Carboxylation reaction with electrophiles

Carboxylic acid derivatives on pyridopyrimidine rings appear to undergo normal reactions with electrophilic reagents, e.g. the 6-amide (70) is dehydrated to the 6-nitrile with phosphorus oxychloride. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

Obviously the COOH species cannot exist, but nevertheless a conversion described by this formal equation has been known to organic chemistry for more than a century. A very simple and familiar reagent, the cyanide anion, serves as an equivalent of the described synthon in the reaction with electrophiles to give nitriles, E-CN. The latter can be hydrolysed to the corresponding carboxylic acids, E-COOH, as illustrated below ... 

Common error alert The reaction of esters, amides, and carboxylic acids with electrophiles occurs on the carbonyl O. Many more resonance structures can be drawn when the carbonyl O is protonated than when the noncarbonyl heteroatom is protonated. 

Regiospecificity demands ort/zo-direction. A surprisingly effective group is a carboxylic acid C02H that acts as its lithium derivative C02Li. One equivalent of BuLi is used to make this 100 from, say picolinic acid 99, and three equivalents of LiTMP to make the C-Li derivative 101. Reaction with electrophiles such as C02 or carbonyl compounds occurs at C-3 102. 

Protons on alkyl groups at the 1,3-azole 2-positions are sufficiently acidic for strong base deprotonation,and are more acidic than methyl groups at other positions even the assistance of an or/Ao-related carboxylate is usually insufficient to overcome the intrinsic tendency for 2-methyl-lithiation, though an adjacent tertiary amide can do this. The side-chain metallated derivatives can be utilised in reactions with electrophiles. The presence of a 5-nitro group allows much milder, base-catalysed condensations to occur. The condensation at the 2-methyl of thiazoles proceeds in organic acid solution. ... 

Unsaturated fatty compounds such as oleic acid [la], 10-undecenoic acid [2a], pet-roselinic acid [3a], erucic acid [4a], and the respective esters, alcohols, and native oils (Fig. 1) are alkenes and contain an electron-rich double bond that can be functionalized in many different ways by reactions with electrophilic reagents. It is therefore remarkable that >90% of oleochemical reactions have been focused on the carboxylic acid functionality and < 10% have been reactions of the alkyl chain and the C,C-dou-ble bond (1). A review on radical additions to unsaturated fatty compounds that appeared in 1989 (2) quoted only very few C,C-bond-forming reactions giving branched and chain-elongated fatty compounds. Since then, modem preparative radical chemistry has been developing and has been applied also to fat chemistry (3-5). We report here on radical additions of activated haloalkanes such as alkyl 2-haloalka-noates and 2-haloalkanenitriles to unsaturated fatty compounds [l]-[4] initiated by electron transfer from copper in solvent-free systems. These additions were also car-... 

Recently, Chi and coworkers reported the NHC-catalysed p-functionalisation of carboxylic anhydrides.The P-carbon behaved as a reactive nucleophilic carbon and underwent asymmetric reactions with electrophiles such as all lidene diketones, chalcones and isatins to give the desired p-carbon functionalised products 228-230 in good yields and with excellent diastereo-and enantioselectivities (Scheme 20.91). 

Products of VNS are generated in the form of carbanions and are isolated upon protonation. Instead of protonation, they can be introduced directly in subsequent reactions with electrophilic partners such as alkylating agents [64a] or aldehydes [64b]. For instance, the VNS in nitrobenzene with carbanion of 2-dichloromethyloxazoline produces nitrobenzylic a-chlorocarbanion that enters the Darzens reaction with aromatic aldehydes to give oxiranes (Scheme 11.40) [64b] whereas the reaction with carbanion of r-butyl dichloroacetate followed by Michael addition gives f-butyl nitroarylcyclopropane carboxylates [64c]. 

Therefore, alkylpyridines and N-alkylpyridinium ions undergo base- or acid-catalyzed reactions with electrophilic reagents preferably at the 2- and 4- heterobenzylic positions. For instance, the CH3 group of 2- or 4-picohne can be alkylated (—> 71), carboxylated —> 72), and acylated (—> 74) by a CiAisEN-like condensation aldol addition 73), multiple aldol addition (—> 76), and aldol condensation 75) are also possible. 

Several papers have appeared dealing with the preparation and chemistry of 2-silylbut-3-enoate species, which, in their Lewis-acid-catalysed reaction with electrophiles behave as 3-alkoxycarbonylallyl anion equivalents. " The chemistry is summarized in Scheme 14, and it is worthy of note that in the preparation from allylsilanes (136) significant y-carboxylation occurs if R is Me this can be avoided by the use of the corresponding dimethylarylsilyl species. 

The nucleophilic reactivity of amines manifests itself in reactions with electrophilic carbon, as in haloalkanes, aldehydes, ketones, and carboxylic acids and their derivatives. 

The reaction of lithio derivatives with appropriate electrophiles has been utilized in the preparation of alkyl, aryl, acyl and carboxylic acid derivatives. Representative examples of these conversions are given in Scheme 79. Noteworthy is the two-step method of alkylation involving reaction with trialkylborane followed by treatment with iodine (78JOC4684). 

---