Enamines with acetylenic esters

Several reactions of enamines with acetylenic esters are reported. " In general, [2 + 2] mode of addition leads to cyclobutene intermediates, which undergo ring opening, yielding dienamines. (V,A(-Dimethyl-isobutenylamine (227) with DMAD, for example, gives the dienamine... 

Hendrickson and co-workers have used the reaction of a-amino-ketones with acetylenic esters for synthesizing pyrrole derivatives. Thus, in the reaction of a-aminopropiophenone with DMAD, an intermediate enamine adduct (56) is formed, which ultimately gives rise to the pyrrole 57 in presence of methanolic HCl [Eq. (16)]. Pandit and Huisman have shown the generality of this scheme in the synthesis of polycyclic pyrrole derivatives. 

Pyridine-Derived Enamines and Related Ylids with Acetylenic Esters... 

Enamines of cyclic ketones react with acetylenic esters in an apolar solvent via [2 + 2] cycloaddition leading to cyclobutenes, which normally undergo a sigmatropic ring opening to a 1,3-diene at room temperature - . Nevertheless, cycloadducts have been isolated, such as cyclobutenes 46 and 47, which are stable solids in inert solvents, or cycloadduct 48 obtained by reaction of a -nitro enamine with dimethyl acetylenedi-carboxylate. ... 

Cycloadducts with more than six carbon atoms have been obtained by reaction of enamines of cyclic ketones (e.g. 14) with acetylenic esters such as 189 in apolar solvents. The reaction involves formation of the [2 + 2] cycloadduct 190 followed by thermal electrocyclic reaction of the cw-fused cyclobutene (see Section It has been... 

The formation of adducts of enamines with acidic carbon compounds has been achieved with acetylenes (518) and hydrogen cyanide (509,519,520) (used as the acetone cyanohydrin). In these reactions an initial imonium salt formation can be assumed. The addition of malonic ester to an enamine furnishes the condensation product, also obtained from the parent ketone (350,521). 

The recently reported (757) conversion of 5-pyrazolones directly to a,j8-acetylenic esters by treatment with TTN in methanol appears to be an example of thallation of a heterocyclic enamine the suggested mechanism involves initial electrophilic thallation of the 3-pyrazolin-5-one tautomer of the 5-pyrazolone to give an intermediate organothallium compound which undergoes a subsequent oxidation by a second equivalent of TTN to give a diazacyclopentadienone. Solvolysis by methanol, with concomitant elimination of nitrogen and thallium(I), yields the a,)S-acetylenic ester in excellent (78-95%) yield (Scheme 35). Since 5-pyrazolones may be prepared in quantitative yield by the reaction of /3-keto esters with hydrazine (168), this conversion represents in a formal sense the dehydration of /3-keto esters. In fact, the direct conversion of /3-keto esters to a,jS-acetylenic esters without isolation of the intermediate 5-pyrazolones can be achieved by treatment in methanol solution first with hydrazine and then with TTN. 

Several cycloaddition reactions of 2,5-dihydrothiophene derivatives have been reported. Compounds possessing an enamine system undergo [2 + 2] cycloaddition with acetylene-dicarboxylic ester (Scheme 215) (77AHC(2l)253). Diels-Alder addition of the 2,5-di-hydrothiophene-3-carboxylic ester (557) with butadiene, followed by desulfurization, leads to the trisubstituted cyclohexane (558) (B-74MI31404). 

As can be seen from equations 2-5, the formation of A -acylenamines proceeds from derivatives of carboxylic acids (having an oxidation level equal to three ), namely anhydrides or add halides RCOX or amides RCONH2, on the one hand, and from carbonyl compounds or their derivatives (oxidation level equal to two ), namely enamines 3, acetylenes 5, or vinyl ethers 6, on the other. Indeed, the acetylenes 5, being the dehydration products of enols, may be regarded as having a masked carbonyl functionwhile the enamines 3 rank with vinyl ethers, vinyl esters and enols, as the heteroanalogs of these carbonyl derivatives (see Section IV). 

Addition of acetylenic esters to cyclic enamines leading by rearrangement ring expansion to cyclic ketones with two more carbon atoms. 

The formation of pyridone products can be accomplished by the use of acetylenic esters. Aza-annulation of 198 with 57 resulted in the formation of 199 (eq. 43).27-68 Compound 199 was converted to 200, which was a key intermediate in the preparation of 4-aza-19-norsteroids. Reaction of 57 with hydrazine enamine 201 gave 202 which allowed access to the aromatized derivative 203 (eq. 44).69 Similarly, annulation of hydrazine enamine 204 with 205 resulted in formation of pyridone 206, which had a -CC Me substituent P to the lactam carbonyl (eq. 45).69... 

