Organic Reactions

ADVISORY BOARD

John E. Baldwin Michael J. MartinelliPeter Beak Stuart W. McCombieDale L. Boger Jerrold MeinwaldGeorge A. Boswell, Jr. Scott J. MillerAndré B. Charette Larry E. OvermanEngelbert Ciganek Leo A. PaquetteDennis Curran Gary H. PosnerSamuel Danishefsky T. V. RajanBabuHuw M. L. Davies Hans J. ReichJohn Fried James H. RigbyJacquelyn Gervay-Hague William R. RoushHeinz W. Gschwend Scott D. RychnovskyStephen Hanessian Martin SemmelhackRichard F. Heck Charles SihLouis Hegedus Amos B. Smith, IIIRobert C. Kelly Barry M. TrostAndrew S. Kende Milán UskokovicLaura Kiessling James D. WhiteSteven V. Ley Peter WipfJames A. Marshall

FORMER MEMBERS OF THE BOARDNOW DECEASED

Roger Adams Louis F. FieserHomer Adkins Ralph F. HirshmannWerner E. Bachmann Herbert O. HouseA. H. Blatt John R. JohnsonRobert Bittman Robert M. JoyceVirgil Boekelheide Willy LeimgruberTheodore L. Cairns Frank C. McGrewArthur C. Cope Blaine C. McKusickDonald J. Cram Carl NiemannDavid Y. Curtin Harold R. SnyderWilliam G. Dauben Boris Weinstein

Organic ReactionsV O L U M E 88

EDITORIAL BOARDScott E. Denmark, Editor-in-Chief

Jeffrey Aubé Paul J. HergenrotherJin K. Cha Jeffrey S. JohnsonAndré Charette Marisa C. KozlowskiVittorio Farina Gary A. MolanderPaul L. Feldman John MontgomeryDennis G. Hall Steven M. Weinreb

Robert M. Coates, SecretaryUniversity of Illinois at Urbana-Champaign, Urbana, Illinois

Jeffery B. Press, SecretaryPress Consulting Partners, Brewster, New York

Linda S. Press, Editorial Coordinator

Danielle Soenen, Editorial Assistant

Dena Lindsay, Editorial Assistant

Engelbert Ciganek, Editorial Advisor

ASSOCIATE EDITORS

Kai C. HultzschAlexander L. Reznichenko

Copyright © 2016 by Organic Reactions, Inc. All rights reserved.

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10 9 8 7 6 5 4 3 2 1

INTRODUCTION TO THE SERIESROGER ADAMS, 1942

In the course of nearly every program of research in organic chemistry, the inves-tigator finds it necessary to use several of the better-known synthetic reactions. Todiscover the optimum conditions for the application of even the most familiar one to acompound not previously subjected to the reaction often requires an extensive searchof the literature; even then a series of experiments may be necessary. When the resultsof the investigation are published, the synthesis, which may have required months ofwork, is usually described without comment. The background of knowledge andexperience gained in the literature search and experimentation is thus lost to thosewho subsequently have occasion to apply the general method. The student of prepar-ative organic chemistry faces similar difficulties. The textbooks and laboratory manu-als furnish numerous examples of the application of various syntheses, but only rarelydo they convey an accurate conception of the scope and usefulness of the processes.

For many years American organic chemists have discussed these problems. Theplan of compiling critical discussions of the more important reactions thus wasevolved. The volumes of Organic Reactions are collections of chapters each devotedto a single reaction, or a definite phase of a reaction, of wide applicability. Theauthors have had experience with the processes surveyed. The subjects are presentedfrom the preparative viewpoint, and particular attention is given to limitations,interfering influences, effects of structure, and the selection of experimental tech-niques. Each chapter includes several detailed procedures illustrating the significantmodifications of the method. Most of these procedures have been found satisfactoryby the author or one of the editors, but unlike those in Organic Syntheses, theyhave not been subjected to careful testing in two or more laboratories. Each chaptercontains tables that include all the examples of the reaction under consideration thatthe author has been able to find. It is inevitable, however, that in the search of theliterature some examples will be missed, especially when the reaction is used as onestep in an extended synthesis. Nevertheless, the investigator will be able to use thetables and their accompanying bibliographies in place of most or all of the literaturesearch so often required. Because of the systematic arrangement of the material inthe chapters and the entries in the tables, users of the books will be able to findinformation desired by reference to the table of contents of the appropriate chapter.In the interest of economy, the entries in the indices have been kept to a minimum,and, in particular, the compounds listed in the tables are not repeated in the indices.

The success of this publication, which will appear periodically, depends upon thecooperation of organic chemists and their willingness to devote time and effort tothe preparation of the chapters. They have manifested their interest already by thealmost unanimous acceptance of invitations to contribute to the work. The editors willwelcome their continued interest and their suggestions for improvements in OrganicReactions.

v

INTRODUCTION TO THE SERIESSCOTT E. DENMARK, 2008

In the intervening years since “The Chief” wrote this introduction to the secondof his publishing creations, much in the world of chemistry has changed. In particu-lar, the last decade has witnessed a revolution in the generation, dissemination, andavailability of the chemical literature with the advent of electronic publication andabstracting services. Although the exponential growth in the chemical literature wasone of the motivations for the creation of Organic Reactions, Adams could never haveanticipated the impact of electronic access to the literature. Yet, as often happens withvisionary advances, the value of this critical resource is now even greater than at itsinception.

From 1942 to the 1980’s the challenge that Organic Reactions successfullyaddressed was the difficulty in compiling an authoritative summary of a prepara-tively useful organic reaction from the primary literature. Practitioners interestedin executing such a reaction (or simply learning about the features, advantages,and limitations of this process) would have a valuable resource to guide theirexperimentation. As abstracting services, in particular Chemical Abstracts andlater Beilstein, entered the electronic age, the challenge for the practitioner was nolonger to locate all of the literature on the subject. However, Organic Reactionschapters are much more than a surfeit of primary references; they constitute adistillation of this avalanche of information into the knowledge needed to correctlyimplement a reaction. It is in this capacity, namely to provide focused, scholarly, andcomprehensive overviews of a given transformation, that Organic Reactions takeson even greater significance for the practice of chemical experimentation in the 21st

century.Adams’ description of the content of the intended chapters is still remarkably

relevant today. The development of new chemical reactions over the past decadeshas greatly accelerated and has embraced more sophisticated reagents derived fromelements representing all reaches of the Periodic Table. Accordingly, the successfulimplementation of these transformations requires more stringent adherence to impor-tant experimental details and conditions. The suitability of a given reaction for anunknown application is best judged from the informed vantage point provided byprecedent and guidelines offered by a knowledgeable author.

