Carboxylic acids cycloalkylation

Garbrecht, W.L., Marzoni, G., Whitten, K.R. and Cohen, M.L. (1988) (8 )-Ergoline-8-carboxylic acid cycloalkyl esters as serotonin antagonists Structure-activity study. J. Med. Ghem., 31, 444—448. 

Situations arise when it is necessary to consider the parent as a one-carbon chain. In such circumstances, RC02H becomes a substituted carboxylic acid. This variation is met most frequently when R is a cycloalkyl or aryl group ... 

C NMR spectroscopic and theoretical studies (DFT, ab initio, IGLO) of a series of cycloacylium ions were performed by Prakash et al.577 The study showed that the cycloalkyl groups have little effect on the shift of the carbocationic carbon. Furthermore, charge calculations showed that the delocalization into the cycloalkyl group is greater than in the protonated carboxylic acid (carboxonium ion), where two oxygen atoms participate in delocalization. 

Prior to our work, fluorenones had been synthesized by methods characterized by the limited accessibility of the starting substrate [28,30,32,33] (substrate being fluorene, biphenyl-1-carboxylic acid, benzophenone, fluoranthene, cyclohexene, phenanthrene or phenylpropionic acid derivatives), a lack of stereoselectivity [28,29,31,33] and poor yields. We therefore developed a simple methodology for synthesizing fluoren-9-ones via domino acylation-cycloalkylation/alkylation-cycloacylation (Chart-19). 

Cunninghamella blakesleeana has been found to be an efficient biocatalyst for stereospecific biohydroxylations of e.g. cycloalkyl carboxylic acids [77] and (also with Mortierella alpina) the respective cycloalkyl benzoxazoles [78]. The role of cytochrome P450 in these reactions is currently being investigated. 

Abe, T. Baba, H. Hayashi, E. Nagase, S. Synthesis of perfluorohicyclic ethers [1]. The electrochemical fluorination of cycloalkyl-suhstituted carboxylic acids. J. Fluorine Chem. 1983, 25(2), 123. 

Benzimidazoles. Further modification of the benzimidazol-one-moiety of oxatomide has led to the synthesis of a large number of benzimidazoles, which are summarized in Table II. These compounds were synthesized as outlined in Scheme 4. Cyclization of IX with the appropriate carboxylic acids or with the bisulphite complexes of the aldehydes gave benzimidazoles XI (9). Successive chlorination with thionylchloride and coupling with l-(a, a -diaryl-methyl)-piperazines (II) afforded the benzimidazoles XIII (R = H, alkyl, aryl, cycloalkyl, aralkyl). 

Prakash GKS, Rasul G, Liang G, Olah GA (1996) 13C NMR spectroscopic and Density Functional Theory (DPT), ab initio, and IGLO theoretical study of protonated cycloalkyl-carboxylic acids (carboxonium ions) and their acyl cations (oxocarbenium ions). J Phys Chem 100 15805-15809... 

Apparently, the amine does not undergo Michael addition to the enone system in 107, but (due to the high electrophihcity of its a-C=0 group) prefers imine formation (—> 109). In the strongly acidic medium, 109 is cyclized (presumably via cation 110 and its SeAc cycloalkylation) to the 1,4-dihydroquinoline system 111, which is oxidized to the quinohne-2-carboxylate 108. 

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