Chapter 1
Hydroamination of Alkenes

Alexander L. Reznichenko

Borealis Polymers Oy, PO Box 330, 06101, Porvoo, Finland

Kai C. Hultzsch

University of Vienna, Faculty of Chemistry, Institute of Chemical Catalysis, Währinger Strasse 38, A-1090, Vienna, Austria

Contents

1. Acknowledgment
2. Introduction
3. Mechanism and Stereochemistry
   1. Alkali, Alkaline Earth, and Rare Earth Metals
   2. Group 4 and Group 5 Transition Metals
   3. Late Transition Metals
4. Scope and Limitations
   1. Ethylene and Other Unactivated Alkenes
      1. Intermolecular Hydroamination of C2-C4 Alkenes
      2. Intermolecular Hydroamination of Unactivated Higher Alkenes
      3. Intramolecular Hydroamination of Aminoalkenes
   2. Hydroamination of Vinyl Arenes
      1. Intermolecular Hydroamination of Vinyl Arenes
      2. Intramolecular Hydroamination of Vinyl Arenes
   3. Hydroamination of Conjugated Dienes
      1. Intermolecular Hydroamination of 1,3-Dienes
      2. Intramolecular Hydroamination of Aminodienes
   4. Hydroamination of Allenes
      1. Intermolecular Hydroamination of Allenes
      2. Intramolecular Hydroamination of Aminoallenes
   5. Hydroamination of Strained Alkenes
      1. Hydroamination of Methylenecyclopropanes
      2. Hydroamination of Norbornene
      3. Intramolecular Hydroamination of Strained Alkenes
   6. Enantioselective Hydroaminations
      1. Enantioselective Intermolecular Hydroamination of Unactivated Alkenes
      2. Enantioselective Intramolecular Hydroamination of Aminoalkenes
      3. Enantioselective Intermolecular Hydroamination of Vinyl Arenes
      4. Enantioselective Intramolecular Hydroamination Reactions of 1,3-Dienes
      5. Enantioselective Intermolecular Hydroamination of 1,3-Dienes
      6. Enantioselective Intramolecular Hydroamination of Aminodienes
      7. Enantioselective Intramolecular Hydroamination of Aminoallenes
      8. Enantioselective Hydroamination of Norbornene
   7. Hydroamination/Carbocyclization
5. Applications to Synthesis
6. Comparison with Other Methods
   1. Hydroelementation/Amination
      1. Catalytic Hydroboration/Amination
      2. Hydrozirconation/Iodination of Aminoalkenes
   2. Cope-Type Hydroamination
   3. Aminomercuration/Demercuration
   4. Radical-Transfer Hydroamination
7. Experimental Conditions
8. Experimental Procedures
   1. 1. (R)-N-Benzylheptan-2-amine (Lanthanide-Catalyzed Asymmetric Intermolecular Hydroamination of an Aliphatic Terminal Alkene)
      2. 5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) (Organolanthanide-Catalyzed Intramolecular Hydroamination of an Aminoalkene)
      3. O-Methylmetazocine (Lithium Amide-Catalyzed Intramolecular Hydroamination of an Aminoalkene)
      4. (S)-(+)-1-Phenylpent-4-enylamine (Kinetic Resolution of a Racemic Aminoalkene])
      5. 1-Phenyl-2,3-dihydroindole (Potassium-Catalyzed Addition of Aniline to 2-Chlorostyrene with Subsequent Cyclization)
      6. (S)-N-Phenyl-N-[1-{4-(trifluoromethyl)phenyl}ethyl]amine (Palladium-Catalyzed Asymmetric Intermolecular Hydroamination of a Vinyl Arene)
      7. 1-Phenylmethyl-4-(2-phenethyl)piperazine (Lithium-Catalyzed Intermolecular Hydroamination of Styrene)
      8. 3-Fluoro-6,6,9-trimethyl-5,6-dihydrophenanthridine (Brønsted Acid-Catalyzed Intramolecular Hydroamination)
      9. (E)-N,N-Diethyl-3,7-dimethyl-2,6-octadien-1-amine (N,N-Diethylgeranylamine) (Lithium-Catalyzed Addition of a Secondary Amine to a Diene)
      10. 8-Phenylmethyl-8-azabicyclo[3.2.1]oct-2-ene (Palladium-Catalyzed Intermolecular Transannular Hydroamination of a Cyclic Triene)
      11. 1-Benzyloxycarbonyl-2-[(E)-prop-1-enyl]piperidine (Organolanthanide-Catalyzed Intramolecular Hydroamination of an Aminodiene with Subsequent Protection)
      12. (3S,5R,8S)-3-(1-Heptyl)-5-methylpyrrolizidine ((+)-Xenovenine) (Organolanthanide-Catalyzed Stereoselective Intramolecular Hydroamination of an Aminoallene)
      13. 2-(4-Fluorophenyl)-6-methyl-2,3,4,5-tetrahydropyridine (Group 4 Metal-Catalyzed Intramolecular Hydroamination of an Aminoallene)
      14. 2-(Cyclohexylidenemethyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine (Gold-Catalyzed Asymmetric Intramolecular Hydroamination of a Protected Aminoallene)
      15. 2-Methyl-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindole (Lanthanide-Catalyzed Sequential Hydroamination/Carbocyclization)
9. Abbreviations Used in the Tabular Survey
   1. Chart 1. Catalysts and Ligands Used in the Tables
   2. Table 1A. Hydroamination of Simple Alkenes
   3. Table 1B. Hydroamination of Vinyl Arenes
   4. Table 1C. Hydroamination of 1,3-Dienes
   5. Table 1D. Hydroamination of Allenes
   6. Table 1E. Hydroamination of Strained Alkenes
   7. Table 2A. Hydroamination/Cyclization of Aminoalkenes
   8. Table 2B. Hydroamination/Cyclization of Vinyl Arenes
   9. Table 2C. Hydroamination/Cyclization of Aminodienes
   10. Table 2D. Hydroamination/Cyclization of Aminoallenes
   11. Table 2E. Hydroamination/Cyclization of Strained Aminoalkenes
   12. Table 3A. Enantioselective Hydroamination of Simple Alkenes
   13. Table 3B. Enantioselective Hydroamination of Vinyl Arenes
   14. Table 3C. Enantioselective Hydroamination of 1,3-Dienes
   15. Table 3D. Enantioselective Hydroamination of Allenes
   16. Table 3E. Enantioselective Hydroamination of Strained Alkenes
   17. Table 4A. Enantioselective Hydroamination/Cyclization of Aminoalkenes
   18. Table 4B. Enantioselective Intramolecular Hydroamination of Vinyl Arenes
   19. Table 4C. Enantioselective Hydroamination/Cyclization of Aminodienes
   20. Table 4D. Enantioselective Hydroamination/Cyclization of Aminoallenes
   21. Table 5. Hydroamination/Carbocyclization of Aminoalkenes
10. References

