3-Aminocrotonate

If the condensation is done with /S-aminocrotonic ester or (2-aminopent-2-en-4-one)enamine, intermediates 245b are also obtained then they are cyclized either to 2--aininothiazoles (243b) under the influence of alkalis or to A-4-thiazol-2-ones by acids (Scheme 125b) (728). 

Displacement of activated chlorine atoms also proceeds with certain types of organic compounds, but only in the presence of Lewis acid catalysts. Particular examples include epoxides, polyhydric alcohols, trialkylphosphites (12), and P-aminocrotonates (13). These additives are commonly used in conjunction with metallic stabilizers to provide complete, high performance, commercial stabilizer packages. 

Specialtyydmines. Some substituted nitrogenous compounds can provide similar benefits. Esters of 2-aminocrotonate and bis-2-aminocrotonate, and appropriately substituted dihydropyridines, eg, 3,5-his-lauryloxycarhoxy-2,6-dimethyl-1,4-dihydropyridine [37044-66-7] and... 

Another important reaction of diketene derivatives is the Hant2sch pyridine synthesis (101). This synthesis is the preparation of 1,4-dihydropyridines (14) starting either from two acetoacetic esters, which react with an aldehyde and ammonia or a primary amine or from 3-aminocrotonates and 2-alkyhdene acetoacetic esters, both diketene derivatives. Several such dihydropyridines such as nifedipine [21829-25-4] (102), nimodipine [66085-59-4] and nicardipine [55985-32-5] exhibit interesting pharmaceutical activity as vasodilators (blood vessel dilation) and antihypertensives (see Cardiovascularagents). 

The Feist synthesis is similar to the Hant2sch method and iavolves condensation of acyloias, eg (11), with aminocrotonic esters, eg (12), ia the presence of 2iac chloride (23). 

The reaction of C2S2 with 2-aminopyridine and /V-pbenylbensamidine yields the higher condensed derivatives C2S2 also reacts with p-aminocrotonate to yield H2NC(CH2)=C(COOC2H2)]2S (7). 

Methoxypyridazine 1-oxide reacts with methyl /3-aminocrotonate in the presence of benzoyl chloride to give a-(6-methoxy-3-pyridazinyl) /3-aminocrotonate (112) which can be converted by mild hydrolysis into the corresponding acetate (113 Scheme 34) <78JHC1425). 

In many pyrimidine ring syntheses, it is possible or even desirable to isolate an intermediate ripe for ring-closure by the formation of just one bond. For example, ethyl 3-aminocrotonate (502) reacts with methyl isocyanate to give the ureido ester (503) which may be isolated and subsequently converted into 3,6-dimethyluracil (504) by the completion of one bond. However, viewed pragmatically, the whole synthesis involves the formation of two bonds and therefore is so classified. On such criteria, only two pyrimidine/quinazoline syntheses involve the formation of only one bond. 

Dimethylpyridine has been isolated from the basic fraction of coal tar and also from the bone oil fraction distilling at 139-142°. It has also been prepared from ethyl aceto-pyruvate and ethyl /S-aminocrotonate. ... 

There is somewhat more interest in the aminocrotonates of the general formula... 

In 1929, Nenitzescu reported that p-benzoquinone (4) was treated with ethyl 3-aminocrotonate (5) in boiling acetone to yield ethyl 5-hydroxy-2-methylindole-3-carboxylate (6). ... 

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted." Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

The more interesting situation arises in quinones which possess two dissimilar substituents. The site of initial carbon-to-carbon condensation is explicable in terms of the relative electronic effects. Thus condensation of 2-chloro-5-methylbenzoquinone (19) with t-butyl 3-aminocrotonate (20) in hot acetic acid furnished the 4-chloro-7-methylindole (21) in 51% yield. ... 

The directing influence of the trifluoromethyl group also competes with that of the strongly electron-donating methoxyl group. Thus 2-methoxy-5-trifluoromethyl-l,4-benzoquinone (26) was treated with ethyl 3-aminocrotonate (5) to furnish 25% of each of the two possible isomeric indoles 27 and 28. °... 

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 ... 

Combinatorial approaches have been applied to this chemistry. In a method amenable to split and pool, PAL, or Rink resin, 89 is modified with an acetoacetate to generate the solid supported aminocrotonate 90. Either a two- or three-component Hantzsch protocol is followed to produce 91. Treatment with TFA carries out the cleavage from the resin and the cyclization to dihydropyridine 92. 

A modihed Hantzsch synthesis has been utilized for the preparation of 1,4-dihydropyridines (Scheme 66). Thus, condensation of formylfurazans 116 with an acetoacetic ester and aminocrotonic acid ester in isopropanol at reflux led to 1,4-dihydropyridine derivatives 117 in about 70% yield (92AE921). Both isomeric furoxan aldehydes reacted in a similar way. 

A process for the preparation of functionalized pyridines from diacetylene and the ethyl ester of /3-aminocrotonic acid and acetylacetonimine (72ZOR1328 75DIS) has been described. Owing to the lower nucleophilicity of nitrogen in the initial enamine esters and enamine ketone, the reaction with diacetylene occurs in the presence of sodium metal (80°C, dioxane, 3 h, yield of up to 20%). 

Reaction of 1 mole of aminals 352 with 4 mol of methyl 3-aminocrotonate in the presence of the solid acids montmorillonte clay (Kio) and ZF520 zeolite as strong Bronsted acidic catalysts, gave 1,4-dihydropyridines 353 and 2-methyl-4//-pyrido[l, 2-n]pyrimidin-4-one (99MI8). 

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]. 

Acetoacetic acid N-benzyl-N-methyiaminoethyl ester -Aminocrotonic acid methyl ester m-Nitrobenzaldehyde... 

A mixture of 4.98 g of acetoacetic acid N-benzyl-N-methylaminoethyl ester, 2.3 g of aminocrotonic acid methyl ester, and 3 g of m-nitrobenzaldehyde was stirred for 6 hours at 100°C in an oil bath. The reaction mixture was subjected to a silica gel column chromatography (diameter 4 cm and height 25 cm) and then eluted with a 20 1 mixture of chloroform and acetone. The effluent containing the subject product was concentrated and checked by thin layer chromatography. The powdery product thus obtained was dissolved in acetone and after adjusting the solution with an ethanol solution saturated with hydrogen chloride to pH 1 -2, the solution was concentrated to provide 2 g of 2,6-dimethyl-4-(3 -nitrophenyl)-1,4-dihydropyridlne-3,5-dicarboxylic acid 3-methylester-5- -(N-benzyl-N-methylamino)ethyl ester hydrochloride. The product thus obtained was then crystallized from an acetone mixture, melting point 136°Cto 140°C (decomposed). 

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