Fluorine and Gold: A Fruitful Partnership - American Chemical Society

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Fluorine and Gold: A Fruitful Partnership Javier Miró and Carlos del Pozo* Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, 46100 Burjassot, Valencia, Spain ABSTRACT: Gold-catalyzed reactions have witnessed an exponential growth in the past decade. When the unique modes of activation exhibited by gold species meet species with either fluorinated building blocks or fluorinating reagents, new opportunities arise for the development of new methodologies in fluoroorganic chemistry. Indeed, gold and fluorine truly formed a very fruitful partnership, and different types of reactivity emerged from their combination. This review gives an overview of such endeavors. The special properties imparted by fluorine to organic molecules have been exploited in gold-catalyzed processes, allowing for the generation of unprecedented fluorinated chemical entities. Thus, the interaction of gold salts with fluorinated building blocks has been revised. In a second section, recent developments in gold-catalyzed nucleophilic fluorinations have been covered. The development of new gold catalysts that stabilize the Au−F bond as well as recent mechanistic studies in the field raised the interest of these types of methodologies for the generation of new C−F bonds. The use of electrophilic fluorine sources enabled new modes of gold catalysis. The incorporation of Selectfluor as an external oxidant constituted a new paradigm in gold chemistry, incorporating the elusive Au(I)/Au(III) redox couple in gold-catalyzed transformations. This strategy provided access to both new fluorinated chemical entities and nonfluorinated derivatives by means of coupling reactions. Those topics have been reviewed in the last two sections.

CONTENTS 1. Introduction 1.1. Brief on Fluorine and Gold Chemistry 1.2. Scope and Organization of the Review 2. Fluorinated Starting Materials in Gold-Catalyzed Reactions 2.1. Fluorinated Building Blocks in Gold-Catalyzed Nucleophilic Additions 2.2. Gold Complexes with Fluorine-Containing Ligands 2.3. Role of Fluorine in Gold-Mediated C(sp2)−X (X = H, C, F) Bond Activation 3. Gold Chemistry with Nucleophilic Sources of Fluorine 3.1. Creation of C−F Bonds by Gold-Catalyzed Nucleophilic Fluorinations 3.2. Creation of C−CF3 Bonds by Gold-Catalyzed Nucleophilic Fluorinations 4. Gold Chemistry with Electrophilic Sources of Fluorine 4.1. Gold-Catalyzed Electrophilic Fluorinations in O-Addition Processes 4.2. Gold-Catalyzed Electrophilic Fluorinations in N-Addition Processes 5. Fluorine in Oxidative Gold-Catalyzed Reactions 5.1. Fluorine-Based Oxidants in Gold-Catalyzed Coupling Reactions 5.2. Fluorine-Based Oxidants in Other GoldCatalyzed Oxidative Reactions 5.3. Fluorinated Building Blocks in Gold-Catalyzed Coupling Reactions © XXXX American Chemical Society

6. Summary and Outlook Author Information Corresponding Author Notes Biographies Acknowledgments References

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1. INTRODUCTION

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1.1. Brief on Fluorine and Gold Chemistry

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Since the successful application of 5-fluorouracil as an anticancer drug,1,2 the incorporation of fluorine atoms into organic molecules has emerged as a common strategy in the drug discovery process.3,4 Both modification of natural compounds as well as a systematic search for more active drug-like molecules became successful approaches within this pursuit. On one hand, the particular physicochemical effects imparted by fluorine5 explain why something so rare in natural organic compounds became so attractive in drug design, thus having a significant impact in a wide range of medical applications, such as anesthetics, antitumor, antibacterial, and antiviral agents, anti-inflammatory drugs, or cholesterol inhibitors.6,7 On the other hand, the use of radioactive 18F nucleus in PET (positron emission tomography) labeling studies broadened the utility of fluorine-containing molecules,8−10 due to its applicability in diverse areas of medicine such as oncology. Consequently, the paramount role played by

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Received: March 31, 2016

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DOI: 10.1021/acs.chemrev.6b00203 Chem. Rev. XXXX, XXX, XXX−XXX

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fluorine in the growth and development of medicinal chemistry is firmly established nowadays, providing remarkable breakthroughs in this arena. Despite its distribution in Nature (fluorine is the 13th most abundant element in the Earth’s crust), the presence of fluorine atoms in natural organic molecules is scarce. Given that most fluorine-containing organic compounds are man-made, the development of new methodologies that give access to fluorinated derivatives is always in great demand. Two main strategies have been tracked in order to access fluorinated organic molecules. Probably the most direct one is the use of either nucleophilic or electrophilic fluorinating reagents.11−16 In this context, the selective fluorination at specified positions of an organic framework is often a challenging task, and for this reason, research for the development of new selective fluorinating reagents able to form C−F bonds from C−H bonds or functional groups is currently ongoing in different laboratories around the world.17−23 A second, and probably more flexible, synthetic strategy relies on the use of simple and readily available fluorine-containing compounds as building blocks for the construction of new molecules around those scaffolds.24−30 This approach plays an important role as a powerful supplement to direct fluorination methods. Regarding the gold atom, despite its ubiquitous presence along history (jewelry, currency, or medicine), not until the end of the last century did it become a precious metal for chemists. This tendency changed after seminal contributions by Utimoto31 and Teles32 describing the utility of gold complexes in the catalytic hydration of alkynes. The power of this methodology allowed its application at an industrial scale, avoiding the use of mercury to carry out that transformation. Since then, homogeneous gold catalysis has become a fundamental and innovative synthetic tool for the generation of carbon−carbon and carbon−heteroatom bonds. This golden age is most likely due to the unique ability exhibited by gold(I) species to act as π-soft Lewis acids toward unactivated multiple carbon−carbon bonds (alkynes, allenes, alkenes, 1,3-dienes, or enynes). Upon activation by gold, the addition of diverse nucleophiles, either inter- or intramolecularly, under mild reaction conditions and high functional-group tolerance leads to a wide variety of new chemical entities.33−40 Even though less Lewis acidic Ag(I) or Pt(II) complexes, among others, can occasionally accomplish gold-catalyzed transformations, none of those late transition metals show the breadth of applications displayed by homogeneous gold(I) complexes. This singular behavior has been attributed to relativistic effects.41 These are crucial to understand the electronic structure of heavy elements and, at the same time, they explain the great strength of gold−ligand bonds and the lower nucleophilicity of gold species reluctant to undergo oxidative addition and reductive elimination. Relativistic effects also account for the high tolerance to oxygen, the superior Lewis acid behavior of gold species when compared to other group 11 metals, as well as the high electronegativity of Au. All these features underline the paramount role of gold catalysis in organic synthesis and organometallic chemistry in the last decades.42,43 Beyond their use as π-carbophilic Lewis acids, gold complexes have been also successfully applied in cross-coupling reactions, regardless of the high redox potential of the Au(I)/ Au(III) redox couple (+1.41 V)44 compared to other transition

metals like Pd(0)/Pd(II) (+0.92 V). For this reason, the development of gold-catalyzed cross-coupling reactions meant a significant challenge. However, the use of external oxidants such as Selectfluo r [1-chlorom eth yl-4- fluoro-1,4diazoniabicyclo[2.2.2]octane-bis(tetrafluoroborate)] allowed catalytic turnover of Au(I) to Au(III) and the final generation of carbon−carbon and carbon−heteroatom bonds via reductive elimination from Au(III) species.45−50 These transformations constitute a new paradigm in gold chemistry, expanding the utility of gold catalysis. The first contribution that merged fluorine and gold chemistry was made by Vaughan and Sheppard: several fluorophenyl isocyanide gold(I) complexes were synthesized in order to study carbon−gold bonding by 19F NMR, taking advantage of the fluorine as an electronic probe to evaluate the effect of the susbtituents in the π system.51 After this pioneering work, other fluorinated ligands were used to perform structural work in gold complexes. This is the case of the robust and inert pentafluorophenyl ligand,52 although the first crystal structure determination of a gold complex bearing this ligand was not reported until 2007.53 The development of gold catalysis also lies in the use of weakly coordinated counterions that can play important roles in the reaction outcome. In this context, the dominance of fluorinated counterions in gold catalysis is noteworthy. Thus, the use of anions such as BF4−, SbF6−, PF6−, NTf2−, or TfO− was found to be crucial for the synthesis and characterization of a wide variety of gold complexes. This provided fundamental understanding of gold-catalyzed processes and set a solid ground base for the development of future transformations. Despite its significance, structural work related to those fluorinated counterions is beyond the scope of this review. 1.2. Scope and Organization of the Review

