Knoevenagel method

The Knoevenagel method (Chapter T 20)was used to control the condensation of (36) to (35) and aluminium amalgam to remove the double bond from (35). 

Condensation (FeCl, ZnClj, HCl) of these amine salts with methyl vinyl ketone produced 4-methylthleno[2,3-/>]thieno[2,3-h]pyridine and 4-methylthieno[3,2-6]thieno[2,3-6]pyridine, respectively , while acetylacetone (ZnClj) afforded the 2,4-dimethyl derivatives. 5-Ethyl-2-formylthieno[2,3-Z>]thiophene (211) and nitromethane by the Knoevenagel method gave 2-/3-nitrovinyI-5-ethylthienol2,3-6]-thiophene (212) (73%) reduction (LAH) of 212 led to the 2-/3-amino-ethyl analog (213) lEq. (69)]. 

The decarboxylation method was discussed on page 162 as it is part of the Knoevenagel method of control. The European cockchafer, a root-eating pest, is lured to traps by butyl sorbate (93), a synthetic pheromone. The ester is obviously made from the acid (94) which can be disconnected at the a, bond to give aldehyde (95), again disconnected at thea,/3 bond. 

Ketones can also be condensed with malonic acid by the Knoevenagel method for example, 3-methyl-2-butenoic acid is formed in 60% yield when malonic acid is heated with acetone in pyridine containing a little piperidine 909 when diethyl ketone is used in this synthesis the yield falls to 35%, and the reaction fails (yield 5%) with cyclohexanone. However, in such cases condensation of ketones with malonic acid is successful if piperidine acetate is used as catalyst. 

Attaching a cyano group drastically improves the fluorescence of PTV materials. Two CN-PTV derivatives, 71 and 72, synthesized by the Knoevenagel method, showed strong fluorescence in the NIR region and have been used to fabricate the rare NIR PLEDs [110]. 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

Literature articles, which report the formation and evaluation of difunctional cyanoacrylate monomers, have been published. The preparation of the difunctional monomers required an alternative synthetic method than the standard Knoevenagel reaction for the monofunctional monomers, because the crosslinked polymer thermally decomposes before it can revert back to the free monomer. The earliest report for the preparation of a difunctional cyanoacrylate monomer involved a reverse Diels-Alder reaction of a dicyanoacrylate precursor [16,17]. Later reports described a transesterification with a dicyanoacrylic acid [18] or their formation from the oxidation of a diphenylselenide precursor, seen in Eq. 3 for the dicyanoacrylate ester of butanediol, 7 [6]. 

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 . 

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

Benzothiepins synthesized by a double Knoevenagel condensation (see Section 2.1.1.2.) contain free carboxylic acid groups if the reaction product is isolated under acidic conditions. Rcesterification can be performed by two methods via formation of the acid chloride and subsequent alcoholysis, or by reaction with diazomethane, e.g. the conversion of 3-benzo-thiepin-2,4-diearboxylic acid (5, R = C02H) with thionyl chloride and methanol gives the dimethyl ester 5 (R = C02Me) in 47% yield, while the diazomethane pathway provides 60% of the dimethyl ester.65 Use of excess diazomethane leads to cycloadducts (see Section 2.2.4.). 

In most cases diazonium salts are not isolated, but are converted into products by reactions that can be carried out in situ. Moreover, it is actually recommended not to isolate these salts, not even for purification purposes, as many of them have a tendency to explode. In addition, the high solubility of most diazonium salts in water makes precipitation from this medium difficult. Therefore, to obtain solid diazonium salts the recommended method for many decades was to carry out diazotizations in ethanol followed by precipitation with ether. As inorganic salts of nitrous acid are scarely soluble in ethanol, Knoevenagel recommended alkyl nitrites (ethyl or isopentyl nitrite) as diazotization reagents as long ago as 1890. Various other solvents have subsequently been used for diazotizations with alkyl nitrites (see Saunders and Allen, 1985, p. 23 ff.), but as a method for obtaining solid diazonium salts this has been superseded by the isolation of diazonium tetrafluoroborates and, to a lesser degree, of hexafluorophosphates. 

The domino Knoevenagel/hetero-Diels-Alder reaction is a prominent example of the great advantage of domino processes as it not only allows the efficient synthesis of complex compounds such as natural products starting from simple substrates, but also permits the preparation of highly diversified molecules. Due to the vast number of reports that have been made, only a few recent publications can be discussed here, although several excellent reviews on this topic have been produced that provide a more detailed insight into this useful method [372]. 

Fig. 2 Representative traditional methods for coumarins synthesis, (a) Perkin synthesis (b) Pechmann-type condensation (c) Knoevenagel-type condensation...

The preparation of glutaric acid by the hydrolysis of trimethylene cyanide has been described in a previous article in this series,2 which includes a bibliography of the literature. The present method is a modification of that of Knoevenagel.3... 

Recently Bogdal [48] observed, using kinetic studies, greater MW rate enhancements when the Knoevenagel reaction of salicylaldehyde with ethyl malonate (vide supra, Scheme 4.15) was performed in toluene than when ethanol was used as the solvent. The calculated rate constants in toluene solution were more than three times higher under MW irradiation than under conventional conditions, whereas the rate constants of the reaction in ethanol were the same, within experimental error, under both heating methods. 

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