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Synthesis 2003(11): 1727-1731
DOI: 10.1055/s-2003-40881
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Robert A. Singer*, Stephane Caron, Ruth E. McDermott, Patrice Arpin, Nga M. Do
Chemical Research and Development, Central Research Division, Pfizer Inc., Eastern Point Road, P.O. Box 8118 Groton, Connecticut 06340-8118, USA
Fax: +1(860)4415540; e-Mail: robert_a_singer@groton.pfizer.com;
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Publication History

Received 14 May 2003
Publication Date:
25 July 2003 (online)

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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:
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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).