Dicarbonyl and Related Compounds

The acidities of 1,3-dicarbonyl compounds are sufficiently high that they can be substantially converted to their conjugate bases by oxyanions such as hydroxide and 

Approximate pK Values for the a-Protons of Carbonyl, Nitrile, and Sulfonyl Compounds  

Note Values are relative to HgO or dimethyl sulfoxide (DMSO values in parentheses). 

Case A—deprotonation by a conjugate base of a weaker acid 

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The other important type of reaction leading to the formation of two bonds between a metal and four-atom fragment is addition of carbenoids, i.e. germylenes and stannylenes, to a-dicarbonyl and related compounds. The process can be classified as redox (4 + 1) cycloaddition since the dicarbonyl fragment is reduced while the carbenoid is oxidized. Formally the simplest example of such reactions is the interaction of methylglyoxal with activated tin metal to give a cyclic stannylene, Sn(II) enediolate (see Scheme 34) <83CL1825>. 

Sulfuration of 1,4-dicarbonyl and related compounds (Paal synthesis)... 

Sulfuration of 1,4-dicarbonyl and related compounds (Paal synthesis) provides one of the most widely used methods for the preparation of thiophenes. P2SS (P4S10), combination of hydrogen sulfide and an acid catalyst, Lawesson s reagent, bis(trialkyltin) sulfides, and hexamethyldisilathiane are the sulfuration reagents used most commonly. 

C-Arylation of 1,3-dicarbonyl and related compounds with arylbismuth(V) compounds... 

The cyclization of 6-aminouracils with three-carbon fragments such as a,B- unsaturated carbonyl compounds, /3-dicarbonyl compounds, acetylenic esters, etc., is dealt with as a [3+3] reaction (see Section 2.15.5.7.2). Reactions with alkoxymethylenemalonates and related compounds are regarded as proceeding through [6 + 0 (y)] cyclizations (see Section 2.15.5.4.2). 

Pyrrolidones have also been prepared59,60 by cycloaddition reactions of monohaptoallyl derivatives of (dicarbonyl)cyclopentadienyliron61 and related compounds (Scheme 30). Processes of this type provide examples of a... 

Table 5 Reductive Cyclization of Oximino Malonates and Related Compounds with /3-Dicarbonyl Compounds...

Hydroxyacetophenone and related compounds are attractive precursors of chromanones, most notably in the synthesis of their 2-phenyl derivatives. Being adjacent to the carbonyl group, the methyl group of the acetophenone is activated and forms a carbanion on treatment with base. Subsequent condensation with a carbonyl compound which lacks an a-hydrogen atom leads to a 1,3-dicarbonyl or an enone system which readily cyclizes to a chromanone. Thus, methyl formate affords the chromanone (591) (53MI22400) and formaldehyde has been used in the synthesis of 3-methylchroman-4-one from o-hydroxypropiophenone (68T949). 

The parent 1,2-dithiolylium ion (4) is readily prepared by treatment of l,2-dithiole-3-thione (3b R = R = H) with hydrogen peroxide in acetic acid (65JCS32). The method may be applied to the alkyl and aryl derivatives with equal success. For cations with 3- and 5-substitution the acid catalyzed reactions of j8-dicarbonyl compounds with hydrogen disulfide or equivalent are best (80AHC(27)l5i), whereas the benzo-1,2-dithiolylium ion (172) and related compounds are best prepared by ring contraction of benzo-l,3-dithiins (171) (63LA(661)84>. 

Conversion of a 1,2-diamine into a pyrazine ring is a common type of reaction (see Section 6.3.1.). In this dinucleophile -I- dielectrophile approach, heteroatoms function as nucleophiles and 1,2-dicarbonyl or related compounds, as the electrophilic component. The difference in relative reactivities at the termini of the individual components may influence the formation of a single product alternatively, the relative reactivities may be so similar that a mixture of isomers is formed. 

Dicarbonyl compounds are valuable intermediates in the preparation of natural products and related compounds containing pyrrole, thiophene, furan or cyclopentenone ring systems. 

