MPhos Ligands & Catalysts

Merck has recently developed a series of highly tunable unsymmetrical Ferrocene ligands, MPhos and their corresponding Palladium (Pd) complexes (Figure 1), by incorporating a bulky di(1-adamantyl)phosphino motif on the ferrocene backbone. This new class of ligands and catalysts are very versatile for many types of C_sp2-C_sp3 (aryl/heteroaryl – alkyl) couplings, i.e. Murahashi−Feringa (Li), Kumada−Corriu (Mg), Negishi (Zn) and Suzuki−Miyaura (B), with broad substrate scope including many “drug-like” molecules, excellent functional group tolerance and branched/linear selectivity.¹ The high tunability of the ferrocene back-bone gives the opportunity to fine-tune the ligand/catalyst structure for different kinds of challenging nucleophiles and electrophiles.

Applications on C_sp2-C_sp3 couplings 

With relatively low catalyst loading, i.e. 1 mol%, (MPhos)PdCl₂ has been demonstrated on the strong ability to effect many kinds of C_sp2-C_sp3 cross-couplings under mild conditions (examples in Scheme 1). Substrates (Aryl halides, electrophiles) with both electron donating and electron withdrawing, as well as steric hindered and/or heterocyclic aryl halides, all worked very nicely with good to excellent isolated yields. Alkyl nucleophiles, i.e. primary alkyl-, secondary alkyl-, cyclic alkyl-, also gave very good isolated yields and minimum isomerization. Sequential C_sp2-C_sp3 coupling of the substrates containing both Cl and Br groups has also been examined and proved to be successful, e.g. 5a, 87% and 5b, 91% from 5a, using our (MPhos)PdCl₂ catalyst system.

Reaction Conditions: ^aKumada−Corriu conditions (Mg): Ar-X (0.8 mmol), RMgX (2.0 equiv.), catalyst (1 mol%), THF, room temperature or 50^oC. Negishi conditions (Zn): Ar-X (0.8 mmol), RZnX (2.0 equiv.), catalyst (1 mol%), THF, room temperature or 50^oC. Suzuki–Miyaura conditions (B): Ar-X (0.8 mmol), RB(OH)₂ (2.0 equiv.), catalyst (1 mol%), K₃PO₄ (3 equiv.), Toluene/H₂O (10/1), 100^oC. Murahashi-Feringa conditions (Li): Ar-X (0.8 mmol), RLi (1.2 equiv., diluted with Toluene to 0.2 M), catalyst (1 mol%), Toluene, room temperature. Slow addition using syringe pump for 2 hours. ^bCatalyst: (tBuMPhos)PdCl₂. ^cCatalyst: (PhMPhos)PdCl₂. ^dReaction temperature: 50^oC. ^eGC yield with branch/linear ratio in parathesis. Branch/linear ratio was determined by GC.

Application of C_sp2-C_sp3 couplings on “drug-like” molecules

Late-stage functionalization on small molecule drugs, i.e. deuterium labelled drugs, especially CD₃ based molecules, and drug molecules with cyclopropane fragment, are prominent in pharmaceuticals (Scheme 2). In this regard, C_sp2-C_sp3 couplings using (MPhos)PdCl₂ as the catalyst was applied on grafting various “alkyl fragments” onto the “drug-like” molecules, i.e. “Chemistry Informer Libraries” developed by Merck & Co to mimic “late stage functionalization” for various cross-coupling chemistries of much more complex drug-like molecules, and proved to be very successful (examples in Scheme 3).

Example for Drug (Drug Candidate) Molecules Containing CD₃ or Cyclopropyl Fragment

Our C_sp2-C_sp3 Coupling Technology on "Chemistry Informer Library" Molecules