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MPhos Ligands & Catalysts – Introduction, Advantages, and Applications

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 Csp2-Csp3 (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.

MPhos ligands and catalysts are a series of highly tunable unsymmetrical Ferrocene ligands.

Figure 1.MPhos and its corresponding (MPhos)PdCl2 complexes, and 2) single crystal structures of (PhMPhos)PdCl2 and (tBuMPhos)PdCl2

Applications on Csp2-Csp3 couplings 

With relatively low catalyst loading, i.e. 1 mol%, (MPhos)PdCl2 has been demonstrated on the strong ability to effect many kinds of Csp2-Csp3 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 Csp2-Csp3 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.

MPhos catalysts are very versatile for many types of couplings, Murahashi−Feringa (Li), Kumada−Corriu (Mg), Negishi (Zn) and Suzuki−Miyaura (B).

Scheme 1.Examples of Csp2-Csp3 coupling using (MPhos)PdCl2 as the catalyst under Kumada-Corriu (Mg), Negishi (Zn), Suzuki–Miyaura (B) and Murahashi-Feringa (Li) conditions.a

Reaction Conditions: aKumada−Corriu conditions (Mg): Ar-X (0.8 mmol), RMgX (2.0 equiv.), catalyst (1 mol%), THF, room temperature or 50oC. Negishi conditions (Zn): Ar-X (0.8 mmol), RZnX (2.0 equiv.), catalyst (1 mol%), THF, room temperature or 50oC. 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), 100oC. 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: 50oC. eGC yield with branch/linear ratio in parathesis. Branch/linear ratio was determined by GC.

Application of Csp2-Csp3 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, Csp2-Csp3 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

Examples of “drug-like” molecules containing CD3 or cyclopropyl fragments.

Scheme 2.Examples of drug molecules containing CD3 or cyclopropane fragment.

Our Csp2-Csp3 Coupling Technology on "Chemistry Informer Library" Molecules

(MPhos)PdCl2 is very successful at grafting “alkyl fragments” onto “drug-like” molecules.

Scheme 3.Csp2-Csp3 couplings on “Chemistry Informer Library” molecules

Materials
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References

1.
Xu G, Gao P, Colacot TJ. 2022. Tunable Unsymmetrical Ferrocene Ligands Bearing a Bulky Di-1-adamantylphosphino Motif for Many Kinds of Csp2-Csp3 Couplings. ACS Catal.. 12(9):5123-5135. https://doi.org/10.1021/acscatal.2c00352
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