Considering the unique modes of activation of unsaturated bonds imparted by gold, its combination with either fluorinated building blocks or fluorine-based reagents has opened avenues for the development of new methodologies in fluoroorganic chemistry. Indeed, gold and fluorine faithfully form a fruitful partnership, and different types of reactivity have arisen from their combination. Thereby, this review intends to give an overview of such endeavors structured in four sections. The general reaction outcomes of gold-catalyzed processes shown in Scheme 1 indicate that elementary steps in goldScheme 1. General Reaction Scheme of Gold-Catalyzed Reactions Involving Fluorinated Substrates and Fluorinating Reagents

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catalyzed reactions involving fluorinated substrates and nucleophilic sources of fluorine (Scheme 1, sections 2 and 3) clearly contrast with the incorporation of gold-redox cycles arising from the combination of gold complexes with electrophilic sources of fluorine (Scheme 1, sections 4 and 5). Section 2 of this review deals with the use of fluorinated starting materials in homogeneous gold-catalyzed processes. Despite the exponential growth witnessed by gold-catalyzed reactions in the past decade, few reports concerning the use of fluorinated starting materials have been devised and many of them have been reported in the past few years. A complete revision of those processes, as useful tools for generating a variety of new fluorinated derivatives, is given in section 2. Additionally, the pioneering work from Larrosa, Nolan, and Zhang on gold-mediated de novo functionalization of C(sp2)− H, C(sp2)−C(sp2), and C(sp2)−F bonds on electron-deficient fluoro(hetero)arenes is disclosed therein. This body of work has certainly had a strong impact in innovative reaction manifolds on gold-catalyzed cross-coupling chemistry (see section 5.3). Sections 3−5 cover gold-catalyzed processes relying on the use of nucleophilic and electrophilic sources of fluorine. Nucleophilic fluorination is still a challenging task, mainly due to the high electronegativity of fluorine and the dual reactivity profile exhibited by fluoride anions as either bases or nucleophiles. This problem can be overcome by using transition metal-catalyzed fluorinations. Among others (e.g., Pd, Cu, Ag, Ru), Au species can activate carbon−carbon multiple bonds toward nucleophilic attack by fluoride under remarkably mild reaction conditions. Herein, section 3 is focused in those processes catalyzed by gold. On the other hand, in the presence of electrophilic sources of fluorine, the fluorination event may effectively replace protodeauration. In 2008, Gouverneur reported the first goldcatalyzed fluorination using an electrophilic source of fluorine.54 After this first report, several gold-catalyzed transformations involving alkynes were combined with the capture of the vinyl− gold intermediates by electrophilic sources of fluorine as a mild methodology to generate carbon−fluorine bonds. Research within this field is covered in section 4. Nevertheless, performing gold-catalyzed reactions in the presence of fluorinating electrophilic reagents does not necessarily lead to fluorinated species. In most cases, however, the source of electrophilic fluorine is likely acting as a sacrificial two-electron exogenous oxidant, performing oxidation on Au(I) metal center to Au(III) in a redox cycle which, ultimately, delivers products from oxidative homo- and/or cross-coupling. Oxidative coupling is a recently emerging area of research within gold catalysis which, when combined with the well-established reactivity of gold as a soft Lewis acid, either promoting nucleophilic additions or C(sp2)−H bond activations, arises as a mild and efficient method for the ready construction of molecular complexity. These gold-mediated oxidative couplings standing on the use of fluorine-based oxidants are compiled in section 5.1. In addition, examples where these species are used in the preactivation of a Au(I) catalyst as an alternative to classical halide abstraction or protonolysis have been included in section 5.2. Finally, goldmediated cross-coupling reactions over fluorinated building blocks in innovative reaction manifolds, including redox orthogonal C−H functionalization and photoredox-mediated processes, are disclosed in section 5.3. Along with the discussion of the processes fitting within section 5, different

mechanistic rationalizations will be outlined, showcasing interesting dichotomies in Au(I)/Au(III)-catalyzed transformations. Even though the number of reviews covering either gold catalysis or organofluorine chemistry is very high due to the great research activity in both areas, gold chemistry is still a hot topic in catalysis and the incorporation of fluorine into organic molecules is extremely relevant in medicinal chemistry. To date, chemistry regarding the combination of gold and fluorine was reviewed to some extent in 2010, and since then,49,55 a great number of new examples have appeared in the literature. In addition, the use of both nucleophilic and electrophilic sources of fluorine in the presence of transition metals was also covered (although not specifically gold-mediated processes),56,57 while the usefulness of Selectfluor in cross-coupling reactions was reported by Gouverneur in 2011.48 Since research concerning the synergistic combination of gold and fluorine chemistry has not been reviewed in a complete manner to date, we expect this review, updating examples described until February 2016, may be helpful for researchers interested in both fields.

2. FLUORINATED STARTING MATERIALS IN GOLD-CATALYZED REACTIONS 2.1. Fluorinated Building Blocks in Gold-Catalyzed Nucleophilic Additions

The use of fluorinated building blocks is one of the main approaches to access fluorinated scaffolds. Its combination with gold species, proficient to promote new activation modes triggering unconventional reactivity patterns, opened new avenues in fluorine chemistry. This partnership allowed the preparation of much demanded fluorinated skeletons that are otherwise difficult to access. Only a few reports concerning the use of fluorinated starting materials in gold-mediated processes have been devised to date. All of them will be discussed in this section. Additionally, since the fluorine atom usually imparts interesting properties to organic molecules, we will also comment on different behaviors of fluorine-containing compounds in the presence of gold species compared to their nonfluorinated counterparts, as well as the special reactivity showcased by those substrates with gold species in comparison to other catalytic systems. The first contribution in this area may be attributed to Hayashi and co-workers. An in-depth study was carried out in their laboratories, aimed at evaluating the aldol condensation of isocyanoacetic acid derivatives 1 with fluorinated prochiral aldehydes,58−60 ketones,61−63 and imines.64 Hydrolysis of the corresponding oxazolines 2 and 3 or imidazolines 4 resulted in a new family of fluorinated α-amino acid derivatives 5−7 (Scheme 2). Among other transition metals, the gold salt was able to coordinate the isonitrile moiety, lowering the pKa of hydrogens at the α position of the isocyanoacetate derivative, in turn promoting an aldol-type condensation with a carbonyl derivative in the presence of a proper base. The participation of gold became essential in enabling mild reaction conditions, since stronger bases employed in conventional aldol-type reactions would adversely affect functional-group tolerance. Even though the stereochemical outcome of this transformation might be influenced by several considerations, such as electronics or the catalyst’s nature, the stereochemical discrimination between substituents at the prochiral carbonyl C


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Scheme 2. Gold-Catalyzed Aldol Condensations of Isocyanoacetic Acids 1 and Fluorinated Aldehydes, Ketones, and Imines

