Organic Reactions

ADVISORY BOARD

John E. Baldwin James A. MarshallPeter Beak Stuart W. McCombieDale L. Boger Jerrold MeinwaldAndré B. Charette Scott J. MillerEngelbert Ciganek Larry E. OvermanDennis Curran Leo A. PaquetteSamuel Danishefsky Gary H. PosnerHuw M. L. Davies T. V. RajanBabuVittorio Farina Hans J. ReichJohn Fried James H. RigbyJacquelyn Gervay-Hague William R. RoushHeinz W. Gschwend Scott D. RychnovskyStephen Hanessian Martin SemmelhackLouis Hegedus Charles SihJeffery S. Johnson Amos B. Smith, IIIRobert C. Kelly Barry M. TrostAndrew S. Kende James D. WhiteLaura Kiessling Peter WipfSteven V. Ley

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 LeimgruberGeorge A. Boswell, Jr. Frank C. McGrewTheodore L. Cairns Blaine C. McKusickArthur C. Cope Carl NiemannDonald J. Cram Harold R. SnyderDavid Y. Curtin Milán UskokovicWilliam G. Dauben Boris WeinsteinRichard F. Heck

Organic ReactionsV O L U M E 91

EDITORIAL BOARDScott E. Denmark, Editor-in-Chief

Jeffrey Aubé Donna M. HurynCarl Busacca Marisa C. KozlowskiJin K. Cha Michael J. MartinelliP. Andrew Evans Gary A. MolanderPaul L. Feldman John MontgomeryDennis G. Hall Steven M. WeinrebPaul J. Hergenrother

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

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

Danielle Soenen, Editorial Coordinator

Landy K. Blasdel, Editorial Assistant

Dena Lindsay, Editorial Assistant

Linda S. Press, Editorial Consultant

Engelbert Ciganek, Editorial Advisor

ASSOCIATE EDITORS

PETR BEIERMIKHAIL ZIBINSKY

G. K. SURYA PRAKASH

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 authors have 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 second ofhis publishing creations, much in the world of chemistry has changed. In particular,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 literaturewas one of the motivations for the creation of Organic Reactions, Adams couldnever have anticipated the impact of electronic access to the literature. Yet, as oftenhappens with visionary advances, the value of this critical resource is now evengreater than at its inception.

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 91

Fluorine has to be the most schizophrenic element in the Periodic Table. In itsnascent form it is the most reactive element, combining indiscriminately and exother-mically with anything it contacts. However, once bound into organic compounds, itrenders them extremely inert, thus imbuing them with highly valued properties inproducts that permeate our everyday lives. Mario Markus sums it up beautifully inhis Chemical Poems: One for Each Element, in which he juxtaposes the dichotomyof hyperreactivity and civility; “The homicidal maniac blinds or kills whoever comesnear . . . ..Why? Because he wants an electron, that’s all. Let us give him the pittancethat he wants. Now we see how calm he becomes… ” The inertness of organofluorinecompounds leads to myriad applications from non-stick frying pans to refrigerants tomedical implants.

However, for the synthetic organic chemist, the extraordinary chemical stabilityof carbon-fluorine bonds has found widespread application in fine-tuning thephysico-chemical properties of pharmaceutical, agrochemical, and liquid crystallinesubstances. In particular the trifluoromethyl group has become a highly prized sub-stituent by dint of its high electronegativity, lipophilicity, steric size, and resistanceto chemical degradation by oxidative, reductive, hydrolytic, photolytic, and thermalinsults. Given the broad utility of the trifluoromethyl group, it is not surprising thatthe number of methods for selective and efficient introduction of this group intomany different organic substrates has been a major focus of research for the pastdecades. This field has grown so rapidly with so many important advances that itwould be impossible to comprehensively cover all such methods even in a singlevolume of Organic Reactions. Accordingly, Volume 91 contains a single chapterdedicated to one of the most useful methods for introducing a perfluoroalkyl group,namely nucleophilic perfluoroalkylation.

We are extremely fortunate that three of the worlds’ leading experts on nucle-ophilic perfluoroalkylation have teamed up to produce the first, comprehensivetreatment of this extremely important transformation. Prof. Petr Beier, Dr. MikhailZibinsky, and Prof. G. K. Surya Prakash have combined their many years offirst-hand research experience and encyclopedic knowledge of the field in a massive,but yet highly accessible and authoritative treatise covering all of the methodsfor delivering perfluoroalkyl groups from dozens of different sources to scoresof different substrates. The resulting matrix of possibilities for combinations ofperfluoroalkyl donor and organic acceptor would inevitably paralyze the practitionerwith a bewildering abundance of options. In view of this challenge, the authors haveprovided tabular listings of the recommended reagents for perfluoroalkylation of themost common substrates. Even if one is not immediately interested in performinga perfluoroalkylation, reading this chapter provides a fascinating overview of theextraordinary diversity of donors ranging from the ubiquitous Rupert-Prakash

vii

viii PREFACE TO VOLUME 91

reagent (trifluoromethyltrimethylsilane) to perfluoroalkyltellurium reagents toperfluoroalkyllithium, −indium, −copper, −silver, and -zinc reagents. A still greatercongregation of electrophiles is covered ranging from organohalides to carbonylgroups to azomethines to carboxyl derivatives all the way to Main Group andTransition Metal electrophiles and even xenon! Finally, the most recent advances forintroducing perfluoroalkyl groups with control of newly created stereogenic centersare also covered.

The Tabular Survey contains over 540 pages of all examples of nucleophilic perflu-oroalkylation contained in the literature through the first quarter of 2014. The tablesare organized by electrophilic substrate, thus allowing the reader to quickly locatethe class of compounds of specific interest. Moreover, extensive subtables have beencompiled that allow direct comparison of different methods that have been applied toa given substrate, thus facilitating an immediate evaluation of the appropriate choicefor that specific target.

Volume 91 represents the thirteenth single chapter volume to be produced in our75-year history (the fourth in a row and sixth in the past twelve volumes!). Suchsingle-chapter volumes represent definitive treatises on extremely important chem-ical transformations. The organic chemistry community owes an enormous debt ofgratitude to the authors of such chapters for the generous contribution of their time,effort, and insights on reactions that we clearly value.

