Amines, tertiary reaction with 1,3-dicarbonyl

Tfce preferred synthetic route to these important intermediates is the Mannich reaction (Chapter 27), The compound is stored as the stable Mannich base and the unstable enone released by elimination of a tertiary amine with mild base, The same conditions are right for this elimination and for conjugate addition, Thus the aw-methylene compounds can be formed in the flask for immediate reaction with the enol(ate) nucleophile, The overall reaction from (3-amino carbonyl to 1,5-dicarbonyl appears to be a substitution but the actual mechanism involves elimination and conjugate addition,... 

In addition to the synthesis of /1-dicarbonyl compounds3,25, the acylation of enamines also gives access to a wide variety of acyclic, carbocyclic and heterocyclic systems. The course of the reaction is often critically dependent upon the type of enamine used, on the substituents present in the two reagents, and on the experimental conditions, such as temperature, solvent, presence of added tertiary amine, etc. In contrast to alkylation, A-acylation is readily reversible. Since enamines are stronger bases than the C-acylated enamines, half an equivalent of the enamine is lost by salt formation in their reaction with acid chlorides. This can be avoided by addition of a tertiary amine179, but this in... 

The best results with regard to solvents were obtained in water. The reaction is catalyzed by tertiary amines. The most efficient catalyst concerning yields, clear reaction, and selectivity is l,8-diazabicyclo[5.4.0]undec-7-ene (20 mol %). This transformation was expanded to several 1,3-dicarbonyl compounds. Due to the symmetry of acetylacetone 5 or dibenzoylacetone 134, identical products were formed by the ketalization step (133 Ri=R2=Me 136 Ri=R2=Ph Scheme 2.29). When used with unsymmetrical 1.3-dicarbonyl compounds, different products were formed via a regioisomeric ketalization step (reactions with benzoylacetone 138 in Scheme 2.29, 139 and 140 Ri=Me, R2=Ph) [44],... 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

Fig. 8 Iron-catalyzed coupling reactions of P-dicarbonyl compounds with ethers, sulfides or tertiary amines...

Compared to diazonium salts, diazo compounds are generally much less reactive towards nucleophiles than towards electrophiles. As a result of this azo coupling reactions of diazo compounds are the exception rather than the rule. Electron withdrawing substituents on the diazo carbon increase the reactivity towards nucleophiles. Consequently the ability to undergo azo coupling reactions increases from diazomethane to diazocarbonyl- and 2-diazo-l, 3-dicarbonyl compounds. Among the earliest reactions known were those with cyanide and sulfite ions Tertiary phosphines, as opposed to amines, can form stable addition complexes with diazoalkanes probably due to the ability of phosphorus to stabilize the betaine with its empty d orbitals (6). 

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. 

The higher activity of primary amines in the reaction involving enones as Michael acceptors has also been extended to the use of different bifunctional catalysts (Scheme 3.19), which usually contain a primary amine functionality connected to a basic site by means of a chiral scaffold, as is the case in the use of 280 and 55. These diamine catalysts have been found to be excellent promoters of the Michael reaction of enones with cyclic 1,3-dicarbonyl compounds and malonates respectively, the tertiary amine basic site present at the catalyst structure being responsible for assisting in the deprotonation of the Michael donor in order to increase the concentration of the nucleophile species. In a different approach, bifunctional thiourea-primary amine catalyst 56a has also... 

The direct organocatalyzed a-amination reaction has been also applied to 1,3-dicarbonyl compounds and related compounds. So, the reaction of aryl cyano-acetates (28, R =aryl and heteroaryl) with diazo compounds 18 catalyzed by tertiary amine 30 (Scheme 4.5) gave the expected products 29. The enantioselectivity of the reaction seems to be dependent on the bulkiness of the diazo compound used. The more bulkier compound 18, the higher enantioselectivity was obtained. This sentence was also true for the ester moiety in 28. The presence of substituents at the aryl group at either meta- or orf/to-position did not have any accountable influence on results. Only a slight decrease in the enantioselectivity was accomplished with... 

The forward scheme is shown here. Methylcyclopentane will undergo radical bromination selectively at the tertiary position, giving a tertiary alkyl bromide. This aUcyl bromide will undergo an elimination reaction upon treatment with a strong base, such as sodium ethoxide. Ozonolysis of the resulting alkene gives a dicarbonyl compound, which can then be converted into the product upon treatment with methyl amine and sodium cyanoborohydride (with acid catalysis) ... 

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