As Adams clearly understood, the ultimate success of the enterprise depends on thewillingness of organic chemists to devote their time and efforts to the preparation ofchapters. The fact that, at the dawn of the 21st century, the series continues to thrive isfitting testimony to those chemists whose contributions serve as the foundation of thisedifice. Chemists who are considering the preparation of a manuscript for submissionto Organic Reactions are urged to contact the Editor-in-Chief.

vi

PREFACE TO VOLUME 88

The Prefaces to Volumes 78 and 85 highlighted the importance of nitrogen andnitrogen-containing compounds in the biosphere and the “chemosphere”. It is impos-sible to overstate the enormous diversity of organonitrogen substances as well astheir critical role as agrochemicals, pharmaceuticals, and high-performance poly-mers. Nitrogen is so central to chemistry and life that it has also inspired writersand poets such as Sam Kean (The Disappearing Spoon) and Mario Markus (Chemi-cal Poems: One for Each Element). However, no writer has matched the great PrimoLevi in his ability to capture and express the personality and unique character ofthe elements as found in his classic compendium, The Periodic Table. In the chapterdedicated to Nitrogen, Levi observes:

“Nitrogen is nitrogen, it passes miraculously from the air into plants,from these into animals, and from animals to us; when its function in ourbody is exhausted, we eliminate it, but it still remains nitrogen, aseptic,innocent. We — I mean to say we mammals — who in general do haveproblems about obtaining water, have learned to wedge it into the ureamolecule, which is soluble in water, and as urea we free ourselves ofit; other animals, for whom water is precious, have made the ingeniousinvention of packaging their nitrogen in the form of uric acid, which isinsoluble in water, and of eliminating it as a solid with no necessity ofhaving recourse to water as a vehicle”.

Whereas the chapter that comprised Volume 85 concerned itself with the intro-duction of nitrogen into aromatic substances through the agency of copper-mediatedcross-coupling reactions, the chapter in this volume focuses on the introduction ofnitrogen into aliphatic substances, both cyclic and acyclic. Although many such meth-ods have been in use for decades, such as nucleophilic displacement with amines,azides, and nitrites, the most atom-economical method involves the addition of anN–H bond across an unsaturated linkage (alkene, alkyne, allene, diene, etc.). Thisconstruct has been the subject of intense investigation only in the past two decades,with a staggering increase in the past ten years. Indeed, the ability to create organo-nitrogen compounds from alkenes and ammonia may become the modern day equiva-lent of the Haber-Bosch process which revolutionized agriculture (and unfortunatelyalso warfare).

The success of the research efforts over the past 20 years forms the basis forthe single chapter in this volume namely, Hydroamination of Alkenes by AlexanderL. Reznichenko and Kai C. Hultzsch. The Board of Editors was hesitant to commis-sion a chapter of this magnitude, but the importance of the chemistry motivated thesearch for authors with expertise and commitment to undertake such a massive effort.Our hopes could not have been better rewarded. The authors, Drs. Reznichenko and

vii

viii PREFACE TO VOLUME 88

Hultzsch, have compiled an enormous (and growing) literature and distilled it intoan extraordinarily useful treatise on all aspects of the hydroamination process. Giventhe myriad types of unsaturated substrates, metal-based catalysts, and reaction con-ditions, the authors have done an outstanding job of identifying the best options forvarious permutations of amine type and alkene structure. This comprehensive treat-ment of so many different options constitutes a dream “field guide” for the perplexedchemist who wants to know how best to approach the formation of a C-N bond in atarget structure to form new stereogenic centers as well as rings of various sizes. Muchof the focus in recent years has been on the development of chiral ligand sets for var-ious metals to effect enantioselective hydroaminations. The authors have compiledthe state of the art in this field in a scholarly, separate section.

The Tabular Survey is logically organized by substrate structure and further sub-divided by inter- and intramolecular reactions as well as enantioselective reactions.This highly user-friendly structure assures the reader to be able to locate relevantprecedent with ease. Given the magnitude of this undertaking, the authors had toestablish the literature coverage at the outset of the project, January 2011. However,they have provided a supplemental reference list that includes all reports appearingbetween February 2011 and April 2015.

Volume 88 represents the tenth single-chapter-volume produced in our 73-year his-tory. Such single-chapter volumes represent definitive treatises on extremely impor-tant chemical transformations. The organic chemistry community owes an enormousdebt of gratitude to the authors of such chapters for the generous contribution of theirtime, effort, and insights on reactions that we clearly value.

It is appropriate here to acknowledge the expert assistance of the entire editorialboard, in particular, André Charette who shepherded this massive chapter to com-pletion. The contributions of the authors, editors, and the publisher were expertlycoordinated by the responsible secretaries, Robert Coates and Jeffery Press. In addi-tion, the Organic Reactions enterprise could not maintain the quality of productionwithout the dedicated efforts of its editorial staff, Dr. Linda S. Press, Dr. DanielleSoenen, and Dr. Dena Lindsay. Insofar as the essence of Organic Reactions chaptersresides in the massive tables of examples, the authors’ and editorial coordinators’painstaking efforts are highly prized.

