Enamines Knoevenagel reaction

Trimethoprim has also been synthesized by condensing 3,4,5-trimethoxybenzaldehyde with malonic acid dinitrile in a Knoevenagel reaction, which forms the derivative (33.1.53), which is partially reduced to the enamine (33.1.54) by hydrogen using a palladium on carbon catalyst, which upon being reacted with guanidine is transformed into trimethoprim [52,53]. 

The Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

There is almost no restriction in the choice of an appropriate electrophile in the Knoevenagel reaction. Aldehydes, ketones, thioketones, imines, enamines, acetals and orthoesters have been used. With less reactive methylene groups, however, drastic reaction conditions may be necessary. Steric effects have a significant influence on the rate and unexpected compounds are often obtained as a result of secondary reactions. Reaction of 1,3-dicarbonyl compounds with carbon disulfide followed by dialkylation with an alkyl halide give diacylketene-S,5-acetals (159). However, even with highly acidic dicarbonyl com-... 

On the other hand, the use of morpholinium acetate suggests Knoevenagel reaction conditions, with enamine intermediacy. The mechanism would change begging in the second step as follows ... 

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). 

Jiang et al. described the proline-catalyzed reaction of several amines 143 with alkynes 141, various aldehydes 142, and 1,3-dicarbonyl compounds 144 to afford 1,4-dihydro-pyridines 145 in moderate to good yields (65-85%) (Scheme 13.37) [62]. Mainly three reactions are involved in the production of those products the first one is a proline-catalyzed Knoevenagel reaction between the aldehydes 142 and the 1,3-dicarbonyl compounds 144 to give Michael acceptors. The second one is a hydroamination reaction of the alkyne 141 to yield enamines, which in the third reaction undergo an enamine-Michael addition/cyclization sequence to provide the desired products. 

Many of the known chemical syntheses such as Wittig [29, 165], Knoevenagel [29], aldol [292], Ugi [29,293], Michael addition [29], Hantzsch [29,156,157], Diels-Alder [294], Azo coupling [136,182], Suzuki coupling [29,155] or enamine [29, 295] reactions (Table 1.8), to name but a few, have been carried out successfully in mi-... 

The domino process probably involves the chiral enamine intermediate 2-817 formed by reaction of ketone 2-813 with 2-815. With regard to the subsequent cy-doaddition step of 2-817 with the Knoevenagel condensation product 2-816, it is interesting to note that only a normal Diels-Alder process operates with the 1,3-bu-tadiene moiety in 2-817 and not a hetero-Diels-Alder reaction with the 1-oxa-l,3-butadiene moiety in 2-816. The formed spirocydic ketones 2-818/2-819 can be used in natural products synthesis and in medidnal chemistry [410]. They have also been used in the preparation of exotic amino adds these were used to modify the physical properties and biological activities of peptides, peptidomimetics, and proteins... 

A second, even more worrying problem is the side reaction, the formation of condensation products. This process is essentially irreversible in most cases. The condensation products can arise either from the aldol product or directly through a Knoevenagel-Mannich type reaction where the enamine reacts with an imininm ion [26, 81, 82]. The condensation process requires only an external Brpnsted acid, whereas the aldol process appears to require simultaneous activation of the carbonyl electrophile by an internal Brpnsted acid/hydrogen bond donor (Scheme 15). 

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

The mechanism of the formation of tricyclic intermediates 56 and 57 is also the important and conflicting matter. For example, Quiroga et al. [83] showed that these MCRs, the most probable, proceed via preliminary Knoevenagel condensation and Michael addition (Scheme 26). At the same time they rejected another pathway including the generation of enamine 60, because no reaction was observed between it and aromatic aldehyde when their mixture was refluxed in ethanol. 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

In this transformation two new C-C-rr-bonds are formed from three different components. The enantioselectivity of this reaction is generally low (< 5%). With cyclic ketones the corresponding products were obtained as single diastereomers. It is proposed that this reaction involves a Knoevenagel-hetero-Diels-Alder sequence where proline utilizes both iminium and enamine catalysis (Scheme 9.20). 

Iminium catalysis directly utilizes the higher reactivity of the iminium ion in comparison to the carbonyl species and facilitates Knoevenagel-type condensations, cyclo- and nucleophilic additions, and cleavage of cr-bonds adjacent to the a-carbon. Enamine catalysis on the other hand involves catalytically generated enamine intermediates that are formed via deprotonation of an iminium ion, and react with various electrophiles or undergo pericyclic reactions. ... 

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