Science of Synthesis

Science of Synthesis is the authoritative and comprehensive reference work for the entire field of organic and organometallic synthesis.

Science of Synthesis presents the important synthetic methods for all classes of compounds and includes:

Methods critically evaluated by leading scientists

Background information and detailed experimental procedures

Schemes and tables which illustrate the reaction scope

Preface

As our understanding of the natural world increases, we begin to understand complex phenomena at molecular levels. This level of understanding allows for the design of molecular entities for functions ranging from material science to biology. Such design requires synthesis and, as the structures increase in complexity as a necessity for specificity, puts increasing demands on the level of sophistication of the synthetic methods. Such needs stimulate the improvement of existing methods and, more importantly, the development of new methods. As scientists confront the synthetic problems posed by the molecular targets, they require access to a source of reliable synthetic information. Thus, the need for a new, comprehensive, and critical treatment of synthetic chemistry has become apparent. To meet this challenge, an entirely new edition of the esteemed reference work Houben–Weyl Methods of Organic Chemistry will be published starting in the year 2000.

To reflect the new broader need and focus, this new edition has a new title, Science of Synthesis, Houben–Weyl Methods of Molecular Transformations. Science of Synthesis will benefit from more than 90 years of experience and will continue the tradition of excellence in publishing synthetic chemistry reference works. Science of Synthesis will be a balanced and critical reference work produced by the collaborative efforts of chemists, from both industry and academia, selected by the editorial board. All published results from journals, books, and patent literature from the early 1800s until the year of publication will be considered by our authors, who are among the leading experts in their field. The 48 volumes of Science of Synthesis will provide chemists with the most reliable methods to solve their synthesis problems. Science of Synthesis will be updated periodically and will become a prime source of information for chemists in the 21st century.

Science of Synthesis will be organized in a logical hierarchical system based on the target molecule to be synthesized. The critical coverage of methods will be supported by information intended to help the user choose the most suitable method for their application, thus providing a strong foundation from which to develop a successful synthetic route. Within each category of product, illuminating background information such as history, nomenclature, structure, stability, reactivity, properties, safety, and environmental aspects will be discussed along with a detailed selection of reliable methods. Each method and variation will be accompanied by reaction schemes, tables of examples, experimental procedures, and a background discussion of the scope and limitations of the reaction described.

The policy of the editorial board is to make Science of Synthesis the ultimate tool for the synthetic chemist in the 21st century.

We would like to thank all of our authors for submitting contributions of such outstanding quality, and, also for the dedication and commitment they have shown throughout the entire editorial process.

October 2000

The Editorial Board

D. Bellus (Basel, Switzerland)

E. N. Jacobsen (Cambridge, USA)

S. V. Ley (Cambridge, UK)

R. Noyori (Nagoya, Japan)

M. Regitz (Kaiserslautern, Germany)

P. J. Reider (New Jersey, USA)

E. Schaumann (Clausthal-Zellerfeld, Germany)

I. Shinkai (Tsukuba, Japan)

E. J. Thomas (Manchester, UK)

B. M. Trost (Stanford, USA)

Volume Editor’s Preface

The chemical and patent literature contains very many monofluorinated compounds; most of them fall outside the scope of this volume because they contain fluorine bound to an aromatic or heteroaromatic nucleus. In these locations, a single fluorine atom can increase bioavailability by increasing hydrophobicity, or block metabolic oxidation; these effects are familiar and much exploited. In the molecules described in this volume, the solitary fluorine atom can modify pKa (and bioavailability), conformation, molecular recognition (through the modulation of hydrogen bonding networks), and serve as a valuable label for NMR studies in vivo and in vitro, and all with minimal perturbation of molecular volume. Chemists working at the interface with biomolecular science often use molecules bearing this remarkable atom, either as candidate drug molecules or to gain insight concerning events in enzyme active sites, or when proteins bind to ligands, at the molecular level. Significant gains await other scientists bold enough to consider solving their problems using selectively fluorinated molecules.

Of course, synthesis is a prerequisite and there are aspects of organofluorine chemistry which are distinctly specialized. However, the various contributors to this volume show clearly how the subject has expanded to admit the non-specialist, through the development of methods which deliver valuable compounds via procedures which can be run at normal temperatures and pressures, in conventional laboratory glassware, and with commercial reagents. The synthetic chemistry described in this volume achieves the exchange of many of the most common functional groups for a single C—F bond. Some of the reagents required are relatively hazardous and require careful handling; others are considerably more amenable to general use.

