Carboxylic acids as nucleophiles

3 Acyl Migration Leading to Diene/Ketone Formation 

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The kinetic resolution of C2-symmetric racemic substrate as shown in Scheme 8E.22 requires differentiation between the starting material and the monoalkylated product 113 in addition to the enantiodiscrimination in the ionization step. With a bulky carboxylic acid as nucleophile, the racemic tetraacetate of conduritol B was efficiently resolved under phase-transfer conditions [68]. Further elaboration of the hydrolytically desymmetrized alcohol resulted in the synthesis of the important glycosidase inhibitor, (+)-cyclophellitol. 

The abnormal Nazarov cyclization reported by Hiyama leads to transposed cyclopentenones by incorporating carboxylic acids as nucleophiles in the reaction medium. Both acyclic and monocyclic divinyl ketones can be employed, as shown in Scheme 15. Dioxolane acetals have also been used successfully in place of the carbonyl group. 

After exploring intermolecular reactions, White and coworkers utilized complex Ll/Pd11 to catalyze the intramolecular oxidative cyclization of 4 to synthesize the macrolide 5 with moderate yield and good regioselectivity (Scheme 7) [23]. Further studies on substrate scope demonstrated that this catalytic system was compatible with various carboxylic acids as nucleophiles, such as aryl acids, vinylic and alkyl acids, leading to the generation of 14- to 19-membered macrolides with remarkable levels of selectivity. 

The esterification of cyclic olefins with carboxylic acids, such as dicyclopentadiene or naturally occurring terpenes, yields compounds of industrial value. For instance, the esterification of dicyclopentadiene with saturated carboxylic acids, such as acetic acid, leads to a starting material for the flavour and fragrance industry, as well as the resulting alcohols in consecutive hydrolysis. By using unsaturated carboxylic acids as nucleophiles, the resulting esters are also useful compounds in the manufacture of binders for polymer concrete (Scheme 1). ... 

Intermolecular Additions of Alcohois and Carboxylates The intermolecular oxidations of olefins with alcohols as nucleophile typically generate ketals, whereas the palladium-catalyzed oxidations of olefins with carboxylic acids as nucleophile generates vinylic or allylic carboxylates. As a result, many of the oxidations with alcohols have been conducted with diols to generate stable cyclic acetal products. Both types of oxidations have been conducted on large industrial scale, and vinyl acetate is produced from the oxidative reaction of ethylene with acetic acid in the gas phase over a supported palladium catalyst. ... 

Esterification of carboxylic acids involves nucleophilic addition to the carbonyl group as a key step In this respect the carbonyl group of a carboxylic acid resembles that of an aldehyde or a ketone Do carboxylic acids resemble aldehydes and ketones m other ways Do they for example form enols and can they be halogenated at their a carbon atom via an enol m the way that aldehydes and ketones can ... 

A standard method for the preparation of an a ammo acid uses a bromo carboxylic acids as the substrate and aqueous ammonia as the nucleophile... 

Although a carboxylate anion is only a relatively modest nucleophile (see Section 6.1.2), it is possible to exploit an Sn2 reaction to prepare esters from carboxylic acids as an alternative to the usual esterification methods (see Section 7.9). Such methods might be useful, depending upon the nature and availability of starting materials. 

In solvent diglyme, the rate of acidolysis of triethylboron by carboxylic acids is found to be greater the weaker is the acid, there being a linear correlation between log k2 and the pK of the carboxylic acid. Thus nucleophilic coordination of the carboxylic acid to the boron atom must be an important feature of the reaction mechanism, and the acidolysis may therefore be denoted as following mechanism SE2(cyclic) or SE2(co-ord), perhaps through a transition state such as (I). ... 

Dienes (allenes) are also used for heteroannulation with 68 and 69. The eight-membered nitrogen heterocycle 78 is constructed by the reaction of 1,2-undecadiene (77) with o-(3-aminopropyl)iodobenzene (76) [34]. The lactones are prepared by trapping the 7i-allyl intermediates with carboxylic acids as an oxygen nucleophile. The unsaturted lactone 81 is prepared by the reaction of /1-bromo-v,/ -unsaturated carboxylic acid 79 with the allene 80 [35]. In the carboannulation of 82 with 1,4-cyclohexadiene (83), the 1,3-diene 85 is generated by / -elimination of 84, and the addition of H-PdX forms the 7i-allylpalladium 86, which attacks the malonate to give 87 [36],... 

Selenocyanates produce selenols or diselenides upon either reduction (e g. with sodium borohydride) or hydrolysis (see Scheme 1). They undergo displacement of the cyanide ion by various nucleophiles and add to alkenes in a maimer similar to selenenyl halides (see equation 14), except that catalysis with Lewis acids is required in the case of unactivated alkenes. The selenocyanates are also popular reagents for the preparation of selenides from alcohols, and (8) from carboxylic acids, as indicated in Scheme 3. 

Racemic or achiral a-azido acids are synthesized by direct azide substitution on commercially available a-bromo carboxylic acids or by radical bromination of carboxylic acids followed by azide substitution. In general, azido acids are stored in the dark to avoid photolytic degradation with loss of nitrogen temperatures above 50 °C should be avoided. Radical a-bromination of a-branched carboxylic acids as required for the synthesis of a,a-dialkyl or a,a-diaryl amino acids is performed with A-bromosuccinimide. This is followed by nucleophilic substitution with sodium azide or other azide donors, e.g. tetrabutylannmonium azide, to produce achiral or racemic a-azido-a,a-diaIkyl or a-azido-a,a-diaryl carboxylic acids (Scheme 74).Synthesis of more sterically hindered a,a-disubstituted azido acids leads to hydroxy compounds when prolonged reaction times are required and not sufficient care is taken to operate under dry conditions and an inert atmosphere.t ... 

Telomerization is defined as an oligomerization of dienes accompanied by addition of a heteroatom or carbon nucleophilic reagent10. It is catalyzed by various organometallic compounds of transition metals, especially palladium compounds. The nucleophiles, such as water, alcohols, amines or carboxylic acids, as well as enamines, nitroalkanes and stabilized carban-ions, are mainly introduced in the terminal position of the dimeric molecule in excellent yield10. It is also possible to direct the reaction towards an internal product functionalization. Telo-merizations with heteronucleophiles are regarded as heterocarborative addition reactions and are described in Section 1.5.8.4. 

Cyanoformamidines, exhibiting nucleophilic and electrophilic properties in the 1,3-positions, react with hexafluoroacetone forming five-membered heterocycles (86CB2127). This ability to form five-membered heterocycles is the major characteristic of hexafluoroacetone, which is also inherent in some perfluorinated and partially fluorinated ketones, aldehydes, and imines in their reactions with a-functional derivatives of carboxylic acids, as well as w-amino, a-N-alkylamino,... 

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