Scott E. DenmarkUrbana, Illinois

CONTENTS

chapter page

1. Hydroamination of AlkenesAlexander L. Reznichenko and Kai C. Hultzsch . . . . . . . . . . . . . . . . . 1

Cumulative Chapter Titles by Volume . . . . . . . . . . . . . . . . . . . . . . 555

Author Index, Volumes 1–88 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571

Chapter and Topic Index, Volumes 1–88 . . . . . . . . . . . . . . . . . . . . . . 577

ix

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

Page

Acknowledgment . . . . . . . . . . . . . . . . 3Introduction . . . . . . . . . . . . . . . . . 3Mechanism and Stereochemistry . . . . . . . . . . . . 4

Alkali, Alkaline Earth, and Rare Earth Metals . . . . . . . . . 4Group 4 and Group 5 Transition Metals . . . . . . . . . . . 6Late Transition Metals . . . . . . . . . . . . . . . 8

Scope and Limitations . . . . . . . . . . . . . . . 11Ethylene and Other Unactivated Alkenes . . . . . . . . . . 11

Intermolecular Hydroamination of C2–C4 Alkenes . . . . . . . 11Intermolecular Hydroamination of Unactivated Higher Alkenes . . . . 15Intramolecular Hydroamination of Aminoalkenes . . . . . . . . 17

Hydroamination of Vinyl Arenes . . . . . . . . . . . . 25Intermolecular Hydroamination of Vinyl Arenes . . . . . . . . 25Intramolecular Hydroamination of Vinyl Arenes . . . . . . . . 30

Hydroamination of Conjugated Dienes . . . . . . . . . . . 33Intermolecular Hydroamination of 1,3-Dienes . . . . . . . . 33Intramolecular Hydroamination of Aminodienes . . . . . . . . 36

Hydroamination of Allenes . . . . . . . . . . . . . 37Intermolecular Hydroamination of Allenes . . . . . . . . . 37Intramolecular Hydroamination of Aminoallenes . . . . . . . . 40

Hydroamination of Strained Alkenes . . . . . . . . . . . 42Hydroamination of Methylenecyclopropanes . . . . . . . . . 42Hydroamination of Norbornene . . . . . . . . . . . . 45Intramolecular Hydroamination of Strained Alkenes . . . . . . . 46

Kai.hultzsch@univie.ac.atOrganic Reactions, Vol. 88, Edited by Scott E. Denmark et al.© 2016 Organic Reactions, Inc. Published 2016 by John Wiley & Sons, Inc.

1

2 ORGANIC REACTIONS

Enantioselective Hydroaminations . . . . . . . . . . . . 46Enantioselective Intermolecular Hydroamination of Unactivated Alkenes . . 46Enantioselective Intramolecular Hydroamination of Aminoalkenes . . . . 47Enantioselective Intermolecular Hydroamination of Vinyl Arenes . . . . 53Enantioselective Intramolecular Hydroamination Reactions of 1,3-Dienes . . 54Enantioselective Intermolecular Hydroamination of 1,3-Dienes . . . . 55Enantioselective Intramolecular Hydroamination of Aminodienes . . . . 55Enantioselective Intramolecular Hydroamination of Aminoallenes . . . . 57Enantioselective Hydroamination of Norbornene . . . . . . . . 57

Hydroamination/Carbocyclization . . . . . . . . . . . . 59Applications to Synthesis . . . . . . . . . . . . . . 60Comparison with Other Methods . . . . . . . . . . . . 64

Hydroelementation/Amination . . . . . . . . . . . . . 64Catalytic Hydroboration/Amination . . . . . . . . . . . 65Hydrozirconation/Iodination of Aminoalkenes . . . . . . . . 66

Cope-Type Hydroamination . . . . . . . . . . . . . 66Aminomercuration/Demercuration . . . . . . . . . . . . 69Radical-Transfer Hydroamination . . . . . . . . . . . . 70

Experimental Conditions . . . . . . . . . . . . . . 72Experimental Procedures . . . . . . . . . . . . . . 72

(R)-N-Benzylheptan-2-amine (Lanthanide-Catalyzed Asymmetric IntermolecularHydroamination of an Aliphatic Terminal Alkene) . . . . . . 72

5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801)(Organolanthanide-Catalyzed Intramolecular Hydroamination of anAminoalkene) . . . . . . . . . . . . . . . 73

O-Methylmetazocine (Lithium Amide-Catalyzed Intramolecular Hydroamination of anAminoalkene) . . . . . . . . . . . . . . . 73

(S)-(+)-1-Phenylpent-4-enylamine (Kinetic Resolution of a RacemicAminoalkene]) . . . . . . . . . . . . . . . 74

1-Phenyl-2,3-dihydroindole (Potassium-Catalyzed Addition of Aniline to2-Chlorostyrene with Subsequent Cyclization) . . . . . . . 75

(S)-N-Phenyl-N-[1-{4-(trifluoromethyl)phenyl}ethyl]amine (Palladium-CatalyzedAsymmetric Intermolecular Hydroamination of a Vinyl Arene) . . . 75

1-Phenylmethyl-4-(2-phenethyl)piperazine (Lithium-Catalyzed IntermolecularHydroamination of Styrene) . . . . . . . . . . . . 76

3-Fluoro-6,6,9-trimethyl-5,6-dihydrophenanthridine (Brønsted Acid-CatalyzedIntramolecular Hydroamination) . . . . . . . . . . . 76

(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) . . . 77

8-Phenylmethyl-8-azabicyclo[3.2.1]oct-2-ene (Palladium-Catalyzed IntermolecularTransannular Hydroamination of a Cyclic Triene) . . . . . . . 77

1-Benzyloxycarbonyl-2-[(E)-prop-1-enyl]piperidine (Organolanthanide-CatalyzedIntramolecular Hydroamination of an Aminodiene with SubsequentProtection) . . . . . . . . . . . . . . . . 78

(3S,5R,8S)-3-(1-Heptyl)-5-methylpyrrolizidine ((+)-Xenovenine)(Organolanthanide-Catalyzed Stereoselective Intramolecular Hydroamination of anAminoallene) . . . . . . . . . . . . . . . 79

2-(4-Fluorophenyl)-6-methyl-2,3,4,5-tetrahydropyridine (Group 4 Metal-CatalyzedIntramolecular Hydroamination of an Aminoallene) . . . . . . 79

2-(Cyclohexylidenemethyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidine (Gold-CatalyzedAsymmetric Intramolecular Hydroamination of a Protected Aminoallene) . . 80

2-Methyl-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindole (Lanthanide-CatalyzedSequential Hydroamination/Carbocyclization) . . . . . . . 80