The volume covers the entire landscape of reagents from elemental fluorine and hydrofluoric acid, to transition-metal catalysts which mediate the introduction of fluorine in novel ways. The chemistry often occurs close to, or at, mechanistic borderlines; there is little real physical organic understanding of any of the transformations described in this volume so reaction outcomes can be unpredictable. Despite this potential difficulty, considerable progress has been made and there are many effective and ingenious methods for use in target synthesis. One of the major challenges in this area of chemistry is sustainability; for example, the fluorinated methanes, a well-known class of building block for the synthesis of monofluorinated compounds, are under considerable pressure as known or potential stratospheric ozone depletors. It is likely that other familiar fluorinated starting materials will become progressively less available.

Much of the primary and review literature upon which this volume is based deals with methodology rather than types of target molecules. The organofluorine literature contains relatively few comparisons between methods, which can make route selection rather difficult. Where the literature is sufficiently extensive, individual contributors have been encouraged to compare and contrast the scope and effectiveness of the available methodologies. These comparisons, and the organization of the volume into target classes and types of functional group exchange reaction, will assist experimentalists in planning synthetic campaigns.

I would like to thank all those who have allowed the delivery of the project, the authors who have contributed to the volume, and especially the editorial staff who have realised the transmutation of manuscripts into volume so extremely professionally.

