Mechanistically Guided One Pot Synthesis of Phosphine‐Phosphite and Its Implication in Asymmetric Hydrogenation

• Published in: European journal of organic chemistry 2022-01, Vol.2022 (2), p.n/a
• Main Authors: Sen, Anirban, Kumar, Rohit, Pandey, Swechchha, Vipin Raj, K., Kumar, Pawan, Vanka, Kumar, Chikkali, Samir H.
• Format: Article
• Language: English
• Subjects: Alkenes; Asymmetric hydrogenation; Asymmetry; Catalysis; Dihydroxyphenylalanine; DOPA synthesis; Enantiomers; Hydrogenation; Ligands; NMR; Nuclear magnetic resonance; Nucleophiles; One pot synthesis; Parkinson's disease; Phosphine-phosphite ligand; Phosphines; Rhodium; Room temperature; Selectivity
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/ejoc.202101447

Although hybrid bidentate ligands are known to yield highly enantioselective products in asymmetric hydrogenation (AH), synthesis of these ligands is an arduous process. Herein, a one pot, atom‐economic synthesis of a hybrid phosphine‐phosphite (L1) is reported. After understanding the reactivity difference between an O‐nucleophile versus C‐nucleophile, one pot synthesis of Senphos (L1) was achieved (72 %). When L1 was treated with [Rh], 31P NMR revealed bidentate coordination to Rh. Senphos, in the presence of rhodium, catalyzes the AH of Methyl‐2‐acetamido‐3‐phenylacrylate and discloses an unprecedented turn over frequency of 2289, along with excellent enantio‐selectivity (92 %). The generality is demonstrated by hydrogenating an array of alkenes. The AH operates under mild conditions of 1–2 bar H2 pressure, at room temperature. The practical relevance of L1 is demonstrated by scaling‐up the reaction to 1 g and by synthesizing DOPA, a drug widely employed for the treatment of Parkinson's disease. Computational insights indicate that the R isomer is preferred by 3.8 kcal/mol over the S isomer. Synthesis of hybrid phosphorus ligands is a multistep, time‐consuming exercise. This limitation has been addressed by meticulous understanding of the process of formation of hybrid ligands and a one pot synthesis of a phosphine‐phosphite ligand (L1) is reported for the first time. L1 coordinates to Rh and catalyzes asymmetric hydrogenation of 15 substrates with a high TOF of 2289 and enantiomeric excess of 92 %.