Abbreviations Used in the Tabular Survey . . . . . . . . . 81

HYDROAMINATION OF ALKENES 3

Chart 1. Catalysts and Ligands Used in the Tables . . . . . . . 84Table 1A. Hydroamination of Simple Alkenes . . . . . . . . 106Table 1B. Hydroamination of Vinyl Arenes . . . . . . . . . 164Table 1C. Hydroamination of 1,3-Dienes . . . . . . . . . . 216Table 1D. Hydroamination of Allenes . . . . . . . . . . 261Table 1E. Hydroamination of Strained Alkenes . . . . . . . . 280Table 2A. Hydroamination/Cyclization of Aminoalkenes . . . . . . 309Table 2B. Hydroamination/Cyclization of Vinyl Arenes . . . . . . 413Table 2C. Hydroamination/Cyclization of Aminodienes . . . . . . 421Table 2D. Hydroamination/Cyclization of Aminoallenes . . . . . . 425Table 2E. Hydroamination/Cyclization of Strained Aminoalkenes . . . . 453Table 3A. Enantioselective Hydroamination of Simple Alkenes . . . . 454Table 3B. Enantioselective Hydroamination of Vinyl Arenes . . . . . 458Table 3C. Enantioselective Hydroamination of 1,3-Dienes . . . . . . 460Table 3D. Enantioselective Hydroamination of Allenes . . . . . . 462Table 3E. Enantioselective Hydroamination of Strained Alkenes . . . . 465Table 4A. Enantioselective Hydroamination/Cyclization of Aminoalkenes . . 468Table 4B. Enantioselective Intramolecular Hydroamination of Vinyl Arenes . . 515Table 4C. Enantioselective Hydroamination/Cyclization of Aminodienes . . 518Table 4D. Enantioselective Hydroamination/Cyclization of Aminoallenes . . 521Table 5. Hydroamination/Carbocyclization of Aminoalkenes . . . . . 532

References . . . . . . . . . . . . . . . . . 537

ACKNOWLEDGMENT

Generous financial support by the National Science Foundation through a NSFCAREER 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–nitrogenbonds has received significant attention over the last one and a half centuries, due tothe importance of nitrogen-containing compounds in biological systems and pharma-ceutical applications.1,2 Although a large number of carbon–nitrogen bond-formingprocesses have been devised during this period, the hydroamination of alkenesrepresents, in principle, one of the most attractive and efficient routes. The catalytichydroamination 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.

+ H N(R2)2

N(R2)2

+ H NR1R2

+ H NR2

NR1R2 and/or

NR2 NR2and/or orNR2

R1

Markovnikov

R1 N(R2)2and/orR1

anti-Markovnikov

NR1R2 NR1

for R2 = H

Scheme 1∗Abbreviations used are defined on pp. 81–83.

4 ORGANIC REACTIONS

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

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

The scope of amine types includes ammonia, primary and secondary aliphaticand aromatic amines, azoles, and hydrazines. Although N-protected amines, such asureas, carboxamides, and sulfonamides do not strictly belong to the amine compoundclass, the addition of these compounds to unsaturated compounds has seen signifi-cant progress, especially through the use of metal-free and late transition metal basedcatalysts. Thus, N-protected ammonia and primary amines are also included in thischapter.

A large variety of catalyst systems are available, ranging from alkali,20 alkalineearth,39,40 rare earth,25,36 Group 4 and Group 5 metals,42 to late transition-metalcatalysts.16,21,24,29,31,35 Less prominent are Brønsted and Lewis acid-based catalystsystems.6,18,37 The mode of operation of the catalyst systems varies significantly andthe different reaction mechanisms will be discussed briefly. Many of the catalystsystems are quite specific in their substrate scope, with only a limited numberapplicable to a broader range of substrates. Further challenges include controlover Markovnikov/anti-Markovnikov regioselectivity23 and 1,2 vs. 1,4 addition todienes, processes that can be controlled to some extent by the proper choice ofcatalyst.

MECHANISM AND STEREOCHEMISTRY

Alkali, Alkaline Earth, and Rare Earth Metals

Generally, hydroamination reactions involving electropositive elements, such asalkali, alkaline earth, and rare earth (including Sc, Y, La to Lu) metal based cata-lyst systems proceed via a metal-amido species that undergoes nucleophilic additionto the alkene (Scheme 2). The regiochemistry of the addition is determined by thesubstituent attached to the alkene. Whereas aliphatic substituents predominantly lead

HYDROAMINATION OF ALKENES 5

to the Markovnikov addition product with a terminal β-aminoalkyl metal interme-diate 1, aromatic substituents produce predominantly the anti-Markovnikov productdue to the electronic stabilization of the benzylic metal intermediate 2 (via electrondelocalization of the negative charge on the benzylic carbon as well as π-interactionof the aromatic ring with the metal center).43,44

H N(R2)2

N(R2)2

MarkovnikovR1

[M] R

[M]

H R

M = Li–Cs, Mg–Ba, Sc, Y, La–LuR = alkyl, amido

N(R2)2R1 N(R2)2

[M]NH(R2)2

R1

[M]

R1 N(R2)2

anti-Markovnikov

R1

H N(R2)2H N(R2)2

R1

R1R1 = alkyl

1 2

= aryl

Scheme 2

The mechanism for the intramolecular hydroamination of aminoalkenes hasbeen studied in more detail (Scheme 3), in particular for rare earth metal basedcatalyst systems,45,46 but alkali, alkaline earth, and actinide catalysts are presumedto operate in a similar fashion.47,48 The resting state of the catalyst is believed to be ametal-amido amine adduct 4 that is in equilibrium with the more electron-deficient,hence more reactive, metal-amido species 3. The insertion of the alkene into themetal-amide bond is approximately thermoneutral and is considered to be therate-determining step (RDS). This is followed by rapid, exothermic protonation ofthe resulting highly reactive metal-alkyl intermediate by excess amine substrate.The cyclization always generates the exocyclic hydroamination product becausethe endo cyclization has a high activation barrier,49–51 presumably as a resultof steric strain. Observation of a significant primary kinetic isotope effect (KIE;kH/kD in the range of 2.3–5.2)45,52 is indicative of a partial N–H bond disruptionin the transition state of the rate-determining alkene insertion step. A plausibleexplanation involves concerted proton transfer from a coordinated amine45,53,54 tothe α carbon in the insertion step (Scheme 4). However, some experimental data,in particular the observation of sequential hydroamination/bicyclization sequences(Scheme 5),43,55–58 is in conflict with these findings, as the latter requires a finitelifetime for the rare earth metal alkyl intermediate. Therefore, the intermediacy ofthe metal-alkyl species 5 (Scheme 3) and its potential lifetime is unclear at presentand is probably strongly dependent on catalyst and substrate structures.