Volume Editor

J. M. Percy

Strathclyde, UK

Volume 34: Fluorine

Preface

Volume Editor’s Preface

Table of Contents

Introduction

J. M. Percy

34.1 Product Class 1: Fluoroalkanes

J. M. Percy

34.1.1 Synthesis by Substitution of Hydrogen

G. Sandford

34.1.2 Synthesis by Substitution of Metals

V. Gouverneur and M. Tredwell

34.1.3 Synthesis by Substitution of Carbon Functionalities

M. A. Carroll

34.1.4 Synthesis by Substitution of Heteroatoms

34.1.4.1 Synthesis by Substitution of a Halogen

T. P. Lequeux

34.1.4.2 Synthesis by Substitution of Hydroxy Groups in Alcohols

K. Dax

34.1.4.3 Synthesis by Substitution of Oxygen and Sulfur Functionalities

T. P. Lequeux

34.1.5 Synthesis by Addition Reactions to Alkenes

G. Haufe

34.1.6 Synthesis with Retention of the Functional Group

T. Yamazaki

34.2 Product Class 2: Fluorocyclopropanes

J. M. Percy

34.3 Product Class 3: (Fluoromethyl)cyclopropanes

J. M. Percy

34.4 Product Class 4: Fluorocyclobutanes

J. M. Percy

34.5 Product Class 5: Propargylic Fluorides

J. A. L. Miles and J. M. Percy

34.6 Product Class 6: Benzylic Fluorides

A. Sai Krishna Murthy, R. Tardivel, and R. Grée

34.7 Product Class 7: Allylic Fluorides

R. Roig and J. M. Percy

34.8 Product Class 8: Homoallylic Fluorides

J. M. Percy

34.9 Product Class 9: β-Fluoro Alcohols

G. Haufe

34.10 Product Class 10: β-Fluoroamines

J. M. Percy

Keyword Index

Author Index

Abbreviations

Table of Contents

Introduction

J. M. Percy

Introduction

34.1. Product Class 1: Fluoroalkanes

J. M. Percy

34.1. Product Class 1: Fluoroalkanes

34.1.1 Synthesis by Substitution of Hydrogen

G. Sandford

34.1.1 Synthesis by Substitution of Hydrogen

34.1.1.1 Method 1: Direct Fluorination with Elemental Fluorine

34.1.1.2 Method 2: Reaction with Selectfluor

34.1.1.3 Method 3: Reaction with Xenon Difluoride

34.1.1.4 Method 4: Reaction with Organic Hypofluorites

34.1.1.5 Method 5: Reaction with Cesium Fluoroxysulfate

34.1.1.6 Method 6: Reaction with Hydrogen Fluoride/Pyridine and Nitrosonium Tetrafluoroborate

34.1.2 Synthesis by Substitution of Metals

V. Gouverneur and M. Tredwell

34.1.2 Synthesis by Substitution of Metals

34.1.2.1 Method 1: Synthesis from Organosilanes

34.1.2.2 Method 2: Synthesis from an Organothallium Compound

34.1.2.3 Method 3: Synthesis from Organomercury Compounds

34.1.2.4 Method 4: Synthesis from Organomagnesium Compounds

34.1.2.5 Method 5: Synthesis from Organolithium Compounds

34.1.2.5.1 Variation 1: Using Molecular Fluorine

34.1.2.5.2 Variation 2: Using Perchloryl Fluoride

34.1.3 Synthesis by Substitution of Carbon Functionalities

M. A. Carroll

34.1.3 Synthesis by Substitution of Carbon Functionalities

34.1.3.1 Method 1: Synthesis from Alkanecarboxylates Using Fluorine

34.1.3.2 Method 2: Synthesis from Alkanecarboxylic Acids

34.1.3.2.1 Variation 1: Using Titanium(IV) Oxide/Silver(I) Fluoride

34.1.3.2.2 Variation 2: Using Xenon Difluoride

34.1.3.2.3 Variation 3: Using Bromine Trifluoride

34.1.3.2.4 Variation 4: Using Triethylamine Trihydrofluoride

34.1.3.3 Method 3: Synthesis from Cyclopropanes

34.1.4 Synthesis by Substitution of Heteroatoms

34.1.4.1 Synthesis by Substitution of a Halogen

T. P. Lequeux

34.1.4.1 Synthesis by Substitution of a Halogen

34.1.4.1.1 Method 1: Substitution of Primary Halides

34.1.4.1.1.1 Variation 1: Using Metal Fluorides

34.1.4.1.1.2 Variation 2: Using Hydrogen Fluoride Complexes

34.1.4.1.1.3 Variation 3: Using Tetraalkylammonium Fluorides

34.1.4.1.1.4 Variation 4: Using Fluorosilicate Derivatives

34.1.4.1.2 Method 2: Substitution of Secondary Halides

34.1.4.1.2.1 Variation 1: Using Metal Fluorides

34.1.4.1.2.2 Variation 2: Using Hydrogen Fluoride Complexes

34.1.4.1.3 Method 3: Substitution of Tertiary Halides

34.1.4.1.3.1 Variation 1: Using Metal Fluorides

34.1.4.1.3.2 Variation 2: Using Base–Hydrogen Fluoride Complexes

34.1.4.1.3.3 Variation 3: Using Silver(I) Tetrafluoroborate

34.1.4.1.3.4 Variation 4: Using Ruthenium Complexes

34.1.4.2 Synthesis by Substitution of Hydroxy Groups in Alcohols

K. Dax

34.1.4.2 Synthesis by Substitution of Hydroxy Groups in Alcohols

34.1.4.2.1 Method 1: Reaction with Fluoro-λ⁴-sulfanes

34.1.4.2.1.1 Variation 1: With N, N-Diethylaminosulfur Trifluoride

34.1.4.2.1.2 Variation 2: With N, N-Bis(2-methoxyethyl)aminosulfur Trifluoride (Deoxo-Fluor)

34.1.4.2.1.3 Variation 3: With Morpholinosulfur Trifluoride

34.1.4.2.1.4 Variation 4: With N, N-Dimethylaminosulfur Trifluoride

