Isocoumarins anhydrides

Homofolic acid, 5,11-methenyl-tetrahydro-biological activity, 3, 327 Homofolic acid, tetrahydro-biological activity, 3, 327 Homoisoflavanones occurrence, 3, 722 thermoisomerization, 3, 722 thermolysis, 3, 728 Homolytic reactions heterocyclic compounds reviews, 1, 74 Homophthalic acid isocoumarins synthesis from, 3, 830 synthesis, 3, 830 Homophthalic anhydride isochroman-l-one synthesis from, 3, 860 20a-Homoporphyrin nomenclature, 1, 30 Homopterocarpin isolation, 4, 998 ( )- D- Homotestosterone synthesis, 1, 453 Homer-Emmons reaction chromene synthesis by, 3, 749 Hortiacine isolation, 3, 149 Hortiamine isolation, 3, 149... 

The reduction of isocoumarin with LAH results in ring opening and the formation of 2-(2 -hydroxymethylphenyl)acetaldehyde (184). Cyclization to the isochromene occurs on boiling in acetic anhydride (Scheme 33) (58CB2636, 65CB3279). The isochromene (186) is obtained directly from the reduction of the dihydronaphthocoumarin (185 equation 5) (56JCS4535). 

Carboxybenzyl aryl ketones are formed together with the isocoumarin when homophthalic anhydride (isochroman-l,3-dione) is used to acylate aromatic molecules under Friedel-Crafts conditions (51JOC1064) and the 7-methoxy derivative behaves in a similar fashion (66JIC615). Some care in the choice of Lewis acid is necessary in view of the formation of the tropone derivative (504) in the acylation of hydroquinone (Scheme 181) (55JCS2244). 

Artemidinal 4<5 can be readily synthesised from homophthalic anhydride (vide infra). Its syntheses from 3-methyl dihydroisocoumarin and 3-methyI isocoumarin are given below... 

Homophthalic anhydrides are valuable synthons for the synthesis of isocoumarins, isoquinolones and particularly for several berbine alkaloids. 

Artemidinal 46, the naturally occurring 3-formyl isocoumarin has been synthesised in good yield, which was then converted to the biologically active isocoumarin-3-carboxylic acid 55 The natural isocoutnarin 56 was also synthesised from the parent homophthalic anhydride as shown below... 

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]. 

In a basic medium, acid reacts with acetyl chloride to give isocoumarins instead of the expected mixed anhydrides. 

The formation of oxetanes by photochemical (2 + 2)-cycloaddition of carbonyl compounds, such as aldehydes, ketones, and quinones, with carbon-carbon double bonds has been reported for various heterocyclic compounds. Maleic anhydride,142 isocoumarin (and its derivatives),143,144 benzol 61 thiophene 1,1-dioxide,144 l,3-dihydroimidazol-2-ones,131,132... 

The decarbonylative addition of (thio)phthalic anhydrides to alkynes for the preparation of valuable (thio)isocoumarins is another application of nickel(O) catalysts for the formation of Ar-C(sp ) bonds (Scheme 22.14) [23a, b]. When the reaction is applied to thiophthalic anhydrides, benzothiophenes or thiochromanones can be prepared selectively in place of thioisocoumarins, depending on the reaction conditions employed [23h]. In related reactions, the nickel-catalyzed... 

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). 

Phthalic anhydrides can be reacted with various internal alkynes to give isocoumarins 41 on catalysis of Ni(COD)2 and co-catalysis of ZnCl2 and PMes [50] ... 

In this decarbonylative cycloaddition process, Ni(0) is thought to be responsible for CO elimination. Unsymmetrical substrates mostly lead to mixtures of regioisomeric isocoumarins terminal alkynes do not react due to their rapid Ni-induced oligomerization. Derivatives of maleic anhydride give rise to 2-pyrones. 

A convenient and efficient route to isocoumarins has been described starting from readily available substituted indan-l-ones, which are first converted to the enol form with trifluoroacetic anhydride, then cleaved with ozone. Isocoumarin-4-carboxylic acid is easily prepared from homophthalic acid by addition of Vilsmeier reagent followed by hydrolysis. 

Kaiser, P., and J. Schnehenburger Acyl Derivatives of Methylene Active Dicarbonyl Compounds Part 12. 3-Substituted Isocoumarins from 4-Acylhomphthalic Anhydrides. Z. Naturforsch. 25B, 1190 (1970). 

Tirodkar, R.B., and R.N. Usgaonkar Isocoumarins. New Findings about the Condensation of Homophthalic Anhydride with Benzoic Anhydride and Benzyl Chloride. New Synthesis for Some 3-Phenylisocoumarins. Current Sci. (India) 41, 701 (1972). 

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