, 1963). Highly regioselective cleavage of the more electron-rich double bond is achieved in the ozonization of dienes (W. KnOll, 1975). 

Most other carboxylic acid derivatives can acylate only ketone enolates that are formed quantitatively. In these reactions, the acylation product is a /J-diketone, i.e., an active-methylene compound. As a consequence it is so acidic that it will be deprotonated quantitatively. This deprotonation will be effected by the ketone enolate. Therefore, a complete acylation of this type can be achieved only if two equivalents of the ketone enolate are reacted with one equivalent of the acylating agent. Of course, proceeding in that manner would mean an unacceptable waste in the case of a valuable ketone. 

Heating 10-(4-methyl-l-piperazinyl) and 10-fluoro-substituted derivatives of ethyl 9-fluoro-3-methylene-7-oxo-2,3-dihydro-7//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylate in a 1 1 mixture of cone. HC1 and AcOH afforded 3-hydroxy-3-methyl-6-carboxylic acid derivatives (92CCC216). 

Such an acid is known but it is not an unsaturated compound. It is what is termed a cyclic compound derived from a hydrocarbon known as tri-methylene, and also as cyclo propane (Pt. II). The acid is thus known as tri-methylene carboxylic acid and also as cyclo propanoic acid. 

Carboxylic Acid Derivative, Lactam Carbonyl or Isocyanide and Methylene... 

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