Isoquinolinium salt cycloaddition

The most recent extension of the 4 + 2 cycloaddition to aromatic quaternary salts has been carried out with isoquinolinium salts (42), in effect, dispensing with ring A of the acridizinium ion. Although there was an earlier claim that the addition of an ynamine to 2-methyl-isoquinolinium iodide led to a 2 1 adduct, the assigned structure... 

Beifuss U, Herde A, Ledderhose S (1996) J Chem Soc Chem Comm 1213. For mechanistic studies on cycloadditions of isoquinolinium salts see Gupta RB, Franck RW (1987) J Am Chem Soc 109 5393... 

Heterocyclic systems with one heteroatom. Condensed heteroaromatic cations are reactive in [2 + 4] cycloaddition reactions with inverse electron demand. For instance, 2-benzopyrylium salts 403 react with vinyl ethyl ether to afford naphthalene derivatives 405 in good yields via initial adducts 404 <1990KGS315>. Similar transformations (Bradsher reaction) are also known for isoquinolinium salts <1984CC761>. 

The use of 2,4-dinitn>i enyl aromatic quatemaiy salts prepared directly from the parent isoquinoline compound and 2,4-dinitrophenyl bromide or chloride enhances the electron-deficient nature of the iso-quinolinium salts, accelerates the rate of their [4 2] cycloaddition reacticms with electron-rich alkenes, and has permitted the use of isoquinolinium salts previously regarded as unmanageable. The application of these observations in the total syntheses of methylamottianamide and 14-epicoiynoline is summarized in Scheme 26. - ... 

Phospholes bearing additional heteroatoms other than phosphorus have also been the subject of further study. Cycloaddition reactions of heterophospholes have received a theoretical treatment and these reactions have also been reviewed. Improvements in the synthesis of fused 1,3-azaphospholes via the reactions of N-alkyl-isoquinolinium salts with phosphorus trichloride have been described and their reactivity towards cycloaddition studied. New fused... 

JCS(P1)249) have established that cycloaddition of isoquinolinium salts with electron-rich alkenes is virtually 100% regiospecific and, for easily polarizable, unsymmetrical alkenes, highly stereospecific. 

The tendency for relatively easy nucleophilic addition to the pyridinium ring in isoquinolinium salts is echoed in the cycloaddition (shown above) of electron-rich dienophiles such as ethoxyethene, which is reversed on refluxing in acetonitrile. "... 

Inverse demand cycloaddition of isoquinolinium salt 1 to chiral enol ethers, acetals and ortho esters 2 gives diastereomeric tetralins 3 and 4 with the diastereoselectivity depending on the nature of the dienophile and on the chiral auxiliary1. The primary tricyclic adduct solvolyzes to the tetralinaldehyde acetal in acidified alcohol. 

The participation of aromatic quaternary salts, including the acridizi-nium and isoquinolinium salts, in inverse electron demand [4+ + 2] cycloadditions with electron-rich, nucleophilic dienophiles as well as typical, electron-deficient dienophiles represent well-defined examples of... 

The [4+ + 2] cycloadditions proceed in a regiospecific manner with the nucleophilic carbon of the electron-rich dienophile attaching to the expected electrophilic site of the aromatic quaternary salt (e.g., C-6 for acridizinium salts, C-l for isoquinolinium salts) and the rate of reaction (ketene aminals, ketene acetals, enamines > cyclopentadiene > 2,3-di-methylbutadiene > styrene > dihydropyran > 2-butene > maleic anhydride) does increase as the nucleophilic character of the dienophile is enhanced [Eq. (66)].l48e 149... 

Two experimental techniques have improved the observed participation of simple aromatic quaternary salts in [4+ + 2] cycloadditions. The addition of hydroquinone, which forms a stabilized 1 2 complex with the isoquinolinium salts, to the reaction mixture accelerates the rate of observed isoquinolinium salt [4+ + 2] cycloaddition.148b In addition, the use of 2,4-dinitrophenyl aromatic quaternary salts, prepared from the parent base and 2,4-dinitrophenyl bromide or chloride, accentuates the electron-deficient character of the quaternary salt and accelerates their participation in [4+ + 2] cycloadditions with electron-rich dienophiles.152 These observations of Falck and co-workers have proved useful for promoting the [4+ + 2] cycloaddition of isoquinolinium systems previously regarded unmanageable. The application of these observations in the total syntheses of 14-epicorynoline (16) and methyl arrnothanamide (17) have been detailed [Eq. (67)],152... 

Isoquinolinium salts represent 2-aza-1,3-butadienes activated by A-arylation. Highly stereoselective cycloadditions with chiral enolethers have been reported leading to enantiomerically pure functionalized tetralines in high yields. 

Initially, the Bradsher cycloaddition reaction was used to gain greater understanding of the Diels-Alder reaction. More recently it has found utility in the constuction of carbon frameworks that provided novel entries into the synthesis of natural products. For example, the Bradsher cycloaddition reaction has been reported on the use of isoquinolinium salts for the stereocontrolled synthesis of substituted tetralins. Reaction of... 

Sammes and co-workers reported studies on an intramolecular variation on the Bradsher cycloaddition reaction. However, the Franck group,publishing on the construction of benz[c,c/]indole frameworks, reported an alternate structure for the product of their reaction. Intramolecular cycloaddition of the isoquinolinium salt 43 initially afforded adduct 44. This intermediate rapidly converted to 45, which gave 48 after acetylation. The Sammes group had assigned 47 to the final compound but the Franck group, based on NMR and crystal structure data from a related system, proposed the alternate structure 48. Thus this chemistry provided... 

C for 24 h gave 30% of the bridged tropane (255) with the isoquinolinium salt (256), cycloaddition gave the unstable (257) which was hydrolysed with dilute aqueous base to the perhydroquinoline (258). A simplified and reproducible procedure for the synthesis of the 6,7-benzomorphan nucleus has been described by... 

Isoquinolinium 369 and [2,7]naphthyridin-2-ium 371 salts have also been used for the preparation of 2,3,8,8a-tetrahydro-57/-oxazolo[3,2-tf]pyridine derivatives (Scheme 98) addition of Grignard reagents to 369 is followed by a spontaneous cyclization to 370 <1998JOC1767> while an asymmetric version of the Bradsher cycloaddition between 371 and chiral enol ether 372 gives 373 in good yield and selectivities <1996TL7019>. 

Several 3-hydroxy-2//-pyrazolo[4,3-c]isoquinolinium inner salts undergo reaction with dipolarophiles in 1,3-cycloaddition reactions <03JOC8700>. The best yields with the cleanest mixture of compounds is when R = PMB and dimethyl acetylenedicarboxylate (DMAD) is the dipolarophile. 

A select set of cationic heteroaromatic azadienes including acridizi-nium, isoquinolinium, quinolinium, and isoxazolium salts have been shown to participate as useful 47t components of [4+ + 2] cycloadditions. These systems have been discussed in Chapter 9, Section 10. 

The thermally induced intramolecular [4+ + 2] cycloadditions of iso-quinolinium salts bearing an unactivated alkenyl side chain have been investigated and shown to proceed with addition across the isolated double bond and the 1,4 positions of the isoquinolinium system to produce tetracyclic adducts [Eq. (71)].155... 

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