Ammonia, reaction with ethyl acetoacetate

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 great majority of 1,4-dihydropyridines are prepared using classical Hantzsch pyridine synthesis or one of its variants. The first dihydropyridine was in fact isolated back in 1882 as a stable intermediate from that method. In its simplest form, the synthesis involves heating an aldehyde such a orf/io-nitrobenzaldehyde (12-1) with ethyl acetoacetate (12-2) and ammonia. The reaction almost certainly involves, as the first... 

A sirup (obtained by treating D-mannose with ammonia) presumably containing D-mannosylamine, treated with ethyl acetoacetate, also gives compound (17). In the reaction with 2,4-pentanedione, 3-acetyl-2-methyl-... 

A re-investigation of the reaction showed, in accordance with VotoCek s hypothesis, that the compounds obtained have properties (for example, color reactions, ultraviolet and infrared spectra, hydrolysis when examined chromatographically) similar to those of the /3-(glycosylamino) a, 8-un-saturated esters or ketones prepared directly from glycosylamines and i3-dicarbonyl compounds. The derivatives from L-rhamnose and ammonia with ethyl acetoacetate and with 2,4-pentanedione are, indeed, identical... 

The Hantzsch pyrrole synthesis is a reaction used to synthesize pyrroles from a p-enaminoketone or ester generated by the reaction between ammonia or an ammonia surrogate with a p-diketone or p-ketoester and an a-haloketone. The initial three coniponent reaction reported by Hantzsch involved the reaction between ethyl acetoacetate 8 and chloroacetone 9 in the presence of aqueous ammonia to give the corresponding pyrrole 10 in approximately 50% yield. ... 

The 1,4-dihydropyridines (DHPs) classes of privileged heterocyclic pharmacophores are well known for their calcium channel blocker activity. Other versatile biological profiles of 1,4-DHPs such as anticonvulsant activity, selective adenosine-A3 receptor antagonism, radioprotective activity, sirtuin activation, and inhibition, etc. have also been well known [186]. Conventionally, 1,4-DHPs could be accessed via the Hantzsch reaction, reduction of pyridines, addition to pyridines or cycloadditions, etc. As a facile and broadly tolerable protocol, the Hantzsch reaction consisting of cyclocondensation reaction of ethyl acetoacetate (2 equivalent) with an aldehyde and ammonia remains as a frequently employed tactic for the synthesis of 1,4-DHPs in a large number of areas such as stereoselective synthesis and green chemistry [187]. 

This reaction consists of the condensation of two molecular equivalents of a 1,3 diketone (or a J3-keto-ester) with one equivalent of an aldehyde and one of ammonia. Thus the interaction of ethyl acetoacetate and acetaldehyde and ammonia affords the 1,4-dihy dro-pyridine derivative (1), which when boiled with dilute nitric acid readily undergoes dehydrogenation and aromatisation" to gb e the diethyl ester of collidine (or 2,4,6-trimethyl-pyridine-3,5 dicarboxylic acid (II)). For the initial condensation the solid aldehyde-ammonia can conveniently be used in place of the separate reagents. 

Gently warm a mixture of 32 g. (32 ml.) of ethyl acetoacetate and 10 g. of aldehyde-ammonia in a 400 ml. beaker by direct heating on a gauze, stirring the mixture carefully with a thermometer. As soon as the reaction starts, remove the heating, and replace it when the reaction slackens, but do not allow the temperature of the mixture to exceed 100-no the reaction is rapidly completed. Add to the mixture about twice its volume of 2A -hydrochloric acid, and stir the mass until the deposit either becomes solid or forms a thick paste, according to the quality of the aldehyde-ammonia employed. Decant the aqueous acid layer, repeat the extraction of the deposit with more acid, and again decant the acid, or filter off the deposit if it is solid. Transfer the deposit to a conical flask and recrystallise it twice from ethanol (or methylated spirit) diluted with an equal volume of water. The i,4-dihydro-collidine-3,5-dicarboxylic diethyl ester (I) is obtained as colourless crystals, m.p. 130-131°. Yield 12 5 g,... 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

To complete the section on the synthesis of 4,4 -bipyridines, we summarize the methods reported for the preparation of some substituted 4,4 -bi-pyridines and 4,4 -bipyridinones. These methods are closely analogous to syntheses already discussed for some of the isomeric bipyridines. Thus the Hantzsch reaction using pyridine-4-aldehyde, ethyl acetoacetate, and ammonia gives 3,5-di(ethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4,4 -bipyridine, which after oxidation, followed by hydrolysis and decarboxylation, afforded 2,6-dimethyl-4,4 -bipyridine. Several related condensations have been reported. Similarly, pyridine-4-aldehyde and excess acetophenone gave l,5-diphenyl-3-(4-pyridyl)pentane-l,5-dione, which with ammonium acetate afforded 2,6-diphenyl-4,4 -bipyridine. Alternatively, 1-phenyl-3-(4-pyridyl)prop-2-enone, A-phenacylpyridinium bromide, and ammonium acetate gave the same diphenyl-4,4 -bipyridine, and extensions of this synthesis have been discribed. Condensation of pyridine-4-aldehyde with malononitrile in the presence of an alcohol and alkaline catalyst produced compounds such as whereas condensations of... 

Reaction LID. Action of Ethyl Acetoacetate on Aldehyde-ammonias (Hantzsch). (A., 215, 1.)—When acetoacetic ester is heated with... 

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. 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

---