34.1.4.2.1.5 Variation 5: With Other Dialkylaminofluoro-λ⁴-sulfanes

34.1.4.2.1.6 Variation 6: With Sulfur Tetrafluoride

34.1.4.2.1.7 Variation 7: With Alkoxysulfur Trifluorides

34.1.4.2.2 Method 2: Reaction with Selenium Tetrafluoride

34.1.4.2.3 Method 3: Reaction with Fluorophosphoranes

34.1.4.2.3.1 Variation 1: With Difluoro(triphenyl)phosphorane

34.1.4.2.3.2 Variation 2: With Trifluoro(diphenyl)phosphorane

34.1.4.2.3.3 Variation 3: With Tetrafluoro(phenyl)phosphorane

34.1.4.2.4 Method 4: Reaction with Fluoroalkylamine Reagents

34.1.4.2.4.1 Variation 1: With 2-Chloro-N, N-diethyl-1, 1, 2-trifluoroethylamine (Yarovenko Reagent)

34.1.4.2.4.2 Variation 2: With N, N-Diethyl-1, 1, 2, 3, 3, 3-hexafluoropropylamine (Ishikawa Reagent)

34.1.4.2.4.3 Variation 3: With N, N-Diethyl(trifluoromethyl)amine

34.1.4.2.4.4 Variation 4: With 1, 1-Difluoro-N, N-dimethyl-1-phenylmethanamine

34.1.4.2.4.5 Variation 5: With N, N-Dimethyl(1, 1, 2, 2-tetrafluoroethyl)amine

34.1.4.2.4.6 Variation 6: With N, N-Diethyl-1, 1-difluoro-1-(3-tolyl)methanamine

34.1.4.2.4.7 Variation 7: With 2, 2-Difluoro-1, 3-dimethylimidazolidine

34.1.4.2.4.8 Variation 8: With Other Fluoroalkylamine Reagents

34.1.4.2.5 Method 5: Reaction with Perfluorocyclobutane Ylides

34.1.4.2.6 Method 6: Reaction with Perfluoro(2-methylpent-2-ene)

34.1.4.2.7 Method 7: One-Pot Versions of the Sulfonate Displacement Route Using Alkane-or Arenesulfonyl Fluorides

34.1.4.2.8 Method 8: Reaction with Hydrogen Fluoride

34.1.4.2.8.1 Variation 1: In Combination with Organic Bases (Amines or Ethers)

34.1.4.3 Synthesis by Substitution of Oxygen and Sulfur Functionalities

T. P. Lequeux

34.1.4.3 Synthesis by Substitution of Oxygen and Sulfur Functionalities

34.1.4.3.1 Method 1: Substitution of Trifluoromethanesulfonates and Imidazolesulfonates

34.1.4.3.1.1 Variation 1: Using Difluorosilicate Derivatives

34.1.4.3.1.2 Variation 2: Using Tetrabutylammonium Fluoride

34.1.4.3.1.3 Variation 3: Using Base–Hydrogen Fluoride Complexes

34.1.4.3.2 Method 2: Substitution of Cyclic Sulfates

34.1.4.3.2.1 Variation 1: Using Ammonium Fluoride

34.1.4.3.2.2 Variation 2: Using Tetrabutylammonium Fluoride for the Substitution of Cyclic Sulfamates

34.1.4.3.3 Method 3: Substitution of Carboxylic Esters and Cyclic Carbonates

34.1.4.3.4 Method 4: Substitution of O, S-Dialkyl Dithiocarbonates

34.1.4.3.5 Method 5: Substitution of Primary Sulfonates

34.1.4.3.5.1 Variation 1: Using Potassium Fluoride

34.1.4.3.5.2 Variation 2: Using an Ionic Liquid and Cesium Fluoride

34.1.4.3.5.3 Variation 3: Using Ammonium Fluorides under High Pressure

34.1.4.3.5.4 Variation 4: Using Ammonium Fluorides or Hydrogen Difluorides

34.1.4.3.5.5 Variation 5: Using Difluorosilicate Derivatives

34.1.4.3.6 Method 6: Substitution of Secondary Sulfonates

34.1.4.3.6.1 Variation 1: Using Potassium Fluoride

34.1.4.3.6.2 Variation 2: Using Ammonium Fluorides

34.1.4.3.6.3 Variation 3: Using Reagents Containing Hydrogen Fluoride

34.1.4.3.7 Method 7: Substitution of Sulfides

34.1.5 Synthesis by Addition Reactions to Alkenes

34.1.5 Synthesis by Addition Reactions to Alkenes

34.1.5.1 Vicinal Chlorofluoroalkanes from Alkenes

34.1.5.1.1 Method 1: Synthesis Using N-Chloro Imides and a Fluoride Source

34.1.5.1.1.1 Variation 1: Using N-Chlorosuccinimide or N-Chlorosaccharin, and Hydrogen Fluoride/Pyridine

34.1.5.1.1.2 Variation 2: Using N-Chlorosuccinimide and Triethylamine Trihydrofluoride

34.1.5.1.1.3 Variation 3: Using Hexachloromelamine and Anhydrous Hydrogen Fluoride

34.1.5.1.2 Method 2: Synthesis Using Chlorine and Silver(I) Fluoride

34.1.5.1.3 Method 3: Synthesis Using Alkyl Hypochlorites and Boron Trifluoride

34.1.5.2 Vicinal Bromofluoroalkanes from Alkenes

34.1.5.2.1 Method 1: Synthesis Using N-Bromo Imides and a Fluoride Source

34.1.5.2.1.1 Variation 1: Using N-Bromosuccinimide and Anhydrous Hydrogen Fluoride in Coordinating Solvents

34.1.5.2.1.2 Variation 2: Using N-Bromosuccinimide or 1, 3-Dibromo-5, 5-dimethylimidazolidine-2, 4-dione, and Hydrogen Fluoride/Pyridine or Polymer-Supported Hydrogen Fluoride/Pyridine

34.1.5.2.1.3 Variation 3: Using N-Bromosuccinimide or 1, 3-Dibromo-5, 5-dimethylimidazolidine-2, 4-dione, and Triethylamine Trihydrofluoride or a Related Amine–Hydrogen Fluoride Reagent

34.1.5.2.1.4 Variation 4: N-Bromosuccinimide or 1, 3-Dibromo-5, 5-dimethylimidazolidine-2, 4-dione, and Tetrabutylammonium and Tetrabutylphosphonium Hydrogen Fluorides

