Amine-ketoester condensation

The most convenient synthesis of 6-hydroxy-2-pyridones is by the condensation of a P-ketoester, eg, ethyl acetoacetate, with an active methylene compound, eg, malonic ester, cyanoacetic ester, and an amine. The amine can be omitted if an acetamide is used and in some cases this modification results in a higher yield. 

A Knorr-type pyrrole synthesis involving the condensation between a-amino-P-ketoesters and P-ketonitriles provided P-cyanopyrroles <06OPRD899>. The former amine substrates were prepared by reduction of the corresponding a-isonitroso-P-ketoesters with Zn/HOAc. 

Hansa yellow org chem Group of organic azo pigments with strong tinting power, but poor opacity in paints used where nontoxIcIty Is Important. han-sa yel o ) Hantzsch synthesis org chem The reaction whereby a pyrrole compound is formed when a p-ketoester, chloroacetone, and a primary amine condense. hansh, sin-tha-sas ... 

The reaction is usually carried out in acid solution, but may also be base catalysed. This is the condensation between aldehydes, ammonia or a primary or secondary amine and a compound containing at least one active hydrogen atom e.g., ketones, b-ketoesters, b-cyanoesters, nitroalkanes, alkynes with C°H). For example. 

The dibasic side chain at position 7 can be alternatively provided by a substituted amino alkyl pyrrolidine. Preparation of that diamine in chiral form starts with the extension of the ester function in pyrrolidone (46-1) by aldol condensation with ethyl acetate (46-2). Acid hydrolysis of the (3-ketoester leads to the free acid that then decarboxylates to form an acetyl group (46-3). The carbonyl group is next converted to an amine by sequential reaction with hydroxylamine to form the oxime, followed by catalytic hydrogenation. The desired isomer (46-4) is then separated... 

One of the most valuable and widely used applications of C=N bond hydrogenation is in the field of reductive alkylation, in which an aldehyde or ketone is condensed with an amine and reduced in situ with an appropriate catalyst to give a substituted product. This very valuable reaction has most notably been employed for the racemic synthesis of amino acids from a-ketoesters and acids. This type of reduction can be very powerful, as illustrated by the synthesis of tetrahydro-b-carbolines 64 (76% yield) by the reductive coupling of 65 and 66 under conditions of 1 atm of hydrogen and palladium on carbon catalyst277. 

The enol content of simple ketones is much lower than that of /1-ketoesters or /3-diketones. For a number of electrophiles it is often too low. Hence, functionalizations with the respective electrophile via the enol form do not succeed in these cases. This problem can be managed, though, by converting the ketone (Formula A in Figure 12.16) into an enamine D with the aid of a condensation with a secondary amine that is in line with Figure 9.29 and the mechanism given there. Enamines are common synthetic equivalents for ketonic and aldehyde enols. 

The first important MCR was developed by Strecker in 1850 (Scheme 1) [20]. In this reaction ammonia, an aldehyde and hydrogen cyanide combine to form a-cyano amines 1, which upon hydrolysis form a-amino acids 2. Also, heterocyclic compounds were obtained using MCRs. An example of this is the Hantzsch reaction, discovered in 1882 [21]. This reaction is a condensation of an aldehyde with two equivalents of a (3-ketoester in the presence of ammonia resulting in the formation of dihydropyridines 3. A comparable reaction is the Biginelli reaction, founded in 1893 ([22] and see for review [23]). This reaction is a 3-component reaction (3CR) between an aldehyde, a (3-ketoester and urea to afford dihydropyrimidines 4. 

In the simplest of these, jS-enaminones are synthesized (equation 129) by the addition of amines to 1,3-diketones or /3-ketoesters. The reaction has been apphed to the Friedlander synthesis of quinolines by condensation of the enaminone and other carbonyl present in the substrate. Substituted pyrroles in equation (130) can be obtained as well when a propargyl group is present, by addition of the enaminone to the triple bond. Alcohols, thiols, and secondary phosphines have been also tested as nucleophiles with good results. A particularly interesting case is found in the condensation of indoles with 1,3-diketones to give substituted indol derivatives in equation (131). ... 

The formation of quinolines and benzoquinolines by the condensation of primary aryl amines with P-diketones followed by an acid catalyzed ring closure of the Schiff base intermediate is known as the Combes quinoline synthesis. The closely related reaction of primary aryl amines with p-ketoesters followed by the cyclization of the Schiff base intermediate is called the Conrad-Limpach reaction and it gives 4-hydroxyquinolines as products. ... 

