Regioselective Hydroformylation of α,β‐Unsaturated Esters: Impact of Reaction Parameters & Reaction Optimization

• Published in: European journal of organic chemistry Vol. 28; no. 19
• Main Authors: Bork, Hannah, Gröger, Harald
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 27.05.2025
• Subjects: Aldehydes; Catalysts; Design of Experiments; Design optimization; Esters; Hydroformylation; Optimization; Parameter identification; Phosphines; Regioselectivity; Rhodium
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202401116

The hydroformylation of α,β‐unsaturated esters represents a highly atom‐economical route towards β‐aldehydes with potential application as precursors for derivatization to pharmaceuticals such as (R)‐Baclofen or Pregabalin. Methyl 4‐chlorocinnamate as an α,β‐unsaturated ester has been rarely studied in hydroformylation, particularly with regard to a parameter screening for reaction optimization. In this work, regioselective hydroformylation of methyl 4‐chlorocinnamate to the desired β‐aldehyde utilizing a phosphine‐free Rh catalyst was investigated with a focus on identification of parameters with a significant effect on regioselectivity and selectivity to the β‐aldehyde amongst all products. Initially, reaction time, solvent, and catalyst loading were screened, followed by a reaction optimization using design of experiments (DoE). The reaction output was analyzed in relation to pressure, temperature and CO/H2 composition revealing that while either regioselectivity or overall selectivity (termed selectivity) can attain high values, none of the conditions leads to optimal levels of both regioselectivity and selectivity. As predicted by the model, the experimental results under two different conditions demonstrated excellent regioselectivity (96 %) with medium selectivity (57 %) and high selectivity (78 %) with good regioselectivity (93 %). Expansion of the substrate scope to substituted methyl cinnamate derivatives showed significant influence of the substituents and, thus, their electronic effects on regioselectivity and selectivity. The hydroformylation of methyl 4‐chlorocinnamate exhibited either high values for regioselectivity (96 %) or selectivity (78 %) for the β‐aldehyde 2 a depending on pressure, CO/H2 composition and temperature in a design of experiments approach. Expanding the substrate scope gave insights into the structure‐activity relationship revealing a significant electronic influence of the substituent on regioselectivity and selectivity for the β‐aldehyde.