Alternative Biarylphosphines for Use in the Palladium-Catalyzed Amination of Aryl Halides

Abstract

Two families of biarylphosphine ligands were prepared for use in the Pd-catalyzed amination reaction. The first series investigated was derived from N-phenylpyrroles, and the second, was derived from N-phenylpyrazoles. While the pyrrole ligands were not as general in substrate scope, one of the readily prepared pyrazole ligands (R = t-Bu) was found to have a fairly broad substrate scope.

Key words

palladium - catalysis - ligands - biaryls - aminations

References

• For reviews on the Pd-catalyzed amination reaction, see:
• 1a Yang BH. Buchwald SL. J. Organomet. Chem.  1999,  576:  125 
• 1b Wolfe JP. Wagaw S. Marcoux J.-F. Buchwald SL. Acc. Chem. Res.  1998,  31:  805 
• 1c Hartwig JF. Angew. Chem., Int. Ed.  1998,  37:  2046 
• 2 Lednicer D. Strategies for Organic Drug Synthesis and Design   Wiley; New York: 1998. 
• 3a Wolfe JP. Tomori H. Sadighi JP. Yin J. Buchwald SL. J. Org. Chem.  2000,  65:  1158 
• 3b Old DW. Wolfe JP. Buchwald SL. J. Am. Chem. Soc.  1998,  120:  9722 
• 4 For the typical preparation of the Buchwald group’s biaryl ligands via a metal-catalyzed cross-coupling or via addition of an arylmagnesium halide to benzyne, followed by addition of a chlorodialkylphosphine, see: Tomori H. Fox JM. Buchwald SL. J. Org. Chem.  2000,  65:  5334 
• 6 Pyrazoles have been shown to ortho-directed deprotonation of an N-aryl group appended to the pyrazole; for an example, see: Micetich RG. Baker V. Spevak P. Hall TW. Bains BK. Heterocycles  1985,  23:  943 
• 9 Balaban AT. Tetrahedron  1968,  24:  5059 

5

Various alkyllithiums were screened for the halogen-metal exchange, including s-BuLi and none provided significantly improved branching ratios. Organomagnesium derivatives were prepared as well but these had significantly poorer reactivity and required copper salts to obtain product. Ultimately, ligand 2 was used impure since the contaminants were not removed easily by recrystallization and were not considered impediments to the reaction.

7

Reactions in toluene with 3 or 4 and a weak base (such as Cs₂CO₃) turned yellow-green and resulted in poor reaction conversions. Adding t-BuONa led to restarting of the reactions and drove them to completion, suggesting t-BuONa can break aggregation of a Pd complex that is not competent in the catalytic cycle.

8

When carrying out the coupling of morpholine and 4-tert-butylphenylbromide in toluene with 1% Pd catalyst, the reaction only reached 22% conversion, while the same reaction in tert-amyl alcohol reached completion in under 2 h. Use of butan-2-ol accelerated the reaction further, but significant dehalogenation of the aryl bromide was observed (due to β-hydride elimination).