Non-Proprietary Phosphine Ligands

By: William Sommer, Aldrich ChemFiles 2007, 7.10, 6.

In the pharmaceutical industry, Pd-catalyzed processes have frequently been relied on for carrying out key bond formations. While there are many ligands that efficiently mediate C–C and C–N bond formations, there is still a need for ligands that address the gaps in the current methodologies. To this end, recent work has been reported by several pharmaceutical companies which detail the application of non-proprietary ligands in key C–C and C–N bond-forming reactions.

The Singer group at Pfizer has reported ligands that are efficient in mediating Pd-catalyzed aminations of aryl halides (Table 1).1 Phenylpyrazole ligand, TrippyPhos, has a fairly broad substrate scope for both amines and aryl halides and is effective in many cases with catalyst loadings down to 1 mol % (Scheme 1).

Table 1

Scheme 1

More recent work by the Singer group1b produced the triphenylbipyrazole ligand, BippyPhos, which displayed an even greater scope than TrippyPhos (Table 2). The BippyPhos system was particularly effective with primary amines, which are often susceptible to β-hydride elimination. Table 2 shows several of the aryl halides and amines tested. Pd2(dba)3 was typically used as the palladium source in the amination reaction (Scheme 2). The use of Pd(OAc)2 did not lead to product formation with primary amines. Increasing the catalyst loading to 2 mol % Pd allowed good conversions with 2-chloropyridine.

Table 2

Scheme 2

The Suzuki-Miyaura cross-coupling reaction of heteroaryl halides is of particular interest to the pharmaceutical industry since many biologically active compounds are accessed through this methodology. Currently, a need for efficient coupling of fivemembered heteroaryl halides or six-membered heteroaryl chlorides bearing heteroatom substituents with boronic acids exists. Catalysts are thought to form inactive complexes with many of these types of substrates, and thus, they typically require high catalyst loadings in order to achieve good yields.

The Guram group at Amgen has recently communicated the development of an air-stable palladium complex, (A-taPhos)2PdCl2, for Suzuki-Miyaura cross-coupling reactions (Table 3).2 The catalyst was very effective at coupling a wide variety of substrates with arylboronic acids, including amino-substituted 2-chloropyridines and five-membered heteroaryl halides (Scheme 3). High product yields and turnover numbers (up to 10,000 TON) are typically observed.

Table 3

Scheme 3

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  1. (a) Singer, R. A. et al. Tetrahedron Lett. 2006, 47, 3727. (b) Singer, R. A. et al. Synthesis 2003, 1727.
  2. Guram, A. S. et al. Org. Lett. 2006, 8, 1787.

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