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

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The hydroformylation of α,β‑unsaturated esters represents a highly atom‐economical route towards β‑aldehydes with the 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, the regioselective hydroformylation of methyl 4‑chlorocinnamate to the desired β‑aldehyde was investigated with a particular focus on the identification of parameters with a significant effect on the regioselectivity and selectivity to the β‑aldehyde amongst all products. The reaction time, solvent, and catalyst loading were initially screened followed by a systematic screening using design of experiments (DoE). The reaction output was analyzed in terms of pressure, temperature and the CO/H2 composition with an unmodified Rh catalyst revealing that while either regioselectivity or overall selectivity (termed selectivity) can attain high values, neither parameter can simultaneously reach optimal levels. As predicted by the model, the experimental results under two different conditions demonstrated excellent regioselectivity (96%) with medium selectivity (57%) and a high selectivity (78 %) with good regioselectivity (93%). Expansion of substrate scope revealed a significant influence of the substituents and thus the electronic effect on the regioselectivity and selectivity.