Acknowledgment

Generous financial support by the National Science Foundation through a NSF CAREER Award (CHE 0956021) and the ACS Petroleum Research Fund (PRF #49109-ND1) is gratefully acknowledged.

Introduction*

The development of efficient synthetic procedures for establishing carbon-nitrogen bonds has received significant attention over the last one and a half centuries, due to the importance of nitrogen-containing compounds in biological systems and pharmaceutical applications.1, 2 Although a large number of carbon-nitrogen bond-forming processes have been devised during this period, the hydroamination of alkenes represents, in principle, one of the most attractive and efficient routes. The catalytic hydroamination of alkenes, allenes, and dienes leads to amines, imines, and enamines. (Scheme 1).3-8 The reactions may also be performed in an intramolecular fashion.

Scheme 1

The simplicity, high atom economy, and the use of readily available and inexpensive starting materials make the hydroamination reaction a highly desirable process for the synthesis of bulk and fine chemicals, as well as pharmaceuticals. Although only sporadic studies had emerged until 20 years ago, the field has drastically evolved over the last decade.7 The hydroamination reaction provides direct, potentially waste-free access to alkyl amines and nitrogen-containing heterocycles, in the simplest cases starting from alkenes and ammonia.

Hydroamination in the context of this review article is defined as the addition of HNR2 across a non-activated, unsaturated carbon-carbon multiple bond. This review focuses on the hydroamination reaction of simple, non-activated alkenes. The addition of amines to slightly activated alkenes, such as vinyl arenes, 1,3-dienes, strained alkenes (norbornene derivatives, methylenecyclopropanes) and allenes is closely related and will be covered. Reactions of alkynes, however, are not covered due to volume size limitations.9-14 Aza-Michael reactions involving the addition of an N-H fragment across the conjugated or otherwise activated double bond of a Michael acceptor often proceed smoothly even in the absence of a catalyst and are therefore not covered herein.15, 16 A number of reviews have appeared on various aspects of hydroamination of alkenes.3-8, 16-41

The scope of amine types includes ammonia, primary and secondary aliphatic and aromatic amines, azoles, and hydrazines. Although N-protected amines, such as ureas, carboxamides, and sulfonamides do not strictly belong to the amine compound class, the addition of these compounds to unsaturated compounds has seen significant progress, especially through the use of metal-free and late transition metal based catalysts. Thus, N-protected ammonia and primary amines are also included in this chapter.

A large variety of catalyst systems are available, ranging from alkali,20 alkaline earth,39, 40 rare...