Reductive cyclization has been used in a novel, recent synthesis of the alkaloids ( )-isoretronecanol (22) and ( )-trachelanthamidine (23) by Borch and Ho. Condensation of the dianion derived from methyl acetoacetate with Z-l,4-dichlorobut-2-ene, followed by cyclization with sodium meth-oxide yielded the cycloheptenone ester intermediate (32) (Scheme 2). Reductive amination of this ketoester with sodium cyanoborohydride and ammonium nitrate gave a mixture of the diastereoisomeric aminoesters 33 and 34. Oxidation with osmium tetroxide and periodate, followed by reductive cyclization, again using sodium cyanoborohydride, gave the two pyrrolizidine esters 35 and 36 in a ratio of 1 2 [gas-liquid chromatography (GLC) analysis]. The esters were separated by preparative layer chromatography, and lithium aluminum hydride reduction of the individual esters gave the two pyrrolizidine alkaloids 22 and 23. 

A completely different product outcome is observed with enamides derived from a-ketoesters. Benzoylation of the product obtained by condensation of methyl pyruvate with benzyl amine led to the formation of enamide 21 (Scheme 6). Irradiation of 21 in methanol produced only a 10% yield of the expected cyclization product 22,... 

An important reaction is the condensation of amines with 1,3-diketones or 3-ketoesters yielding -enaminoesters which are important intermediates for the synthesis of natural products (Scheme 10.10). The step preceding the formation of the enamine involves zwitterionic intermediates such as those in the addition of amines to a,yS-unsaturated compounds. The electrostrictive effect contributes to the magnification of the pressure effect. Lanthanide catalysis and use of 300 MPa pressure can be an excellent way to produce enamino compounds in high yields [39] (Table 10.10). 

The most important general methods for enaminone preparation are (i) direct condensations of ammonia or amines with 1,3-diketones or 3-ketoesters, (ii) nucleophilic reactions of lactams or related compounds with vinylogous acid chlorides, (iii) transformations catalyzed by organopalla-dium complexes, and (iv) the reactions of active methylene compounds with formamide acetals. This last method (iv) has been reviewed in detail... 

The Hantzsch pyrrole synthesis is the condensation of p-ketoesters with primary amines (or ammonia) and a-haloketones to give substituted pyrroles. 

It is possible that the mechanism of the Hantzsch pyrrole synthesis commenced with the condensation between the amine and the ketoester. The resulting imine then undergoes an Sn2 replacement reaction with the a-haloketone via the intermediacy of an enamine. The adduct as an enamine ketone then undergoes an intramolecular C-N bond formation to deliver the final pyrrole after extrusion of a molecule of water. 

For ketoester the substrate, the hydrazone forms exclusively between the hydrazine and with more active ketone. The corresponding hydrazone-ester then cyclizes to produce the pyazolone. Mechanistically, the more basic and less substituted hydrazine amine condenses with the ketone. The resultant hydrazine-ester then cyclizes to the pyrazolol, which could also tautomerize to the corresponding pyrazolone. 

This reaction was first reported by Conrad and Limpach in 1887. It is the synthesis of 4-quinolones, which often isomerize (or aromatize) to 4-hydroxyquinolines through the thermal condensation of primary aromatic amines with the carbonyl group of -ketoesters followed by the cyclization of Schiff base intermediates (alkyl P-... 

This reaction was first reported by Hantzsch in 1890. It is the preparation of 2,5-dialkyl or 2,4,5-trialkylpyrrole derivatives from the condensation of of-halo-ketones, )0-ketoesters and ammonia or amines. Therefore, it is often known as the Hantzsch pyrrole synthesis or simply the Hantzsch synthesis. During this synthesis, ammonia or amine reacts quickly with y0-keto esters to form enamine esters or 3-amino crotonates that cyclize with of-halo-ketones to form pyrrole derivatives upon heating, and the regioselectivity strongly depends on the substituents on the starting materials. Thus, this reaction can directly start from 3-amino crotonates or enamines of 0-keto esters. Further extension of this reaction from aromatic amines results in the formation of indole derivatives, or carbazole derivatives if cyclized with a-halo-cyclohexanones. The synthesized pyrroles have wide application in medicinal chemistry, conducting polymers, molecular optics, sensors,etc. 

The traditional Hantzsch pyrrole synthesis consists of a one-pot reaction between P-ketoesters with ammonia, ammonia derivatives or primary amines, and a-haloketones. This process, known as the three-component (3CP) Hantzsch pyrrole synthesis, has been largely replaced by a two component (2CP) Hantzsch synthesis using preformed enamines. Preformed enamines help provide better control over the regioselectivity of the reaction. In addition, the use of preformed enamines helps reduce the side products produced from the self condensation of P-ketoesters. 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

Ketoesters could be exploited to generate iminium intermediate employed as hydride acceptor. Gong et al. reported a chiral Brpnsted acid 85-catalyzed asymmetric cascade [1,5]-hydride transfer/cyclization of 2-pyrrolidinyl phenyl ketoesters 82 with anilines 83, which produced the enantio-enriched cyclic aminals 84 (Scheme 29) [113]. The iminium subunit in intermediate I served as hydride acceptor, which was generated in situ through the condensation of o-aminoben-zoketone 82 with aniline 83 in the presence of 85. 

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