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HomeCross-CouplingYlide-functionalized Phosphines (YPhos)

Ylide-functionalized Phosphines (YPhos)

Coupling Reactions Under Mild Conditions

Professor Viktoria Gessner and coworkers from the Ruhr-University Bochum have developed a class of ylide-substituted phosphines (YPhos) which contain a bulky ylide-substituent directly bound at the phosphorus atom.[1] These ligands are especially electron-rich and thus allow for palladium catalyzed coupling reactions at remarkably mild reaction conditions. They enable the conversion of often challenging aryl chlorides in good yield with short reaction times. For example, keyPhos™ (913294) and joYPhos™ (912042) perform excellently in the Buchwald-Hartwig aminations at room temperature. JoYPhos™ also readily converts aryl halides (including chlorides) with organolithium, Grignard and zinc reagents. The strongest donor trYPhos™ (913030) is best suited for challenging alpha-arylations.

A diagram displaying three chemical structures labeled as keYPhos (913294), trYPhos (913030), and joYPhos (912042). Each structure features a phosphine group with various substituents, including a cyano group (Cy3P), a methyl group (Me), and a phenyl group (Ph) in the case of joYPhos. The structures indicate different configurations of the phosphine ligands.

Key Advantages of YPhos Ligands

  • Facile coupling of aryl halides, especially aryl chlorides
  • Mild reaction conditions
  • High activity in C-N and C-C cross coupling reactions
  • Coupling of organolithium, magnesium and zinc reagents

Representative Applications of YPhos Ligands

keYPhos™ with a methyl group in the ylide-backbone is a valuable ligand for the palladium catalyzed coupling of aryl chlorides with primary and secondary alkyl and aryl amines at room temperature. The ligand performs well with common palladium sources such as Pd2(dba)3, Pd(OAc)2, [Pd(allyl)Cl]2 or [Pd(cinamyl)Cl]2.[2,3]

A reaction scheme illustrating the coupling of an aryl chloride (ArCl) with an amine (H2N-R') using 0.25 mol% Pd2(dba)3 and 0.5 mol% keYPhos in THF at room temperature for 1 hour, with 1.5 equivalents of KOtBu. Below the reaction, various products are shown, each with their respective yields indicated as percentages. The structures include different substituents on the aromatic rings, such as methyl (Me), fluoro (F), trifluoromethyl (F3C), methoxy (MeO), and tert-butyl (tBu). The yields range from 56% to 99%.

JoYPhos™ featuring a phenyl group at the ylide substituent is also an excellent ligand for Buchwald-Hartwig aminations[4,5] as well as for C-C coupling reactions. It allows the previously unprecedented direct coupling of alkyllithium reagents with aryl chloride.[6]

A reaction scheme showing the coupling of an aryl chloride (ArCl) with an amine (H2N-R') using 0.5 mol% of either Pd(cinnamyl)Cl2 or Pd(indenylyl)Cl2 and 0.5 mol% of joYPhos in THF at room temperature with KOtBu. The upper section displays various products with yields ranging from 86% to 96%. The lower section features a second reaction using 0.5 mol% Pd2(dba)3 or Pd(indenylyl)Cl2 in toluene at room temperature for 1 hour. Several products are shown, each labeled with their respective yields, including variations with different substituents like ethyl (Et), methoxy (O), and trifluoromethyl (CF3), with yields ranging from 66% to 94%.

In this series, trYPhos™ is the most electron-rich YPhos ligand and was found to be active for alpha-arylation of aliphatic cyclic ketones.[7]  

A reaction scheme depicting the coupling of an aryl chloride (Ar-Cl) with a compound containing a carbonyl group (R) using 1 mol% Pd2(dba)3 and 2 mol% trYPhos in THF at room temperature for 16 hours, with 1.5 equivalents of NaOtBu. Below the reaction, various products are illustrated with their respective yields indicated as percentages. The structures include different substituents such as alkyl and nitrogen groups, showing yields ranging from 12% to 89%.
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References

1.
Scherpf T, Schwarz C, Scharf LT, Zur J, Helbig A, Gessner VH. 2018. Ylide-Functionalized Phosphines: Strong Donor Ligands for Homogeneous Catalysis. Angew. Chem. Int. Ed.. 57(39):12859-12864. https://doi.org/10.1002/anie.201805372
2.
Weber P, Scherpf T, Rodstein I, Lichte D, Scharf LT, Gooßen LJ, Gessner VH. 2019. A Highly Active Ylide-Functionalized Phosphine for Palladium-Catalyzed Aminations of Aryl Chlorides. Angew. Chem. Int. Ed.. 58(10):3203-3207. https://doi.org/10.1002/anie.201810696
3.
Scharf LT, Rodstein I, Schmidt M, Scherpf T, Gessner VH. 2020. Unraveling the High Activity of Ylide-Functionalized Phosphines in Palladium-Catalyzed Amination Reactions: A Comparative Study with CyJohnPhos and PtBu3. ACS Catal.. 10(2):999-1009. https://doi.org/10.1021/acscatal.9b04666
4.
Tappen J, Rodstein I, McGuire K, Großjohann A, Löffler J, Scherpf T, Gessner VH. 2020. Palladium Complexes Based on Ylide-Functionalized Phosphines (YPhos): Broadly Applicable High-Performance Precatalysts for the Amination of Aryl Halides at Room Temperature. Chem. Eur. J.. 26(19):4281-4288. https://doi.org/10.1002/chem.201905535
5.
Rodstein I, Prendes DS, Wickert L, Paaßen M, Gessner VH. 2020. Selective Pd-Catalyzed Monoarylation of Small Primary Alkyl Amines through Backbone-Modification in Ylide-Functionalized Phosphines (YPhos). J. Org. Chem.. 85(22):14674-14683. https://doi.org/10.1021/acs.joc.0c01771
6.
Scherpf T, Steinert H, Großjohann A, Dilchert K, Tappen J, Rodstein I, Gessner VH. 2020. Efficient Pd-Catalyzed Direct Coupling of Aryl Chlorides with Alkyllithium Reagents. Angew. Chem. Int. Ed.. 59(46):20596-20603. https://doi.org/10.1002/anie.202008866
7.
Hu X, Lichte D, Rodstein I, Weber P, Seitz A, Scherpf T, Gessner VH, Gooßen LJ. 2019. Ylide-Functionalized Phosphine (YPhos)-Palladium Catalysts: Selective Monoarylation of Alkyl Ketones with Aryl Chlorides. Org. Lett.. 21(18):7558-7562. https://doi.org/10.1021/acs.orglett.9b02830
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