Scheme 3. Gold-Mediated Synthesis of Fluorinated Hexoses 11

alternative tested catalytic systems. Just gold proved capable to catalyze this transformation in an efficient manner. The accessed fluorinated dihydropyranones 9 were valuable scaffolds, for instance, for the synthesis of fluorinated carbohydrate analogues. Thus, the same group showcased their applicability and, based on the above-mentioned goldcatalyzed cyclization, prepared a small library of novel racemic di- and trifluorinated hexoses 11, which were employed to study the feasibility of hydrogen bonding C−F···H−X interactions.66 Performing a diastereoselective reduction under Luche conditions over the obtained difluorodihydropyranones 9, they accessed the key glycal precursor 10 in a straightforward and efficient manner compared to prior methodologies, which usually encompassed more steps and lower yields (Scheme 3). This type of gold-catalyzed alkoxycyclization has been also exploited in the synthesis of diversely substituted βfluorofurans. According to the significance of the furan ring featuring lead compounds and biologically active natural products,67,68 fluorinated derivatives may provide implemented pharmacological profiles. Previously reported methodologies to access those compounds were scarce and operated in low yields or with poor selectivity, normally entailing aggressive conditions.69 The first attempt in this context was due to Hammond and co-workers, who tried to access β-fluorofurans starting from gem-difluorohomopropargyl alcohols in a tandem 5-endo-dig cyclization−aromatization sequence.70 Despite what was previously observed for the nonfluorinated analogues, gold complexes were unable to promote this cyclization in synthetically useful yields. Instead, AgNO3 appeared as a competent catalyst in the activation of such an electrondeficient triple bond. However, hydrogen fluoride elimination via silica gel chromatography did not work efficiently, and 3,3difluoro-2,3-dihydrofuran intermediates remained as the final products. Later, in 2010, Dembinski and co-workers proposed an alternative strategy.71 Instead of starting from gem-difluorohomopropargyl alcohols, whose aromatization after transition metal-catalyzed cyclization works inefficiently, they proposed the use of monofluoroynones 13. These ketones were readily accessed by electrophilic monofluorination of silyl enol ethers 12, derived from the corresponding nonfluorinated ynones, with Selectfluor (Scheme 4). Whereas AuCl3 gave rise to complex reaction mixtures, probably due to its higher reactivity, combination of Au(PPh3)Cl and AgOTf in DCM at room temperature provided unsymmetrically 2,5-substituted-3-fluorofurans 14 in almost quantitative yields (Scheme 4, eq 1).

component governed the addition, rendering final products with good levels of diastereoselection. The enantioselective version was performed in the reaction with aldehydes by using the ferrocenyl-derived chiral ligand indicated in Scheme 1, giving rise to oxazolines 2 in moderate to good ee’s. This former contribution lacked from the singularity commonly ascribed to gold, since other transition metal complexes such as Cu(I), Pd(II), Ag(I), or Rh(I), enabled the transformation as well. This feature might be significant regarding the role played by gold in this process, performing a σ-Lewis activation rather than a π-Lewis activation. Precisely the latter behavior is closely related to gold’s recent breakthroughs in organometallic catalysis as a soft Lewis acid. Taking this into account, Gouverneur’s reported work in 200854 may be considered at the starting line of this ongoing race. On one hand, the relatively late stage of this report compared to the gold rush in the early 200065 is meaningful. On the other hand, the relevance of this pioneering work went beyond being one of the first examples combining fluorinated building blocks and gold catalysis: it placed the first stone on one of the most fruitful outcomes resulting from the discussed partnership, as it constituted one of the first examples of goldmediated C−F bond formation. Such endeavors will be covered in sections 4 and 5. Discussion of the significance of Gouverneur’s work fits better in section 4, wherein it will be remarked. The aforementioned work described the Au(I)-catalyzed 6endo-dig heterocyclization of β-hydroxy-α,α-difluoroynones 8 leading to a new family of fluorinated dihydropyranones 9. Starting difluoroynones 8 were readily accessible in two steps by alkynylation of commercially available 2-halo-2,2-difluoroacetates 7 and the subsequent Reformatsky-type reaction with different aldehydes. Cyclization of ynones 8 was efficiently promoted by AuCl (5 mol %) in DCM, independently of the alkyne substitution or the ancillary group attached to the βhydroxy group (Scheme 3). Despite this transformation was also extensive to the nonfluorinated counterparts, significantly, gem-difluoro substitution was not innocent. Fluorine does reduce the nucleophilicity of the proximal hydroxyl group preventing cyclization under basic or acidic conditions or by D


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against aromatase, preventing its estrogen production and, in turn, becoming an encouraging candidate to reduce cancer cell proliferation in hormone-dependent breast cancer. Besides oxygen-containing heterocycles, gold catalysis has opened new and efficient synthetic routes toward the preparation of fluorinated nitrogen-containing heterocycles by means of an intramolecular hydroamination reaction. Fluorinecontaining pyrroles, pyrazoles, imidazoles, isoindolines, and isoquinolines, among others, constitute a class of important structural units for both pharmaceutical and agrochemical industries. Hence, the development of new methods to access these privileged structures is of high value.75 In 2009 De Kimpe and co-workers reported the preparation of 3-fluoropyrroles 22, readily accessible by means of a goldcatalyzed 5-endo-dig cyclization and spontaneous dehydrofluorination of electron-deficient gem-difluorohomopropargylN-tosylamines 21 (Scheme 6).76 Starting amines 21 were

Scheme 4. Gold-Catalyzed Cycloisomerization of Fluoroalkynones 13

Scheme 6. Synthesis of 3-Fluoropyrroles 22 Nevertheless, this methodology was restricted to the preparation of trisubstituted furans. Since such type of gold-catalyzed transformations involved the intermediacy of vinyl gold species, the authors envisioned that, in the presence of an electrophilic halogen source and under properly reaction conditions, a halodeauration event would render the corresponding 3,4-dihalofurans, opening the door for the preparation of entirely diverse substituted 3fluorofurans 15.72,73 However, the electron-withdrawing effect imparted by fluorine atom diminishes the nucleophilicity of the corresponding vinyl gold intermediate toward the electrophilic reagent, thus preventing halocyclization unless a cocatalyst is used. Finally, gold-assisted halocyclization of ynones 13 was accomplished in the presence of 20 mol % of ZnBr2 using NIS or NBS as the electrophilic source and AuCl as the catalyst (Scheme 4, eq 2). Presumably, this Lewis acid activates the Nhalosuccinimide via coordination through the carbonyl group, promoting its heterolytic dissociation and enhancing its electrophilic character. Alternatively, the enolization of the ynone via coordination through the oxygen atom of the carbonyl group may not be overruled. As the electrophilic halogen might be capable of promoting its own halocyclization, it is noteworthy to point out that in the absence of gold catalyst side products were formed and reaction times were enlarged from a few minutes to several hours. The most recent example of gold-catalyzed synthesis of fluorinated oxygen-containing heterocycles was published in 2014.74 The preparation of a small family of fluorinated isoflavonones 18 was described by means of a microwaveassisted gold-catalyzed annulation reaction starting from fluorinated o-hydroxybenzaldehydes 16 and fluoro(hetero)aryl acetylenes 17, albeit in low yields (Scheme 5). The accessed fluorinated isoflavonones 18 showed in vitro inhibitory activity

prepared by addition of gem-difluoropropargyl bromides 20, developed by Hammond and co-workers,77 to the corresponding N-tosylimines 19, previous lithium−bromine exchange. These fluorinated building blocks 20 were used as well in the preparation of gem-difluoropropargyl amides 23. Intramolecular 4-exo-dig and 5-endo-dig hydroamination reactions of amides 23 have been reported under palladium catalysis and basic conditions, respectively, rendering fluorinated β- and γ-lactams regioselectively.78 However, hydroamination was not accomplished under gold catalysis. Instead, in the presence of Au(III) salts an unprecedented head-to-head dimerization of compounds 23 was observed.79 This novel reactivity pattern seems to be induced by the gem-difluoro moiety, which played a critical role. According to the electron-withdrawing effect imparted by fluorine, the nuleophilicity of the nitrogen atom is decreased to such an extent to prevent hydroamination but, at the same time, assists gold catalyst to activate the triple bond toward the intermolecular nucleophilic addition of a halogen atom from the gold salt. Vinyl Au(III) intermediate 25 underwent an additional alkyne activation−halogen nucleophilic addition sequence to generate divinyl intermediate 26, which finally yielded dienes 27 by means of reductive elimination (Scheme 7). Attempts to perform the process catalytically by adding external oxidants and halogen sources failed, so the process was stoichiometric in gold. Gold complexes worked efficiently, catalyzing the formation of 5-difluoropyrazoles 29 with high selectivity from fluorinated alkynyl ketones 28 and hydrazines (Scheme 8).80 The authors sustained that the observed regioselectivity resulted from a

