The Isoquinolones

In the case of 489, the product 490 cyclizes to the isoquinolone 491, and the amide substituent is a required part of the target molecule" . However, it frequently occurs that the amide substituent is not required in the final product, and the acid-sensitive alkenyl substituent of 492 has been used as a solution to the problem of cleaving a C—N bond in the product (Scheme 193) ° °. Weinreb-type amides 493 can also be laterally lithiated, and the methoxy group removed from 494 by TiCU" . Hydrazones similarly can be laterally lithiated and oxidatively deprotected. ... 

On studying the hydrolysis ofp-tolylcarbonitrile the highest activity was observed for the isoquinolone homo-complex [100% conversion after 20 h, maxTOF = 20 (mol amide)/(mol catalyst) h [. The hetero-complex was less active (90% conversion. 

Ylide (364) has been obtained by heating (363) in pyridine. Isoquinoline yields a stable ylide upon reaction with ethoxycarbonylcarbene (70TL941) and the relative rates of reaction of ethoxy-carbonylcarbene with pyridine, quinoline, and acridine have been studied (88JOC4374). However, the isoquinolone (365) undergoes attack at the isoquinoline double bond to give (366). 

Quinoline and isoquinoline with MP in ether yield benzoindolizines,382 on exact analogy with the pyridine series. Isoquinoline with but-l-yn-3-one in acetonitrile give the isoquinolone 330, doubtless due to the presence of traces of water, but in ether an uncommon reaction giving an oxazine (331) is observed.299 In the presence of proton donors, isoquinoline behaves like pyridine with MP241,382 or but-l-yn-3-one,299 but the anion only reacts at position 1, giving products such as 332. The anion adds at position 4 in a few similar reactions involving quinolines.241,299... 

Several isoquinolones have also been examined (17). The carbonyl group at C-l in the isoquinolones, noroxohydrastinine (17) (7), corydaldine (18)... 

Thalistyline, a monoquaternary salt from the quaternary fraction of the chloroform-soluble alkaloids of Thalictrum longistylum and T. podocarpum, has strong hypotensive action at 1.0 mg kg-1 in normotensive dogs and rabbits. It has the structure (46), and both the related bis-tertiary base and bis-quaternary salt have been isolated in small quantities from the same plants.61 The structure of (46) was determined by its fission with sodium in liquid ammonia to form the bases (47) and (48), and by its oxidation to the isoquinolone (49) and the acid (50) when it reacted with potassium permanganate.61... 

The outcome of the photocyclization of the enamide 266 (Ar = / -MeOC6H4) depends on conditions irradiation under argon in methanolic sodium methoxide gives the dihydroisoquinolone 267 if air is present the isoquinolone 268 is formed. Under reducing conditions, i.e. in the presence of sodium borohydride, the tetrahydroisoquinolone 269 is obtained136. 

Narciclasic aldehyde (16 R = CHO), a key degradation product in the structural elucidation of the alkaloid narciclasine, has been synthesized via the isoquinolone... 

R = H). Bromination gave the 4-bromo-derivative which afforded (16 R = CN) and (16 R = CHO) by successive cyanization and Raney nickel reduction/ The reported synthesis of the isoquinolone alkaloid thalactamine from 2,3.4-trimethoxyphenethylamine is unexceptional but an alternative synthesis involving bromination of 6,7-dimethoxy-2-methyl-l(2//)-isoquinolone followed by methan-nolysis in methanolic sodium methoxide is somewhat surprising/ A number of new methods for preparing AT-substituted l(2//)-isoquinolones include reaction of homophthalic acids with Vilsmeier reagentand borohydride reduction of homophthalimides. The effect of various substituents on the fluorescence of such isoquinolones has been studied. 

Simple isoquinolines are not found in the Menispermaceae of South America. The isoquinolone thalifoline (1) was identified from Abuta pahni [32], Benzyltetrahydroisoquinolines are the biogenetic precursors for aporphines, proaporphines, and oxoaporphines. Yet the only such compound isolated from South American Menispermaceae is (+) coclaurine (2) obtained from Sciadotema eichleriam [52] and Caryomene olivascens [37-38]. The chemistry of simple isoquinolines [65], isoquinolones [66], and benzyltetrahydroisoquinolines [67] have been reviewed. 

Homophthalic acid surprisingly yields an isoquinoline upon Vilsmeier formylation, apparently by rearrangement and cyclization of the side-chain formylated intermediate (Scheme 25). This intermediate may be isolated at low temperatures.64 In a related manner the isoquinolone (87) has been synthesized from the toluic acid (86).64a... 

