Sterically Demanding Carboxylic Acids

Side Reactions in Organic Synthesis. Florencio Zaragoza Dorwald Copyright 2005 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 3-527-31021-5 

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Despite the huge structural diversity of known carboxylic acids, most of these are readily converted into esters or amides. Even sterically hindered acids, for example pivalic, triphenylacetic [1], or 2,6-disubstituted benzoic acids [1, 2], can be converted into suitable acylating reagents for alcohols or amines (Scheme 7.1). Esters of sterically demanding carboxylic acids can, alternatively, also be prepared by O-alkylation of the corresponding carboxylates [3, 4]. 

Kazmaier and coworkers have observed the formation of eight-membered rings or linear side products when ammonia is used as amine partner in the aforementioned reaction [122]. The desired amino acids are obtained as minor product or only in traces. These side reactions can be avoided when nonnucleophilic alcohols are used like trifluoroethanol sterically demanding aldehydes, like pivalaldehyde and sterically demanding carboxylic acids. 

TBDMSCl, imidazole, DMF, 25°, 10 h, high yields. This is the most common method for the introduction of the TBDMS group on alcohols with low steric demand. The method works best when the reactions are mn in very concentrated solutions. This combination of reagents also silylates phenols, hydroperoxides, and hydroxyl amines. Thiols, amines, and carboxylic acids are not effectively silylated under these conditions. ... 

Extensive studies have been carried out on the metal enediolates of carboxylic acids and the influence of substrate structure on kinetic aldol diastereoselection (eq. [26]). For all but the most sterically demanding substituents (Rj = t-C4H9, mesityl, 1-adamantyl) the condensations exhibit only modest threo diastereoselection (Table 13). The reader is referred to Table 4 for the analogous thermodynamically controlled aldol data. 

For this selective addition, the best catalyst precursors were Ru(methallyl)2(dppe) 1 and Ru(methallyl)2(dppb) 2. The choice of the appropriate complex depended on the steric demand of both the alkyne and the carboxylic acid. A large variety of carboxylic acids and alkynes have been used, including N-protected amino acids, a-hydroxy acids, and functionalized alkynes such as enynes, diynes and propargylic ethers [21-23] (Scheme 10.4). The addition took place under mild conditions and carboxylic adds of... 

Ester Pyrolysis is a syn-elimination yielding an alkene, similar to the Cope Elimination, for which -hydrogens are needed. The carboxylic acid corresponding to the ester is a byproduct.The cyclic transition state can only be achieved if the steric environment is not too demanding. 

Asymmetric alkylation of carboxylic acid derivatives has been studied intensively for about 20 years. [1] Numerous auxiliaries, tailor-made structures with high steric demands for effective RelSi face differentiation, have been synthesized and their efficiency tested. [1, 2] In recent years besides the preparative aspects of enolates, physico-chemical investigations into their structure-reactivity relationships have gained interest. [3] Crystal structure analyses, osmometric measurements, and NMR studies in solution are helpful in the investigation of the factors that may control enolate reactions. [3-5]... 

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