Scheme 5. Synthesis of Fluorinated Isoflavonones 18

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Scheme 7. Gold-Catalyzed Head-to-Head Dimerization of Difluoropropargyl Amides 23

groups reduce amine’s nucleophilicity, affecting the efficiency of the overall process. In contrast to terminal alkynes, the use of internal propargyl amines completely changed the regioselectivity, rendering 1,4-dihydropyrimidines 34 in high yield resulting from a 6-endo-dig cyclization (Scheme 9, eq 1). An interesting mechanistic aspect was discussed therein. It was commonly assumed that gold-catalyzed nucleophilic additions get to completion by electrophilic attack from a proton over a vinyl gold species, as demonstrated, for instance, in the gold-catalyzed cyclization of propargyl amides by Hashmi and co-workers.82 Nevertheless, in an attempt to access this vinyl gold species using a preformed propargyl amine gold acetylide, the isolated intermediate corresponded to alkyl gold 35, which did not evolve to the final imidazole 33 when treated under acidic media but decomposed. A fluorine effect was invoked to explain those results. Affected by the fluorine moiety, which reduces the nucleophilicity of the vinyl gold intermediate, isomerization was favored over the protodeauration event, explaining the intermediacy of alkyl gold species 35. This issue, besides the postulated intermediacy of zwitterionic species, determined a final step that might be conceived as a proton−gold exchange or intramolecular protodeauration event over intermediate 36. Furthermore, attempts to functionalize imidazoles by trapping alkyl or vinyl gold intermediates with NIS resulted in the formation of fluorinated imidazole-5carbaldehydes 37. Mechanistic studies revealed a radical process after gold-catalyzed cyclization in which carbonyl oxygen came from O2 (Scheme 9, eq 2). A nice example to illustrate the implications that fluorine substitution may have in gold-catalyzed reactions was reported by Fustero and co-workers in 2013.83 They proved that fluorine substitution plays a critical role in the regiochemical outcome of the intramolecular hydroamination of o-alkynylbenzyl carbamates 38. In general, regioselectivity in such type of processes was highly dependent on the electronics of the aryl substituent at the alkyne moiety. Indeed, while electron-donating substituents induced 6-endo-dig cyclization (being the major products isoquinolines 40), electron-withdrawing substituents favored a 5-exo-dig pathway (with the preferred formation of isoindolines 39) (Scheme 10). In Fustero’s work, it is likely that a steric rather than an electronic effect was imparted by fluorine, since gradual introduction of fluorine atoms at the α position of the benzyl carbamate promoted a 5-exo-dig cyclization pathway over 6-endo-dig, leading to isoindoline derivatives 39 as the major products, in striking contrast to the nonfluorinated counterparts.84−87 Regiochemistry was also critical in the intramolecular hydroamination of N-(ortho-alkynyl)aryl-N′-substituted trifluoro- and bromodifluoro-acetamidines 41,88 since up to three types of cyclization pathways may operate: 7-endo-dig, 6-

kinetic control, since nucleophilic attack by the primary amine is less sterically hindered. Scheme 8. Synthesis of 5-Difluoropyrazoles 29

On the other hand, fluorinated propargyl amidines 32 underwent, in the presence of Au(I) complexes, a 5-exo-dig cyclization to afford 2-fluorinated 5-methylimidazoles 33 (Scheme 9, eq 1).81 Under optimized conditions, their Scheme 9. Gold-Catalyzed Cyclizations of Propargyl Amidines 32

preparation could be set in a one-pot procedure from the corresponding fluorinated imidoyl chlorides 30 and propargyl amines 31. While the overall process showed good compatibility to several functional groups, its efficiency was affected by electronics on the arylamine, being slightly lowered with electron-deficient ones. Even though the protodeauration step used to be the rate-limiting step when dealing with basic amines, reported results point to electronic activation as the higher barrier to overcome. Presumably, electron-withdrawing F


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Scheme 10. Influence of Fluorine Substitution in the Regiochemical Outcome of the Intramolecular Hydroamination of Carbamates 38

hydroamination−formal aza-Diels−Alder reaction sequence (Scheme 12).99,100

exo-dig, or 5-endo-dig. While copper and silver salts gave low conversions and poor selectivities, respectively, 5-endo-dig cyclization took place efficiently in the presence of 5 mol % NaAuCl4·2H2O in toluene at room temperature to render indoles 42 in good yields (Scheme 11). The process was highly

Scheme 12. Tandem Hydroamination−Formal aza-Diels− Alder Reaction of Fluorinated Homoproparyl Amines 43

Scheme 11. Regioselective Cyclization of Fluorinated Acetamidines 41

selective independently of the electronics on the substituents at the alkyne moiety, unless terminal alkynes were employed. Under basic reaction conditions, 6-exo-dig regioisomers could be accessed but in slightly lower yields and entailing harsh conditions. Homopropargyl amines are ubiquitous substrates in goldcatalyzed processes.89−98 Indeed, a wide variety of nitrogencontaining heterocycles, such as piperidines, pyrrolidines, or tetrahydroquinolines, among others, have been prepared using this chemistry. However, homopropargyl amine derivatives bearing fluorinated substituents and a quaternary stereocenter had not been tested versus gold catalysts until Fustero’s work in 2013.99 This study was carried out employing fluorinated propargyl-α-amino esters as starting materials. Gold catalysis led the authors to access different fluorinated nitrogencontaining heterocycles just by modifying the substitution pattern on the nitrogen atom. Remarkably, all of the final products contain at least one quaternary α-amino acid unit. In an attempt to access a new family of fluorinated proline derivatives by means of an intramolecular hydroamination reaction over substrates 43 containing an N-aryl amine moiety, a new gold-catalyzed tandem reaction was discovered. Under optimized conditions, these substrates gave rise to the intricate tetracyclic frameworks 44 in good yields as single diasteroisomers. Their formation could be envisaged as a tandem

This unprecedented tandem sequence is initiated by means of an intramolecular hydroamination reaction of the starting amine over the Au(I)-activated triple bond, rendering intermediate A in equilibrium with the iminium salt B. Intermediate B partly evolves toward pyrroline 45 by protodeauration. Likewise, intermediate B can be trapped by the hydroamination product 45 by means of an intermolecular enamine attack, rendering intermediate C. The latter is then prone to undergo an additional enamine attack but in an intramolecular fashion through the ortho position of the aromatic ring, building the tetracyclic skeleton D. Rearomatization and a final protodeauration step would yield the final product 44 and complete the catalytic cycle (Scheme 13). This mechanistic proposal arose from an in-depth theoretical study by using density functional theory (DFT), which bears out the experimental results and shows this reaction pathway as the less energetic one, while helping to rationalize the stereochemical outcome of the tandem protocol.99 The diastereoselectivity of the process is determined in the first enamine attack. The stereochemistry of such attack seems to be determined by the higher steric requirements imparted by the trifluoromethyl group, thus occurring with both bulkier G


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Scheme 13. Mechanistic Proposal for the Formation of Tetracycles 44

fluorine residues in an anti relative position (see Scheme 13: enamine attack of 45 to intermediate B). This stereoselection, in turn, would address the directionality of the subsequent intramolecular attack, rendering a stereospecific process. Despite several authors postulating that analogous hydroamination products could be protonated by a BrØnsted acid, giving rise to the corresponding iminium intermediate B and thus initiating the dimerization protocol, or alternatively that gold complexes could activate enamines and enol ethers toward nucleophilic attack, control experiments showed that the hydroamination product 45, by itself, did not undergo the tandem reaction. These results pointed at the enamine addition of the pyrroline 45 to the iminium intermediate B as the key step for the success of the tandem protocol. A recent study by Hammond and co-workers categorized gold-catalyzed nucleophilic additions whether electronic activation or deauration was the rate-limiting step, while demonstrating how the nature of the ligands influenced each stage of the catalytic cycle.101 Concerning the process under discussion, the authors assumed protodeauration as the ratedetermining step. In the presence of basic nucleophiles such as amines, the acidity of the triflic acid, in situ generated in the reaction medium, would be diminished, slowing down the deauration event. Hence, the effective concentration of the iminium salt B in the media would be increased, thus favoring the intermolecular pathway. Under this scenario, the authors found that the electronics on the aryl amine were critical for the success of the tandem protocol. In amino esters 43 (see Scheme 12), the aromatic amine functionality is flanked with two electron-withdrawing groups (R1 = RF and ester), which compromise its basicity.