34.1.5.2.1.5 Variation 5: 1, 3-Dibromo-5, 5-dimethylimidazolidine-2, 4-dione and Metal Fluoride–Hydrogen Fluoride Salts

34.1.5.2.2 Method 2: Synthesis Using Bromine Monofluoride Prepared In Situ

34.1.5.2.2.1 Variation 1: Preparation from Bromine and Fluorine

34.1.5.2.2.2 Variation 2: Preparation from Bromine and Silver(I) Fluoride

34.1.5.2.3 Method 3: Synthesis Using Other Fluoride Sources

34.1.5.3 Vicinal Fluoroiodoalkanes from Alkenes

34.1.5.3.1 Method 1: Reaction with Iodine Monofluoride Prepared In Situ

34.1.5.3.1.1 Variation 1: Prepared from Iodine and Fluorine

34.1.5.3.1.2 Variation 2: Prepared from Iodine and Metal Fluorides

34.1.5.3.2 Method 2: Reaction with N-Iodosuccinimide and Hydrogen Fluoride

34.1.5.3.2.1 Variation 1: In Coordinating Solvents

34.1.5.3.2.2 Variation 2: In Water with Phase-Transfer Catalysis

34.1.5.3.2.3 Variation 3: Using Hydrogen Fluoride/Pyridine

34.1.5.3.2.4 Variation 4: Using Polymer-Supported Hydrogen Fluoride/Pyridine

34.1.5.3.2.5 Variation 5: Using Triethylamine Trihydrofluoride

34.1.5.3.2.6 Variation 6: Using Metal Fluoride–Hydrogen Fluoride Salts

34.1.5.3.2.7 Variation 7: Using Ammonium Hydrogen Fluorides

34.1.5.3.2.8 Variation 8: Using Tetrabutylphosphonium Hydrogen Fluorides

34.1.5.3.2.9 Variation 9: Using Hexafluoropropene/Diethylamine Complex

34.1.5.3.3 Method 3: Reaction with Iodonium Equivalents Other Than Iodine or N-Iodosuccinimide and a Fluoride Source

34.1.5.4 Vicinal Fluoro(sulfanyl)alkanes

34.1.5.4.1 Method 1: Fluorosulfanylation of Alkenes

34.1.5.4.1.1 Variation 1: Using Dimethyl(methylsulfanyl)sulfonium Tetrafluoroborate and Triethylamine Trihydrofluoride

34.1.5.4.1.2 Variation 2: Using Benzenesulfenyl Chloride and Silver(I) Fluoride

34.1.5.4.1.3 Variation 3: Using N-(Phenylsulfanyl)phthalimide and Hydrogen Fluoride/Pyridine

34.1.5.4.1.4 Variation 4: Using Trifluoromethanesulfenyl Fluoride

34.1.5.5 Vicinal Fluoro(selanyl)alkanes

34.1.5.5.1 Method 1: Synthesis Using Benzeneselenenyl Bromide or Chloride and Silver(I) Fluoride

34.1.5.5.2 Method 2: Synthesis Using N-(Phenylselanyl)phthalimide and Triethylamine Trihydrofluoride

34.1.5.5.3 Method 3: Synthesis Using Diphenyl Diselenide and Xenon Difluoride

34.1.5.6 Vicinal Nitro-and Nitriminofluoroalkanes

34.1.5.6.1 Method 1: Nitrofluorination of Alkenes

34.1.5.6.2 Method 2: Nitriminofluorination of Alkenes

34.1.6 Synthesis with Retention of the Functional Group

T. Yamazaki

34.1.6 Synthesis with Retention of the Functional Group

34.1.6.1 Method 1: α-Functional Group Elimination

34.1.6.1.1 Variation 1: Free-Radical-Mediated Dehalogenation with Tributyltin Hydride

34.1.6.1.2 Variation 2: Ring Expansion with Dehalogenation Mediated by Palladium Oxide or Acid

34.1.6.1.3 Variation 3: By Desulfonylation

34.1.6.1.4 Variation 4: By Denitration

34.1.6.2 Method 2: β-Functional Group Elimination

34.1.6.2.1 Variation 1: By Dehalogenation

34.1.6.2.2 Variation 2: By Ionic Deoxygenation

34.1.6.2.3 Variation 3: By Radical Deoxygenation

34.1.6.2.4 Variation 4: By Deselenation

34.1.6.3 Method 3: Hydrogenation of Unsaturated Compounds Containing Fluorine

34.1.6.3.1 Variation 1: Hydrogenation of Vinylic Fluorides

34.1.6.3.2 Variation 2: Hydrogenation of Allylic and Propargylic Fluorides

34.1.6.3.3 Variation 3: Reduction of Fluorinated Arenes

34.2 Product Class 2: Fluorocyclopropanes

J. M. Percy

34.2 Product Class 2: Fluorocyclopropanes

34.2.1 Synthesis of Product Class 2

34.2.1.1 Method 1: Radical Dechlorination of Chlorofluorocyclopropanes Using Tributyltin Hydride

34.2.1.2 Method 2: Debromination of Bromofluorocyclopropanes with Zinc Powder

34.2.1.3 Method 3: Carbene and Carbenoid Additions to Fluoroalkenes