It is appropriate here to acknowledge the expert assistance of the entire editorialboard, in particular Michael Martinelli who oversaw the early development of thischapter. The contributions of the authors, editors, and the publisher were expertlycoordinated by the board secretary, Robert M. Coates. In addition, the Organic Reac-tions enterprise could not maintain the quality of production without the dedicatedefforts of its editorial staff, Dr. Danielle Soenen, Dr. Linda S. Press, Ms. Dena Lind-sey, and Dr. Landy Blasdel. 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. Nucleophilic Additions of Perfluoroalkyl GroupsPetr Beier, Mikhail Zibinsky, and G. K. Surya Prakash . . . . . . . . . . . . 1

Cumulative Chapter Titles by Volume . . . . . . . . . . . . . . . . . . . . . . 743

Author Index, Volumes 1–91 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761

Chapter and Topic Index, Volumes 1–91 . . . . . . . . . . . . . . . . . . . . . . 767

ix

CHAPTER 1

NUCLEOPHILIC ADDITIONS OF PERFLUOROALKYL GROUPS

Petr Beier

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of theCzech Republic, Prague, 166 10 Czech Republic, beier@uochb.cas.cz

Mikhail Zibinsky

FLX Bio, Inc., 561 Eccles Avenue, South San Francisco, CA 94080,mzibinsky@flxbio.com

G. K. Surya Prakash

Loker Hydrocarbon Research Institute and Department of Chemistry,University of Southern California, Los Angeles, California 90089,

gprakash@usc.edu

CONTENTS

Page

Acknowledgments . . . . . . . . . . . . . . . 5Introduction . . . . . . . . . . . . . . . . . 5Mechanism and Stereochemistry . . . . . . . . . . . . 7Scope and Limitations . . . . . . . . . . . . . . . 10

Overview and Preparation of Nucleophilic Perfluoroalkyl Reagents . . . . 11Deprotonation of Trifluoromethane and Polyfluoroalkanes . . . . . . 11Reduction of Perfluoroalkyl Halides . . . . . . . . . . . 12Non-Metallic Perfluoroalkyl Salts from Addition of Fluoride

to Perfluoroalkenes . . . . . . . . . . . . . . 13Carbon–Boron Bond Cleavage from Perfluoroalkyl Boron Reagents . . . 15Carbon–Carbon Bond Cleavage from Perfluoroalkyl Carbonyl Reagents and their

Derivatives . . . . . . . . . . . . . . . . 15Carbon–Silicon Bond Cleavage from Perfluoroalkyl Silicon Reagents . . . 20Carbon–Tin Bond Cleavage from Perfluoroalkyl Tin Reagents . . . . . 22Carbon–Nitrogen Bond Cleavage from Perfluoroalkyl Nitrogen Reagents . . 23Carbon–Phosphorus Bond Cleavage from Perfluoroalkyl Phosphorus

Reagents . . . . . . . . . . . . . . . . 23

petr.beier@uochb.cas.czOrganic Reactions, Vol. 91, Edited by Scott E. Denmark et al.© 2016 Organic Reactions, Inc. Published 2016 by John Wiley & Sons, Inc.

1

2 ORGANIC REACTIONS

Carbon–Bismuth Bond Cleavage from Perfluoroalkyl Bismuth Reagents . . 24Carbon–Sulfur Bond Cleavage from Perfluoroalkyl Sulfur Reagents . . . 24Carbon–Tellurium Bond Cleavage from Perfluoroalkyl Tellurium Reagents . . 26Perfluoroalkyl Organometallic Reagents . . . . . . . . . . 26

Perfluoroalkyllithium Reagents . . . . . . . . . . . 26Perfluoroalkylmagnesium Reagents . . . . . . . . . . 27Perfluoroalkylcalcium Reagents . . . . . . . . . . . 28Perfluoroalkylzinc Reagents . . . . . . . . . . . . 28Perfluoroalkylcadmium Reagents . . . . . . . . . . . 28Perfluoroalkylindium Reagents . . . . . . . . . . . 29Perfluoroalkylcopper Reagents . . . . . . . . . . . 30Perfluoroalkylsilver Reagents . . . . . . . . . . . . 35

Perfluoroalkyl Addition to Carbon Electrophiles . . . . . . . . . 35Alkenes . . . . . . . . . . . . . . . . . 35Alkynes . . . . . . . . . . . . . . . . . 42Arenes . . . . . . . . . . . . . . . . . . 43Heteroarenes . . . . . . . . . . . . . . . . 46Alkyl, Alkenyl, and Aryl Halides and Pseudohalides . . . . . . . 47

Alkyl Halides and Pseudohalides . . . . . . . . . . . 47Alkenyl Halides and Pseudohalides . . . . . . . . . . 52Aryl and Heteroaryl Halides and Pseudohalides . . . . . . . 54

Alcohols . . . . . . . . . . . . . . . . . 66Epoxides . . . . . . . . . . . . . . . . . 67Amines . . . . . . . . . . . . . . . . . 68Aldehydes . . . . . . . . . . . . . . . . . 68

Diastereoselective Perfluoroalkyl Addition to Aldehydes . . . . . 78Enantioselective Perfluoroalkyl Addition to Aldehydes . . . . . . 80

Ketones . . . . . . . . . . . . . . . . . 86Diastereoselective Perfluoroalkyl Addition to Ketones . . . . . . 95Enantioselective Perfluoroalkyl Addition to Ketones . . . . . . 99

Thioketones . . . . . . . . . . . . . . . . 104Acylsilanes . . . . . . . . . . . . . . . . . 105Imines and Iminium Salts . . . . . . . . . . . . . 105

Unactivated Imines . . . . . . . . . . . . . . 105Activated Imines . . . . . . . . . . . . . . . 108Iminium Salts . . . . . . . . . . . . . . . 115Other . . . . . . . . . . . . . . . . . 120

Azirines . . . . . . . . . . . . . . . . . 120Hydrazones . . . . . . . . . . . . . . . . 121Nitrones . . . . . . . . . . . . . . . . . 122Diazo Compounds . . . . . . . . . . . . . . . 124Acid Halides . . . . . . . . . . . . . . . . 124Anhydrides . . . . . . . . . . . . . . . . . 128Esters and Lactones . . . . . . . . . . . . . . . 130Imides . . . . . . . . . . . . . . . . . . 134Amides . . . . . . . . . . . . . . . . . 136Imidoyl Halides . . . . . . . . . . . . . . . 139Imino Esters . . . . . . . . . . . . . . . . 139Nitriles . . . . . . . . . . . . . . . . . 140Cyanates, Thiocyanates, and Their Isoforms . . . . . . . . . 140Other Carboxylic Acid Derivatives . . . . . . . . . . . 140Other . . . . . . . . . . . . . . . . . . 141

Perfluoroalkyl Addition to Heteroatom Electrophiles . . . . . . . 142Boron Electrophiles . . . . . . . . . . . . . . . 142

NUCLEOPHILIC ADDITIONS OF PERFLUOROALKYL GROUPS 3

Silicon Electrophiles . . . . . . . . . . . . . . 143Germanium Electrophiles . . . . . . . . . . . . . 144Tin Electrophiles . . . . . . . . . . . . . . . 144Lead Electrophiles . . . . . . . . . . . . . . . 144Nitrogen Electrophiles . . . . . . . . . . . . . . 144Phosphorus Electrophiles . . . . . . . . . . . . . 145Arsenic Electrophiles . . . . . . . . . . . . . . 147Antimony Electrophiles . . . . . . . . . . . . . . 147Bismuth Electrophiles . . . . . . . . . . . . . . 147Sulfur Electrophiles . . . . . . . . . . . . . . . 148Selenium Electrophiles . . . . . . . . . . . . . . 152Tellurium Electrophiles . . . . . . . . . . . . . . 154Chlorine Electrophiles . . . . . . . . . . . . . . 154Bromine Electrophiles . . . . . . . . . . . . . . 154Iodine Electrophiles . . . . . . . . . . . . . . 154Xenon Electrophiles . . . . . . . . . . . . . . 155Transition-Metal Electrophiles . . . . . . . . . . . . 155