Whereas propargyl amino esters bearing an electron-rich aromatic ring such as p-methoxyphenyl (PMP) underwent the process efficiently, since the basicity on the nitrogen was preserved, less activated aromatic rings, such as phenyl or ptolyl, led to the pyrroline 45 as the major product. Since basicity loss is not compensated, intermolecular enamine attack is not fast enough to compete with deauration, which gives rise to the hydroamination product. Inspired by the aforementioned study, Fustero and coworkers envisioned the use of an electron-poor gold catalyst to slow down deauration, driving the process in the desired way toward the tetracyclic frameworks. This strategy led them to identify suitable conditions to enlarge the scope of this transformation to less nucleophilic aryl amines. On the other hand, when starting amino esters bearing an aromatic substituent were alkylated at the nitrogen atom (46), the aforementioned tandem sequence was inhibited. Instead, a tandem hydroarylation−isomerization process was operating, giving access to a new family of fluorinated dihydroquinolines 47 (Scheme 14).102 Scheme 14. Gold-Catalyzed Tandem Hydroarylation− Isomerization of Amino Esters 46

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yields (Scheme 16, eq 2). Those compounds appeared as novel fluorinated analogues of the nonproteinogenic pipecolic acid. Furthermore, the piperidine scaffold is a structural motif present in a large variety of biologically active natural alkaloids and drugs. Among the reported gold-catalyzed reactions to access the piperidine substructure,90,91,105,106 Fustero’s autocatalysis proposal fulfills the principle of synthetic efficiency. Besides confirming oxazine intermediacy in the dihydropyridone formation, control experiments evidenced that gold did mediate in this transformation. While most of the goldcatalyzed reactions were based on its ability to act as a soft Lewis acid, activating C−C multiple bonds, it has also proved its competency toward the formation of σ-complexes with heteroatoms. Within this context, the authors suggested that, after intramolecular carbonyl addition, σ-complexation of the gold complex with intermediate oxazine 54 would promote nucleophilic addition of an external nucleophile (methanol) to form a mixed acetal 55 and then undergo a gold-catalyzed Petasis−Ferrier rearrangement. Methanol elimination and further isomerization would render final dihydropyridone 53 (Scheme 15, eq 2). According to Patil and co-workers’ categorization,107 this process constitutes a new example on the challenging self-relay catalysis (also named autocatalysis), as up to three distinct reactionscarbonyl addition−nucleophilic addition−Petasis− Ferrier rearrangementwere promoted by the same gold catalyst, exploiting dual ability of gold species to act as σ and π Lewis acids. To date, just a few examples have been described where gold imparts simultaneously both acidities, not only in self-relay processes108−110 but also in an orthogonal relay catalysis, combining two gold salts with different hard−soft character, i.e., the so-called dual hard−soft gold catalysis.111 Very recently, Krause and Rurack reported the synthesis of two highly fluorinated BODIPY dyes 59,112 which display excellent spectroscopic properties and photostability and, in turn, would have potential applications in functional-group labeling or in cell imaging. Tailored pyrrole precursors 58 were synthesized via gold-catalyzed hydroamination of fluorinated sulfonamides 57 in ionic liquids, which allowed catalyst recycling (Scheme 17).

Additionally, when homopropargyl amines were functionalized as Boc-carbamates 48, oxazinones 49 were generated in an efficient manner by means of a carbonyl addition with concomitant loss of isobutene, showing the same reactivity pattern depicted by their nonfluorinated counterparts (Scheme 15).89 Scheme 15. Gold-Catalyzed O-Addition with Concomitant Loss of Isobutene

These tert-butylcarbamate derivatives 48 were easily converted into the corresponding homopropargyl amides 50.103 When amides 50 were treated with Au(PPh3)Cl (5 mol %) in combination with AgOTf (5 mol %) in DCM, oxazines 51, the O-addition products, were formed according to “classical” reactivity imparted by gold salts as soft carbophilic πLewis acids. In order to get synthetically useful yields, oxazines 51 needed to be generated in the presence of molecular sieves to prevent hydrolysis. In the presence of water, these species formally evolved into the alkyne hydration products 52 in very good yields (Scheme 16, eq 1). Thus, hydration of the triple bond under gold catalysis was assisted by the carbonyl moiety through oxazine formation and subsequent hydrolysis. Solvent screening showcased the bifunctional character imparted by gold complexes, previously highlighted by Gevorgyan.104 In the presence of methanol, exclusive formation of dihydropyridones 53 was observed in good to excellent Scheme 16. Exploiting σ- and π-Dual Ability of Gold Salts: Synthesis of Fluorinated Dihydropyridones 53

Scheme 17. Gold-Catalyzed Synthesis of Fluorinated BODIPY Dyes 59

2.2. Gold Complexes with Fluorine-Containing Ligands

In 2011, Rabinovich and co-workers described the preparation of a square planar fluorinated Au(III) corrole 63 (Scheme 18), which in preliminary investigations exhibited long wavelength phosphorescence at room temperature.113 Related Au(III)− porphyrins have found application as anticancer drugs or as acceptors in photosynthesis-mimicking dyads and triads but also in catalysis mediating, for example, the cycloisomerization of allenones. Besides this example, the preparation of diverse fluoro(hetero)aryl Au(I) species has been reported by Larrosa and I


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Scheme 18. Synthesis of Gold-Containing Fluorinated Corroles 63

became highly valuable intermediates not only in proto- or halodeauration processes but also in the design of novel metalcatalyzed transformations, as will be discussed in the last section of this review. Nolan’s C−H auration system simply consisted of an airstable NHC−gold hydroxide 65 (Scheme 19, eq 1), readily accessible from the corresponding gold chloride Au(IPr)Cl in the presence of an alkali metal hydroxide.116,117 Nolan and coworkers further demonstrated auration with NHC ligands, indeed, does not require the isolation of the gold hydroxide complex 65. Instead, it can be in situ generated in the presence of hydroxyl alkalis. Likewise, reaction times and temperatures could be diminished from hours to minutes and from 60 to 80 °C to room temperature when mechanochemical grinding methods of mixing in the solid state were applied against solvent-based protocols.118 Instead, Larrosa and co-workers reported a catalytic system consisting of a phosphine-ligated gold complex 67 in combination with Ag2O, K2CO3, and PivOH (Scheme 19, eq 2).119 They proposed two plausible pathways for the reaction: (a) a concerted metalation−deprotonation where pivaloate ligand acts as a proton acceptor via a six-membered ring transition state (see proposed transition state 69 in Scheme 19) or (b) an oxidative addition mechanism via a transient Au(III) hydride species. However, the high primary kinetic isotope effect registered was suggestive of the former σ-bond metathesis pathway. Likewise, a silver-mediated C−H activation−transmetalation sequence could be ruled out by experimental results. Despite working in a less basic media, Larrosa’s auration system showed higher activity and broader scope than gold hydroxide species, though both methodologies were limited to the preparation of aryl−Au(I) complexes bearing at least two electron-withdrawing ortho substituents (Chart 1).

Nolan. Nevertheless, given the significance of this pioneering work on gold-mediated C−H and C−C bond activation, these results will be discussed in a separate section. 2.3. Role of Fluorine in Gold-Mediated C(sp2)−X (X = H, C, F) Bond Activation

Gold complexes have been demonstrated to be efficient catalysts in C−O, C−N, and C−C bond formation but also in the construction of C−F bonds,114 as we will discuss in the following sections. However, the use of these complexes in C(sp2)−X (X = H, F, C) bond activation constitutes an underexplored field. The seminal work from Larrosa, Nolan, and Zhang highlights the potential of this early growing area of research, which certainly had a strong impact in de novo coupling reaction manifolds. In 2010, the Larrosa and Nolan groups independently demonstrated that Au(I) complexes bearing strong σ-donor ligands can perform the regioselective activation of C(sp2)−H bonds on electron-deficient fluoroarenes under significantly milder reaction conditions compared to other metal species such as Cu, Pd, or Rh (Scheme 19).115 Accessed aryl−Au(I) compounds were remarkably stable, not just to air or moisture but also to other common decomposition pathways affecting related organometallic species, such as protodemetalation or metal center reduction. Arguably, these aryl−Au(I) compounds Scheme 19. Seminal Reports on Au(I) C(sp2)−H Bond Activation