In addition to directed aromatic lithiation reactions, lithiation of aromatic methyl groups can also furnish the isoquinolones. Examples of these are the following ... 

Nagao et al. reported that the ring expansion of the hydroxy methoxyallenylisoindolinones 222 occurred in the presence of a Pd(0) catalyst to give the isoquinolones 223 in high yields (Scheme 72).146 Oxidative addition of an O—H bond of 222 to palladium ) gives the hydridopalladium species 224, and subsequent intramolecular hydropalladation of... 

In an extension of earlier work on pyridones and quinolones, the photo-initiated addition of aUcenes to the isoquinolone (77) has been carried out a subsequent reaction of the adduct with a Lewis acid gave the corresponding cyclobutene (Scheme 50). ... 

No biogenetic details of simple isoquinolone were elucidated, but it is likely to yield the isoquinolones from the oxidation of benzylisoquinolines. There are a few isoquinolones in the Annonaceae. Only three simple isoquinolones, doryphomine (A-7), cherianoine (A-8) and thalifoline (A-9), were isolated from the stems of A cherimola [14,15]. 

The benzoyidihydroindole shown formed by the reaction of 3,4-methylenedioxybenzoyl chloride and 7-bromo-5-nitrodihydroindole in pyridine at 100°C upon reaction at 155°C in dimethyl sulphoxide containing potassium carbonate and BTAC was cyclised to the isoquinolone derivatives (B) and (C) (1 1) in 27% yield. This ring closure was considered to proceed by way of a radical intermediate, (ref. 100) and constituted a route to the alkaloid ungeremine (A) after three more steps on compound (B) consisting of the conversions, -NO2... 

Irradiation of the adduct (178) obtained from benzyne and a mesoionic thiazol-4-one in benzene-methanol solution resulted in extrusion of sulphur and formation of the isoquinolone (179).108 This is in complete contrast with the... 

Benzyne (from anthranilic acid) cycloadds to mesoionic pyrimidines 320 the adducts 321 were obtained in 42-62% yields. Examples include R = Ph or CH2Ph, R = Ph or CH3 and R = alkyl or CH2Ph. Thermal decomposition of 321 (70-210°C depending on substitution) gave near-quantitative yields of isoquinolones 322. If the initial benzyne addition is conducted at elevated temperatures and if phenyl isocyanate elimination from the initial adduct 321 occurs at relatively low temperatures, then benzyne cycloadducts of the isoquinolones may also be formed (cf additions to 312). 

Intramolecular cyclization of the unsaturated amide (153) is effected by treatment with palladium(ii) acetate and triphenylphosphine reduction of the resulting mixture of geometrically isomeric esters (154) gives the isoquinolone (155) (Scheme 63)/ ... 

The base-catalysed reaction of the nitrophthalimide (156) with methyl isocyanoacetate gives the oxazole (157), which is converted into the isoquinolone... 

A patent for the preparation of quaternary salts of papaverine from C5, Ce, and Cg halides been published. N-Alkyl-papaverinium salts have been found to undergo oxidation by oxygen either photolytically or in the presence of cuprous chloride, to give the isoquinolones (25). The corresponding dihydro-papaverinium salts (26), with oxygen and cuprous chloride, do not suffer fission, and oxidation of the N-methyl compound (26 R = Me) in this way, followed by reduction of the product with sodium borohydride, affords a- and -hydroxy-laudanosines 21) The n.m.r. spectrum of laudanosine has been studied in detail. 

The isoquinolone doryanine (4) has been isolated from Doryhora sassafras, and its structure has been confirmed by synthesis from methylenedioxyhomophthalic anhydride."... 

The structure of magnolamine has been revised to (45) following spectroscopic studies and the oxidation of magnolamine triethyl ether to the isoquinolone (46) and the dicarboxylic acid (47). ... 

It is known that tetrahydrobenzylisoquinolines can be cleaved to isoquinolones using potassium permanganate. A method has now been developed for the oxidation of isoquinolinium salts. Taking papaverine methiodide as an example, this salt is first treated with aqueous alkali to supply the enamine 5. Treatment of a benzene solution of the enamine with oxygen in the presence of cuprous chloride provides the isoquinolone 6 in 0% yield. (For the oxidation of bisbenzylisoquinolines to isoquinolones, see Secs. 5.4 and 6.1.)... 

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