6 ORGANIC REACTIONS

[M] R

HN[M]

HN[M]

H2N

H2N

H R

M = Li–Cs, Mg–Ba, Sc, Y, La–LuR = alkyl, amido

HN

[M]n

n

catalyst activation

olefin insertion (RDS)H ~ 0 kcal/mol

protonolysis (fast)ΔH ~ –13 kcal/mol

n = 1, 2, 3 Keq

S = H2NR1, HNR1R2

HN[M]

nS

NH

4

3

5

n

nn

n

Δ

Scheme 3

HN[Ln] H

N[Ln]n

nHN N H

R2 δ+

δ+δ+δ−

δ−

R1

NH[Ln]

N R2

n

R1

R2

R1

Scheme 4

NCp*2Sm

N

HN

Cp*2SmCH(SiMe3)2

(1.5 mol %)

C6H6, 21°, 5 d

(93%)trans/cis = 55:45

H

Scheme 5

Group 4 and Group 5 Transition Metals

The hydroamination of allenes catalyzed by Group 4 metals proceeds by amechanism closely related to that of alkynes.10,11,14,59–63 The catalytically activemetal-imido species 7 is generated via reversible α elimination of an amine fromthe bis-amido precursor 6. A reversible, rate-determining [2 + 2]-cycloaddition ofthe imido species with the allene yields the azametallacyclobutane intermediate8 (Scheme 6). Subsequent protonation of the azametallacyclobutane produces an

HYDROAMINATION OF ALKENES 7

enamide amido complex 9 that undergoes α elimination of the enamine, regeneratingthe catalytically active imido species. Depending on the steric demand of the imidoligand and the ancillary ligands, the imido species is also in equilibrium withthe bridged imido dimer 10, favoring the dimeric species with decreasing stericdemand of the ancillary and imido ligands. Hence, many sterically less-encumberedcatalyst systems perform better with sterically demanding amines and the rate ofthe reaction generally does not correlate linearly with the concentration of thecatalyst.

[M]R1

R1

2 R2NH2

[M] NR2

[M]N

[M]N

1/2

[M]

NHR2

NHR2

+ R2NH2 – R2NH2

NHR2

[M] NR2

R2NH2

[M]

N

NHR2

R2

R2

R2

M = Ti, ZrR1 = alkyl, amido

NR2

7

89

10

6

•

Scheme 6

The mode of operation of Group 5 metal catalysts in the hydroamination ofallenes is unclear at present. The fact that only primary amines react with allenes(and alkenes) seems to support a metal-imido intermediate. However, mechanisticstudies on the tantalum-catalyzed hydroamination of alkynes are unable to confirmthis mechanistic scenario.64–66

The mechanism of alkene hydroamination is much less well understood thanthe mechanism for alkyne and allene hydroamination and is still under significantdebate.48,53,67–71 On the basis of the observation that most neutral Group 4 andGroup 5 metal alkene hydroamination catalysts are unreactive towards secondaryaminoalkene substrates, a mechanism analogous to that for alkyne and allenehydroamination involving metal-imido species as catalytically active species has

8 ORGANIC REACTIONS

been proposed (Scheme 7).67,68,70 The reversible72,73 [2+2]-cycloaddition of themetal imido species 11 with the alkene moiety leads to an azametallacyclobutane 12that is protolytically cleaved to regenerate the metal-imido species and release thehydroamination product. The significant activation barrier61 for this protonation stepand the facile cycloreversion of the azametallacyclobutane 12 to the metal-imidospecies 11 is most likely responsible for the limited scope of neutral Group 4and Group 5 metal based catalyst systems in the hydroamination of non-activatedsimple alkenes and the harsh reaction conditions required to achieve catalyticturnover.

[M]

N(R1)2

N[M]

H2N

H2N

2 HN(R1)2R1 = Me, Et

N[M]

n = 1, 2M = Ti, Zr, Hf, Ta

N(R1)2

R2 R2

R2

R2

R2

R2

N[M]

R2

R2

R2 R2

n

n

n

n

n[M]

HN

NH

R2

R2

R2

R2n

n

H2NR2 R2

n

n

NH

R2

R2

11

12

2

Scheme 7

However, a few (achiral) neutral, Group 4 metal catalyst systems are reportedto catalyze the cyclization of secondary aminoalkenes and it is suggested that alanthanide-like σ-bond metathesis mechanism (Scheme 3) is operating in thesecases.48,69,74

Late Transition Metals

The mechanism of late transition metal catalyzed hydroaminations is less inten-sively studied and they are much less well understood compared to early transitionand rare earth metal catalyzed hydroaminations. However, it is established that latetransition metal catalyzed hydroaminations may proceed via different mechanismsdepending on the substrate and the catalyst employed. Generally, the reactions arethought to involve either amine activation (Scheme 8) or alkene activation (Scheme9).21,75,76 Cleavage of the β-aminoalkyl metal species can occur either via direct

HYDROAMINATION OF ALKENES 9

protonation from an external acid or via reductive elimination of a metal-hydridoalkyl intermediate (Scheme 9).

Ir(PEt3)2ClPhNH2

Ir(PEt3)2(NHPh)(H)Cl

NIr

Et3P

Et3P

H

Cl Ph

Ir(PEt3)(H)(NHPhC7H10)Cl

HPhHN

H

oxidative additionreductive elimination

olefin insertion

+ PEt3

+ PEt3– PEt3

Scheme 8

[LnM]

[LnM]

[LnM]

directprotonation

RNH2

NH2R

[LnM]NHRH

NHR

[H+]

reductiveelimination

proton transferto M

nucleophilic attack+

–

Scheme 9

The amine activation mechanism includes oxidative addition of an amino group,followed by insertion of the unsaturated carbon–carbon bond into the metal-amidebond and final reductive elimination. It is established that the iridium(I)-catalyzedhydroamination of strained alkenes, such as norbornene, with anilines proceedsvia this mechanism (Scheme 8).77–79 Although amines other than anilines, such asammonia, are also reported to undergo N–H oxidative addition to iridium80–82 andruthenium83 metal centers, no related catalytic systems are known. The syn insertionof an olefin into a palladium-amide bond has also been observed.84,85 However,these particular systems are not directly related to hydroamination processes. Nev-ertheless, the platinum-catalyzed intramolecular hydrohydrazination of N-protectedalkenyl hydrazides proceeds via NH-activation/olefin insertion rather than throughnucleophilic attack to a coordinated alkene.86

10 ORGANIC REACTIONS

Key steps of the alkene activation mechanism (Scheme 9) include nucleophilicattack of the amine on the metal-coordinated olefin, leading to a zwitterionic inter-mediate. Proton transfer from nitrogen to the metal produces a β-aminoalkyl metalspecies that then undergoes reductive elimination, cleaving the metal–carbon bond.The direct protonolysis of the metal–carbon bond in the zwitterionic ammoniumintermediate is also possible in principle, but this step is less kinetically favorablethan the stepwise process via reductive elimination.

