4- -3-isochromanon

Simple cyclobutanes do not readily undergo such reactions, but cyclobutenes do. Ben-zocyclobutene derivatives tend to open to give extremely reactive dienes, namely ortho-c]uin(xlimethanes (examples of syntheses see on p. 280, 281, and 297). Benzocyclobutenes and related compounds are obtained by high-temperature elimination reactions of bicyclic benzene derivatives such as 3-isochromanone (C.W. Spangler, 1973, 1976, 1977), or more conveniently in the laboratory, by Diels-Alder reactions (R.P. Thummel, 1974) or by cycliza-tions of silylated acetylenes with 1,5-hexadiynes in the presence of (cyclopentadienyl)dicarbo-nylcobalt (W.G, Aalbersberg, 1975 R.P. Thummel, 1980). 

Benzoxepin-4-carbaldehyde, dihydro-from chromones, 3, 713 Benzoxepin-4(3H)-one from isochromanone, 3, 726 [l]Benzoxepino[3,4-d]selenazoles synthesis, 6, 345 Benzoxepins... 

The parent, unsubstituted isochromanone has been caused to react with a variety of aromatic amines to prepare Ar-substituted 1,4-dihydro-3(2.ff)-isoquinolones,4 and with amines to give amides.5 The 6,7-methylenedioxy-3-isochromanone was an intermediate in the synthesis of protopine and its allied alkaloids,6 and for the synthesis of the berberine ring system.7 The 6-methoxy analog was prepared as a potential intermediate in a camptothecin synthesis8 and 8-methoxy-4,5,6,7-tetramethyl-3-isochromanonc was an intermediate in the synthesis of sclerin.9 The compound herein described was the basis of a facile synthesis of ( l )-xylopmins,10 and its reaction with hydrazine has been reported.11... 

Heteroatoms can also participate in the ring expansion reaction mentioned above. For example, a hydroxyl methoxyallenylphthalan gave rise to a 4-isochromanone derivative. A hydroxymethoxyallenylisoindolinone afforded an isoquinolinedione derivative efficiently (Scheme 16.23) [27, 28]. 

These cycloadditions with o-quinodimethanes provide a broad variety of useful fullerene functionalizations, since o-quinodimethanes can be prepared using several routes and the resulting cycloadducts are thermally stable [42], There exist several alternatives to the iodide-induced bromine 1,4-elimination of 1,2-bis (bromomethyl)-benzenes [44-47]. o-Quinodimethanes have been prepared by thermolysis of 3-isochromanone (42) [43], benzocyclobutenes (43) [48-50], isobenzothiophene 2,2-dioxides (44) [42] and sultines [51,52] or by photolysis of o-alkylphenones such as 45 [53-55] and could be added to Cjq in good yields (Scheme 4.7). Indene, thermally rearranged to isoindene, also adds to Cjq in similar fashion to quinodimethanes [56]. 

Information about the electronic structure of the 4,5-dimethoxy-o-quinodimethane adduct 46 in the solid state, prepared from 6,7-dimethoxy-3-isochromanone 42 (Rj = R4 = H R2 = R3 = OMe), comes from ESCA measurements [43]. In accord with the crystal structure analysis [43, 58], this cycloadduct, which contains the electron-rich dimethoxyphenyl moiety, shows an intermolecular donor-acceptor interaction, in particular, of the methoxy oxygen to the unit. 

Ion-exchange resins 55, 3 Iron, tricarbonyldiene complex, 57, 16 Iron pentacarbonyl, 57, 108,58, 61 Isobutyl fluoride, 57, 73 3-ISOCHROMANONE.6.7-D1METHOXY-, 55,45... 

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. 

The compounds covered in this section include dihydropyranones, tetrahydropyranones and their benzologues (dihydrocoumarins, chromanones and isochromanones). The area of greatest interest is undoubtedly the chromanones because of their relationship to a number of natural products and presumably also because of their ease of formation, stability and value as precursors of other heterocycles. Tetrahydropyran-2-ones comprise one of those nebulous areas of heterocyclic chemistry and usually feature in text books as 5-lactones under derivatives of hydroxy acids. 