Chart 1. Differential Reactivity of Gold Complexes 66 and 68

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of the arene by the base and the following nucleophilic attack onto an electrophilic Au(I) complex. The Larrosa group found that Au(I) complexes bearing strong σ-donor ligands enable the C(sp2)−C(sp2) bond activation of electron-poor fluoroaryl carboxylic acids 71 (Scheme 21).122 As in their seminal contribution, silver additive Ag2O was necessary to carry out decarboxylation. Moreover, this basic species permitted the direct use of the carboxylic acid instead of the carboxylate salt. The presence of the silver additive resulted in two plausible reaction outcomes, whether silver or gold was the actual species prompting decarboxylation. However, NMR studies were consistent with transmetalation occurring prior to C−C activation, i.e., a gold-mediated decarboxylation. Additionally, the value of the accessed fluoroaryl Au(I) species 72 as synthetic intermediate was exemplified by their one-pot trapping with electrophilic halogen sources, yielding haloarenes 73 and 74 in excellent yields. As we depicted in section 1.1, C−F bonds are characterized by high bond energy. Actually, they are the strongest bonds makes by carbon, even stronger than with hydrogen atoms. This is what made C−F bond activation such a challenging topic.123−127 Beyond known active transition metal complexes toward C−F bonds, like Pd, Ni, Rh, Pt, or Ru complexes, among others, the search for new metal catalysts to promote such reactivity patterns is still required. Although metal hydrides have appeared as important intermediate species in C−F bond activation128−134 and despite the progress achieved in both gold fluoride and gold hydride complexes,135 the first step in such endeavors ruled out the intermediacy of a gold hydride species. Even though a dinuclear bridged μ-H−Au2-type species was detected, it was unreactive toward C−F bonds. Alternatively, experimental and theoretical mechanistic studies pointed to the direct oxidative addition of a C−F bond on a Au(I) cationic complex as the key step. Specifically, Zhang and co-workers reported C−F bond activation of perfluoro(hetero)arenes 77 in the presence of silanes as the hydrogen source by tricoordinated Xantphosderived Au(I) complexes (Scheme 22).136 The use of exogenous ligand to prevent Au(I) reduction and acetic acid to replace the counterion afforded complete conversions and provided higher para regioselectivity over the ortho position. Furthermore, the sterically hindered t-BuXantphos ligand attained a higher reactivity since it prevented the formation of unreactive tetracoordinated L2Au+ species observed for less

With more electron-rich arenes, C−H activation became more difficult or did not proceed. A high withdrawing− inductive effect imparted by fluorine was critical for C−H functionalization. Over other commonly employed substrates in C−H activation processes, fluoroarenes do not entail the installation of additional functional groups that are known to interact with the metal center or that may assist in the reaction. The reactivity profile observed by both Larrosa and Nolan groups simply stands on the acid−base principle, i.e., the most electron-deficient C−H bond is regioselectively functionalized. The difference of reactivity between both procedures can be explained by several reasons. First, they employed different solvents (THF/toluene versus DMF), which may alter the acidity of the aromatic protons. Second, silver salts have been previously used in electrophilic aromatic substitutions. Similarly, Ag2O, beyond performing halide abstraction from gold, may be activating the π system, thus lowering the pKa of the aromatic protons. Nolan further studied “silver effects” in their catalytic system, with NHC−Au(I) complexes.120 The addition of stoichiometric amounts of silver salts such as Ag2O, AgF, or AgOAc, in combination with NHC−Au(I) hydroxide species did promote the C−H activation on previously unreactive 1,3,5-trifluorobenzene. Nevertheless, a different role rather than as a mere Lewis acid might be ascribed to the silver salt, since stoichiometric amounts were necessary and other metal salts such as Al2O3, AlCl3, or ZnBr2 did not promote the reaction. Unlike Larrosa’s results, the authors hypothesized that silver might be implicated in a transmetalation reaction with gold. On the other hand, the Larrosa group further demonstrated that shifting to stronger bases such as NaOH or NaOt-Bu also allowed the direct C−H auration of fluoro(hetero)arenes with Au(PR3)Cl complexes without the need of silver additives (Scheme 20).121 The exact nature of the active gold species Scheme 20. Preparation of Gold(III) Complexes 68

was, however, not clear. The intermediacy of Au(PR3)OR, or higher order species {[Au(PR3)]nOR}X, was suggested by the authors. Likewise, they did not discard the direct deprotonation

Scheme 21. Gold-Catalyzed Decarboxylative Synthesis of Haloarenes 73 and 74 from Benzoic Acid 71

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yields with more electron-deficient systems (Scheme 23). This protocol tolerated the presence of formyl, alkynyl, ketone, ester, and carboxylate groups, endorsing the chemoselectivity showcased by this catalytic system.

Scheme 22. Gold-Catalyzed C−F Bond Activation in Perfluoroarenes 77

Scheme 23. “π−π Interaction-Assisted C−F Bond Activation” In Perfluoroarenes 77

sterically bulky Xantphos-derived gold complexes, for which an equilibrium between bi- and tetracoordinated gold complexes may operate. The process worked chemoselectively, promoting C−F bond activation in the presence of ketones, esters, and carboxylates, without reduction of the carbonyl group. Hydrodefluorination was accomplished even in the presence of alkynyl, alkenyl, and amide groups, albeit in diminished but still synthetically useful yields (Scheme 22). Likewise, the electronics on the perfluoroarenes played a critical role, giving better results in the presence of electron-withdrawing substituents. In a brilliant illustration of the synergy commonly featured among nature’s catalytic systems, i.e., enzymes, the Zhang group demonstrated as well the operability of gold hydrides to activate C−F bonds in a catalytic assisted hydrodefluorination reaction.137 As it is well demonstrated, oxidative addition of strong bonds can be accomplished over electron-rich low-valent transitionmetal complexes. Nevertheless, NHC−gold hydrides proved to be not reactive enough to overcome high activation barriers imparted by C−F bonds. NMR and UV−vis studies, besides DFT computational calculations, all showed a labile interaction between these gold hydrides and perfluoroarenes. The authors envisioned to take advantage of the electronwithdrawing effect imparted by fluorine in order to establish a π-stacking interaction between an electron-deficient perfluoroarene and an electron-rich additive, which may lower the activation barrier enough to induce C−F bond activation by a gold hydride. They proved that electron-rich pyridine 4(dimethylamino)pyridine (DMAP) could efficiently play the role as the electron donor, lowering this barrier nearly 9 kcal/ mol. Indeed, the operability of this π−π interaction was supported on theoretical calculations and on NMR and UV−vis studies as well, registering the deshielding of the protons at DMAP. Hence, in the presence of DMAP, a π−π stacking interaction is established, prompting in turn proton transfer from gold hydride to the pyridyl nitrogen atom of the former, followed by oxidative addition of a C−F bond over Au(I) species. Final reductive elimination from Au(III) species gave rise to the hydrodefluorinated arene 78. Addition of silanes as hydrogen source rendered the process catalytic, since it restored gold hydride through H−F exchange with gold−fluoride species released after reductive elimination. Remarkably, the formation of strong a Si−F bond should not be overruled as an additional thermodynamic driving force. The so-called “π−π interaction-assisted C−F bond activation” enabled the regioselective para-hydrodefluorination of perfluoro(hetero)arenes 77 in good yields, reaching higher

3. GOLD CHEMISTRY WITH NUCLEOPHILIC SOURCES OF FLUORINE Many nucleophilic and electrophilic fluorine sources are currently available suitable to react with electron-rich, electron-neutral, or electron-deficient substrates under acidic, basic, and neutral conditions. However, those reagents frequently are incompatible with many functional groups or require harsh conditions. The success of transition metal complexes in the generation of C−C and C−heteroatom bonds has inspired the extension of this strategy to the creation of C− F bonds. Thus, transition metal-catalyzed transformations involving fluorinated reagents open new perspectives in this emerging area of research, driven by the maintained importance over several decades of fluoroorganic compounds in medicinal chemistry and drug development.3,4 The design of C−F bond-forming catalytic cycles is not straightforward. The main difficulty arises in the reductive elimination step, which is one of the keys for the regeneration of the catalytically active species and the release of the final products. C−F reductive elimination remains rare when compared to other types of C−X reductive elimination (X = e.g., C, N, O, Cl, Br, I) despite the large thermodynamic driving force provided by formation of strong C−F bonds.138 Additionally, the choice of the most adequate fluorine source is also of paramount importance. Although great progress has been made in the field of transition-metal-catalyzed fluorinations, most examples rely on electrophilic fluorinating reagents, while the use of fluoridebased reagents remained clearly underdeveloped. However, the reactions presented in this section indicate that gold-catalyzed nucleophilic fluorination reactions can be useful tools for those purposes by fine tuning the ligands and the nucleophilic fluorine source, allowing the fluorination of poorly activated substrates. 3.1. Creation of C−F Bonds by Gold-Catalyzed Nucleophilic Fluorinations

