1.3- Dicarbonyl substrates

The coupling of arenediazonium compounds 1 to 1,3-dicarbonyl substrates 2 (Z = COR) is known as the Japp-Klingemann reaction As suitable substrates, /3-ketoacids (Z = COOH) and /3-ketoesters (Z = COOR) can be employed. As reaction product an arylhydrazone 4 is obtained. 

In general the reaction is conducted in aqueous solution under basic conditions—e.g. in the presence of KOH. The 1,3-dicarbonyl substrate is deprotonated to give the corresponding anion 5, which then couples to the arenediazonium species 1, to give the diazo compound 3 ... 

In classical Hantzsch procedure, an enaminocarbonyl is formed in sim by condensation of ammonia source onto the 1,3-dicarbonyl substrate. But many groups have used a three-component modified-Hantzsch protocol in which the preformed enamine is introduced as a partner. Thus, utilization of cyclic or acyclic 1,3-dicarbonyl compounds, aldehydes, and acyclic or cyclic enamines has been reported, leading regioselectively to diversely substituted 1,4-DHP derivatives (Scheme 7). The sequence involving such starting materials was performed in numerous efficient systems, and more particularly in the following (1) microwave-assisted reaction in acetic acid [50], DMF [51], or an acetic acid/DMF system [52] (2) sonification in ethylene glycol [53] and (3) use of ionic liquids such as [bmim]BF4 [54]. 

When the 1,3-dicarbonyl substrate reacts twice via its activated methylene due to the presence of heteroatoms blocking the enolization process on other positions, spiranic systems are formed in the presence of two equivalents of aldehyde and an equivalent of urea (Scheme 15) [85]. The reaction can be promoted either in acetic acid as solvent or neat under microwave irradiations or in the presence of H3PW12O40 as catalyst. Finally, this technique for generating spiroheterocyclic products has been transferred to solid-supported methodology by immobilizing the 1,3-dicarbonyl partner onto a resin [86]. 

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

Fig. 6.8 Deng s selectivity model for 1,4-additions of 1,3-dicarbonyl substrates.

Fluorinalion of 1,3-dicarbonyl compounds. 1,3-Dicarbonyl compounds that exist partly in the enol form are converted by 1 into the 2-fluoro derivative in moderate yield. The yield is generally improved by reaction with the corresponding sodium enolate. When the enol content of the 1,3-dicarbonyl substrate is small, no reaction occurs with 1, although the corresponding metal enolate does react. 

An alternate approach to these useful 1,3-dicarbonyl substrates may be achieved through enolate orthoester acylation. Titanium enolates have been employed to effect this transformation (eq 19). Similarly, treatment of the titanium enolate of p-ketoimide with dioxolane orthoesters results in the formation of a masked tricarbonyl compound (eq 20). Trimethyl orthoacetate and Triethyl Orthoacetate are not appropriate partners in these coupling reactions. ... 

Catalytic asymmetric construction of nitrogen-substituted quaternary stereocenter has been another important and challenging task in asymmetric synthesis. The first a-amination using cinchona alkaloids was shown in 1,3-dicarbonyl substrate systems. In 2004, Pihko and coworkers showed enantioselective a-amination of cyclic fi-ketoesters 130, with dibenzyl azodicarboxylate (131) in the presence of... 

This chapter is a continuation from Part I of this review of fluorine-containing heterocycles recently published (03AHC(86)129). Part II deals with the synthesis of fluorine-containing heterocycles by condensations of two or more precursors. Major attention is paid to the use of mono- and 1,3-dicarbonyl substrates, and their nitrogen analogs. 

The chemistry of 1,3-dicarbonyl substrates was subsequently extended further to the class of 2-cyano acetates [26]. This class of substrates is more challenging since their monodentate coordination behavior would suggest a less rigid coordination mode and hence a decrease in face differentiation. While initial exploration of the reaction with BINAP-Pd complexes such as 2-Pd led only to minor enantiomeric excesses of about 50% ee, Kim was able to devise a suitable protocol employing his cationic Pd complex [27] (Scheme 7). 

This theme was elaborated by Zhang who employed the 1,3-dicarbonyl substrate... 

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