Generation of Tertiary and Quaternary Stereocentres through Palladium‐Catalysed Intramolecular Heck‐Type Reactions for the Stereocontrolled Synthesis of Pyrrolo[1,2‐b]isoquinolines

Abstract

The generation of quaternary and tertiary stereocentres at C‐10 of the pyrroloisoquinoline skeleton through intramolecular Mizoroki–Heck reactions of 2‐alkenyl‐substituted pyrroles and pyrrolidines has been studied. The cyclizations proceeded in moderate to good yields (up to 81 %), but with low enantioselectivity when chiral phosphanes such as (R)‐BINAP were used as ligands. However, enantiomerically pure 10‐substituted pyrrolo[1,2‐b]isoquinolines were efficiently obtained by a diastereoselective approach using chiral nonracemic pyrrolidines as substrates, generating a tertiary stereocentre.

Carbopalladation/Suzuki Coupling Cascade for the Generation of Quaternary Centers: Access to Pyrrolo[1,2-b]isoquinolines

“…Thus, 3ba and 3bc were obtained only in low yields. This type of reactivity has been shown to be competitive in Heck reactions with related substrates, using Pd/phosphane catalytic systems, especially when a cationic mechanism is favored. , In this case, formation of pyrrolo­[2,1- a ]­isoindoles was not observed when the alkene is substituted with an alkyl group, and 3cc was obtained from 1c , (R 2 = Et) with similar yield. The reaction could also be extended to benzylpyrroles with different substitution patterns on the aromatic ring ( 1d – h ), obtaining the corresponding pyrroloisoquinolines with moderate to good yields (Table ).…”

“…In this context, we have reported an enantioselective Heck–Heck cascade using related substrates, showing that it is possible to control the enantioselectivity of the carbopalladation step using ( R )-BINAP . However, it was not possible to induce stereocontrol using ( R )-BINAP or other chiral nonracemic phosphane ligands for the generation of quaternary stereocenters through Heck reactions on related alkenylpyrroles . Once again, we selected the reaction of 1a with 2c as a model for optimization of the reaction conditions.…”

“…However, the overall yields obtained are moderate in many cases, as the competitive 7endo cyclization/elimination leading to 5 could not be completely suppressed under these conditions. Although we had previously shown that the formation of quaternary stereocenters via Heck reaction was possible on related substrates in the presence of phosphane ligands, 27 the use of Pd(PPh 3 ) 4 on the coupling of 1a with 2a led to a nonselective reaction (Table 1, entry 11). With these precedents, we carried out a further optimization of the reaction conditions, studying the effect of a phosphane ligand, using the reaction of 1a with boronic acid 2c (Table 4), which had given a moderate yield of 3ac under the phosphane-free reaction conditions (60%, Table 2, entry 3).…”

“…7 However, it was not possible to induce stereocontrol using (R)-BINAP or other chiral nonracemic phosphane ligands for the generation of quaternary stereocenters through Heck reactions on related alkenylpyrroles. 27 Once again, we selected the reaction of 1a with 2c as a model for optimization of the reaction conditions. Although different ligands, solvents, and reaction conditions have been tested, only modest enantioselectivities [up to 44% enantiomeric excess (ee)] have been obtained so far.…”

Facile synthesis of pyrrolo[2,1-a]isoquinolines by domino reaction of 1-aroyl-3,4-dihydroisoquinolines with conjugated ketones, nitroalkenes and nitriles

“…The synthetic methods for the preparation of pyrrolo[2,1a]isoquinolines are mainly based on two strategies: annulation of the pyrrole ring to the isoquinoline moiety or annulation of the isoquinoline core to the pyrrole or lactam cycle. When the formation of the pyrrolo[2,1-a]isoquinoline moiety proceeds via annulation on the pyrrole core, it is necessary to use palladium-catalyzed reactions, in particular the Mizoroki-Heck coupling reaction [19,20]. For N-alkylated pyrroles, the intramolecular Heck reaction using Pd(PPh 3 ) 4 as a catalyst with sodium acetate as a base or Pd(PPh 3 ) 2 Cl 2 and Ph 3 P as a catalyst with potassium carbonate as a base allows to obtain pyrroloisoquinolines with good yields [21,22].…”