Titanium Complexes . . . . . . . . . . . . . . 155Rhodium Complexes . . . . . . . . . . . . . . 155Nickel Complexes . . . . . . . . . . . . . . 155Palladium Complexes . . . . . . . . . . . . . 156Platinum Complexes . . . . . . . . . . . . . . 157Copper Complexes . . . . . . . . . . . . . . 158Silver Complexes . . . . . . . . . . . . . . 158Gold Complexes . . . . . . . . . . . . . . . 158Zinc and Cadmium Complexes . . . . . . . . . . . 158

Comparison with Other Methods . . . . . . . . . . . . 158Electrophilic Perfluoroalkyl Additions . . . . . . . . . . . 158Radical Perfluoroalkyl Additions . . . . . . . . . . . . 159Transition-Metal-Assisted Perfluoroalkyl Additions . . . . . . . . 161

Experimental Conditions . . . . . . . . . . . . . . 165General Comments . . . . . . . . . . . . . . . 165Reactions with (Trifluoromethyl)trimethylsilane . . . . . . . . . 166Reactions with Perfluoroalkyllithium Reagents . . . . . . . . . 166Reactions with Perfluoroalkylmagnesium Reagents . . . . . . . . 167Reactions with Perfluoroalkylcopper Reagents . . . . . . . . . 167

Experimental Procedures . . . . . . . . . . . . . . 167Phenyl Trifluoromethyl Sulfide [Trifluoromethylation of Diphenyl Disulfide Using

Trifluoromethane] . . . . . . . . . . . . . . 168(Trifluoromethyl)triethylsilane [Preparation from Trifluoromethyl Phenyl

Sulfone] . . . . . . . . . . . . . . . . 168(Trifluoromethyl)triethylsilane [Trifluoromethylation of Chlorotriethylsilane Using

Trifluoromethane] . . . . . . . . . . . . . . 169(Trifluoromethyl)trimethylsilane [Trifluoromethylation of TMSCl Using

CF3Br . . . . . . . . . . . . . . . . . 169Ethyl 5-Phenyl-2-trifluoromethylpenta-2,4-dienoate [Trifluoromethylation of a Vinyl

Iodide with FSO2CF2CO2Me] . . . . . . . . . . . 1691-Nitro-4-(trifluoromethyl)benzene [Trifluoromethylation of an Iodoarene with CF3Cu

Prepared from 2,2,2-Trifluoroacetophenone] . . . . . . . . 1702,2,2-Trifluoro-1-(6-methoxynaphthalen-2-yl)ethanol [Trifluoromethylation

of an Aromatic Aldehyde Using a Sulfur-Based TrifluoromethylatingReagent] . . . . . . . . . . . . . . . . 170

1-(Trifluoromethyl)cyclohexanol [Trifluoromethylation of an Enolizable Ketone UsingTMSCF3 and TBAF] . . . . . . . . . . . . . 171

4 ORGANIC REACTIONS

(S)-1,1,1-Trifluoro-5,5-dimethyl-2-phenylhex-3-yn-2-ol [EnantioselectiveTrifluoromethylation of a Non-Enolizable Ketone Using TMSCF3 and a ChiralPhase-Transfer Catalyst] . . . . . . . . . . . . 171

Benzyl (2,2,2-Trifluoro-1-phenylethyl)amine [Trifluoromethylation of an Imine UsingTMSCF3 under Acidic Conditions] . . . . . . . . . . 172

(S*,R*)-Methyl 3-Methyl-2-[(1-phenyl-2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoroheptyl)amino]butanoate [Diastereoselective Perfluorohexylation of anImine with Perfluoro-n-hexyllithium] . . . . . . . . . 172

2-Biphenyl-4-yl-1,1,1,3,3,3-hexafluoropropan-2-amine [Trifluoromethylation of a NitrileUsing TMSCF3] . . . . . . . . . . . . . . 173

Tabular Survey . . . . . . . . . . . . . . . . 173Chart 1. Catalysts, Reagents, and Initiators Used in Tables . . . . . . 176Table 1. Perfluoroalkyl Addition to Alkenes . . . . . . . . . 182Table 2. Perfluoroalkyl Addition to Alkynes . . . . . . . . . 194Table 3. Perfluoroalkyl Addition to Arenes . . . . . . . . . 199Table 4. Perfluoroalkyl Addition to Heteroarenes . . . . . . . . 208Table 5A. Perfluoroalkyl Addition to Alkyl Halides and Pseudohalides . . . 217Table 5B. Perfluoroalkyl Addition to Alkenyl Halides and Pseudohalides . . 235Table 5C. Perfluoroalkyl Addition to Aryl and Heteroaryl Halides and

Pseudohalides . . . . . . . . . . . . . . . 250Table 6. Perfluoroalkyl Addition to Alcohols . . . . . . . . . 319Table 7. Perfluoroalkyl Addition to Epoxides . . . . . . . . . 320Table 8. Perfluoroalkyl Addition to Amines . . . . . . . . . 321Table 9. Perfluoroalkyl Addition to Aldehydes . . . . . . . . 323Table 10. Perfluoroalkyl Addition to Ketones . . . . . . . . . 423Table 11. Perfluoroalkyl Addition to Thioketones . . . . . . . . 541Table 12. Perfluoroalkyl Addition to Acylsilanes . . . . . . . . 542Table 13. Perfluoroalkyl Addition to Imines and Iminium Salts . . . . 543Table 14. Perfluoroalkyl Addition to Azirines . . . . . . . . . 574Table 15. Perfluoroalkyl Addition to Hydrazones . . . . . . . . 575Table 16. Perfluoroalkyl Addition to Nitrones . . . . . . . . . 579Table 17. Perfluoroalkyl Addition to Acid Halides . . . . . . . 582Table 18. Perfluoroalkyl Addition to Anhydrides . . . . . . . . 595Table 19. Perfluoroalkyl Addition to Carboxylic Acids, Esters,

and Lactones . . . . . . . . . . . . . . . 599Table 20. Perfluoroalkyl Addition to Nitriles . . . . . . . . . 623Table 21. Perfluoroalkyl Addition to Imides . . . . . . . . . 624Table 22. Perfluoroalkyl Addition to Amides . . . . . . . . . 630Table 23. Perfluoroalkyl Addition to Other Carboxylic Acid Derivatives . . 640Table 24. Perfluoroalkyl Addition to Imidoyl Halides . . . . . . . 644Table 25. Perfluoroalkyl Addition to Imino Esters . . . . . . . . 646Table 26. Perfluoroalkyl Addition to Cyanates, Thiocyanates, and their

Isoforms . . . . . . . . . . . . . . . . 647Table 27. Perfluoroalkyl Addition to Other Carbon Electrophiles . . . . 648Table 28. Perfluoroalkyl Addition to Boron Electrophiles . . . . . . 649Table 29. Perfluoroalkyl Addition to Non-Carbon Group 14 Electrophiles . . 654

