Ethyl 3-aminocrotonate, condensation with

Ethyl 8-aminocrotonate, condensation with acetylace-tone amine, 634 Ethyl 2-amino-4-ethoxymethyl-... 

The 1,4-dihydropyridines 161 were also obtained in 60-77% yields when MWI was used to induce the condensation of ethyl 3-aminocrotonate (160) with methyl acetoacetate (159, R = Me) and aldehydes without a solvent for 4-10 min. The substituents attached to the benzene ring of benzaldehyde may facilitate or retard the condensation through their electronic effects (Scheme 32) (95SC857). 

Condensation of ethyl /3-aminocrotonate (29) with the 3-keto-isothiocyanate (30) in hydrocarbon solvents results in the formation of the 2-thioio-pyrimidine (32) as the major product and the 2-amino-1,3-thiazine (33) as the minor component. However, the use of ether, chloroform, or acetonitrile as solvents reverses the product ratio. This observation points towards the feasibility of formation of the tautomeric intermediate (31), which through attack of nitrogen (31a) or sulphur (31b) at the carbonyl followed by dehydration and enamine hydrolysis leads to (32) and (33), respectively (cf. Scheme 3). Thus, in solvents of higher dielectric constant. 

Condensation of the TV-substituted p-aminocrotonic acid ester 15 with p-benzoquinone (4) has been successfully carried out to furnish the 5-hydroxyindole 29 when the substituent R on the nitrogen of the aminocrotonic acid ester was methyl, ethyl, -propyl, isopropyl, or -butyl, -hexyl, p-cyanoethyl, p-hydroxyethyl, carbethoxymethyl, benzyl, phenyl, o-tolyl, dimethylaminopropyl, y-hydroxypropyl etc ... 

Random incorporation of two different acetoacetates can also be avoided by converting one of the acetoacetates to a derivative which carries the future pyridine nitrogen. For example, treatment of ethyl acetoacetate with ammonia gives the corresponding P-aminocrotonate 32. The aldehyde (34) required for preparation of such an unsymmetrical compound is prepared by reaction of the product from direct metallation of 33 with dimethylformamide. Condensation of that aldehyde with methyl acetoacetate and the p-aminocrotonate from isopropyl acetoacetate leads to isradipine (35) [9]. The same aldehyde with ethyl acetoacetate and the P-aminocrotonate from ethyl acetoacetate gives darodipine (36) [10]. In much the same vein, condensation of the ben-zaldehyde 37 with methyl acetoacetate and its P-aminocrotonate derivative affords riodipine (38) [11]. 

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 synthesis of these compounds involves, as a first step, Knoevenagel condensation between benzaldehyde derivatives (17) and ethyl acetoacetate (18). The Knoevenagel product (19) can be converted in a consecutive step into dihydropyridine derivatives (20) by reaction with an aminocrotonic derivative (Scheme 10). 

A second route to ricinine was suggested by the observation that ethyl 2 4-dihydroxy-6-methyl-nicotinate is obtained from the condensation of ethyl malonate and ethyl /3-aminocrotonate in the presence of sodium ethylate (59). This substituted ethyl nicotinate when converted to the amide by means of alcoholic ammonia and dehydrated with phosphorus oxychloride gives rise to 2 4-dichloro-3-cyano-6-methylpyridine (LXXXYIII). Condensation of LXXXVIII with benzaldehyde followed by oxidation yields the acid (LXXXIX) and this on treatment with sodium methylate... 

From -Aminocrotonic Esters Type C). The synthesis of isothiazoles from j3-aminocrotonic esters (see Vol. 1, p. 370) has been exemplified by the condensation of p-nitrobenzoyl and 2-furoyl isothiocyanates (6) with ethyl j8-methylamino-crotonate (7), which produces pyrimidine derivatives (5) in the absence, and substituted isothiazoles (8) in the presence, of oxidizing agents such as bromine. 

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