34.2.1.3.1 Variation 1: Simmons–Smith Reaction of Fluoroallylic Alcohols Using a Zinc/Copper Couple

34.2.1.3.2 Variation 2: Diastereoselective Simmons–Smith Reaction Using Diethylzinc(II)/Diiodomethane

34.2.1.3.3 Variation 3: Addition of Diazoacetic Esters to Fluoroalkenes

34.2.1.3.4 Variation 4: Diastereoselective Addition of Diazoacetic Esters to Fluoroalkenes

34.2.1.3.5 Variation 5: Addition of Diazomethane to Ethyl (2E)-3-Fluoro-2-phenylacrylate with Adduct Photolysis

34.2.1.3.6 Variation 6: Intramolecular Carbenoid Addition to an Ethyl (2Z)-2-Fluoroalk-2-enoate

34.2.1.4 Method 4: Fluorohalocyclopropanes via Fluorohalocarbene Addition to Alkenes

34.2.1.4.1 Variation 1: Phase-Transfer-Catalyzed Formation of Chlorofluorocyclopropanes

34.2.1.4.2 Variation 2: Titanium-Mediated Formation of Chlorofluorocyclopropanes

34.2.1.4.3 Variation 3: Generation of Chlorofluorocyclopropanes from Methyl Dichlorofluoroacetate

34.2.1.4.4 Variation 4: Bromofluorocarbene Addition to Alkenes Using Phase-Transfer Catalysis

34.2.1.5 Method 5: Direct Fluorocarbene Addition to Alkenes

34.2.1.6 Method 6: Intermolecular Addition of Fluoroiodoacetate to Alkenes and Subsequent Anionic Cyclization

34.2.1.7 Method 7: Fluorination of Cyclopropanes and Their Conjugate Bases

34.2.1.7.1 Variation 1: Electrophilic Fluorination of Methylenecyclopropane Carboxylate Esters with N-Fluorobis(phenylsulfonyl)amine

34.3. Product Class 3: (Fluoromethyl)cyclopropanes

J. M. Percy

34.3. Product Class 3: (Fluoromethyl)cyclopropanes

34.3.1 Synthesis of Product Class 3

34.3.1.1 Method 1: Fluorodehydroxylation of Cyclopropylmethanol with N, N-Diethylaminosulfur Trifluoride

34.3.1.2 Method 2: In Situ Formation and Fluoride Ion Displacement of a Cyclopropylmethyl 4-Toluenesulfonate

34.3.1.3 Method 3: Ring Contraction of Cyclobutanols

34.3.1.4 Method 4: Transannular Epoxide Opening with Trimethylamine Trihydrofluoride

34.4 Product Class 4: Fluorocyclobutanes

J. M. Percy

34.4 Product Class 4: Fluorocyclobutanes

34.4.1 Synthesis of Product Class 4

34.4.1.1 Method 1: Fluorodehydroxylation of Cyclobutanols by Reaction with N, N-Diethylaminosulfur Trifluoride

34.4.1.2 Method 2: Reaction of Halocyclobutanes with Fluorinating Agents

34.4.1.2.1 Variation 1: Reaction of Iodocubane with Xenon Difluoride

34.4.1.3 Method 3: Reaction of (Iodomethyl)cyclopropane with Xenon Difluoride

34.4.1.4 Method 4: Addition of Iodine Fluoride to Methylenecyclobutanes

34.5. Product Class 5: Propargylic Fluorides

J. A. L. Miles and J. M. Percy

34.5. Product Class 5: Propargylic Fluorides

34.5.1 Synthesis of Product Class 5

34.5.1.1 Method 1: Nucleophilic Substitution of Propargylic Alcohols with 1-Fluoro-N, N-diisopropyl-2-methylprop-1-en-1-amine

34.5.1.2 Method 2: Nucleophilic Substitution of Silyl Ethers with Piperidinosulfur Trifluoride

34.5.1.3 Method 3: Reaction of Prop-2-yn-1-ol with 2-Chloro-N, N-diethyl-1, 1, 2-trifluoroethanamine

34.5.1.4 Method 4: Nucleophilic Substitution with Tetrabutylammonium Fluoride

34.5.1.5 Method 5: Ring Opening of Oxetanes Using Silicon Tetrafluoride

34.5.1.6 Method 6: Nucleophilic Substitution Using Sulfur Tetrafluoride

34.5.1.7 Method 7: Nucleophilic Substitution of Propargylic Alcohols with N, N-Diethylaminosulfur Trifluoride

34.5.1.7.1 Variation 1: Inverse Addition of a Propargylic Alcohol Precursor to a Cold Solution of N, N-Diethylaminosulfur Trifluoride without Low Temperature Quenching

34.5.1.7.2 Variation 2: Inverse Addition of a Propargylic Alcohol Precursor to a Cold Solution of N, N-Diethylaminosulfur Trifluoride with Low Temperature Quenching

34.5.1.7.3 Variation 3: From Propargylic Alcohols by Inverse Addition to a Cooled Solution of N, N-Diethylaminosulfur Trifluoride

