Stereoselective Synthesis
of Saturated Heterocycles via Palladium-Catalyzed Alkene Carboetherification
and Carboamination Reactions

John P. Wolfe

doi:10.1055/s-0028-1087339

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Synlett 2008(19): 2913-2937
DOI: 10.1055/s-0028-1087339

ACCOUNT

Stereoselective Synthesis of Saturated Heterocycles via Palladium-Catalyzed Alkene Carboetherification and Carboamination Reactions

John P. Wolfe*
Department of Chemistry, University of Michigan, 930 N. University Avenue, Ann Arbor, MI 48109-1055, USA
Fax: +1(734)6153790; e-Mail: jpwolfe@umich.edu;

Further Information

Publication History

Received 9 June 2008
Publication Date:
12 November 2008 (online)

Abstract
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Abstract

The development of palladium-catalyzed carboetherification and carboamination reactions between aryl or alkenyl halides and alkenes bearing pendant heteroatoms is described. These transformations effect the stereoselective construction of useful heterocycles, such as tetrahydrofurans, pyrrolidines, imidazolidin-2-ones, isoxazolidines, and piperazines. The scope, limitations, and applications of these reactions are presented, and current stereochemical models are described. The mechanism of the product formation, which involves an unusual intramolecular syn-insertion of an alkene into a palladium-heteroatom bond, is also discussed in detail.

1 Introduction

2 Palladium-Catalyzed Synthesis of Tetrahydrofurans from γ-Hydroxyalkenes and Aryl or Alkenyl Halides

2.1 Mechanism of the Tetrahydrofuran Formation

3 Palladium-Catalyzed Synthesis of Pyrrolidines from γ-Aminoalkenes and Aryl or Alkenyl Halides

3.1 Tandem Palladium-Catalyzed N-Arylation-Carboamination Reactions of Primary Amines

3.2 Palladium-Catalyzed Carboamination Reactions of N-Protected γ-Aminoalkenes

3.3 Mechanism of the Palladium-Catalyzed Carboamination Reactions: Surprises and Utility

3.4 Application of the Palladium-Catalyzed Carboamination of N-Protected γ-Aminoalkenes to the Stereoselective Synthesis of (+)-Preussin and Its Analogues

4 Synthesis of Imidazolidin-2-ones via Palladium-Catalyzed Carboamination Reactions

5 Synthesis of Isoxazolidines via Palladium-Catalyzed Carboetherification Reactions

6 Synthesis of Piperazines via Palladium-Catalyzed Carboamination Reactions

7 Summary and Future Outlook

Key words

alkenes - catalysis - heterocycles - palladium - stereoselective synthesis

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21

Rossi, M. A.; Wolfe, J. P. unpublished results.

23

Definitions of ligands (see also Figure [³] ):
Dpe-phos = bis[2-(diphenylphosphino)phenyl] ether; Xantphos = 9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene; NiXantphos = 4,6-bis(diphenylphosphino)-phenoxazine; dppe = 1,2-bis(diphenylphosphino)ethane;
dppp = 1,3-bis(diphenylphosphino)propane; dppb = 1,4-bis-(diphenylphosphino)butane.

28

A small amount of a regioisomer analogous to 18 was also formed in this reaction.

31

Lira, R.; Wolfe, J. P. unpublished results.

37

We have recently developed conditions to effect the Pd-catalyzed carboamination of N-Boc- and N-acyl-protected substrates bearing 1,1- and 1,2-disubstituted alkenes: Bertrand, M. B.; Neukom, J. D.; Wolfe, J. P. J. Org. Chem. 2008, in press; DOI: 10.1021/jo801631v.

82

Surprisingly, the stereochemical outcome of the piperazine-forming reactions is opposite to that predicted by the allylic strain model, similar to that shown in Scheme [¹¹] . Our current working hypothesis suggests that the piperazine-forming reactions proceed through a transition state in which the N-aryl group is rotated to minimize allylic strain interactions, and the structure around the cyclizing nitrogen atom is pyramidal. Investigations into this hypothesis are currently underway.