Thermal Cycloisomerization of Putative Allenylpyridines for the Synthesis of Isoquinoline Derivatives

Abstract

A cascade (cyclo)isomerization/elimination process produces novel isoquinoline derivatives of potential interest for pharmaceutical, biomedical, and energy-related research. Mechanistic experiments support a putative allenylpyridine (reminiscent of the Garratt-Braverman cyclization) as a key intermediate in the cascade process.

Reactions Involving Tryptamines and δ‐Allenyl Aldehydes: Competition between Pictet‐Spengler Reaction and Cyclization to 1‐Aminotetralins

“…Shortly after this report, Dudley reported a similar cyclization from alkynylpyridines bearing a vinyl sulfide, leading to isoquinoline derivatives . The same kind of intermediate (an allenylpyridine in this case) was invoked.…”

Synthesis of Isoquinolinones via Regioselective Palladium-Catalyzed C–H Activation/Annulation

“…Next, common solvents, such as THF, DMF, and 1,2-dichloroethane, were screened. Toluene proved to be the best choice, while the reactions in other solvents were less effective (ClCH 2 CH 2 Cl) or totally ineffective (DMF, THF) (entries [15][16][17].…”

“…Traditionally ortho-difunctionalized benzene starting materials are required for the construction of the heterocylic ring system [16,17]. A more general and efficient approach involves annulation of mono-functionalized arene with conventional synthetic methods, such as rearrangement [17,18], Fridel-Crafts reaction and ortho-lithiation, etc.…”

Optimizing Amine‐Mediated Alkyne–Allene Isomerization to Improve Benzannulation Cascades: Synergy between Theory and Experiments

“…Spectroscopic data were identical to the reported data from the literature. [1] Computational Details: To gain deeper insight into the origin of observed selectivities, we have evaluated the relative thermodynamic stabilities using the meta-hybrid M06-2X functional. The M06-2X functional has demonstrated good thermodynamic trends for organic reactions.…”

“…We recently reported the tandem cycloisomerization/elimination reaction outlined in Scheme 1 for producing substituted isoquinolines. [1] The scope of the process was reasonably broad, and the methodology produced several novel isoquinoline structures. However, there were some obvious practical drawbacks to the reported conditions.…”