A. Silicon . . . . . . . . . . . . . . . 654B. Germanium . . . . . . . . . . . . . . 661C. Tin . . . . . . . . . . . . . . . . 662D. Lead . . . . . . . . . . . . . . . . 664

Table 30. Perfluoroalkyl Addition to Group 15 Electrophiles . . . . . 665A. Nitrogen . . . . . . . . . . . . . . . 665B. Phosphorus . . . . . . . . . . . . . . 666C. Arsenic, Antimony, and Bismuth . . . . . . . . . 674

NUCLEOPHILIC ADDITIONS OF PERFLUOROALKYL GROUPS 5

Table 31. Perfluoroalkyl Addition to Group 16 Electrophiles . . . . . 676A. Sulfur . . . . . . . . . . . . . . . 676B. Selenium . . . . . . . . . . . . . . . 696C. Tellurium . . . . . . . . . . . . . . . 699

Table 32. Perfluoroalkyl Addition to Group 17 Electrophiles. . . . . . 700A. Chlorine . . . . . . . . . . . . . . . 700B. Bromine . . . . . . . . . . . . . . . 701C. Iodine . . . . . . . . . . . . . . . 702

Table 33. Perfluoroalkyl Addition to Xenon Electrophiles. . . . . . . 704Table 34. Perfluoroalkyl Addition to Transition-Metal Electrophiles . . . 705

References . . . . . . . . . . . . . . . . . 718

ACKNOWLEDGMENTS

The authors thank the Institute of Organic Chemistry and Biochemistry, Academyof Science of the Czech Republic, FLX Bio, Inc., and the Loker HydrocarbonResearch Institute and Department of Chemistry, University of Southern California,Los Angeles for support. We are also greatly indebted to Dr. Engelbert Ciganek forhelp with the Tabular Survey, Dr. Michael J. Martinelli and Prof. Scott E. Denmarkfor helpful guidance, and to Dr. Linda Press for editorial assistance.

INTRODUCTION

Trifluoromethyl- and perfluoroalkyl-containing organic compounds often possessproperties that make them suitable for diverse applications in material science, agro-chemistry, and the pharmaceutical industry. High electronegativity and lipophilicitytogether with oxidative, hydrolytic, and thermal stability make these groups unique.The trifluoromethyl group has electronegativity similar to that of oxygen1 and asize between isopropyl and tert-butyl groups.2 The higher lipophilicity enables thetrifluoromethyl-containing compounds to traverse lipid membranes readily in com-parison with their nonfluorinated analogues. Long-chain perfluoroalkyl groups haveconformationally rigid helical structures due to repulsive 1,3-difluoro interactions.3,4

The introduction of long perfluoroalkyl groups into an organic molecule changes itsreactivity and physical properties dramatically. This strategy has been used mainlyfor separations by immobilization into fluorous phases5 and also for fine-tuningsolid phase properties of novel liquid crystalline materials.6

The trifluoromethyl or perfluoroalkyl unit can be constructed using various fluo-rination methods: (1) from a trichloromethyl group using anhydrous HF, (2) froma carboxylic acid group by treatment with HF/SF4 or related reagents, (3) fromdithiocarboxylic acids with XeF2, (4) by oxidative desulfurization/fluorination withamine–HF complexes or (5) by fluorination of hydrocarbons with F2, halogenfluorides, high oxidation state metal fluorides, or electrochemical fluorinations.6–8

Direct introduction of perfluoroalkyl groups can be achieved by ionic (nucleophilicor electrophilic) or radical reactions. Nucleophilic perfluoroalkyl addition has beenperhaps the most attractive approach during the last few decades. It is considered to

6 ORGANIC REACTIONS

be an efficient, selective, and reliable method for introducing perfluoroalkyl groups(trifluoromethyl in particular) into organic molecules. This chapter focuses primarilyon reactions between an electrophilic compound and perfluoroalkyl carbanionicspecies providing stable perfluoroalkylated products. The most common, synthet-ically useful methods to generate perfluoroalkyl carbanions are summarized inScheme 1. Addition of fluoride ions to perfluoroalkenes also provide perfluoroalkylcarbanions (Scheme 2).

E+

RFE

:CF2F –

RF = CnF2n+1, n = 1, 2, 3 ...X = Br, IM = Li, Mg, Cu, Zn, CdR = alkyl, arylZ = S, Cm = 1, 2E = electrophileTDAE = tetrakis(dimethylamino)ethylene

RF–

RFH

RFX

RFI

RFX

RFSiR3

RFZOmR

base

(R2N)3P

M or RM

Lewis base

RFZONR2

RO–

RO–

TDAE

Scheme 1

F

FRF

F+ F–

RF CF3

F–

RF = CnF2n+1, n = 0, 1, 2, 3...

Scheme 2

This chapter is limited to the discussion of nucleophilic additions of saturatedperfluoroalkyl groups to various electrophiles that have appeared in the literature upto the end of the first quarter of 2014. All electrophilic species of carbon and othergroup 13–18 elements as well as transition-metal electrophiles are reviewed. Reac-tions of only those perfluoroalkyl addition reagents or reactive species that possessnucleophilic (carbanionic) character are considered. Although reaction mechanismsfor some metalloorganic species may at some point employ radicals, all reactionsthat have nucleophilic addition pathways are included. Reactions under typical radicalconditions (UV light, radical initiator) are excluded. For example, perfluoroalkylmer-cury reagents generally do not display nucleophilic character and tend to undergohomolytic Hg–RF bond dissociation.9

A number of reviews and book chapters about nucleophilic perfluoroalkyltransfer have appeared.3,6,10–13 Others cover various aspects of the topic such asusing organosilicon reagents,14–27 perfluoroalkyl organometallics,9,28–32 fluorinatedcarbanions,33,34 as well as asymmetric35–40 and enantioselective41–46 nucleophilicperfluoroalkyl additions.

NUCLEOPHILIC ADDITIONS OF PERFLUOROALKYL GROUPS 7

MECHANISM AND STEREOCHEMISTRY

As the title of the chapter suggests, nucleophilic perfluoroalkyl additioninvolves the generation of carbanionic perfluoroalkyl species from the precursors(see Schemes 1 and 2) and their reactions with electrophilic partners to formperfluoroalkyl-containing products. Perfluoroalkyl carbanions are stabilized bythe negative inductive effect of their fluoro and perfluoroalkyl substituents. At thesame time, α-fluoro carbanions are destabilized by electronic p–π repulsion of thefluorine lone electron pairs and at the anionic center. This property is reflected inthe relatively weak acidity of CHF3 in comparison with the other haloforms, eventhough fluorine has the highest electronegativity. The pKa values of the various tri-halomethanes are 30.5 (CHF3), 22.4 (CHCl3), 22.7 (CHBr3), and 68–70 (CH4).47–48

β-Fluorocarbanions are stabilized by negative hyperconjugation in addition to nega-tive inductive effects. Clear experimental evidence of negative hyperconjugation isobtained from X-ray structure analysis of the perfluoro-1,3-dimethylcyclobutanideanion (stable, mp 160–162∘), which shows that the cyclobutane ring and the anioniccenter are planar (Scheme 3).49

