PERKIN Carboxylic acid synthesis

PERKIN Carboxylic Acid (Ester) Synthesis Synthesis of cycloalkane cartxixylic acids Irom o,ci>-dihaloalkanes and diethyl sodiummalonate. 

PERKIN Carboxyle acid(estar) synthesis 293 PERKIN Coumann rearrangement 293 PERKOW Vinyl phosphate synthesis 294... 

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

The constitution of carvestrene has been determined, subject to the limitation above referred to as to the constitution of isocarvestrene, by the masterly synthesis achieved by W. H Perkin, Jr., and his colleagues. The starting-point of this synthesis was t-hydroxy-benzoic acid, which was reduced by sodium and alcohol to cyclohexanol-3-carboxylic acid, of the formula—... 

Cohare and co-workers reported that aristolactam BU (22) was prepared, following Kupchen s method, by Perkin condensation of 6-bromo-3,4-di-methoxy phenyl acetic acid (119) and o-nitrobenzaldehyde (120) (Scheme 14). The 2-bromo-4,5-dimethoxy-2 -nitro-ds-stilbene-a-carboxylic acid (121) was obtained. The nitro group of 121 was reduced with ferrous sulfate and ammonium hydroxide, and the resulting 2-bromo-4,5-dimethoxy-2 -amino-cw-stilbene-a-carboxylic acid (122) without purification was submitted to the Pschorr phenanthrene synthesis to yield l-bromo-3,4-dimethoxyphen-anthrene-lO-carboxylic acid (123). The phenanthrylamine 124 was prepared from 123 via a Schmidt reaction, and, by treatment with n-butyllithium and CO2, 124, afforded 22 (42). 

The Perkin reaction involves the condensation of a carboxylic acid anhydride and an aldehyde in the presence of a weak base, often the sodium or potassium salt of the acid or triethylamine, to give unsaturated carboxylic acids (equation 1). The first example of this reaction was described by Perkin in 1868 and involves a synthesis of coumarin by heating the sodium salt of salicylaldehyde with acetic anhydride (equation 2). The reaction is generally applicable only to aromatic aldehydes and is particularly useful for the preparation of substituted cinnamic acids, as illustrated by equation (3). ... 

Synthesis of a,/3- and /3,y-unsaturated carboxylic acids a. Perkin synthesis... 

In the course of this reaction, derivatives of coumarin-3-carboxylic acid are produced. This synthesis proceeds under much milder conditions than the condensation based on the Perkin reaction which involves condensation of salicylaldehydes with acetic anhydride/acetate. 

Trifluoroacetic acid CF COOH Carboxylic acids COOBu-t -> COOH from their tert-huiyl esters s. 76,201 s. a. B. Kurtev, C. Kratdianov, and N. Kirtchev, Synthesis 1975, 106 R. A. Battersby et al., Soc. Perkin I 1976, 1008 ... 

Davies, S.G., Ichihara, O., Lenoir, I., and Walters, I.A.S. (1994) Asymmetric synthesis of (-)-(lR,2S)-cispentacin and related cis- and traras-2-amino cyclopentane- and cydohexane-1-carboxylic acids. J. Chem. Soc., Perkin Trans. 1, 1411-1415. 

Compound 20 is a 1,5-difunctional compound. Therefore one can design a synthesis that proceeds via intermediates that only contain odd difimctional relationships. Propose such a synthesis and indicate potential problems with your approach. If you can t get started, have a look at the following reference Ballester, P Costa, A. Raso, A. G. Gomez-Solivellas, A. Mestres, R. Dienediolates from Unsaturated Carboxylic Acids. Michael Addition of Dilithium 1,3-Butadiene-1,1-diolate (from Crotonic Acid) to Unsaturated Ketones J. Chem. Soc., Perkin 1 Organic and Bio-Oi anic Chemistry 1988, 1711-1717. (Unnatural Products-2)... 

Belgaonkar, V.H., and R.N. Usgaonkar Isocoumarins Part XIX. Synthesis of 8-Hydroy-3-methylisocoumarin and ( )-Mellein from w-Dinitrobenzene and a Convenient Synthesis of 3-Methoxyhomophthalic Acid. Indian J. Chem. 17B, 430 (1979). Bellinger, G.C.A., W.E. Campbell, R.G.F. Giles, and J.D. Tobias Formation of Some 3-Aryl-3,4-dihydroisocoumarins by Thermal Ring Closure of Stilbene-2-carboxylic Acids. J. Chem. Soc. Perkin Trans. 1 1982, 2819. 

AspinaU IH, Cowley PM, Mitchell G, Raynor CM, Stoodley RJ. Asymmetric synthesis of (35)-2,3,4,5-tetrahydropyrida-zine-3-carboxylic acid and its methyl ester. J. Chem. Soc., Perkin. Trans. 1. 1999 2591-2599. 

As exemplified by equation (2), the Perkin condensation of o-hydroxybenzaldehydes is an important method for the synthesis of substituted coumarins. An interesting variation on this procedure has been reported recently. Heating a mixture of o-fluorobenzaldehyde, 2-thiopheneacetic acid, acetic anhydride and triethylamine affords directly the coumarin (20 equation 13) instead of the expected cinnamic acid (21). The reaction proceeds similarly with several arylacetic acids. The reaction presumably proceeds through the cinnamic acids (21). The observed product can conceivably arise by direct nucleophilic displacement involving the carboxylate or by an elimination/addition (benzyne) mechanism. The authors note that when 2-fluorobenzaldehyde is replaced by its 2-bromo analog in this reaction, the substituted cinnamic acid (22) is the major product and the corresponding coumarin (20) is obtained only in low yield. It is suggested that since it is known that fluoride is displaced more rapidly in nucleophilic aromatic substitution reactions, while bromo aromatic compounds form benzynes more rapidly, this result is consistent with a nucleophilic displacement mechanism. 

Bateson, J. H., A. J. G. Baxter, P. M. Roberts, T. C. Smale, and R. Southgate Olivanic Acid Analogues. Part 1. Total Synthesis of the 7-Oxo-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylate System and Some Related P-Lactams. J. Chem. Soc. Perkin 1 1981, 3242. 

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