Disubstituted diesters

The mechanism of the Krapcho dealkoxycarbonylation is dependent on the structure of the substrate ester and the type of anion used. In the case of a,a-disubstituted diesters (especially the methyl esters), the anion from the salt (cyanide ion in the scheme) attacks the alkyl group of the ester in an Sn2 fashion and the decarboxylation results in the formation of a carbanionic intermediate that is quenched by the water. In the case of a-monosubstituted diesters the cyanide attacks the carbonyl group to form a tetrahedral intermediate, which breaks down to give the same carbanionic intermediate and a cyanoformate, which is hydrolyzed to give carbon dioxide and an alcohol. 

Phthalic anhydride and diethyl phthalate are easily converted with hydrazine into 4-hydroxyphthalazin-l(2/f)-one. Its substituted derivatives have been prepared using substituted hydrazines, substituted phthalic anhydrides, or diesters or disodium salts of substituted phthalic acids (Scheme 81). However, condensation of phenylhydrazine with phthalic anhydride gives only a small amount of the corresponding phthalazine, the main product being 2-anilinophthalimide. This can be rearranged in the presence of base into the phthalazine derivative. For the preparation of 2,3-disubstituted derivatives, 1,2-disub-stituted hydrazines are reacted with the appropriate phthalic anhydrides or phthaloyl chlorides. Derivatives of 4-amino- or 4-hydrazino-phthalazin-l(2iT)-one have been prepared either from the corresponding monothiophthalimide and 3-aminoisoindolin-3-one (1S4) or from ethyl 2-cyanobenzoate (155) and hydrazine hydrate (Scheme 82). Similarly,... 

Lactam 299 was prepared from tryptamine and cyano diester 298 by reductive alkylation in about 12% yield. Phosphorus oxychloride cyclization of 299, followed by catalytic reduction, resulted in the corresponding trans disubstituted indolo[2,3-a]quinolizine 300. After transesterification, formylation and methyla-tion were carried out in two subsequent steps with ethyl formate in the presence of triphenylmethylsodium and with an excess of diazomethane to supply ( )-dihydrocorynantheine (163). 

Succinylosuccinic diester is cyclized according to the common route by using chlorinated or methylated aniline. Starting from anilines which are substituted in 2- or 4-position, the reaction affords the symmetrical 4,11- or 2,9-disubstitution products. Reaction with 3-substituted anilines, on the other hand, produces a mixture of both of the symmetrical 1,8- and 3,10-disubstitution products, as well as un-symmetrical 1,10-disubstituted compound. The following chart illustrates this point. 

Bemtsson, P. B., Carlsson, S. A. I., Gaarder, J. O., and Ljung, B. R. (1981). 2,6-Dimethyl-4-2, 3-disubstituted pbenyl-l,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-as3mimetric diesters... 

The occurrence of the diester structures of the malonic acid moiety in natural anthocyanin pigments has so far been reported in pigments from flowers of Eichhornia crassipes and chive. Allium schoenoprasum, where the anthocyanin-flavone and anthocyanin-flavonol disubstituted malonate structures were exhibited, respectively (Figure 10.8 and Figure 10.9). In some anthocyanins from flowers of Anemone coronaria, malonic acid is esterified with galactose in one end and tartaryl in the other end. ... 

Reactions of a number of l-phenylimidazole-2-carboxamides with chlorine in acetic acid, NCS, or hypochlorite failed to introduce chlorine into the 4- or 5-positions (80JHC409). Chlorination of a variety of 2,4-disubstituted imidazoles, however, was quite facile, Thus, 2,4-diesters [83JCS(P1)809] and 2-amino-4-aryl compounds [80IJC(B)526] were readily 5-chlorinated, and even when both the 4- and the 5-positions were blocked, as in 5-aminoimidazole-4-carboxamide, 2-chlorination with iodine monochloride was possible (89MI5). When all three carbons were substituted (e.g., in 2,4,5-triphenyl-, 2-chloro-4,5-diphenyl-, and 2-trichloromethyl-... 

The cycloaddition of allenes to symmetrically disubstituted alkenes gives mixtures of cyclobutanes with stereochemical equilibration of the substituents. The reaction of 1,3-dimethylallenc with either diethyl fumarate or diethyl maleate produces a mixture of the /raw.v-bis(ethoxycar-bonyl)cyclobutanes.s The same nonstereoselectivity was observed for phenylallene and 1,1-dimelhylallene cycloadditions to maleic and fumaric acid diesters.9 10... 

Reaction of excess 2,5-dimethylfuraft with DMAD gives a monoadduct but at 100 °C the diadduct (129) is formed (Scheme 63). The disubstituted double bond may be selectively reduced and pyrolysis then results in 2,5-dimethylfuran (131), the diester (130) and ethylene (70JOC3897). 2,2 -Bifuryl and DMAD give the adducts (132) and (133) (67JCS(C)2327). The... 

A significant feature in the synthesis of 2,2-disubstituted tetrahydropyrans from diethyl malonate is the selective chlorination by trifluoromethanesulfonyl chloride of carbanions which can be formed using triethylamine or DBU as the base (79TL3645). Monoalkylation of the diester with l-bromo-4-tetrahydropyranyloxybutane leads to the alcohol (237 R = H)... 

The intermediacy of >/2-cyclopropene complexes of nickel has been proposed in catalyzed 2+1 reactions of free cyclopropene with electron-poor olefins, to give vinylcyclo-propanes. For example, the reaction of fumarate esters with 3,3-disubstituted cyclopropenes in the presence of Ni(COD)2 catalyst gave vinyl-substituted trans-2,3-cyclopropane dicarboxylate esters (equation 235)72 302. However, when maleic esters were used instead, a mixture of both cis and trans vinylcyclopropane diesters is obtained. 

The synthesis of the disubstituted malonic ester cannot be achieved by successive ethylation and phenylation procedures [cf. Section 5.11.6, p. 680] since for the latter reaction the aryl halide is not sufficiently reactive. The procedure described below (formulated in Expt 8.37) provides a suitable indirect alternative route. This involves a mixed Claisen ester condensation (cf. Section 5.14.3, p. 738) between ethyl phenylacetate and diethyl oxalate, followed by decarbony-lation of the a-keto diester on heating to 175 °C. 

Treatment of the diesters (497) with 1,4-disubstituted thiosemicarbazides gives the antiaromatic derivatives (498) <85KGS960>. 

Substituted pyrroles such as verrucarine E (208), an antimitotic agent, have been synthesized by methods that incorporate a rDA reaction as a key step. In order to prepare 3,4-disubstituted pyrroles in reasonable yields, an electron-withdrawing N-substituent must be present. Therefore, as shown in equation (90), N-benzoylpyrrole (205) was subjected to a DA-rDA sequence with acetylene elimination to produce diester (207), which was transformed into verrucarine E (208). ... 

The voltammetric behavior of disubstituted alkyl pyridine and benzene esters 121 and several of their dithioic 5,5 -diesters 122 analogs have recently been reported... 

Scheme 7-116 From chiral cyclopropanonc ketals to ge/n-disubstituted keto-esters or -diesters.

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