CF3

CF3

F FF

FF

CF2

CF3

F FF

FF

CF3

CF3

F F

FF–

CF3 CF3

FF

F F

(Me2N)3S+ Me3SiF2–

(1 equiv)

(Me2N)3S+ (Me2N)3S+ F– (Me2N)3S+ F–

THF, –10° to rt; then rt, 15 min

– Me3SiF (72%)

Scheme 3

Thus, in contrast to conventional alkyl organolithium and organomagnesiumreagents, trifluoromethyllithium and trifluoromethylmagnesium reagents areextremely unstable and cannot be used, not even at low temperatures.50 The rapiddegradation by α-fluoride elimination to difluorocarbene and metal fluorides forceshigher equivalents of the trifluoromethyl carbanion to be employed. However,long-chain perfluoroalkyl organometallics display much higher stability and canbe used synthetically, with the main degradation pathway being the β-fluorideelimination to terminal perfluoroalkenes.7

An effective way to stabilize the trifluoromethyl carbanion is to attach the CF3group to an atom with more covalent character such as copper, zinc, cadmium,silicon, tin, bismuth, sulfur, or carbon. Perfluoroalkyl copper species can be obtainedin a number of ways, for example by reaction of perfluoroalkyl iodides with copperpowder,51–53 by reaction of copper complexes with TMSCF3,54,55 by direct cupra-tion of fluoroform,56,57 or by reaction of CuI with readily available CF3CO2Na.58,59

The most common use of perfluoroalkyl copper species is cross-coupling withalkyl, alkenyl, and aryl halides to afford the corresponding perfluoroalkyl alkanes,alkenes, and arenes. The mechanism of the trifluoromethylation of 4-substitutediodoaromatic compounds with the sodium trifluoroacetate/CuI system has beenstudied. The positive ρ value of +0.46 obtained from a Hammett plot confirms the

8 ORGANIC REACTIONS

nucleophilic nature of the trifluoromethyl copper species.59 However, using CF3Cuobtained by direct cupration of fluoroform with CuCl and t-BuOK, the ρ value of+0.97 is obtained in the reaction of 3-substituted iodoaromatic compounds (usingσm substituent constants) and +0.91 in the reaction of 4-substituted iodoaromaticcompounds (using σp

–), clearly establishing nucleophilic attack of the aromaticring and –M interactions in the 4-substituted iodoaromatics.60 The efficiency ofthe reaction depends on the solvating power of the medium for the Cu(I) complex;DMF, NMP, pyridine, and DMSO afford the highest yields. The order of reactivityof the halogens as the aromatic leaving groups is I > Br ≫ Cl. Using AgI insteadof CuI for the decarboxylation of sodium trifluoroacetate does not transfer theCF3 group to the aryl iodide. The mechanism of copper-mediated cross-couplingof iodoarenes is unknown and several pathways for the reaction between simplephenyl iodide and CF3Cu have been proposed (Scheme 4): (1) σ-bond metathesis(SBM);6,30,59 (2) a radical pathway;60 (3) oxidative addition and formation of Cu(III)species.60–62 The trifluoromethylation reaction of a variety of aryl halides withfluoroform-derived CF3Cu has been studied by experimental (radical clock, kinetic,Hammett correlation) and computational methods.60 The combined data set points toa bimolecular process involving Ar−X oxidative addition to DMF-stabilized CF3Cuas the rate determining step, followed by Ar−CF3 reductive elimination from aCu(III) intermediate. The computed barrier for the trifluoromethylation of iodoben-zene (ΔG‡ = 21.9 kcal/mol at 298 K) is in good agreement with the experimentalvalue of ΔG‡ = 24 kcal/mol at 298 K. A radical mechanism has been ruled out onthe basis of both experimental and computational data. The latter have also shownprohibitively high barriers to SET (both outer and inner sphere) as well as classicalSNAr, SBM, and HAT (halogen atom transfer) processes previously proposed in theliterature for some other copper-mediated coupling reactions of aryl halides.60

L

– L3CuI

I+ CF3

CuL L

CF3

I

σ-bond metathesis

radical pathway

oxidative addition

or

I

L3CuCF3

CF3

CuI

CF3L CF3reductive elimination

Scheme 4

(Trifluoromethyl)trimethylsilane (TMSCF3), known as the Ruppert–Prakashreagent, is the most important reagent for nucleophilic addition of a trifluoromethylgroup.14,17 To exhibit nucleophilic properties, TMSCF3 must be activated with a

NUCLEOPHILIC ADDITIONS OF PERFLUOROALKYL GROUPS 9

Lewis base to generate a five-coordinate complex that serves as an equivalent oftrifluoromethyl carbanion (Scheme 5).14

TMSCF3LB–

LB– = F–, RO–, RCO2–, Me3N+O–

E+ = electrophile

Si MeCF3Me

MeLB

E+

–

E CF3– TMS LB

Scheme 5

Several Lewis bases (LB) can be employed to activate TMSCF3, among whichfluoride and oxygen nucleophiles (acetate, phenolate, carbonate) are the mosteffective and the most often used. The generation of five-coordinate species[Me3Si(CF3)LB]– is confirmed by low-temperature NMR studies (LB = F–),63

and one such complex (LB = CF3–) has been characterized by X-ray diffraction

analysis.64 The formation of five- and six-coordinate structures bearing a CF3 group atsilicon has also been studied computationally65 and a single-crystal X-ray structure ofTMSCF3

66 shows a distorted tetrahedral geometry at the silicon atom and the longestknown Si–C distance [Si–CF3, 1.943(12) Å], which helps to explain the facile cleav-age of the Si–CF3 bond and CF3 group transfer. (Trifluoromethyl)trimethylsilane inthe presence of an activator behaves as a hard nucleophile and undergoes 1,2- ratherthan 1,4-addition to α,β-unsaturated carbonyl compounds.14

Trifluoromethyl derivatives of ketones, esters, amides, hemiaminals, hemiketals,sulfoxides, sulfones, sulfinates, and sulfinamides can be activated by alkoxides tofunction as sources of CF3

– (Schemes 6–8). To avoid strong bases, derivatives con-taining trimethylsilyl ethers are often used to generate the alkoxides, convenientlyusing fluoride ions and after an intramolecular attack of the carbon or sulfur atom,the adjacent trifluoromethyl group is released as a carbanionic species.

