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Ylide-functionalized Phosphines (YPhos)

Professor Viktoria Gessner and coworkers from the Ruhr-University Bochum have developed a class of ylide-substituted phosphine ligands (YPhos) that contain a bulky ylide-substituent directly bound at the phosphorus atom.1 These electron-rich phosphines facilitate 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, keYPhosTM and joYPhosTM 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, trYPhosTM , is best suited for challenging alpha-arylations.

Black and white image of three phosphine structures with ylide groups labeled keYPhos™, trYPhos™, and joYPhos™, each with distinct phosphine ligands.

Figure 1.Three ylide-substituted phosphines: keYPhos™, trYPhos™, and joYPhos™.

Key Advantages of YPhos Ligands for Palladium-Catalyzed Coupling Reactions

  • 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
Black and white image displays a reaction scheme using keYPhos™ and Pd₂dba₃ for C–N coupling, with 20 diverse aryl amine products and their yields.

Figure 2.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

Black and white image shows two joYPhos™-catalyzed reactions—one for amination, one for C–C coupling—each with products and yields from various substrates.

Figure 3.JoYPhos™ featuring a phenyl group at the ylide substituent is also an excellent ligand for Buchwald-Hartwig aminations4,5 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 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%.

Figure 4.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

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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