DFT calculations suggest that the amine activation pathway is less favored than thealkene activation pathway for the intermolecular hydroamination of simple alkeneswith aliphatic amines catalyzed by Group 9 and 10 metal complexes.87 Similar stud-ies of the platinum-catalyzed addition of aniline to ethylene show a high barrier foroxidative amine addition and reveal that nucleophilic attack on the coordinated ethyl-ene is the rate-determining step.88,89

The iridium-catalyzed intramolecular hydroamination of aliphatic aminoalkenesis also proposed to proceed via alkene activation (Scheme 10).90 DFT calculationssuggest that the irreversible metal–carbon bond cleavage is rate-limiting, which is inline with the observed large negative activation entropy. It should be noted that coor-dination of the alkenyl moiety of the substrate to the metal center may be disfavoredby a competitive coordination of the amino group, which will not result in productformation. This explains why primary aminoalkenes are significantly less reactivethan more sterically encumbered (and thus less prone to coordinate through nitro-gen) secondary aminoalkenes for most late transition metal based systems. Anotherimportant observation is that not all late transition metal catalyzed systems are limitedin turnover by the protonolysis step, given that some examples of “fast” protonoly-sis in a rhodium catalyst system with a κ3-P,O,P-xanthene-based ligand system areknown.91

[Ir] HN R

[Ir]N

H R[Ir]

NH

R

[Ir] NR

NR [Ir] H

NR

[Ir]N

HR

HN R

[Ir] = (COE)IrCl

+–

–

+

Scheme 10

Analogous alkene activation mechanisms are also proposed for a number ofhydroaminations utilizing N-protected amines or less nucleophilic amines, such

HYDROAMINATION OF ALKENES 11

as anilines. Mechanistic studies suggest that the protonolysis of the metal–carbonbond is the rate-determining step in the PNP-palladium-catalyzed [PNP = 2,6-bis((diphenylphosphanyl)methyl)pyridine] intramolecular hydroamination of alkenylcarbamates and carboxamides.92 A DFT study of the (phosphine)Au(I)-catalyzedaddition of carbamates to 1,4-dienes leads to a similar conclusion.75

It is important to note that in certain cases the role of the metal catalyst may belimited to the generation of an acid via ligand exchange with the N-protected aminefollowed by protonolysis of the alkene. This activates the alkene to nucleophilic trans-formations, since the addition of N-protected amines to alkenes is also efficientlycatalyzed with Brønsted acids such as TfOH (Scheme 11).93,94

+ R1NH2 OTf –

R2+OTf–R2

OTfL2Pt

OTf

NH2R1L2Pt

OTf+

NHR1L2Pt

OTf++

Scheme 11

SCOPE AND LIMITATIONS

Ethylene and Other Unactivated Alkenes

Simple alkenes are readily available feedstock in the chemical industry. Therefore,it is desirable to utilize them in highly atom-economical functionalization reactions,such as the hydroamination reaction. Although significant progress has been madein the area of intermolecular hydroamination of unactivated alkenes, overall, the pro-cess remains challenging and very few reactions have found synthetic or industrialapplication. The intermolecular hydroamination of unactivated alkenes is presentedin Table 1A. Intramolecular hydroaminations of aminoalkenes are significantly morefacile and will be covered in a later section.

Intermolecular Hydroamination of C2–C4 Alkenes. Although the reaction ofsimple alkenes and amines is thermodynamically feasible (ΔG0 ≈ –14.7 kJ mol–1

for the addition of ammonia to ethylene),17 the uncatalyzed process is kineticallydisfavored.95 Even if equilibrium can be reached it may favor the starting materialsunder the reaction conditions required to catalyze the process. Elevated temperaturesand pressures are required in most cases, as well as the presence of a transition metalor main group metal catalyst. Robust, non-transition metal based heterogeneous cat-alysts can also facilitate the desired transformation. Various zeolites96–99 are activecatalysts for the hydroamination of ethylene with ammonia. Harsh reaction conditions(up to 370∘) are employed and typical conversions do not exceed 20%. An additionaldrawback is the uncontrolled polyalkylation of ammonia to give mixtures of mono-(13) and diethylamine (14) (Scheme 12).

12 ORGANIC REACTIONS

CatalystH-Y ZeoliteH-Erionite

13/1481:1997:3

Yield (%) 13 + 141218

NH3 +

1413

EtNH2 Et2NH+ zeolite cat.

365°, 24 h2 equiv

Scheme 12

A low selectivity to form the primary amine hydroamination product is alsoobserved for the analogous reaction of propylene.97,100 The selectivity can beincreased to >97% for propylene101 and >98% for isobutylene102 by use of apentasil-type zeolite catalyst,101,103 with the latter process being commercializedby BASF (Scheme 13) as an industrial-scale approach to tert-butylamine. Thecatalytic activity is very sensitive to the amount and strength of Brønsted acid siteson these solid catalysts, and linear correlations between the SiO2/Al2O3 ratio ofH-MFI, H-Mordenite, and H-FAU solid catalysts are observed.104 Overall, the harshconditions restrict the use of heterogeneous zeolite-type catalysts to the reactions ofC2–C4 alkenes with ammonia.104,105

borosilicate pentasil

300 bar, 300°NH3

NH2+

1.3 equiv(15 %) >98% selectivity

Scheme 13

Somewhat milder conditions for the hydroamination of “small” alkenes, whichare not restricted to ammonia as a nitrogen source, are required for alkali metal cat-alysts. Whereas elemental lithium,106 sodium,107,108 and potassium107 require highreaction temperatures, more reactive alkali metal amides109–111 or hydrides112 aremore efficient catalysts. In general the process is not selective when ammonia is used;however, tertiary amines may be obtained selectively when secondary amines reactwith ethylene (Scheme 14).112

