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Buchwald G6 Precatalysts: Oxidative Addition Complexes

The efficient generation of L–Pd(0) active species is critical to the development of efficient and robust cross-coupling reactions.1 Therefore, precatalysts with a pre-associated ligand to the metal center typically affords higher activity, shorter reaction time, and lower catalyst loading than a similar catalyst system which requires in-situ coordination of a ligand to the metal center.

Buchwald and coworkers have developed a family of Pd(0) precatalysts based on Pd(II) palladacycles with N,C-chelating ligands (Figure 1). This family of precatalysts is comprised of five generations (G1 through G5), which are distinguished by structural variations to the N,C-chelating ligand and/or the anion X. Although the activation mode is the same for each precatalyst generation: deprotonation of the nitrogen leads to reductive elimination and generation of L–Pd(0); each generation has unique advantages and disadvantages, which are described in previously published Technology Spotlights.2,3

General breakdown of the main components of the first five generations of Buchwald precatalysts.

Figure 1.General Structures of Buchwald Precatalysts G1 to G5 (L = ligand)

The Buchwald G6 precatalysts are oxidative addition complexes (OACs), which exhibit the same advantages as the previous generations of Buchwald precatalysts: quantitative generation of L–Pd(0),  thermal stability, air stability, moisture stability, ease of handling, and high efficiency (Figure 2).4 Furthermore, G6 Buchwald precatalysts demonstrate several comparative advantages over the previous generations of Buchwald precatalysts.

Distinct Advantages of Buchwald G6 Precatalysts

  • Catalyst activation does not require base and generates innocuous byproducts.
  • OAC precatalysts are “on-cycle” intermediates that typically have higher reactivity and selectivity.
  • Precatalyst synthesis is performed in a single step at room temperature.
  • Versatile and tunable precatalyst design:
    • Each of the three ligand types (X, L, and Ar) can be independently tuned to create a nearly endless number of precatalyst variations
    • Improved solubility, greater stability, increased reactivity, and/or easier purification can be achieved by design or selection of X, L, and Ar
    • Bulky ligands (e.g., tBuBrettPhos, AdBrettPhos, and AlPhos) are easily accommodated by G6 precatalysts
General structure with 3 available catalog examples including two with tBuBrettPhos ligand with differing Ar groups

Figure 2.General Structure and Catalog Examples of Buchwald G6 Precatalysts

Representative Coupling Applications and Reaction Scope

Buchwald G6 precatalysts and other OACs have been applied as effective catalysts for the formation of C–C, C–N, C–O, C–F, and C–S bonds.4-9 Screening and comparison studies of a variety of catalyst systems and precatalysts typically show that OAC precatalysts have superior reactivity, selectivity, reaction scope, and/or yields.

Table 1.Table of Buchwald G6 and Other OAC Precatalysts.

Fluorination of Aryl Bromides4

Reaction scheme showing the fluorination of an aryl bromide using P1 precatalyst from Table 1.

Fluorination of Aryl Triflates4

Reaction scheme showing the fluorination of an aryl triflate using P2 precatalyst from Table 1

Amino Acid Ester Arylation4

Reaction scheme showing the arylation of an amino acid ester using P3 precatalyst from Table 1

Alcohol and Hydroxide Coupling4

Reaction scheme showing alcohol-hydroxide coupling using P3 precatalyst from Table 1

Buchwald-Hartwig Amination of Aniline5

Reaction scheme showing a Buchwald-Hartwig amination of aniline using both P4 and P5 precatalysts from Table 1 and COD(AlPhos-Pd)2

Buchwald-Hartwig Amination6

Reaction scheme showing a Buchwald-Hartwig amination with different conditions using P6, P7, and P8 precatalysts from Table 1

Buchwald-Hartwig Amination7

Reaction scheme showing a Buchwald-Hartwig amination using P9 precatalyst from Table 1 with different X groups including I, OTf, Br, and Cl on different Ar-R1

Suzuki-Miyaura Coupling8

Reaction scheme showing a Suzuki-Miyaura Coupling using P10 precatalyst from Table 1

Aliphatic Thiol Coupling of Hetero(Aryl) Bromides9

Reaction schemes showing aliphatic thiol coupling of hetero(aryl) bromides with either P3 or P11 precatalysts from Table 1
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References

1.
Shaughnessy KH. 2019. Development of Palladium Precatalysts that Efficiently Generate LPd(0) Active Species. Isr. J. Chem.. 60(3-4):180-194. https://doi.org/10.1002/ijch.201900067
2.
2011. Technology Spotlight: 2nd Generation Buchwald Precatalysts. [Internet]. Available from: http://www.sigmaaldrich.com/technical-documents/technical-article/chemistry-and-synthesis/cross-coupling/2nd-generation-buchwald-precatalysts
3.
2015. Technology Spotlight: G3 and G4 Buchwald Precatalyst. [Internet]. Available from: https://www.sigmaaldrich.com/technical-documents/technical-article/chemistry-and-synthesis/cross-coupling/g3-and-g4-buchwald-precatalysts
4.
Ingoglia BT, Buchwald SL. 2017. Oxidative Addition Complexes as Precatalysts for Cross-Coupling Reactions Requiring Extremely Bulky Biarylphosphine Ligands. Org. Lett.. 19(11):2853-2856. https://doi.org/10.1021/acs.orglett.7b01082
5.
Dennis JM, White NA, Liu RY, Buchwald SL. 2018. Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use of a Common Soluble Base in C-N Coupling. J. Am. Chem. Soc.. 140(13):4721-4725. https://doi.org/10.1021/jacs.8b01696
6.
Baumgartner LM, Dennis JM, White NA, Buchwald SL, Jensen KF. 2019. Use of a Droplet Platform To Optimize Pd-Catalyzed C-N Coupling Reactions Promoted by Organic Bases. Org. Process Res. Dev.. 23(8):1594-1601. https://doi.org/10.1021/acs.oprd.9b00236
7.
McCann SD, Reichert EC, Arrechea PL, Buchwald SL. 2020. Development of an Aryl Amination Catalyst with Broad Scope Guided by Consideration of Catalyst Stability. J. Am. Chem. Soc.. 142(35):15027-15037. https://doi.org/10.1021/jacs.0c06139
8.
Chen L, Francis H, Carrow BP. 2018. An "On-Cycle" Precatalyst Enables Room-Temperature Polyfluoroarylation Using Sensitive Boronic Acids. ACS Catal.. 8(4):2989-2994. https://doi.org/10.1021/acscatal.8b00341
9.
Xu J, Liu RY, Yeung CS, Buchwald SL. 2019. Monophosphine Ligands Promote Pd-Catalyzed C-S Cross-Coupling Reactions at Room Temperature with Soluble Bases. ACS Catal.. 9(7):6461-6466. https://doi.org/10.1021/acscatal.9b01913
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