Isocoumarins ester

Isocoumarin-3-carboxyIic acid, 8-methoxy-synthesis, 3, 834 Isocoumarin-4-carboxylic acid methyl ester synthesis, 3, 832... 

Isocoumarin-3,4-dicarboxylic acid diethyl ester hydrolysis, 3, 691 Isocoumarins... 

Diels-Alder cycloaddition of 3,4-bis(trifluoromethyl)furan with ethyl propynoate involved addition of two a,/3-unsaturated esters followed by acid-catalyzed ring opening, rearrangement, and elimination of ethanol to give a 6,7-bis(trifluoromethyl)isocoumarin-3-carboxylate [92JFC(56)359]. 

Solid extracts of (1) alfalfa and (2) red clover (used in food flavorings) were examined by GC/MS. 389 of 450 detected components were identified in (1), vs. 210 of 309 components detected in (2). In both extracts, predominant compounds identified were esters (1) 105, (2) 55 acids (1) 42, (2) 31 alcohols (1) 34, (2) 31 and hydrocarbons (1) 28, (2) 14. Many other compounds were also found, including cannabinol, caffeine, scopolamine, isocoumarin, phenylpentadienal, phenylhexadiene, and nepetalactone.25... 

A facUe synthesis of 3,4-disubstituted isocoumarins and their benzologues is based on the Pd-catalysed annulation of internal alkynes by 2-iodobenzoate esters (Scheme 27). Tri- and tetra- substituted pyran-2-ones are also available by this route <99JOC8770>. 3-Substituted isocoumarins result from the Pd-catalysed 6-endo-dig cyclisation of 2-ethynylbenzoic acids. The 5-exo-dig products, phthalides, are also formed when there is a terminal bulky group on the alkyne moiety <99S1145>. 

The cumulation reactions, which start from carboxylic acids and esters usually lead to the formation of pyrone derivatives. Methyl (Z)-3-iodoacrylate and 3-hexyne gave, for example, 5,6-diethyl-2-pyrone in acceptable yield (4.38.). Inclusion of the acrylate into a six membered ring starting from ethyl 2-bromocyclohexen-l-carboxylate, led to a condensed ring system, giving a partially reduced isocoumarin derivative.50... 

The two ester groups of diethyl isocoumarin-3,4-dicarboxylate (334) exhibit a curious lability to treatment with hydrochloric acid in that the 4-carboxyl group is lost on refluxing with 10% aqueous acid while 37% acid at 70 °C hydrolyzes the 3-carboxylate group only (Scheme 20) (57JGU2342). 

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. 

Esters of 2-acetonylbenzoic acid are formed when methyl 2-bromobenzoates are treated with 7r-(2-methoxyallyl)nickel bromide (77JOC1329). Cyclization to the isocoumarin occurs on treatment with sodium hydride in benzene with a trace of t-butanol (Scheme 183). A... 

Several examples of intramolecular solvomercuration of arylalkynes have been reported (equations 81 to 83).200 The mercury moiety can be removed by protiodemetallation or converted to a variety of other functional groups. The use of a methyl ether as the nucleophilic functionality is noteworthy, as is the change in the regioselectivity (equation 82 versus equation 83). A bromocyclization related to equation (83) using a phenylethynylbenzoate ester also gives an isocoumarin derivative via 6-endo cyclization.201 Palladium-catalyzed cyclizations of 3,y-alkynic ketones or 2-methyl-3-alkyn-l-ols to form substituted furans are discussed in Chapter 1.4, Section 3.1.3 in this volume. 

Irradiation of the isocoumarin (223) in ethanol yields the two esters (224a) and (224b). The process is thought to involve ring opening to a ketene (225),... 

Heating the keto ester (26.7) with sodium hydride and a catalytic amount of t-butyl alcohol converts it into the isocoumarin in good yield. A 2-acyl(or formyl)indole-3-acetic acid is cyclized by heating in acetic anhydride or on stirring with the anhydride for 36 h [3741,3937]. The latter process is sometimes shortened by addition of boron trifluoride dietherate [3742]. 

Isocoumarin may be synth zed in high yield by heating an o-ethoxyvinyl-benzoate ester with mineral add. An o-hydroxy (or ethoxy)malonyIidene mono-nitrile gives a high yield of a fused pyran-2-one by heating with hydrochloric acid. 

Substitution reactions. Alkyl 2-alkynylbenzoates are activated by the Au(I) salt toward formation of isocoumarin, thereby weakening the O—C(aik) bond of the esters. Attack of nucleophiles results in the cleavage of the esters.Particularly noteworthy is the formation of tetralins by way of an intramolecular reaction involving an aromatic ring (a C-nucleophile). ... 

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). ... 

Coumarins, and isocoumarins, react with Grignard reagents, as do esters, and can give mixtures of products, resulting from ring opening of the initial carbonyl adduct the reaction of coumarin with methylmagnesium iodide illustrates this. ... 

Although ester groups do not normally participate in organopalladium reactions, o-halobenzoate esters react with internal alkynes in the presence of a palladium catalyst to produce good yields of isocoumarins (Eq. 36) [72,77,78]. 

Studies on thebiomimetic synthesis of quinone antibiotics [191] led Krohn to yet another type of enantioselective transformation, namely microbial conversion of an achiral substrate into enantiomericaUy pure anthracych-nones. An adroit synthesis of the microbial transformation substrate, 4-deoxyaklanonic acid (202) [192] (Scheme 38), started from homophthahc ester 196 [193] with addition of diUthiated tert-butyl acetoacetate (197) and subsequent cychzation to isocoumarine 198 [194]. Reaction of 198 with the dilithium salt 199 gave anthrone 200 [195[. Aeration of 200 in the pres-... 

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). 

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