34.5.1.7.4 Variation 4: From Hexacarbonyldicobalt-Protected Propargylic Alcohols

34.5.1.8 Method 8: Synthesis From 3-Substituted 1, 1, 3-Tribromo-1-fluoropropanes via (Alk-1-ynyl)fluorocarbenes

34.6. Product Class 6: Benzylic Fluorides

A. Sai Krishna Murthy, R. Tardivel, and R. Grée

34.6. Product Class 6: Benzylic Fluorides

34.6.1 Synthesis of Product Class 6

34.6.1.1 Nucleophilic Fluorination

34.6.1.1.1 Method 1: Dehydrofluorination

34.6.1.1.1.1 Variation 1: Electrochemical Methods

34.6.1.1.1.2 Variation 2: Photochemical Methods

34.6.1.1.2 Method 2: Dehydroxyfluorination

34.6.1.1.2.1 Variation 1: With N, N-Diethylaminosulfur Trifluoride and Related Reagents

34.6.1.1.2.2 Variation 2: With Nonafluorobutanesulfonyl Fluoride with a Trialkylamine Trihydrofluoride and a Base

34.6.1.1.2.3 Variation 3: With Fluoroalkylamines and Related Reagents

34.6.1.1.2.4 Variation 4: Fluorination with Rearrangement

34.6.1.1.3 Method 3: Desulfurative Fluorinations

34.6.1.1.4 Method 4: Halogen-Exchange Reactions

34.6.1.1.5 Method 5: Nucleophilic Substitutions

34.6.1.2 Electrophilic Fluorination

34.6.1.2.1 Method 1: Fluorination of Alkylbenzenes with Cesium Fluoroxysulfate

34.6.1.3 C—C Bond Formation of Fluorinated Compounds

34.6.1.3.1 Method 1: Transition-Metal-Catalyzed Reactions

34.6.1.3.2 Method 2: Cycloadditions to Vinylic Fluorides

34.7. Product Class 7: Allylic Fluorides

R. Roig and J. M. Percy

34.7. Product Class 7: Allylic Fluorides

34.7.1 Product Subclass 1: Allyl Fluorides

34.7.1.1 Synthesis of Product Subclass 1

34.7.1.1.1 Method 1: Deoxofluorination of Allylic Alcohols with N, N-Diethylaminosulfur Trifluoride

34.7.1.1.1.1 Variation 1: Deoxofluorination of Allylic Alcohols with Bis(dialkylamino)sulfur Difluorides

34.7.1.1.2 Method 2: Addition to α-Fluoroalkynes

34.7.1.1.3 Method 3: Electrophilic Fluorination of Alkenes

34.7.1.1.3.1 Variation 1: Electrophilic Fluorination of Alkenes with Acetyl Hypofluorite

34.7.1.1.3.2 Variation 2: Electrophilic Fluorination of Activated Alkenes with Elemental Fluorine

34.7.1.1.3.3 Variation 3: Electrophilic Fluorination of Alkenes with N-Fluoropyridinium Salts

34.7.1.1.4 Method 4: Nucleophilic Substitution of Allylic Halides

34.7.1.1.4.1 Variation 1: Nucleophilic Substitution of Allylic Halides with Tetraethylammonium Fluoride

34.7.1.1.4.2 Variation 2: Heterogeneous Fluorination of Allylic Halides by the Combination of Lead(II) Fluoride and a Sodium Salt

34.7.1.1.4.3 Variation 3: A Facile Method for the Fluorination of Phenyl Thioethers via Sulfonium Salts Using Cesium Fluoride

