Malonic ester synthesis arylation

When an aromatic ring is treated with diethyl oxomalonate, (Et00C)2C=0, the product is an arylmalonic acid derivative, ArC(OH)(COOEt)2, which can be converted to an arylmalonic acid, ArCH(COOEt)2. This is therefore a way of applying the malonic ester synthesis (10-104) to an aryl group (see also 13-12). Of course, the opposite mechanism applies here The aryl species is the nucleophile. 

Anhydrides—Continued reduction to alcohols, 155 reduction to lactones, 535 Arenes, see Hydrocarbons, aromatic Amdt-Eistert reaction, 433, 487, 573 Aryl esters. Fries rearrangement, 344 hydrolysis, 169 preparation, 169 Aryl halides, see Halides Atyloxy acids, preparation, by aceto-acetic ester synthesis, 430 by malonic ester synthesis, 429 from atyloxy alcohols, 419 from atyloxy cyanides, 414 preparations listed in table 48, 460 Aryloxy acyl halides, preparation, 547 preparations listed in table 61, 553 Aryloxy esters, preparations listed in table 55, 516... 

With Malonic Ester.— The malonic ester synthesis (p. 274) is also applicable in this case, the sodium malonic ester reacting with aryl halides Just as it does with alkyl halides ... 

Labeled a-bromomethyl derivatives can be prepared from the ketones by treatment with pyridinium tribromide elementary bromine, or CuBr2. One example of the preparation and use of such intermediates is the extension of the aliphatic side chain by two carbon atoms using the malonic ester synthesis to produce the 4-aryl-4-oxo[4- C]butyrate (7) in good yield (Figure 6.7). 

Figure 6.7 Chain extension of aryl methyl [ " C]ketones via malonic ester synthesis...

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. 

With malonic esters and amides substituted at the central carbon atom, triazole formation is accompanied by decarboxylation and 4-alkyl- or 4-aryl-5-hydroxytriazoles are isolated (69ACS(B)i09i). The 4-methoxybenzyl group has recently been found to be a versatile W-protecting group for the synthesis of AT-substituted 1,2,3-triazoles (82jcs(pi)627). 

Extending the Hantzsch synthesis and in the course of producing new 4-aryl-l,4-dihydropyridines related to the powerful calcium antagonist Nifedipine (Adalat),16 arylalkylideneacetoacetates, ketones, and malonic esters (18 and 21) have been treated with ketenaminals (19) to give 2-amino-l,4-dihydropyridine-3-carboxylic esters 20 and 2217 (Scheme 7). This reaction was also applied to 4-arylalkylidene-2-methyl-l,3-oxazolinone-5.18... 

A one-pot MW-accelerated synthesis of selective glycine receptor antagonists 3-aryl-4-hydroxyquinolin-2(lH)-ones has been developed via amidation of malonic ester derivatives with anilines and subsequent cydization of the intermediate, ma-londianilides under solvent-free conditions (Scheme 8.71) [180]. 

Aryl-4-hydroxyquinolin-2(li-f)-ones, which are of pharmaceutical interest, were readily obtained in a one-pot procedure by formal amidation of malonic ester derivatives with an aniline then cyclization of the intermediate malondianilides (Scheme 10.103) [200]. The synthesis of Merck s glycine NMDA receptor or antagonist l-701,324 is illustrative. It can be prepared in one step by use of this procedure whereas the previously reported synthetic procedure comprises several reaction steps. 

The synthesis of polyfunctional l,2,3-triazolin-5-ones was investigated somewhat earlier than the alkyl and aryl derivatives discussed in Chapter 13. For example, Curtius and his students prepared a variety of such compounds from sulfonylazides and malonic esters but failed to present evidence of the yields obtained (Eq. 1). ... 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

Solid phase synthesis of highly substituted thiophene derivatives 15 using a cyclic malonic acid ester resin 14 was also reported. Highly pure thiophene derivatives were reported to have been prepared by this solid phase synthesis <0314851>. While alkyl or aromatic substitutions on the P position to the carbonyl yielded the corresponding 5-alkyl/aryl substituted 2-acyl aminothiophene, acetaldehyde did not produce the corresponding 2,3- disubstituted thiophene. 

Indanones are very useful and versatile intermediates in the synthesis of metallocene catalysts. Scheme 1 has the synthetic scheme originally used for the preparation of 2-alkyl-4-aryl-substituted ansa metallocenes [9-11]. In the first part of this sequence, the biaryl unit is assembled and the missing carbon atoms are introduced as a side chain. The reaction of 2-phenylbenzyl bromide with malonic acid ethyl ester under basic conditions, followed by a decarboxylation, affords the 2-(2-phenylbenzyl)propionic acid. Chlorination and Friedel-Crafts acylation yields the 2-methyl-4-phenylindanone in 93 % yield. From here, only a few standard transformations are required to complete the synthesis, finally yielding the desired metallocene. 

Enders et al. developed an asymmetric synthesis of polyfiinctionalized pyrrolidines based on Mannich-Michael cascade strategy (Scheme 2.42). Under the promotion of 10mol% thiourea catalyst 140b, y-malonate-substituted a,P-unsaturated esters 149 and N-protected aryl aldimines 148 underwent Mannich reaction to afford chiral amine intermediates, which then underwent an intramolecular aza-Michael reaction to yield pyrrolidine derivatives 150 with moderate to good enantioselectivities [60]. 

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