Carboxylic acids 1,6-dicarbonyls, synthesis

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

The two major characteristic oxidation processes of alkynes are their transformation to 1,2-dicarbonyl compounds and their cleavage reaction to carboxylic acids.710 The structure of the starting compounds has a decisive effect on the selectivity of oxidation. Since 1,2-dicarbonyl compounds proved to be intermediates in further oxidations, carefully controlled reaction conditions are often necessary to achieve selective synthesis. Certain oxidizing agents such as peroxyacids and ozone are nonselective oxidants. 

The procedure has been extended to tlie synthesis of 2-fluoro-l,3-dicarbonyl compounds from 2-fluoro-2-phosphonyl-1,3-dicarbonyl compounds readily obtained by reaction of diethyl 1-fluoro-l-(ethoxycarbonyl)methylphosphonate with aromatic carboxylic acid chlorides or alkyl chloroformates. The reaction proceeds smoothly by the MgCl2-induced P-C bond cleavage at room temperature of 1-acyl or 1-(alkoxycarbonyl)- -fluoro-l-fethoxycarbonyDmethylphosphonates. ... 

Rubottom oxidation reactions have been conducted on enolsilanes derived from a number of different carbonyl derivatives including carboxylic acids and esters.15 For example, the Rubottom oxidation of bis(trimethylsilyl)ketene acetal 30 provided a-hydroxy carboxylic acid 31 in 81% yield. Use of alkyl trimethylsilyl ketene acetal substrates generates a-hydroxy esters, as seen in the conversion of 32 to 33.16 The synthesis of 3-hydroxy-a-ketoesters (e.g., 36) has been accomplished via Rubottom oxidation of enolsilanes such as 35 that are prepared via Homer-Wadsworth-Emmons reactions of aldehydes and ketones with 2-silyloxy phosphonoacetate reagent 34.17 The a-hydroxylation of enolsilanes derived from P-dicarbonyl compounds has also been described, although in some cases direct oxidation of the P-dicarbonyl compound is feasible without enolsilane formation.18... 

Hence the retroanalytical operation a (addition of H2O to C-4 and C-6, and bond fission at N-l/C-6 and N-3/C-4) suggests 1,3-dicarbonyl compounds and N-C-N systems of an amidine type as building blocks for a pyrimidine synthesis. The retroanalytical operation b (addition of H2O at C-2 followed by bond disconnection at N-l/C-2 or N-3/C-2 giving 1 or 2) points to the alternative starting materials, diaminoalkenes 3 and carboxylic acids. 

Sodium benzenesulfinate resin 43 can also be used to prepare a traceless solid-phase synthesis for 3,4-dihydropyrimidine-2-ones 54 and 55 (Scheme 12.13). This strategy highlighted the sulfinate acidification to yield resin-bound benzenesulfinic acid 52, followed by the condensation of urea or thiourea with aldehydes and sulfinic acid. A one-pot cyclization-dehydration process with 1,3-dicarbonyl compounds or )8-ketoesters (generated in situ by treating the latter reagents with KOH/EtOH) afforded 54, while cyclization with a mixture of pyrrolidine and /8-ketoacid in ethanol followed by the addition of TsOH HaO gave the ester form of 55. When THF was used as a solvent, the free carboxylic acid form of 55 was obtained in comparable yields. 

The venerable Hinsberg synthesis (e.g. Scheme 42) [71] involves two consecutive aldol cmidensations between a 1,2-dicarbonyl compound and diethyl 2,2 -thiobisacetate and produces thiophenes carrying ester and carboxylic acid groups at the 2- and 5-positi(Mis, respectively, via a Stobbe-type mechanism [72]. Reactions are often worked up via hydrolysis to afford a diacid as the isolated product. Scheme 43 indicates a reasonable sequence for the condensation and explains the formation of an acid-ester product. 

In the previous section, synthesis of pyrimidine derivatives bearing fluorinated alkyl substituent at C-2 atom was discussed. Derivatives of fluorinated carboxylic acids and related compounds were used as the fluorine sources. The most important method for the preparation of other chain-fluorinated pyrimidines is the principal synthesis from fluoroalkyl-substituted three-carbon bis-electrophiles (e.g. p-dicarbonyl compounds). A huge number of fluorinated bis-electrophiles were introduced in the principal synthesis of pyrimidines bearing fluoroalkyl substituent at C-4 atom of the heterocyclic ring (Fig. 24), including fluorine-containing ... 

The carbenoid reaction between alkyl diazoacetates and enol ethers, enol acetates and silyl enol ethers furnishes P-oxycyclopropane carboxylates (see Tables 2, 4, 5, 6, 7 and Scheme 5). The recently recognized synthetic versatility of these donor/acceptor-substituted cyclopropanes i 2,io3) (precursors of 1,4-dicarbonyl and P, 7-unsaturated carbonyl compounds, 4-oxocarboxylic acids and esters, among others) gave rise to the synthesis of a large number of such systems with a broad variation of substituents p-acetoxycyclopropanecarboxylates , p-alkoxy- or p-aryloxysubstituted cyclopropanecarboxylates 2-alkoxy-1-methyl-1-cy-... 

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