The Knoevenagel condensation is a base-catalyzed aldol-type reaction, and the exact mechanism depends on the substrates and the type of catalyst used. The first proposal for the mechanism was set forth by A.C.O. Hann and A. Lapworth Hann-Lapworth mechanism) In 1904." When tertiary amines are used as catalysts, the formation of a p-hydroxydlcarbonyl Intermediate is expected, which undergoes dehydration to afford the product. On the other hand, when secondary or primary amines are used as catalyst, the aldehyde and the amine condense to form an Imlnlum salt that then reacts with the enolate. Finally, a 1,2-ellmlnatlon gives rise to the desired a,p-unsaturated dicarbonyl or related compounds. The final product may undergo a Michael addition with the excess enolate to give a bis adduct. 

Knoevenagel condensation Condensation of aldehydes and ketones with active methylene compounds to afford a,P-unsaturated dicarbonyl or related compounds. 242... 

The Knoevenagel condensation is the method of choice for the preparation of a,p-unsaturated dicarbonyl compounds and related compounds and only a few alternative methods have been developed. However, with the traditional Knoevenagel condensation there are problems with the reactivity of ketones, with the competitive Michael addition occuring in the reaction of some active methylene compounds. There is also a problem with steieocontrol in the synthesis of Knoevenagel products from unsymmetrical 1,3-dicarbonyl compounds. An alternative method is the addition of Grignard reagents to vinylogous carbamates (see Section 11.2.6). Another possibility is the reaction of a metal ketimate with malonodini-trile to yield ylidenemalonodinitriles (see Section 11.3.1.7). ... 

A highly enantioselective organocatalytic Michael addition of 4-hydroxycouma-rines and related compounds to a,p-unsaturated ketones has been also achieved using imidazolidine catalyst 137 [213]. The reaction, which gives high yields and enantioselectivities for a wide range of cyclic 1,3-dicarbonyl compounds and enones, has been successfully employed for the asymmetric synthesis of the anticoagulant warfarin (Scheme 2.78) and derivatives [213], With respect to the reaction mechanism, very recent studies have demonstrated that the truly active catalyst in the process was the chiral diamine 138, which is formed in catalytic amounts under the reaction conditions by reaction with the hydroxycoumarine (Schane 2.79)... 

After these initial results by Tsuji, this elementary step was incorporated into a catalytic process by Hata and co-workers at Toray Industries and by Atkins and co-workers at Union Carbide. These groups reported reactions of allylic phenyl ethers, allylic alcohols, and allylic acetates with carboxylates, alcohols, primary and secondary amines, and methyl acetoacetate catalyzed by Pd(0) complexes and precursors to Pd(0) complexes (Equation 20.3). - After these initial reports, early developments focused on reactions of "soft" carbanions derived from 3-dicarbonyl compounds, cyanoesters, and related compounds containing two electron-withdrawing groups attached to the nucleophilic carbon. Although these reactions occur with allylic halides in the absence of a catalyst, these reactions are greatly accelerated by palladium catalysts. Thus, the palladium catalyst allows these reactions to occur under mild conditions with allylic acfetates, which are more accessible than allylic halides, and with selectivities that are altered by the metal catalyst. 

Thiophen Analogues of Quinoline and Related Compounds.—Convenient methods for the synthesis of the thiophen analogues of quinoline have been worked out. By the condensation of 2- and 3-thienylanunonium hexachlorostannates with malonic aldehyde tetraethyl acetal, thieno-[2,3-6]pyridine (538) and thieno[3,2-6]pyridine (539) were obtained in 44% and 77% yields. With other /5-dicarbonyl compotmds, substituted derivatives were obtained. Thus, acetoacetaldehyde dimethyl acetal gave... 

The asymmetric 1,4-addition of nucleophiles to a,p-unsaturated carbonyl and related compounds is also an important and valuable method for preparation of highly functionalized aUcyl chains. While chiral Brpnsted base-catalyzed asymmetric transformation has been intensively explored (for reviews of asymmetric 1,4-addition reactions of 1,3-dicarbonyl compounds, see [26-33] for reviews of asymmetric 1,4-addition reactions of glycine Schiff bases, see [34—37] for reviews of asymmetric [3-1-2] cycloaddition reactions, see [38-41]), chiral alkaline-earth metal catalysts have been also successfully employed in this reaction. 

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 ... 

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