Annulated isoindoles

An intramolecular heteroaryl Heck was the pivotal step in the synthesis of 5-butyl-1-methyl-l//-imidazo[4,5-c]quinolin-4(5//)-one (63), a potent antiasthmatic agent [46], The optimum yield was obtained under Jeffery s ligand-free conditions, echoing Ohta s observation for the intermolecular version. Once again, the Caryi—Caryi bond was constructed at the C(5) position of the imidazole ring. Another intramolecular heteroaryl Heck cyclization of pyrrole and imidazole derivatives was also reported to assemble annulated isoindoles [47]. 

Free-radical reaction of vinyl iodides having dienoate function in the presence of (TMS)3SiH and AIBN in refluxing benzene caused a tandem cyclization reaction to produce (4 - -1) and (4 - - 2) annulated compounds [94]. Reaction (7.83) shows the transformation resulted from a tandem 5-exo, 6-endo cyclization to give the isoindole skeleton where the stereogenic centres were highly controlled, whereas Reaction (7.84) proceeded via a tandem 6-exo, 5-exo cyclization to furnish a (4 -b 1) cycloadduct. 

While both 2- and 3-furylcarbene complexes 99 and 103 gave [fo -annulated benzofurans (100 and 104), only the 2-pyrrolyl carbene complex 105 afforded the aromatic indole skeleton (106). In contrast, annulation of the 2,5-dimethylated 3-pyrrolylcarbene complex 107 occurred at the 4-position to give isoindole quinone 108 after oxidative work-up [82g]. 

In the benzo[/ ]-annulated series the order of aromaticity is similar, as described by the DRE values (kcalmoP ) naphthalene (33.6) > benzo[ ]thiophene (24.8) > indole (23.8) > benzo[ ]furan (20.3) for the dibenzo series, phenan-threne > dibenzothiophene (44.6) > carbazole (40.9) > dibenzofuran (39.9) (Figure 25). Benzo[r]-annulation causes an inversion between NH- and S-heterocycles isoindole (11.6) > benzo[r]thiophene (9.3) > benzo[r]furan (2.4) . 

The completion of the synthesis of aspidospeimidine relied on a protocol introduced by Heathcock [72] for annulating the E-ring to the ABCD-framework of 228. Thus, as shown in Scheme 23, acylation of target compound 242 with a-chloroacetyl chloride followed by a Finkelstein reaction afforded the a-iodoacetamide 243 that upon treatment with silver triflate effected an intramolecular alkylation reaction and the formation of the isoindole-based lactam 244. Finally, reduction of this last compound with hthium aluminium hydride gave the racemic modification of aspidospermidine (228) (32%). 

A wide range of polycyclic pyridoisoindole derivatives can be synthesized by the reaction of arynes with indol-izines and annulated indolizines. Xu and coworkers reported a facile synthesis indolizino[3,4,5-al7]isoindoles 43 by the reaction of arynes with indolizines 41 (Scheme 20) [45]. The reaction was carried out using CsF, in MeCN, at 90 °C,... 

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