R1 CF3

O R2O–

R1 CF3

O OR2–E+

ECF3 +R1 OR2

O R1 = Ph, R2O, (R2)2NR2 = alkylE+ = electrophile

Scheme 6

R1 CF3

XO N(R2)2 base (X = H)

F– (X = TMS) R1 CF3

O N(R2)2– E+

ECF3 +R1 N(R2)2

O R1 = H, PhR2 = alkylE+ = electrophile

Scheme 7

R1 SO

OCF3

R1 = Ph, R2O, (R2)2NR2 = alkylE+ = electrophile

SR1O

OCF3

OR2R2O––

E+ECF3 + R1 S

O

OOR2

Scheme 8

10 ORGANIC REACTIONS

Perfluoroalkyl carbanion salts can be prepared by the addition of fluoride saltsto perfluorinated olefins.49,67,68 Tertiary perfluoroalkyl carbanions are rather stable(their tris(dimethylamino)sulfonium (TAS+) salts are stable solids) but secondarycarbanions are not observed due to rearrangement to the tertiary anions (Scheme 9)68

or dimerization by addition to another molecule of olefin and subsequent rearrange-ment (Scheme 10).68

FF

FF

CF3

CF3(Me2N)3S+ F–

CF3 C–

F

FCF3

CF3

–

(Me2N)3S+ (Me2N)3S+

CF3CF3

CF3

F F

Scheme 9

–

F

FFF

FF

F F

(Me2N)3S+ F–

THF

C F

FFF

FF

F F

F(Me2N)3S+

C

F F F

FF

FF

FFFF

FFF

F F

C

F F F

FF

FFF

FFFF

FFF

F FF –

F

FFF

FF

F F

(Me2N)3S+ (Me2N)3S+

–

Scheme 10

Preparation of perfluoroalkyl addition reagents, generation and stability ofnucleophilic species, and scope and limitations of reactivity, selectivity, and stereo-chemical considerations of electrophiles are covered in the next section. From theelectrophile point of view, perfluoroalkyl reagents undergo nucleophilic substitution(in the case of alkyl halides, triflates, cyclic sulfates, and halogenated heteroatomelectrophiles), or nucleophilic addition or addition–elimination sequences (in thecase of unsaturated substrates, arenes, aryl halides, carbonyl compounds, nitrogen-containing electrophiles derived from carbonyl compounds, and transition-metalcomplexes).

SCOPE AND LIMITATIONS

This section is divided into two parts. In the first part, different types of nucleo-philic perfluoroalkyl addition reagents are introduced and their preparation isdescribed. In the second part, the scope and limitations of perfluoroalkyl additionsto various types of electrophiles is described in detail.

NUCLEOPHILIC ADDITIONS OF PERFLUOROALKYL GROUPS 11

Overview and Preparation of Nucleophilic Perfluoroalkyl Reagents

Nucleophilic perfluoroalkyl species can be generated in various ways from chemi-cally diverse precursors (see Scheme 1 for the most common methods). The followingsection provides an overview of the preparation and properties of nucleophilic per-fluoroalkyl reagents and is organized by the type of precursor. The description ofreactivity of those reagents with electrophilic partners is kept to a minimum. Detaileddiscussion of the scope and limitations for each type of electrophile is found in thenext section.

Deprotonation of Trifluoromethane and Polyfluoroalkanes. Fluoroform(bp –82.1∘) is a side-product of the industrial synthesis of Freon 22 (CHF2Cl), akey intermediate in the multistep synthesis of Teflon. Deprotonation of fluoroformwith Grignard reagents or alkyllithium species generates the trifluoromethyl anion,which quickly decomposes to difluorocarbene even at low temperature.50 Despitethis limitation, trifluoromethane can effectively be employed for nucleophilictrifluoromethylation by using various bases with or without solvent stabilization.Thus, trifluoromethyl anion can be formed by the deprotonation of fluoroform withvarious electrochemically generated bases 1 derived from 2-pyrrolidinone in DMFat –50∘ (Scheme 11).69

NH

O N O–

e–, R14NOTs

Pt electrodes, DMF, rtR1

4N+

R1 Et n-Bu n-C8H17

1a1b1c

DMF, –50 to –10°

CF3H, R2 R3

O

R2 R3

HO CF3

1

Scheme 11

Phenyl anion (Ph–), produced by electroreduction of a large excess of iodobenzenein DMF, can deprotonate fluoroform or pentafluoroethane, allowing perfluoroalkyl-ation of aldehydes or alkyl halides. Only those electrophiles that are not more easilyreduced than iodobenzene can be used.70 Other bases such as t-BuOK in DMF, potas-sium dimsylate, KHMDS in toluene or THF, and (TMS)3N together with a fluorideion source and a catalytic amount of DMF in THF are used for the deprotonation offluoroform and further perfluoroalkylation.48,71–78 The solvent plays a crucial rolein the stabilization of the trifluoromethyl anion. When fluoroform is added at lowtemperature (–50 to –10∘) into a mixture of t-BuOK or dimsyl potassium in DMF,the trifluoromethyl anion is trapped in situ by the weak electrophile DMF to formthe amino alcoholate 2 (Scheme 12).71,72 Intermediate 2 is a masked and relativelystable form of the trifluoromethyl anion at temperatures below –10∘, but a rapiddegradation occurs at room temperature.48 Intermediate 2 reacts with electrophiles

12 ORGANIC REACTIONS

such as aldehydes, ketones, or disulfides to form the trifluoromethylated productsand DMF is regenerated (Scheme 12). Alternatively, hydrolysis of intermediate 2produces fluoral.48,71,72 Solvents such as THF or DMF dimethyl acetal afford verylow yields of the trifluoromethylated product due to carbenoid degradation. However,other dialkylformamides such as N-formylmorpholine can replace DMF in stabilizingthe trifluoromethyl anion. DMF is also found to enhance the efficiency of trifluo-romethylation of benzophenone using [18F]-fluoroform for PET (positron emissiontomography) applications.79

or t-BuOK (2.2 equiv)

DMF, –50 to –10°CF3H

DMFCF3K

CF3 NMe2

OK E+

CF3E

2 E = aldehyde, ketone, disulfide

KH (2 equiv), DMSO

Scheme 12

In contrast to previous findings, recent reports show that fluoroform in THF ortoluene solution at low temperature is deprotonated with KHMDS, allowing trifluo-romethylation of TMSCl, sulfur, trialkyl borates, and carbonyl electrophiles in mod-erate to high yields.77 Trifluoromethanide anion with the [K(18-crown-6)]+ cationis prepared from fluoroform, t-BuOK, and 18-crown-6 in THF and is found to bestable at –78∘ for a few days, allowing its characterization by NMR spectroscopy.80

Deprotonation of fluoroform with t-BuOK in DMF and NMP followed by captur-ing trifluoromethyl anionic species with copper salts is a very important method toprepare CF3Cu reagents.56,57

The sterically demanding P4-t-Bu phosphazene base developed by Schwesingerand co-workers is able to deprotonate fluoroform under suitable conditions (THF, –30to – 40∘). The resulting salt or binary complex (P4-t-Bu/H)+CF3

– is not observed byNMR spectroscopy;81 however, the mixture is able to trifluoromethylate a variety ofelectrophiles such as aldehydes, ketones, carbon dioxide, acid chlorides, esters, diaryldisulfides, and even epoxides.81,82

Pentafluoroethane and higher polyfluoroalkanes are converted into perfluoroalkyl-lithium reagents by reaction with methyllithium and are subsequently used for per-fluoroalkyl additions. The perfluoro tert-butyl anion is generated from (CF3)3CH andtriethylamine. Subsequent reactions with electrophiles such as tropylium bromide,83

paraformaldehyde,84 electron-deficient alkenes,85–87 and alkynes88 provide the cor-responding perfluoro tert-butyl containing products.