KH (7 mol %)

100°, 9 hEt2NH

50 bar

Et3N+ (55%)

Scheme 14

A variety of late transition metal complexes have been tested as homogeneouscatalysts for the hydroamination of C2–C4 alkenes. In nearly all of these studiesthe addition of HNR2 to both alkenes and alkynes proceeds with Markovnikovregioselectivity. Catalysts employing iron,113 ruthenium,113–116 rhodium,117–120

and platinum93,117,121–124 are reported for the hydroamination of C2–C4 alkenes.It is noteworthy that no transition metal based catalyst system for the additionof ammonia has been reported. So far, most catalyst systems are restricted to

HYDROAMINATION OF ALKENES 13

weakly basic anilines or N-protected amines (amides, carbamates, sulfonamides).A typical hydroamination of aniline with ethylene is accompanied by a secondhydroamination as well as oxidative arylation side reactions (Scheme 15).121 Morebasic alkylamines are unreactive under these conditions, presumably due to facilecatalyst decomposition.125

+

PtBr2 (0.3 mol %), P(OMe)3 (0.6 mol %)NH2 NHEt NEt2 N

+ +

(32%) (0.3%) (3.7%)

n-Bu4PBr, 150°, 10 h25 bar

Scheme 15

When a sterically hindered and electronically deficient aniline is employed, achemoselective transformation can be achieved (Scheme 16).121

25 bar

+PtBr2 (1 mol %), TfOH (3 mol %)

n-Bu4PBr, 150°, 72 h

NH2 NHEt(95%)

Cl Cl

Scheme 16

A catalytic system based on rhodium trichloride shows high activity and excellentselectivity for the hydroamination of N-ethylaniline (Scheme 17).120

25 bar

RhCl3•3H2O (0.3 mol %), PPh3 (0.6 mol %), n-Bu4PI (19 mol %)NHEt NEt2

(75%)+I2 (0.6 mol %), 150°, 24 h

Scheme 17

Most late transition metal based catalysts are applicable to less basic anilines.Reports on the reactivity of aliphatic amines are rare119 and typically involve cyclicsecondary amines (Scheme 18).117

+RhCl3•3H2O (1 mol %)

THF, 200°, 3 h

HN

3.5 equiv

NEt

(70%)

Scheme 18

Whereas late transition metal catalyzed hydroaminations of alkenes with unpro-tected amines require high temperatures, even with anilines, reactions of N-protected

14 ORGANIC REACTIONS

amines (e.g. amides, sulfonamides) are generally more feasible. Thus, the platinum-catalyzed reaction of benzamide with ethylene proceeds at 120∘ (Scheme 19).122

O

NH2 (98%)+

O

NH

Et

3.5 bar

[PtCl2(C2H4)]2 (15, 2.5 mol %)

PPh3 (5 mol %), dioxane, 120°, 24 h

PtCl

PtCl

Cl

Cl

15 Zeise's dimer

Scheme 19

The addition of tosylamide to the less reactive (Z)-2-butene is also catalyzed bythe Zeise dimer 15 after activation with AgBF4 (Scheme 20).93

TsNH2NHTs

(95%)

1 atm

+15 (5 mol %), AgBF4 (10 mol %)

1,2-Cl2C6H4, 85°, 3 h

Scheme 20

An analogous reaction of a carboxamide with propylene gives exclusively theMarkovnikov hydroamination product in good yield (Scheme 21).122

(73%)n-Bu

O

NH2n-Bu

O

NH

+15 (5 mol %), PPh3 (10 mol %)

dioxane, 120°, 80 h

Scheme 21

The intermolecular Markovnikov addition of cyclic ureas to alkenes catalyzed bya cationic gold(I) phosphine complex is reported.126 The reaction is not limited toC2–C4 and higher terminal alkenes but also succeeds with the sterically more chal-lenging isobutylene (Scheme 22).

8 bar

(o-C6H5C6H4)P(t-Bu)2AuCl (10 mol %)

AgSbF6 (10 mol %), dioxane, 100°, 48 hMeN N

O

NHMeN

O

(72%)+

Scheme 22

HYDROAMINATION OF ALKENES 15

Intermolecular Hydroamination of Unactivated Higher Alkenes. Inorganiczeolites and clays are significantly less efficient in the hydroamination of higheralkenes with unprotected amines and ammonia. However, heterogeneous catalystscan be successfully employed in the hydroamination of more reactive N-protectedamines.127 For example, H-montmorillonite clay can catalyze the addition of tosyl-amide to cyclohexene in good yield (Scheme 23). The analogous addition to acyclicterminal or internal alkenes proceeds with low regioselectivity and is accompaniedby double bond migration.127

H-montmorillonite (30 wt %)

heptane, 150°, 2 hTsNH2

NHTs

2 equiv

+ (90%)

Scheme 23

The intermolecular lanthanide-catalyzed alkene hydroamination is feasible withthe sterically open ansa-neodymocene 16-Nd, but the number of examples remainssmall (Scheme 24).43,128 The reaction proceeds regioselectively in a Markovnikovfashion, but a large excess of alkene is required and the reaction is 2–3 orders ofmagnitude slower than the intramolecular process.

NH2

73 equiv

HN(90%)+

Si NdMeMe CH(SiMe3)2

16-Nd (20 mol %)

C6D6, 60°

TOF 0.4 h–1

16-Nd

Scheme 24

Although the base-catalyzed hydroamination of higher alkenes is less developedthan that of lower alkenes and vinyl arenes, activated allylarenes react smoothlyunder mild conditions in the presence of an alkyllithium or lithium amide.129,130

The enhanced reactivity presumably results from isomerization of allylbenzeneto the more reactive β-methylstyrene derivative prior to the hydroamination step(Scheme 25).130

2 equiv

n-BuLi (20 mol %)

THF, rt, 24 hN (88%)

NBn

HN NBn

+

Scheme 25

16 ORGANIC REACTIONS

A limited number of late transition metal catalyzed, intermolecular hydroamina-tions of higher alkenes with N-unprotected amines are known using catalysts based onplatinum123,131 and rhodium.132 The reaction is limited to less nucleophilic anilinesas the amine component (Scheme 26)123 and the catalytic efficiency is predictablylower in comparison to reactions involving ethylene. The Markovnikov product 17 isformed preferentially to its isomer 18.