The main problem associated with the combination of fluoride with transition metals is the dual reactivity profile of this anion as a nucleophile and as a base. In its unsolvated form, fluoride is L


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Scheme 24. Synthesis and Reactivity of the First Gold−Fluoride Complex 81

Scheme 25. Alkyne−Hydrofluorination with NHC−Gold Complexes

fluoride and gold across the triple bond (83) was observed, with a trans relationship between gold and fluorine, as an equilibrium mixture with starting complex 81. Only after the addition of trifluoroacetic acid, the hydrofluorination product 84a was isolated in almost quantitative yield (Scheme 24). This trans arrangement of gold and fluorine can be explained via initial displacement of fluorine from the alkyne and subsequent nucleophilic attack to the gold−alkyne complex. After this interesting finding, the authors developed the catalytic version of this process.143 Gold chloride complex 79 reacted with 3-hexine (82a) in the presence of AgBF4 to render cationic complex 85, which upon treatment with HF·Et3N as the nucleophilic fluoride source was converted into the corresponding fluoroalkene 84a in 64% yield (Scheme 25, eq 1). In this case, no equilibrium was observed since the presence of HF promoted the hydrodeauration of the vinyl gold intermediate. Under optimized conditions, gold complexes 86/AgBF4 or 87 were the catalyst of choice; HF·Et3N complex was used as nucleophilic fluorine source, and powdered KHSO4 in conjunction with the DCM-soluble acid cocatalyst PhNMe2−HOTf (10 mol %) was used as the proton source to effect the hydrodeauration of alkynes 82 and regeneration of the catalytic species. The overall process took place with good to high levels of diastereoselectivity, giving rise to the formation of the trans products 84 exclusively (Scheme 25, eq 2). Both (hetero)aryl and alkyl substituents were compatible with the

strongly basic and solvation through hydrogen bonding significantly modifies its ability to act as a nucleophile. On one hand, the successful development of new methodologies of nucleophilic fluorination mediated by transition metals is directly related to the availability of more soluble and less basic fluoride sources. On the other hand, fluoride complexes of late transition metals are labile and reactive. The fluoride ion is mismatched with those metal cations in low oxidation states, promoting destabilizing interactions with filled d orbitals. That explains why the AuF molecule was only detected by spectroscopic techniques in the gas phase139 or the highly reactive nature of AuF3 which clearly compromises its use in synthetic organic chemistry.140 Those problems could be overcome by using N-heterocyclic carbene (NHC) ligands, as demonstrated by the pioneering work of Sadighi, Gray, and co-workers, providing less reactive complexes and preventing reduction to gold metal.141 The use of these ligands allowed them the isolation of the first gold fluoride complex.142 Thus, 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene gold chloride 79 (SIPrAuCl) was transformed into the tert-butoxide complex 80 after treatment with t-BuONa. This was in turn reacted with the HF complex of Et3N to form gold fluoride complex 81 as a colorless precipitate. The structure of 81 was unambiguously determined by X-ray analysis. When complex 81 was treated with an excess of 3-hexyne (82a), the product arising from the addition of M


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complex 93 in DCE at 55 °C to afford good yields of the corresponding fluoroalkenes 84 (Scheme 28, eq 1). The

hydrofluorination. With substrates bearing alkyl and aryl substituents the predominance of the β-fluorostyrene product was observed, probably due to the higher electrophilicity of the benzylic position. Miller and co-workers reported an elegant extension of the aforementioned methodology.144 By using a directing group they were able to perform a gold-catalyzed hydrofluorination of alkynes in a predictable manner with excellent regio- and stereoselectivity. The 2,2,2-trichloroethoxycarbonyl (Troc) group was found to be the best choice for protected propargylic amines 88 in terms of stability and directing ability. Good yield and stereoselectivities of (Z)-fluoroalkenes 89 were observed, and both alkyl and aryl substituents in the starting amines were compatible with the process (Scheme 26). Tertiary amines proved to be inert under these conditions, probably due to inactivation of the catalyst.

Scheme 28. HF·DMPU Reagent in Gold-Catalyzed Hydrofluorination Reactions of Alkynes

Scheme 26. Protecting-Group-Directed Hydrofluorinations of Propargyl Amines 88

process was highly regioselective, and it was also compatible with terminal alkynes (not compatible with NHC fluorides 81), affording the internal regioisomer and showing a high functional group tolerance. Furthermore, the process was also highly chemoselective, showing a strong preference toward triple bonds in comparison with alkenes. By using an acidic additive it was also possible to perform the dihydrofluorination of alkynes 82 with high efficiency to the gem-difluoroderivatives 94 with an excess of HF·DMPU reagent (Scheme 28, eq 2). The last example of hydrofluorination of alkynes was reported very recently by Nolan and co-workers taking advantage of a gold bifluoride NHC-complex 96.146 A new methodology for the preparation of new NHC−gold bifluorides 96 was devised by the authors. It involved the use of the NHC−gold hydroxydes 95 as starting materials. Treatment with diluted Et3N·3HF (Et3N·2HF) afforded gold bifluorides 96 as moisture- and air-stable solids. Gold monofluoride species 97 could also be accessed by exposure of these gold bifluorides 96 to KOt-Bu or alternatively from starting gold hydroxides 95 by treatment with KHF2 (Scheme 29). The ability of gold difluoride complexes in the formation of C−F bonds was tested in the hydrofluorination reaction of alkynes. Under optimized conditions, alkynes 82 were treated with bulky catalysts 96a,b in refluxing DCM in the presence of 3 equiv of Et3N·3HF and NH4BF4 as a cocatalyst. Good yields of fluoroalkenes 84 were obtained with symmetrical alkynes with various substitution partners. With alkynes bearing an alkyl (at R2) and an aryl substituent (at R1), the process was regioand diastereoselective, giving rise to the exclusive formation of

These observations could be rationalized on the basis of the more stable 6-membered ring gold complex 91 (when compared with 7-membered ring complex 92) formed with the nucleophilic attack of the fluoride atom opposite to the propargylic position after the initial complexation of the gold salt with the triple bond (Scheme 27, via A). Additionally, the other attack is less favored sterically, especially with bulky groups at R1 (Scheme 27, via B). More recently, Hammond and Xu designed a new nucleophilic fluorinating agent: HF·DMPU complex, with improved properties in comparison with the pyridine and trietylamine complexes of HF.145 The new reagent displayed high acidity, weaker nucleophilicity, and weaker coordination ability with metals, which reduced the interferences with metal catalysts. Those features converted HF·DMPU in a promising reagent for the transition metal-catalyzed fluorination reactions. In this case, the proof of concept was performed with the goldcatalyzed hydrofluorination of alkynes 82. Under optimized conditions, alkynes 82 reacted with HF·DMPU and imidogold Scheme 27. Regiochemical Control Exerted by Gold Complex 91

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Scheme 29. Synthesis of NHC−Gold Fluoride Complexes 96 and 97

the Z isomer with the fluorine placed next to the alkyl group. An inversion of the regioselectivity was observed with electronwithdrawing substituents, affording the fluoride-conjugated addition product 98 almost exclusively (Scheme 30).