The three isomers which are discussed in this section are isochroman-l-one or 3,4-dihydroisocoumarin (617), isochroman-3-one (618) and isochroman-4-one (619). None of them enjoy an extensive chemistry although a small number of natural products contain an isochromanone nucleus. 

The acid has been formed by the reduction of 2-carboxyphenylacetaldehyde, itself available from indene by ozonolysis (57JA3165). This is one of the most convenient methods of synthesis of isochroman-l-one, which is obtained in a 70% overall yield from indene (Scheme 236), and has been used in the synthesis of isochromanones with specific deuterium labels <8ljcs(Pl)l685). 

Vinylbenzoic acids on cyclization yield either isochroman-l-ones or phthalides or a mixture of both types. The direction of ring closure is influenced by both steric and electronic factors (62AC(R)1070). The presence of an a-substituent in the vinylbenzoic acid (621 R = Ph) leads to phthalides, whereas only isochromanones result when no such substituent is present (621 R = H Scheme 238). Ring closure presumably involves attack by the carbonyl group at the centre of lowest electron density. Thus, 2-(l-methylethenyl)benzoic acid yields the phthalide, but 2-(2-methylpropenyl)benzoic acid gives the isochroman-l-one on halolac-tonization. 

Intermolecular acylation of 3,4-dimethoxyphenylacetic acid occurs in polyphosphoric acid, leading to 2-(3,4-dimethoxyphenylacetyl)-4,5-dimethoxyphenylacetic acid (622). Cyclization to the isochromanone takes place when the keto acid is heated in decalin (Scheme 240) (72JHC853). 

The dilithio derivative of N-methyl-o-toluamide reacts with aromatic aldehydes and ketones to give hydroxyamides. Thermal cyclization affords 3-phenylisochroman-l-ones (64JOC3514). Spiroannelated isochromanones result when the organolithium compound reacts with fluorenone or alicyclic ketones. 

A convenient synthesis of isochroman-3-one is based on the reaction of phenylacetic acids with formalin and concentrated hydrochloric acid (760S(55)45>. An indication of the value of the isochromanone as a synthetic intermediate is given in this procedure. 

Bromophenyl)ethanol undergoes a palladium-catalyzed carbonylation which results in the formation of isochroman-l-one (79H(12)92l). It is considered that the reaction involves formation of an aryl-palladium complex (624) through insertion of the zerovalent palladium complex (623) into the aryl halide. Insertion of carbon monoxide followed by reductive elimination of the metal as a complex species leads to the isochromanone (Scheme 242). 

An alternative approach utilizes an intramolecular Perkin reaction on the dicarboxylic acid (626), which gives a mixture of the isochromanone and its enol acetate (627). Alkaline... 

Acylation of the keto acid (637) leads to the isobenzopyrylium salt (638) (77CHE1183). However, the isobenzopyrylium salt (639), a potential intermediate for the synthesis of analogues of berberine alkaloids, results from the formylation of the substituted ketone or the isochromanone (640) using dichloromethyl butyl ether (Scheme 251) (81CHE221). A second product, the 5-oxoniachrysene (641), is formed and this compound may also be obtained by reaction of the isobenzopyrylium salt with phosphorus pentachloride and then with triethylamine. The intermediacy of a cyclic vinyl ether is proposed. 

Keto esters also react with salicylaldehyde to yield fused pyrylium salts. For instance ethyl 2-oxocyclohexanecarboxylate affords the tetrahydroxanthylium salt (645), whilst the isochromanone derivative (646) yields the tetracyclic molecule (647), which possesses the skeleton of the anthocyanidin, peltogynidine, isolated from the heartwood of Peltogyne porphyrocardia (Scheme 253) (58JCS3174). 

It should be noted that such a disturbance of aromaticity, on thermolysis, was detected for isochromanone 233 (84T4383), which may be considered as a reduced form of 3-hydroxy-benzo[c]pyrylium salt 52... 

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