n-Bu

NH2

2 equiv

PtBr2 (0.3 mol %), n-Bu4PBr (18 mol %)

Cl

HN n-Bu

HN

+

Cl Cl

17 + 18 (56%), 17/18 = 95:5

18

+

17

n-Bu[PhNH3]HSO4 (0.8 mol %),

150°, 96 h

Scheme 26

The gold(I)-catalyzed hydroamination with sulfonamides can also be applied tomore sterically encumbered trisubstituted alkenes. Exclusive Markovnikov additionis seen (Scheme 27).133

AcO

4 equiv

TsNH2

Ph3PAuCl (5 mol %),AgOTf (5 mol %) AcO

TsHN+ (44%)toluene, 85°, 48 h

Scheme 27

An analogous reaction with a non-conjugated diene proceeds smoothly to a pyrrol-idine product, as the intermediate secondary sulfonamide is also active in the gold-catalyzed hydroamination reaction (Scheme 28).133

Ph3PAuCl (5 mol %), AgOTf (5 mol %)

TsNH2 (64%) cis/trans = 37:63NTs

+toluene, 95°

Scheme 28

A variety of functional groups, such as hydroxyl, ether, ester, and carboxylic acidsare tolerated in the gold(I)-catalyzed Markovnikov addition of cyclic ureas to alkenes;however, a large excess of the alkene is required (Scheme 29).126

10 equivAgSbF6 (5 mol %),dioxane, 100°, 24 h

NHMeN

O

MeN N

O

R

Rn-C6H13

HO(CH2)3

Yield (%)9895

R

P(t-Bu)2AuCl

+(5 mol %)

Scheme 29

HYDROAMINATION OF ALKENES 17

Although homogeneous Brønsted acid catalyzed hydroaminations of C2–C4alkenes are not known, higher alkenes are reported to undergo this reaction smoothlyin the presence of triflic acid (Scheme 30).134 However, reactions with analogousacyclic alkenes lack regioselectivity.135 Several metal-mediated hydroaminationreactions with protected amines are believed to proceed via an acid-catalyzedpathway.37

TsNH2

4 equiv

TfOH (1 mol %)

toluene, 85°, 22 h+

NHTs(88%)

Scheme 30

Although intermolecular Bronsted acid catalyzed hydroamination processes aremost efficient for protected amines; however, some reactions with unprotected aminesof low basicity such as hydrazines,136,137 azoles,138–141 and anilines142,143 are known.A significant drawback of Brønsted acid catalyzed hydroamination reactions involv-ing aniline derivatives is the formation of hydroarylation byproducts as illustrated byconstitutional isomers 19 and 20 resulting from the HI-catalyzed addition of anilineto cyclohexene (Scheme 31).143

NH2

5 equiv

HI (5 mol %)

toluene, 135°, 21 d

HN

NH2

++

19 20

19 + 20 (59%), 19/20 = 86:14

Scheme 31

Intramolecular Hydroamination of Aminoalkenes. In contrast to allenes,dienes, and strained alkenes, unactivated alkenes exhibit significantly differentmodes of reactivity in inter- vs. intramolecular hydroamination, with the latterprocess being much more facile. The vast majority of catalysts that operate inintramolecular aminoalkene hydroamination reactions cannot be applied to the morechallenging intermolecular processes. Intramolecular aminoalkene hydroaminationhas captured the attention of many research groups, and the results are fully coveredin Table 2A. A large number of catalyst systems based on alkali, alkaline earth, andearly and late transition metals efficiently mediate the cyclization of aminoalkenes.

Relatively simple lithium-based precatalysts ranging from n-BuLi andLDA144–148 to more elaborate axially chiral lithium amides149 (see “Enantio-selective Intramolecular Hydroamination of Aminoalkenes” later in the text) can beemployed for the intramolecular hydroamination of aminoalkenes. The cyclization ofprimary and secondary alkenyl amines affords pyrrolidine and piperidine derivatives.The formation of azepanes or larger azacycles has not yet been reported withthese catalyst systems. The basicity of alkali metal based catalysts often results in

18 ORGANIC REACTIONS

undesired side reactions, such as double bond migration. For the simple n-BuLicatalyst system this side reaction can be suppressed by using a THP–toluene solventmixture (Scheme 32).148

n-BuLi (16 mol %)

THP–toluene, 100°, 5 d(86%)NH2 N

H

Scheme 32

The reaction proceeds exclusively as an exo cyclization, similar to rare earth andearly transition metal catalyzed cyclizations. The high nucleophilicity and basicity oforganolithium reagents significantly limits the range of tolerated functional groups.

Alkaline earth metal-based systems featuring magnesium, calcium, strontium,and barium are in general more reactive and less basic than lithium-based catalysts,however, they display similar limitations with respect to their functional grouptolerance.47,150–155 Azacycles with ring sizes ranging from 5- to 7-membered ringsare accessible via exclusive exo cyclization of the corresponding aminopentenes,aminohexenes, and aminoheptenes. The rate of reaction significantly decreases withthe increasing number of substituents on the double bond. Whereas gem-disubstitutedalkenes still undergo the cyclization (Scheme 33),47 1,2-disubstituted alkenes andhigher substituted alkenes are unreactive even at elevated temperatures.

(5 mol %)(94%)NH2

NH

PhPhPh

Ph

NCa

NDiPP DiPP

THF N(SiMe3)2

C6D6, rt, 30 min

Scheme 33

With the exception of alkaline earth metal catalysts, rare earth metal based cata-lysts are by far the most active catalysts for the intramolecular hydroamination of N-unprotected primary and secondary amines.7,25,36 Similar to alkali and alkaline earthmetal based catalyst systems, all cyclizations proceed with exclusive exo selectivityand allow the synthesis of 5- to 7-membered rings. The rate of cyclization decreaseswith increasing ring size (5 > 6 ≫ 7), and the presence of increasingly stericallydemanding gem-dialkyl substituents156 results in significantly enhanced reactivity ofthe substrates (Scheme 34).45 The rate of cyclization also increases with an increas-ing ionic radius of the rare earth metal and increasing openness of the coordinationsphere.45 Although metallocene catalysts are generally superior in reactivity, elab-orate ligand frameworks are not necessarily required, as exemplified by the simplehomoleptic tris(amides) Ln[N(SiMe3)2]3 (Ln = Y, Nd, La).157,158