Knoevenagel reaction variation

This variation of the Knoevenagel reaction will give somewhat higher yields of product than the preceding method. The reason for the higher yield is the use in this method of toluene as solvent, and the placement of a Dean Stark trap above the flask to remove water from the mixture as it is formed. Removal of water favors the formation of greater quantities of nitroalkene. 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

The modified two component Hantzsch (Baeyer-Knoevenagel modification) was also examined. Shorter reactions times (2-3 h) were noted in this variation using 82 and 85 with slightly better yields (78-85%) being observed for the formation of 84. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

The Linstead variation of the Knoevenagel condensation catalysed by a series of supported guanidines prepared via different routes, was also investigated by us in collaboration with Macquarrie s group, and revealed excellent results. This condensation reaction can be used for the synthesis of the precursor of coconut oil lactone, a fragrance component ( Scheme 9.8).11741... 

The catalysts were evaluated in two reactions - the base catalysed epoxidation of electron deficient alkenes),[15] and in the Linstead variation of the Knoevenagel condensation to give 3-nonenoic acid. This reaction utilises malonic acid, and leads to an unusual dehydration, giving the P/y-unsaturated acid, rather than the more typical a,P-enoic acid.[21-24] The product can be used as a precursor to the lactone, which is a flavour component of coconut oil. 

Supported guanidines are prepared via different routes, and their activity compared in two reactions of interest. The base-catalysed epoxidation of electron-deficient alkenes is described, and proceeds with excellent conversions and selectivities, when the surface is passivated by silylation. The Linstead variation of the Knoevenagel condensation is also described, and gives excellent conversions to partially decarboxylated products. 

The Knoevenagel condensation is a variation of aldol condensation using a 3-dicarbonyl compound as the source of the enolate reaction partner. Its mechanism is the same as that of the aldol ... 

In addition, measurements of the intrinsic reaction rate (free of external and internal diffusion limitations) were achieved by the strict control of the thickness of SIM shell on SIM/alumina beads. The Hnearity observed between the variation of the MOF layer thickness and the conversion observed for the Knoevenagel condensation demonstrated that the reaction takes place inside the whole MOF layer through the porosity and not just at the external surface. 

In this section, we have seen two variations on the aldol theme, the Knoevenagel condensation and the Michael reaction. In all of these reactions, a single nucleophile adds to a single electrophile. The reactions are fundamentally the same as the aldol condensation the variations arise from the structural differences of the nucleophiles. 

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