Synthesis of Isoquinolines. IV.¹ 4-Benzylisoquinolines

Synthesis and Mechanism of Action Studies of a Series of Norindenoisoquinoline Topoisomerase I Poisons Reveal an Inhibitor with a Flipped Orientation in the Ternary DNA−Enzyme−Inhibitor Complex As Determined by X-ray Crystallographic Analysis

“…Then a bimolecular reaction with a benzaldehyde derivative occurs followed by a second critical cyclization. Compounds such as 4 , which do not require a second cyclization, have been prepared successfully using the Bobbitt conditions. − These arise from the bimolecular reaction of the aminoacetal-derived intermediates with benzaldehydes.…”

“…Such hydroxyl derivatives are unstable products that have been isolated before when the reaction was run at low (room) temperature . Loss of methanol from intermediate 39 results in the formation of the 1,2-dihydroisoquinoline 40 , an unstable compound that is considered to be an intermediate in the modified Pomeranz−Fritsch reactions. ,, The first cyclization does not depend on the presence of the nitrogen atom in the 2 position. Precedents exist when the nitrogen atom was either acylated, tosylated (the Jackson modification), or altogether absent from the molecule, and yet the first step proceeded successfully for phenyl rings activated by electron-donating substituents.…”

“…Compounds such as 4, which do not require a second cyclization, have been prepared successfully using the Bobbitt conditions. [11][12][13] These arise from the bimolecular reaction of the aminoacetal-derived intermediates with benzaldehydes.…”

“…The first cyclization begins with the elimination of methanol from the protonated intermediate 16, followed by the attack of the aromatic ring on the resulting cation 37. This first step is the same as in the Pomeranz-Fritsch isoquinoline synthesis as well as in its improved versions such as the Bobbitt 13 or Jackson modifications. 19 In the traditional Pomeranz-Fritsch synthesis the presence of the protonated imine group results in partial deactivation of the phenyl ring, 17 an effect that was overcome in the later versions such as in the Bobbitt reaction by using the corresponding amine, which is more stable to hydrolysis.…”

Untersuchungen zur Benzylierung von Tetrahydroisochinolinen mit Benzaldehyd bzw. substituierten Benzaldehyden (Rügheimer‐Burrows‐Reaktion)

“…2-Formylbenzoesaure ist es uns gelungen, 59% 4-Benzylisochinolin (2) bzw. 54% 4-(2-Carboxybenzy1)-isochinolin (7)…”