A more conventional cycloaddition occurs with activated acetylenes, however, the intermediate cyclobutene adducts undergo rearrangement to give insertion of two carbon atoms into the enamine chain (55). Thus the enamine (16) reacted with methyl propiolate to give the dienamino ester (73), presumably via the cycloaddition product (65a). 

Acetylenemonocarboxylic esters are more stable at ambient temperatures than the diesters but, nevertheless, the trimer, trimethyl trimesate (benzene-1,3,5-tricarboxylate) (19), has been isolated from reactions involving MP. Other products obtained from this acetylene in situations where water, or ammonia, can be produced are the geometric isomers 20 and 22,24 and the enamine 21, respectively.25 Methyl propiolate with water in benzene yields 20.28... 

Since the report by Carboni and Lindsey in 1959 on the cycloaddition reaction of tetrazines to multiple bonded molecules as a route to pyridazines, such reactions have been extensively studied. In addition to acetylenes and ethylenes, enol ethers, ketene acetals, enol esters and enamines, and even aldehydes and ketones have been used as starting materials for pyridazines. A detailed investigation of various 1,2,4, 5-tetrazines in these syntheses revealed the following facts. In [4 + 2] cycloaddition reactions of 3,6-bis(methylthio)-l,2,4,5-tetrazine with dienophiles, which lead to pyridazines, the following order of reactivity was observed (in parenthesis the reaction temperature is given) ynamines (25°C) > enamines (25-60°C) > ketene acetals (45-100°C) > enamides (80-100°C) > trimethylsilyl or alkyl enol ethers (100-140°C) > enol... 

This process works best when the tetrazine has electron-withdrawing snbstitnents, but 1,2,4,5-tetrazine itself will react with a range of simple aUcynes, enamines and enol ethers, nnder quite moderate condi-tions. A wide range of substitnents can be incorporated via the acetylene, including nitro and trimethyl-silyl, affording the means to access other snbstitnted pyridazines. The preparation of a boronic ester is another example. 

Early extensive accounts of the 4v participation of a,/)-unsaturated carbonyl compounds in [4 + 2] cycloadditions detailed their reactions with electron-deficient dienophiles including a,/3-unsaturated nitriles, aldehydes, and ketones simple unactivated olefins including allylic alcohols and electron-rich dienophiles including enol ethers, enamines, vinyl carbamates, and vinyl ureas.23-25 31-33 Subsequent efforts have recognized the preferential participation of simple a,/3-unsaturated carbonyl compounds (a,/3-unsaturated aldehydes > ketones > esters) in inverse electron demand [4 + 2] cycloadditions and have further explored their [4 + 2]-cycloaddition reactions with enol ethers,34-48 acetylenic ethers,48 49 ke-tene acetals,36-50 enamines,4151-60-66 ynamines,61-63 ketene aminals,66 and selected simple olefins64-65 (Scheme 7-1). Additional examples may be found in Table 7-1. 

Pyrroles.—Formation. A general synthesis of 2-aryl-pyrroles (112) is by cycliz-ation of the esters (111), which are obtained from unsaturated aldehydes and methyl azidoacetate. Thermolysis of the acetylene (113 Ar = p-MeC6H4) gives Al-(p-tolyl)pyrrole with the elimination of p-thiocresol. The pyrrole derivative (115) is the product of the action of benzylamine on tri-(t-butylthio)cyclopropenylium perchlorate (114). Azoalkenes combine with fi-dicarbonyl compounds or with enamines to yield derivatives of Al-aminopyrrole thus the ester (116) and ethyl acetoacetate form (117). The base-catalysed addition of methyl propiolate to toluene-p-sulphonylmethyl isocyanide, T0SCH2NC, gives the ester (118). The dipolar cyclo-adduct (120) of piperidinocyclopentene to the azo-compound (119) forms the A-(tosyl-amino)pyrrole derivative (121) and piperidine on heating. ... 

The a-pyrone analogues (101) have been synthesized by a [24]cycloaddition reaction between cyclic a-keto-enamines (100) and di(thioethyl)ketene/ 5-Enamino- 8-keto-esters, derived from the corresponding acetylenic keto-esters, undergo smooth alkylation to give /35-diketo-esters, which can be cyclized to 4-hydroxy-a-pyrones with hot polyphosphoric acid/ ... 

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