Reduction of Perfluoroalkyl Halides. tetrakis(Dimethylamino)ethylene(TDAE) is a strong electron donor that reacts with CF3I (but not CF3Br) in polarsolvents such as dichloromethane or benzonitrile at low temperature to form a deepred charge-transfer complex. The complex decomposes slowly above 0∘; however, inthe presence of an electrophilic compound, trifluoromethylation becomes the mainreaction pathway (Scheme 13).89

NUCLEOPHILIC ADDITIONS OF PERFLUOROALKYL GROUPS 13

CF3INMe2

NMe2Me2N

Me2N NMe2

NMe2Me2N

Me2N++

I–CF3–

E+

H+

> °C CF3

Me2N NMe2

CF3

NMe2

NMe2Me2N

Me2N++

I–I–

+ + CF3HTDAE

CF3E

Scheme 13

An alternative method to CF3I/TDAE is the combination of tris(dialkylamino)phos-phine and CF3Br. The reaction of CF3Br with TMSCl mediated by (Et2N)3P providesTMSCF3 in high yields90 and proceeds via a bromophilic attack of the phosphorusatom of (Et2N)3P to CF3Br. The formed phosphonium salt is in equilibrium with thepentacoordinate phosphorus intermediate which transfers the CF3 group to TMSCl(Scheme 14).16,17,91,92

TMSCF3

CF3Br + (Et2N)3P

[(Et2N)3P(CF3)]+ Br– (Et2N)3P(CF3)BrTMSCl

(Et2N)3P+Br Cl– +

[(Et2N)3PBr]+ (CF3)–

Scheme 14

Although CF3I is more expensive than CF3Br, one important advantage of usingthe TDAE rather than tris(dialkylamino)phosphine method is that trifluoromethyl-tris(dialkylamino)phosphonium salts are usually soluble in the reaction medium,often making the separation from the perfluoroalkylated product difficult. On theother hand, the oxidation product of TDAE is a dication, which is only slightlysoluble in the above-mentioned solvents, and can be removed by filtration. Trifluo-roiodomethane in combination with TDAE acts as an efficient trifluoromethylatingreagent for halogenated silanes, phosphines, boranes, fluorinated alkenes, aromaticcompounds, carbonyl compounds, disulfides, diselenides, carboxylic acid halides,imines, cyclic sulfates, and other electrophiles.

Electrochemical reduction of CF3Br or CF3I and the trapping of the formedtrifluoromethyl anion by TMSCl or DMF has also been reported.93–96

Non-Metallic Perfluoroalkyl Salts from Addition of Fluoride to Perfluoro-alkenes. Stable perfluoroalkyl carbanion salts are isolated by the reactionof fluorinated olefins with TASF (tris(dimethylamino)sulfonium fluoride)(Scheme 15).67,68,49 For example, carbanion 3 (Scheme 16)68 is stable up to60∘ and is used for perfluoroalkylation of various simple electrophilic substratessuch as Cl2, Br2, NOF, NOCl, or BnBr.68 By contrast, the corresponding cesium saltsare much less stable and in some cases cannot be detected by 19F NMR spectroscopy.

14 ORGANIC REACTIONS

R2

R2R1

R1

(Me2N)3S+R1

R1

– R2

F R2

R1 = CF3, C2F5 R2 = F, CF3, C2F5

(Me2N)3S+ F–

Scheme 15

(Me2N)3S+

CF3

CF3

n-C3F7

–F

C2F5CF3

CF3

3

(Me2N)3S+ F–

Scheme 16

Strong electron donors such as TDAE or trimethylamine react with unsaturated flu-orocarbons such as hexafluoropropene or tetrafluoroethylene to produce fluoride saltsthat are soluble in organic solvents.97 These fluoride salts oligomerize in the presenceof excess unsaturated fluorocarbons (Scheme 17)97 or can undergo perfluoroalkyl-ation reactions with activated fluoroaromatic compound such as pentafluoropyridine,tetrafluoropyrimidine, trifluorotriazine, or 2,4-dinitrofluorobenzene.97,98

NMe2

NMe2Me2N

Me2N

TDAE

CF2=CFCF3 (80 equiv)

rt, 24 h NMe2

NMe2Me2N

Me2N+ F–

FF

CF3

Q+ [(CF3)2CF]–CF2=CFCF3

(88%)

60°, 24 h

(82%)

Q+F–

CF3

CF3 F

F FCF3

F–

Q+ rt

– Q+ F– CF3

CF3 F

FCF3

F

CF3

CF3

F FCF3

F–

Q+

F

– Q+ F– CF3

CF3

FCF3

F F

CF2=CFCF3

Scheme 17

Another source of metal-free anhydrous fluoride for addition to perfluoroalkenes isdimethylfluoromethylamine and dimethyldifluoromethylamine, which dissociate inpolar solvents to form iminium fluorides. Reactions with unsaturated fluorocarbonsafford perfluoroalkyl carbanions, which collapse to form dimethylpolyfluoroalkyl-amines (Scheme 18).99,100

NUCLEOPHILIC ADDITIONS OF PERFLUOROALKYL GROUPS 15

Me2NCHXF (Me2N+=CHX) F–

X = H, F

CF2=CFCF3 (1.8 equiv)diglyme, 60°X = H

(Me2N+=CH2) –CF(CF3)2

(CF3)2C=CF2 (2 equiv)diglyme, rt

X = F

(Me2N+=CHF) –C(CF3)3

Me2NCH2CF(CF3)2 + poly(perfluoropropene)

(29%)(59%)

Me2NCHFC(CF3)3 + + (CF3)3CH(35%) (—) (—)

Me2N+=CF–

Scheme 18

Tris(dimethylamino)fluoromethane reacts with perfluoroisobutylene to afford thestable solid perfluoro-tert-butyl anion quantitatively. Reaction of this anion with ben-zoyl chloride provides phenyl perfluro-tert-butyl ketone in high yield (Scheme 19).101

diglyme, –20°

PhCOClPh

O

(88%)(Me2N)3C+ F– (Me2N)3C+ –C(CF3)3

F

F CF3

CF3 CF3

CF3 CF3

Scheme 19

Carbon–Boron Bond Cleavage from Perfluoroalkyl Boron Reagents. Potas-sium trialkoxy(perfluoroalkyl)borates, prepared by the reaction of trialkoxyborateswith TMSRF in the presence of KF, are stable reagents for efficient nucleophilic per-fluoroalkyl additions to mainly non-enolizable aldehydes, ketones, N-tosylaldimines,iminium salts, and aryl iodides (under copper catalysis).102–104

Carbon–Carbon Bond Cleavage from Perfluoroalkyl Carbonyl Reagentsand their Derivatives. Derivatives of trifluoroacetaldehyde, trifluoromethyl ketones,and perfluoroalkanoic acids have been investigated as nucleophilic perfluoroalkyladdition reagents.48,71,72,105–107 Trifluoroacetaldehyde hydrate acts as a nucleophilictrifluoromethylating reagent for non-enolizable aldehydes and ketones in the presenceof excess t-BuOK. Density functional theory calculations suggest that transfer of theCF3 group takes place from the double deprotonated trifluoroacetaldehyde hydrate(Scheme 20).106

