Binuclear Pd(I)–Pd(I) Catalysis Assisted by Iodide Ligands for Selective Hydroformylation of Alkenes and Alkynes

Abstract

Since its discovery in 1938, hydroformylation has been thoroughly investigated and broadly applied in industry (>10 7 metric ton yearly). However, the ability to precisely control its regioselectivity with well-established Rh-or Co-catalysts has thus far proven elusive, thereby limiting access to many synthetically valuable aldehydes. Pd-catalysts represent an appealing alternative, yet their use remains sparse due to undesired side-processes. Here, we report a highly selective and exceptionally active catalyst system that is driven by a novel activation strategy and features a unique Pd(I)− Pd(I) mechanism, involving an iodide-assisted binuclear step to release the product. This method enables β-selective hydroformylation of a large range of alkenes and alkynes, including sensitive starting materials. Its utility is demonstrated in the synthesis of antiobesity drug Rimonabant and anti-HIV agent PNU-32945. In a broader context, the new mechanistic understanding enables the development of other carbonylation reactions of high importance to chemical industry.

Palladium‐Catalyzed Hydroformylation of Alkenes and Alkynes

“…As mentioned in the previous section, our group developed a selective iodide-assisted palladium-based protocol for the hydroformylation of alkenes in the absence of any acidic cocatalyst. [48] Gratifyingly, numerous unsymmetric internal alkynes were also compatible with this catalytic protocol, furnishing α,β-unsaturated aldehydes in high yields, (E)-stereoselectivities, and β-regioselectivities. Remarkably, the acid-free conditions of the reaction provide an extended substrate scope that illustrates the excellent functional group tolerance, including moieties such as N-Boc, amide, ester, ether, etc.…”

“…As mentioned in the previous section, our group developed a selective iodide‐assisted palladium‐based protocol for the hydroformylation of alkenes in the absence of any acidic co‐catalyst [48] . Gratifyingly, numerous unsymmetric internal alkynes were also compatible with this catalytic protocol, furnishing α,β‐unsaturated aldehydes in high yields, ( E )‐stereoselectivities, and β‐regioselectivities.…”

“…Studies towards improv- ing the catalytic efficiency would be valuable in order to enable lowering the rather high loading of the catalyst (5 mol % Pd and 10 mol % ligand). [48] Copyright (2020), with permission from American Chemical Society. Figure 6.…”

“…The synthetic utility of this method was also shown by successfully incorporating this transformation into a modular synthesis of polysubstituted bisarylpyrazoles (Scheme 13). [48] However, the protocol proved unsuitable for hydroformylation of terminal alkynes.…”

“…Binuclear mechanistic proposal of the Pd-catalyzed hydroformylation of alkenes assisted by iodide anion. Reproduced from ref.,[48] Copyright (2020), with permission from American Chemical Society.…”