Homophthalic esters

A vigorous Claisen condensation ensues when a homophthalic ester and methyl formate are treated with sodium ethoxide and the active methylene group is formylated. Cyclization takes place with ease in acidic media to produce a methyl isocoumarin-4-carboxylate (50JCS3375). Hydrolysis under acid conditions is sometimes accompanied by polymerization, but the use of boron trifluoride in acetic acid overcomes this problem. Decarboxylation may be effected in the conventional manner with copper bronze, though it sometimes accompanies the hydrolysis. 

Two homophthalic ester isomers are ordinarily generated when reacting diethylmalonate with an insitu benzyne intermediate as illustrated in Eq. 1 ... 

Another route for preparing homophthalic esters is through the condensation of diethyl-diacetonedicarboxylate and diketene (1) illustrated Eq. 2 ... 

An early example of aryne insertion into C—C single bonds was described by Guyot et al. in the addition of diethyl malonate anion to arynes and the subsequent rearrangement to homophthalic esters, such as 33 (Scheme 12.13) [30]. However, the reported yield was quite low and the desired product accompanied by numerous undesirable side products. 

In the total synthesis of fredericamycin A reported by Kita et al, the condensation of dimethyl malonate anion with aryne 36 was used to construct the AB-ring system. The intermediate homophthalic esters 37 and 38 were thus obtained in a 58% combined yield with a modest regioselectivity (2 3) (Scheme 12.14) [32]. 

SCHEME 12.41 Synthesis of homophthalic esters via C—C o-bond insertion. 

The construction of isocoumarin natural products offers another instructive comparison between DoM and more conventional methodologies. Thus, in the synthesis of hydrangenol 37 (Scheme 12), [31a] a five-step, one-pot process directly furnishes the heteroannelated product 36, a sequence involving a low-temperature DoM of a dimethyl amide, an LDA-induced chain extension, and a base-mediated cyclization. BBr3 treatment leads to the natural product 37 in good overall yield. The chosen classical alternative, [31b] involving Claisen condensation of 39 with 40 to give 38, is achieved in low over l yield due to the an inefficient preparation of the homophthalic ester 39 (from 3-nitrophthalic anhydride), a memento of an earlier DoM- classical route comparison (Scheme 3). 

The products of the base-catalyzed Stobbe condensation of 3-formylindole and of 2-formylpyrroles undergo acid-catalyzed cyclization to yield l-hydroxycarbazole-3-carboxylic esters and 4-hydroxyindole-6-carboxylic esters, respectively (73JPR295, 74JPR386, 76JPR816). The analogous condensation of dimethyl homophthalate with 2-formyi-l-methylpyrrole and with 3-formylindole produces (443 Hetero= l-methyl-2-pyrrolyl, 3-indolyl), (444) and (445) under acidic conditions (76JHC83). 

The conversion of the substituted 1,3-dicarbonyl compound into homophthalic acid is remarkably facile loss of the acetyl group by a retro-Claisen condensation and hydrolysis of the ester group are complete in a few minutes in aqueous sodium hydroxide. The overall synthesis of homophthalic acids from o-bromobenzoic acids occurs in high yield and provides an attractive route. 

The Claisen rearrangement has only recently been used to provide functionalized derivatives. Thus, mandelate esters react with orthoacetates and orthopropionates to give the corresponding homophthalates. ... 

Analogously, it has been observed that treatment of dimethyl homophthalate with dimethyl 1-lithiomethylphosphonate provides only very low yields of the desired P-ketophosphonate. Competitive enolization of the acidic benzylic methylene appears to be the dominant reaction under these conditions. The unwanted enolization is partially suppressed when the monomethyl ester is used as substrate. ... 

Isocoumarins. - Indanones such as (203), as their enol esters, have been ozon-olysed to give the dihydroisocoumarin-3-ol, which yielded the isocoumarin (204) when heated with toluene-p-sulphonic acid. 3-Arylisocoumarins have been synthesized, in good yield, by heating homophthalic acids with aroyl chlorides. Phthalaldehydic esters (205) react with A/ -acylglycines to give isocoumarin-3-carboxylic acids, e.g (206). ... 

The bixanthenyl 55 which possesses the ring system of the secalonic acids has been obtained from the 7-bromoxanthene via the arylboronic ester and a subsequent Suzuki coupling <04JOC6830>. The anionic polycondensation of acetonaphthones 56 with homophthalates gives dibenzo[Z7j]xanthones and offers an approach to the naturally occurring hypoxyxylerone system <04SL2693>. 

Arylation of fi-dicarbonyl compounds (5,163-164). Experimental details are available for the preparation of homophthalic acids by arylation of j3-keto esters with 2-bromobenzoic acids with copper catalysts. ... 

Reaction with homophthalic acid. If the reaction of homophthalic acid with POCI3 and DMF is carried out at 0°, the major product is the isochromane-1,3-dione (2). If the reaction is conducted at 100°, the major product is the iso-quinolone (3). Treatment of (2) with hydrochloric acid in methanol results in formation of the methyl ester of isocoumarin-4-carboxylic acid (4). 

An improved method for the synthesis of homophthalic acids (9), in 85—90% yield, involves generation of the bis-anions of o-toluic acids using two equivalents of lithium di-isopropylamide followed by condensation with dimethyl carbonate. Cyclohexylidenesuccinic acids (10) and dibenzylidenesuccinic acid s have been prepared by a modified Stobbe condensation. The same reaction, but using a-keto-esters as starting materials, leads to acids of type (11) in two steps. ... 

Homophthalic acid esters from 1,3-cyclohexadienes and allene-l,3-dicarboxylic acid esters... 

Reactions of Thiophen Aldehydes and Ketones.— The Stobbe condensation of some thienylcarbonyl compounds with dimethyl methylsuccinate in the presence of potassium t-butoxide or sodium hydride gave predominantly the ( -half esters of (156), while condensation with dimethyl homophthalate gave predominantly the (Z)-half ester of (157). Thiophen-2-aldehydes were shown to add smoothly to a -unsaturated ketones and nitriles, under the catalytic influence of cyanides, to form (158) and (159), respectively. Thiophen-2-aldehydes have been condensed with aliphatic amines and phenylenediamine to give Schiff bases ... 

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