Synthesis of Isocoumarins

An alternative approach to the synthesis of isocoumarins which probably proceeds through the intermediacy of 2-carboxybenzyl ketones is based on the oxidative cleavage of indan-1-ones (76JCS(P1)1438). Although ozonolysis of the silyl enol ether (505) leads to the 2-hydroxy-2-methylindan-l-one (506), periodate oxidation of which gives the isocoumarin, a more convenient and direct route involves ozonolysis of the enol trifluoroacetate (Scheme 182). This synthesis is especially attractive for the preparation of isotopically labelled isocoumarins, since the precursors of the indanones, arylpropanoic acids or acrylophenones, are readily available bearing labels at specific sites. 

Oxidation of dihydroisocoumarins is conveniently achieved through bromination with NBS followed by dehydrohalogenation with triethylamine (62JOC4337, 71T6171). Since the oxidation of isochromans to isochromanones proceeds readily using chromium trioxide, this method effectively constitutes a synthesis of isocoumarins from isochromans. 

Pyridopyrimidines and pyrimidines fused with five- or six-membered heterocycles can be prepared via the ring closure of intermediate ethynylpyrimidines, which are themselves obtained by the Pd-catalyzed cross-coupling of halopyrimidines with alkynic compounds (Scheme 34). ° ""° o-Alkynylanilines such as (51), which are made by Pd-catalyzed coupling reactions of alkynes with o-haloaniline precursors, are easily cyclized to the indoles in the presence of base (Scheme 35). " " Similar meth( s can be employed in the synthesis of isocoumarins," thienopyridines," furopy-ridines" and the marine alkaloid asptamine." ... 

An interesting synthesis of isocoumarins uses the n-allyl nickel halides and n-olefin palladium complex, while another involves an aromatic nucleophilic substitution by the carbanion derived from acetone... 

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

Pd-catalysed cyclisations also feature in the synthesis of isocoumarins. Outstanding in this context is the cascade carbopalladation in which the pentacyclic compound (17) is formed in 66 % yield from the acyclic precursor (16). The range of examples given enable the course of reactions involving competing Pd-catalysed processes to be predicted (94JA7923). 

Suzuki T, Yamada T, Watanabe K, Katoh T (2005) Mdium-catalyzed oxidative lactonization and intramolecular Tishchenko reaction of 6-ketoaldehydes for the synthesis of isocoumarins and 3,4-dihydroisocoumarins. Bioorg Med Chem Lett 15 2583-2585... 

Synthesis and reactions of isoflavone analogs, 3-hetarylchromones 99KGS3. Synthesis of cyclopenta[ ]pyran skeleton of natural lactones 97T14507. Synthesis of isocoumarins 970PP631. 

In a synthesis of isocoumarins, intermediates 977 are obtained, albeit in modest yields, by carbonylation of pyridones 976 with diphenyl carbonate (DPhC) [686]. 

Scheme 2.158 Copper-catalyzed synthesis of isocoumarins and phthalides.

Reaction Procedure (Scheme 2.158) Synthesis of isocoumarin. 2-Iodo-benzoic acid derivative (2.0 mmol) and CS2CO3 (4.0 mmol) were added to a vial containing anhydrous DMSO (8 mL), followed by addition of the appropriate acetylene derivative (2.2 mmol) and Cul (0.2 mmol). The suspension was stirred for 12 h at 100 °C. After cooling, the mixture was poured into the EtOAc (50 mL) and washed with water (2x25 mL) and brine (2x25 mL), then dried over Na2S04. Evaporation of the solvent under reduced pressure provided the crude product, which was purified by column chromatography (hexane-EtOAc, 20 1) or re-crystallized from hexane to afford the final product. 

Isocoumarins are an important class of heterocyclic scaffolds that exhibit a wide range of biological activities, such as antifungal, antibacterial, and antidiabetic effects. In 2012, several copper-catalyzed procedures for the synthesis of isocoumarins were developed. Xi and co-workers developed an... 

Scheme 3.47 Cu-catal zed synthesis of isocoumarin derivatives from 2-iodobenzoic acids.

Reaction Proceduie (Scheme 3.47) General procedure for the synthesis of isocoumarin 2-iodobenzoic acid derivative (2.0 mmol) and CS2CO3 (1.30 g, 4.0 mmol) were added to a vial containing anhydrous DMSO... 

Scheme 3.48 Pd-catafyzed synthesis of isocoumarins from internal allgines.

The intramolecular versions are especially efficient and very useful. In the following example, even the oxygen atom of a conveniently located enolate plays the role of the nucleophile for the synthesis of isocoumarines ... 

Matsui, M., K. Mori, and Y. Ozawa Synthesis of Isocoumarins II Oospolactone. Agric. Biol. Chem. 30,193 (1966). 

Watanabe, M., M. Sahara, M. Kubo, S. Furkawa, R.J. Billedeau, and V. Snie-KUS Ortho-lithiated Tertiary Benzamides. Chain Extension via f>-Toluamide Anion and General Synthesis of Isocoumarins Including Hydrangenol and Phyllodulcin. J. Organ. Chem. (USA) 49, 742 (1984). 

Although only a few examples have been reported, palladium-catalyzed C—O bond formation has proved useful in the synthesis of isocoumarins. Wang and Shen utilized an intramolecular C—O bond formation in tandem with an intermolecular Stille reaction to produce isocoumarin products such as 66 in excellent yields from gem-dibromovinylarene substrates such as 65 (Scheme 24.37) [129], The Stille reaction was postulated to occur first with the E-alkenyl bromide before the intramolecular C—O bond-forming cyclization and ensuing elimination of methyl bromide. Tadd et al. reported a palladium-catalyzed carbonylative isocoumarin synthesis, beginning with the same a-(o-haloaryl) ketone substrates as those used previously in benzofuran synthesis (Scheme 24.30) [130]. 

In 2007, the Mlura group reported a Rh(III)-catalyzed oxidative coupling of benzoic acids with internal alkynes to the synthesis of isocoumarins via aromatic C-H activation (Scheme 6.24a) [38]. Importantly, the reaction of benzoic acids with alkynes takes place efficiently even with a reduced amount (5mol%) of Cu(0Ac)2-H20 under air (Scheme 6.24b) [5b]. The same group also developed the rhodium-catalyzed coupling of acrylic acids with alkynes to provide corresponding a-pyrone via vinylic C-H bond cleavage (Scheme 6.24c) [5c]. In 2015, Wen and coworkers described a Rh(III)-catalyzed synthesis of... 

Scheme 6.26 Synthesis of isocoumarins from W,W-diethyl-0-benzoylhydroxylamine and alkynes.

A similar route is followed for the synthesis of isocoumarin derivatives from stilbene carboxylic acids (Scheme 7.78) [321]. 

Scheme 7.78 Synthesis of isocoumarins by the cychzation of stilbene carboxylic acids catalyzed by diphenyl diselenide...

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