From 3-Aminocrotonic Esters

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. 

From Aminocrotonic Esters (Type E).— A novel direct ring synthesis of 5-hydroxyisothiazoles involves the condensation of a p-aminocrotonic ester (22) with perchloromethanethiol in the presence of base the heterocyclic products (23) are obtained directly (30—40%), presumably by the reaction sequence shown. ... 

Pyrroles can also be obtained from aminocrotonates by oxidation. The transformation is actually a dimerization resulting from a two-electron oxidation of the enamine (Scheme 12) (83T793). 1,4-Addition of nitrometh-ane to the vinilogous ester of A A in presence of l,8-diazabicyclo[5.4.0]un-dec-7-ene (DBU) gave a 1 1 diastereomeric mixture of adducts which, upon reduction, spontaneously cyclized into a mixture of pyrrolidinones, formed in a ratio of 8 2 (Scheme 13) (93TL7529). 

The construction of the furan ring in a Feist-Benary type reaction starting from 4-hydroxy-6-methylpyran-2-one (66) has also proved to be useful for the synthesis of furo[3,2-c]pyridines (Scheme 14) (75JHC461, cf. 71BSF4041). Quite recently the synthesis of the hitherto unknown furo[3,2-c]pyridin-3-ols has been described (79LA371). 4-Hydroxypyridine-3-carboxylates (e.g. 69), which are available from diketene and /3-aminocrotonic esters, react with a-halogenoketones in the presence of potassium carbonate to give compounds of type 70. 

The Hantzsch pyridine synthesis affords 1,4-dihydropyridines 214, although spontaneous oxidation to pyridines often occurs. In its simplest form it involves the condensation of two molecules of a -keto ester with an aldehyde and ammonia (Scheme 119) . Compounds resulting from the condensation of ammonia with one of the carbonyl components can be used in the Hantzsch synthesis. Thus, -aminocrotonic ester 215 can replace the ammonia and one mole of acetoacetic ester in Scheme 119. The mechanism of the Hantzsch synthesis has been clarified by 13C and 1SN NMR spectroscopy <1987T5171>. 

N-Substituted 3-aminocrotonic esters (67) tend to adopt a planar or near-planar structure. As a consequence of their push-pull nature these molecules show an increased facility for Z-67-is-67 isomerization around the C=C double bond as well as restricted rotation around the C—N and C—COOR2 single bonds. The IR and XH-NMR spectra of simple 3-(alkylamino)crotonic esters have shown that these substances exist either in the liquid state or in solution as equilibrium mixtures of the Z and E configurations, respectively. The position of the equilibrium is solvent-dependent, and the energy difference between the isomers varies from ca 7.3 kJ mol-1 in non-polar solvents to ca 0.8 kJ mol"1 in dimethyl sulphoxide, the intramolecularly bonded Z-form 68 or 69 being the most stable111-113. 

Senary, E. Synthesis of Pyridine Derivatives from Dichioroether and P-Aminocrotonic Ester. Ber. 1911,44, 489-493. 

The synthesis of the thiazole nucleus from aminothiocyanogen and ketones (these Reports, Vol. 2, p. 589) is also applicable to enamines derived from jS-dicarbonyl compounds. Thus, 3 aminocrotonic ester (10) or 2-aminopent-2-en-4-one (11) yield the intermediate enamines (12), which are cyclized to 2-aminothiazoles (13) under the influence of alkalis, and to A -thiazol-2-ones (14) by acids. ... 

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). 

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%). 

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). 

When some dihydropyridines were prepared by the Hantzsch one-pot synthesis from alkyl 3-aminocrotonates (85CPB3787), the same type of products were formed by Michael addition of esters of amidinoacetic acid to aralkylidene-/3-ketoesters (81AF1173). 

Furo[3,4-r]pyridine derivatives are generated from the reaction of 2,3-dihalopropenyl ketones with the ethyl ester of / -aminocrotonic acid. Initial reaction products are substituted nicotinic acids which can be partially converted into the furopyridines under harsh vacuum distillation conditions (Scheme 12) <2005CHE1009>. 

The same group successfully obtained symmetrical DHPs (3, Scheme 17.5) by using a similar reaction but exchanging the methyl yS-aminocrotonate for ammonium acetate [31b]. Later, Ohnberg et al. [31c] performed a similar reaction in a monomode closed-vessel MW synthesizer. In their approach, an aldehyde, a j8-keto ester, and aqueous ammonia were reacted in a one-pot condensation to form a small library of DHPs 3 (Scheme 17.5). The reaction mixture was irradiated with MW for 10-15 min at 140-150 °C and the desired DHPs 3 were obtained in 51-92% yield. Under conventional heating conditions the reaction mixture was heated under reflux for 12 h with yields ranging from 15-72% [30]. 

---