CF3 OH

OH

•2H2O or 1/2H2O

t-BuOK (4–5 equiv)

DMF, –50° CF3 O–K+

O–K+R1C(O)R2

DMF, –50° R1 R2

HO CF3+ HCO2K

Scheme 20

16 ORGANIC REACTIONS

Amino alcoholate 2 (Scheme 12) is too unstable to be isolated, but other morestable derivatives have been prepared. Transmetalation of compound 2 with CuIaffords the copper(I) alkoxide, which upon warming to room temperature decom-poses to a trifluoromethylcopper species able to form 4-trifluoromethylanisole from4-iodoanisole in low yield.48 This method of perfluoroalkylcopper generation isdiscussed later in the chapter. Hemiaminals 4 and 5 are prepared from fluoral in verygood yields (Scheme 21),105 and are used for trifluoromethylation of benzaldehydein DMF in the presence of t-BuONa.105 Although TMS-protected hemiaminal 6forms from fluoroform, its isolation is difficult and the compound has a limited shelflife74,75,108 (Scheme 22).75

CF3 OH

OH P2O5, H3PO4CF3CHO

R2NH

THF, –40 to –20° CF3 NR2

OH

45

REtn-Bu

Yield (%)9090

Scheme 21

CF3H +(TMS)3N, Me4NF (cat.)

THF, –10° CF3 NMe2

OTMS

6 (—)

H NMe2

O

Scheme 22

More stable hemiaminals 7 and 8 and their TMS derivatives 9 and 10 are efficientlyprepared from the methyl hemiacetal of fluoral109,110 (Scheme 23).41 Compound 9 isalso prepared from fluoroform (Scheme 24).74 In general, reagents 7 and 8 require theuse of a strong base such as t-BuOK, whereas trimethylsilyl derivatives 9 and 10 areactivated by a fluoride salt. All reagents trifluoromethylate non-enolizable carbonylcompounds, disulfides, and diselenides. 41,74,108–112

Y

N

CF3 OH

Y

N

CF3 OTMS

Y

HN

CF3 OMe

OH+

4 Å MS

CH2Cl2, rt, 48 h THF, rt, 4 h

78

YOBnN

Yield (%)9075

910

YOBnN

Yield (%)100100

NN TMS

Scheme 23

NUCLEOPHILIC ADDITIONS OF PERFLUOROALKYL GROUPS 17

CF3H +(TMS)3N, TMAF (cat.)

THF, –10°O

N

O

N

CF3 OTMS

9 (78%)

CHO

Scheme 24

The stable and non-hygroscopic amidinate salt of hexafluoroacetone hydrate (11)precipitates from an ethereal solution of hexafluoroacetone hydrate upon additionof DBU. This salt effects trifluoromethylation of non-enolizable aldehydes, ketones,and diphenyl disulfide (Scheme 25).107 It also decomposes to trifluoroacetate andfluoroform in the reaction with DBU.

CF3 CF3

HO OH•2H2O

DBU (1 equiv)

Et2O, rtCF3 CF3

HO O–N

NH

+

11 (89%)

1. R1C(O)R2 (0.83 equiv), t-BuOK (3.67 equiv), n-Bu4NCl (3.67 equiv), DMF, –30° to rt2. NH4Cl, H2O, rt

R1 R2

HO CF3 PhSCF3

(73%)(78–96%)

DBU (1 equiv)60°, 20 h

CF3CO2– + CF3H

N

NH

+

PhSSPh (0.8 equiv), t-BuOK (3.67 equiv),n-Bu4NCl (3.67 equiv), DMF, –30° to rt

Scheme 25

Phenyl trihalomethyl ketones undergo haloform cleavage in sodium hydroxide.The rate constants for the reaction of trichloro- or tribromoacetophenone aremany orders of magnitude higher than for trifluoroacetophenone.113 Similarly, thehydrated form of trifluoroacetophenone undergoes cleavage with NaH in DMFto afford sodium benzoate and fluoroform.114 These observations suggest thepossibility of generating the trifluoromethyl carbanion from trifluoromethyl ketonesfor further trifluoromethylation reactions. Indeed, in the presence of t-BuOK,trifluoroacetophenone trifluoromethylates non-enolizable ketones.115 Aromaticaldehydes do not react under these conditions.

The trimethylsilyl-protected hemiketal 12, derived from trifluoroacetophenone, isanother shelf-stable trifluoromethylating reagent for non-enolizable aldehydes andketones116,117 (Scheme 26).117

18 ORGANIC REACTIONS

Ph

O

CF3 Ph

Me2N

CF3

OTMS

12 (87%)

Me2NTMS (1 equiv)

neat, 110°, 16 h

Scheme 26

Esters of perfluoroalkanoic acids undergo cleavage reactions with sodium ethoridein ethanol to provide diethyl carbonate and perfluoroalkanes in ca. 70% yields. Inthe case of CF3CO2Et, trifluoromethane is obtained in only 43% yield and a sig-nificant amount of fluoride forms in the reaction mixture, the latter arising fromdecomposition of the intermediate trifluoromethyl carbanion.118 In the presence oft-BuOK, methyl trifluoroacetate serves as a trifluoromethylating reagent toward non-enolizable ketones in moderate yields,119 and in the presence of CsF or CsCl and CuIunder heating constitutes a valuable trifluoromethylating system for aromatic iodidesand bromides.120

A number of trifluoroacetamides 13a–g are capable of trifluoromethylating non-enolizable ketones in the presence of 1 equivalent of t-BuOK.119 Interestingly, cyclicamine derivatives 13e–g provide better yields than acyclic amides 13a–d.119

Y

N

CF3 O

CF3 NR1

R2

OYOBnNCH2

13e13f13g

13a13b13c13d

R1

Men-BuMei-Pr

R2

Men-BuBni-Pr

The more reactive trifluoroacetamides 14a–o derived from O-silylated β-aminoalcohols (Scheme 27) 41,42,121 allow slow delivery of the alcoholate by fluoride-induced desilylation followed by intramolecular attack on the amide carbonyl.Collapse of the tetrahedral intermediate to yield oxazolidinones 15 with concomitanttrifluoromethylation of carbonyl compounds completes the catalytic cycle, as shownin Scheme 28.121

Indeed, amides 14, with the exception of 14e, 14f, and 14o, trifluoromethylate var-ious carbonyl compounds in the presence of a catalytic amount of a fluoride source.The lack of reactivity of amide 14o is explained by invoking an unfavorable con-former equilibrium121 (Scheme 29).42

The remaining amides 14 are good trifluoromethylating agents for both enolizableand non-enolizable aldehydes and ketones using catalytic amounts of CsF in DME orTBAT (tetrabutylammonium difluorotriphenylsilicate) in THF. Amides without sub-stitution in the α-position relative to nitrogen (14a–c) need thermal activation up to80∘ for efficient CF3 transfer, whereas those with substitution (14d–n) are more reac-tive and require lower temperatures (40∘ or rt). The exception is amide 14k, which isable to transfer the CF3 group only very sluggishly at rt. Many of the amides 14 are