Carboxylic synthesis, regiospecific

Pyrrole-2-carboxylate is employed in the synthesis of various pharmaceuticals" and a potential herbicide. A number of organic syntheses have been described " However, they require multiple steps and result in low yields. Furthermore, the chemical carbonation of pyrrole with K2CO3 depends on high pressure and temperature. The one-step enzymatic conversion has advantages with regard to regiospecificity, yield, and mild reaction conditions. 

Carboxylic mixed anhydrides are very important for the rapid synthesis of peptides by the stepwise procedure,however the use of carboxylic mixed anhydrides,e.g.those derived from pivalic acid and a protected amino acid (1),suffers from two disadvantages. Firstly,regiospecificity of attack at the desired carboxyl function is largely determined by steric effects and will not be 100% for all coupling reactions.Secondly,such mixed anhydrides have a propensity towards disproportionation to symmetric anhydrides which is highly undesirable in terms of reaction efficiency.This latter process can be depressed by operation of the reaction at -15 °C, but with the concurrent decrease in reaction rate and,on large scale manufacture,increased costs. 

Sodium cyanide in DMF at 120 °C has been used for the decarboxylation of 1-substituted-4-oxoquinoline-3-carboxylic acids <94TL(35)8303>. Quinoline Reissert adducts have been epoxidized at the 3,4-bond. Its reaction with amine nucleophiles gave regiospecifically substituted 1,2,3,4-tetrahydroquinolines <95H(41)897>. Successive Claissen rearrangements of 2-(8-quinolinoxymethyl)-3-(8-quinolinoxy)-l-propene gave a product which shows excellent ability to extract heavy metal ions <95TL(36)5567>. An Eschenmoser approach has been used in a facile synthesis of monofunctional and difunctional A -substituted-4-alkylidenequinolines (54) (Scheme 39) <95S(St)56>. 

A convenient synthesis of pyridazine-3,4-dicarboxylic acid based on [4 + 2] cycloaddition of an electron deficient diazadiene has been developed (Scheme 102) and carried out on a molar scale. The azadiene is generated in situ from the precursor (124) (prepared from diethyl oxaloacetate and methyl carbazate followed by chlorination with sulfuryl chloride) and trapped with ethyl vinyl ether. The regiospecific cycloaddition gives the tetrahydropyridazine (125) as a mixture of cis and trans isomers which, with bromine in acetic acid, are transformed into diethyl pyridazine-3,4-dicar-boxylate. Saponification gives the diacid in an overall yield of 52% <90JHC579>. In a similar approach from the readily available ethyl 2-chloro-3-oxobutanoate, an efficient route to ethyl 3-methylpyridazine-4-carboxylate has been developed which gives the product in 56% overall yield. This route is claimed to be a practical alternative to the radical ethoxycarbonylation of pyridazines <91JHC1043>. 

Patra et al. described the regiospecific synthesis of benz[a]anthracene-5,6-dione 9 and their efficient conversion to benzo[h]fluorenones 11 through the carboxylic acid 10. The transformation of 9 to 10 has been effected by benzilic acid rearrangement employing the method of Toda et using powdered KOH in dioxane. Several other conditions such as NaOH in water, KOH in a mixture of ethanol and water, KOH in a mixture of dioxane and water and NaOEt in ethanol did not give satisfactory results. 

Knobloch DJ, Toomey HE, Chirik PJ. Carboxylation of an ansa-zirconocene dinitrogen complex regiospecific hydrazine synthesis from N2 and CO2. J Am Chem Soc. 2008 130 4248-4249. 

A new stereocontrolled diene synthesis via a palladium-catalysed decarboxy-lative elimination of the adducts from a,jS-unsaturated aldehydes and carboxylate enolate has been reported and applied to the synthesis of insect pheromones and to regiospecifically substituted cyclohexadienes (Scheme 32). ... 

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