34.7.1.1.5 Method 5: Fluoroalkenation of 1, 3-Bis(tert-butyldimethylsilyl) Ethers

34.7.1.1.6 Method 6: Oxidative Elimination of β-Fluoro Selenides

34.7.1.1.7 Methods 7: Additional Methods

34.7.2 Product Subclass 2: α-Fluoroallyl- and 3-Fluoroalk-1-enylphosphonate Esters

34.7.2.1 Synthesis of Product Subclass 2

34.7.2.1.1 Method 1: Deoxofluorination of α-Hydroxyallylphosphonate Esters with N, N-Diethylaminosulfur Trifluoride

34.7.2.1.2 Method 2: Coupling of α-Fluoro Phosphonate Esters with Vinylic Halides

34.7.2.1.3 Method 3: Catalytic Hydrogenation of α-Fluoropropargylphosphonate Esters

34.7.3 Product Subclass 3: γ-Fluoro α, β-Unsaturated Esters

34.7.3.1 Synthesis of Product Subclass 3

34.7.3.1.1 Method 1: Horner–Emmons Condensation of α-Fluoro Aldehydes and Ketones

34.8. Product Class 8: Homoallylic Fluorides

J. M. Percy

34.8. Product Class 8: Homoallylic Fluorides

34.8.1 Synthesis of Product Class 8

34.8.1.1 Method 1: Ring Opening of Cyclopropylmethanols with a Fluoride Ion

Source

34.9. Product Class 9: β-Fluoro Alcohols

G. Haufe

34.9. Product Class 9: β-Fluoro Alcohols

34.9.1 Synthesis of Product Class 9

34.9.1.1 Method 1: Synthesis Using Hydrogen Fluoride

34.9.1.1.1 Variation 1: Aqueous Hydrogen Fluoride

34.9.1.1.2 Variation 2: Anhydrous Hydrogen Fluoride in Coordinating Solvents

34.9.1.1.3 Variation 3: Anhydrous Hydrogen Fluoride in the Presence of Lewis Acids

34.9.1.2 Method 2: Synthesis Using Metal Fluorides and Metal Hydrogen Fluorides

34.9.1.2.1 Variation 1: Alkali Metal Hydrogen Fluorides in Coordinating Solvents

34.9.1.2.2 Variation 2: Potassium Hydrogen Difluoride or Silver(I) Fluoride in the

Presence of a Chiral Lewis Acid

34.9.1.3 Method 3: Synthesis Using Alkylammonium and Alkylphosphonium

Fluorides

34.9.1.3.1 Variation 1: Tetrabutylammonium and Tetrabutylphosphonium Fluorides

34.9.1.3.2 Variation 2: Tetraethylammonium Fluorides

34.9.1.4 Method 4: Synthesis Using Amine Polyhydrofluorides

34.9.1.4.1 Variation 1: Hydrogen Fluoride/Pyridine

34.9.1.4.2 Variation 2: Alkylamine Hydrofluorides

34.9.1.5 Method 5: Synthesis Using Boron Trifluoride–Diethyl Ether Complex

34.10. Product Class 10: β-Fluoroamines

J. M. Percy

34.10. Product Class 10: β-Fluoroamines

34.10.1 Synthesis of Product Class 10

34.10.1.1 Method 1: Reduction of β-Fluoro Azides

34.10.1.2 Method 2: Displacement of β-Fluoro 4-Toluenesulfonates by Amines

34.10.1.3 Method 3: Ring Opening of Aziridines with Hydrogen Fluoride Equivalents

34.10.1.3.1 Variation 1: Ring Opening of Aziridines by Fluoride Ion

34.10.1.3.2 Variation 2: Ring Opening of Azabicyclo[1.1.0]butanes with Hydrogen

Fluoride/Pyridine

34.10.4 Method 4: Ring Opening of Cyclic Sulfamates with Fluoride Ion

Keyword Index

Author Index

Abbreviations

Introduction

J. M. Percy

This volume covers the synthesis of compounds containing a single fluorine atom bonded to an sp³ carbon, excluding α-fluorocarbonyl compounds {aldehydes, ketones, and acids and their derivatives (covered in Science of Synthesis, Volumes 25, 26, and 20, respectively) and 1,1-dihalides [including geminal difluorides (Volume 29)]}. The volume content is organized firstly according to the different classes of fluorinated molecule, and then by the methods of synthesis. The distribution of content is shown in ▶ Table 1, along with the appropriate section number.

▶ Table 1 Classes of Compounds Covered in Volume 34

Product Class and Method | Structural Formula | Section
fluoroalkanes | missing link |
by substitution of hydrogen |  | 34.1.1
by substitution of metals |  | 34.1.2
by substitution of carbon functionalities |  | 34.1.3
by substitution of a halogen |  | 34.1.4.1
by substitution of hydroxy groups in alcohols |  | 34.1.4.2
by substitution of oxygen and sulfur functionalities |  | 34.1.4.3
by addition reactions to alkenes |  | 34.1.5
by retention of the functional group |  | 34.1.6
fluorocyclopropanes | missing link | 34.2
(fluoromethyl)cyclopropanes | missing link | 34.3
fluorocyclobutanes | missing link | 34.4
propargylic fluorides | missing link | 34.5
benzylic fluorides | missing link | 34.6
allylic fluorides | missing link | 34.7
homoallylic fluorides | missing link | 34.8
ß-fluoro alcohols | missing link | 34.9
ß-fluoroamines | missing link | 34.10

References to reviews on the different classes of compounds are given wherever possible, but much of the literature upon which this volume is based deals with methodology rather than type of target molecule. The organofluorine literature contains relatively few comparisons between methods, which can make route selection rather difficult. Where the literature is sufficiently extensive, individual contributors have been encouraged to compare and contrast the scope and effectiveness of the available methodologies. Selected compound data (¹⁹F NMR chemical shifts) and experimental details have been reported as fully as possible. In some cases, the original reports of important methodologies contain minimal detail. The material covered in the volume is selective in some chapters and more exhaustive in others, reflecting the fact that there are very few ways of making some of the subclasses of molecule described.

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