All examples shown above for the creation of C(sp2)−F bonds involved the use of alkynes as starting materials in a hydrofluorination step, but they were not amenable for the generation of aryl fluorides or C(sp3)−F bonds. To this end, a reductive elimination of the organometallic species is likely to be the key turnover step to set up these transformations in a catalytic manner. However, examples of reductive elimination of gold fluoride complexes are exceedingly rare. Buchwald and co-workers demonstrated recently in a pioneering work that the use of BrettPhos-type ligands was decisive for the successful reductive elimination of palladium(II) complexes, allowing for the preparation of aryl fluorides in a very simple manner, employing a nucleophilic fluorine source.147,148 This method was a breakthrough in the area, and similar transformations with other metals have been reported.149−152 However, the extension of those protocols to gold complexes is not straightforward due to their reluctance to undergo reductive elimination. In this context, Toste and co-

Scheme 30. Alkyne Hydrofluorination Mediated by Complexes 96

Scheme 31. Reductive Elimination in Difluoro Gold(III) Complexes 100

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workers identified systems that could undergo this reductive elimination, taking advantage of the Au(I)/Au(III) redox couple, thereby opening new perspectives in the creation of C(sp3)−F bonds.153 Alkyldifluoride gold(III) intermediates 100, prepared by oxidation of the corresponding alkyl gold(I) derivatives 99 with XeF2, underwent reductive elimination in different extension depending on the nature of the alkyl group. Methyl substituent was unreactive, and more hindered substituents rendered a mixture of fluoroalkanes arising from C(sp3)−F reductive elimination and alkenes resulting from formal β-H elimination, together with the IPrAuF complex. Substituents bearing cyclic alkyl groups, which should disfavor the competitive β-hydride elimination, gave better yields of the corresponding fluoroalkanes. Finally, substituents lacking β-hydrogens showed again a dual profile: reductive elimination and carbocation-like behavior (Scheme 31). Kinetic studies and DFT calculations indicated that the observed reactivity was due to the three-coordinate complex 101, which in turn arose from the starting square planar ciscomplex 100 by fluoride dissociation. This T-shaped intermediate 101 could undergo reductive elimination via a 3-centered transition state; alternatively, deprotonation of the β position by F− would promote β elimination. Additionally, the fluoro ligands increased the positive charge on the Au−alkyl bond, conferring the unusual carbocation-like behavior observed (Scheme 32).

Scheme 33. Oxidant-Free Redox Au(I)−Au(III) Couple in Aromatic Fluorinations of Substrates 102

difficulty of these types of complexes to generate aryl trifluorides. A recent discovery by Toste and co-workers, with important implications in the development of new related goldcatalyzed processes, showed that this process could take place at room temperature.161 They found that oxidative addition of CF3−I to aryltrialkyl- and aryltriarylphosphinegold(I) complexes 106 could be performed under photochemical irradiation. A detailed mechanistic study of this process indicated that is a rare oxidation of gold(I) to gold(III) by means of a free radical chain mechanism with a trifluoromethyl radical as propagating species. The resulting Au(III) complexes 107 were purified by flash chromatography and subjected to reductive elimination. When complex 107 was heated in toluene-d8 at 110 °C, aryl iodides 109 and Ph3PAuCF3 (110) were formed in 20 min, indicating that Caryl−I reductive elimination in complex 108 was faster than Caryl−CF3 reductive elimination. In order to direct the process to the formation of the aryl trifluoride, iodide abstraction from complex 107 has to be performed. Indeed, when the process was performed in the presence of AgSbF6, the reaction proceeded at room temperature in a quantitative manner to afford the Caryl−CF3 reductive elimination product 111, together with the gold salt 112 (Scheme 34).

Scheme 32. Role of T-Shaped Intermediate 101 in Reductive Elimination Processes

Scheme 34. Caryl−CF3 Reductive Elimination in Complex 107

When this process was performed with an analogous diiodo gold(III) complex, the clean reductive elimination of C−I was observed, indicating that fluorine clearly imparts a differential reactivity in those complexes. Very recently, Ribas and co-workers demonstrated that it is possible to perform aromatic fluorinations using an external oxidant-free Au(I)−Au(III) redox couple mediated by appropriate pincer ligands and AgF as the nucleophilic fluorine source.154 Thus, aryl halides 102 (R−X; X = Cl, Br, I) bearing a macrocyclic ligand were transformed into the corresponding aryl fluorides 105 using a catalytic source of Au(I) and 2 equiv of AgF, providing the best results with cationic NHC−gold complex 103b. Mechanistic and theoretical studies of this process, together with the isolation of analogous species of aryl−Cu(III)155,156 and aryl−Ag(III),157 indicated that the reaction should proceed through the aryl−Au(III) species 104, although it was not possible for them to detect this intermediate (Scheme 33).

Additionally, further studies demonstrated that this reductive elimination step was halide dependent.162 The treatment of complexes 107 with AgX salts (X = F, Cl, Br) resulted, after sonication, in a clean halogen exchange rendering metathesis products 113 (Scheme 35). Thermolysis of those complexes gave valuable information about the competitive Caryl−X and Caryl−CF3 reductive elimination from Au(III). While thermolysis of complex 107 (X = I) gave exclusively Caryl−I bond formation, complex 113 (X = F) was completely selective for Caryl−CF3 bond formation (Scheme 35). A detailed study of

3.2. Creation of C−CF3 Bonds by Gold-Catalyzed Nucleophilic Fluorinations

On the other hand, several fluoro- and fluoroalkyl complexes of gold have been isolated in recent years, but those complexes were not well suited for fluorination or fluoroalkylation reactions to date.158−160 Caryl−CF3 reductive elimination still remains a challenging step, since it usually requires high temperatures and long reaction times, which explains the P


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the active catalyst. In this context, several groups have reported the trapping of these intermediates, prior to protodeauration, using N-halosuccinimides as electrophilic sources of chlorine, bromine, and iodine.163−170 On the basis of this assumption, the first gold-catalyzed fluorination process using an electrophilic fluorine source was reported by the Gouverneur group in 2008 by means of a tandem 6-endo-dig cyclization−fluorination protocol starting from β-hydroxy-α,α-difluoroynones 8.54 Thus, fluorinated compounds 8 (R2 = F) underwent intramolecular hydroalkoxylation over the triple bond in the presence of AuCl to generate the corresponding vinyl gold intermediate, which evolved by means of two competitive pathways: either in a prodoteauration event to render compounds 115 or in an oxidative fluorination manifold promoted by Selectfluor to compounds 9 (Scheme 36). Nonfluorinated starting materials 8 (R2 = H) afforded, under similar conditions, a mixture of the difluorinated pyranones 116 and ring-opened fluorinated ketones 117 in variable amounts (Scheme 36). This seminal report demonstrated the compatibility of Selectfluor with gold species and the ability of electrophilic fluorine sources to generate C−F bonds in goldcatalyzed processes. Compounds 115 did not undergo fluorination with Selectfluor, even in the presence of AuCl, while substrates 8 remained unreacted in the presence of Selectfluor without the gold salt, which indicated that fluorination took place through the vinyl gold intermediate. Nevertheless, there are distinct mechanistic proposals for the formation of the C−F bond under these conditions. Although Gouverneur proposed a fluorodeauration event to explain the formation of fluorinated pyranones 9, the recent tendency is to ascribe to Selectfluor the role of oxidant from Au(I) to Au(III) species. After Gouverneur’s seminal report, several gold-catalyzed transformations involving alkynes and allenes were combined with electrophilic sources of fluorine as a mild methodology for the generation of C−F bonds.

Scheme 35. Halogen-Dependent Reductive Elimination Pathways in Complexes 113

those processes revealed that the strength of the Au(III)−X bond dictates the selectivity of the reductive elimination. These results clearly indicate the ability of Au(III) cations to form aryl trifluorides by reductive elimination. However, the generation of the reactive cation by iodine abstraction or halide metathesis avoids a catalytic process involving Au(III) intermediates, and a dissociation step of the iodine is necessary in order to develop this aryl trifluoromethylation in a catalytic manner.

4. GOLD CHEMISTRY WITH ELECTROPHILIC SOURCES OF FLUORINE Despite the increasing number of contributions shown in section 3 regarding gold-catalyzed fluorination based on nucleophilic fluorine sources, the dominance of processes relying on electrophilic fluorine sources is undeniable. The combination of Selectfluor as an external oxidant with gold catalysts has emerged as a powerful tool for synthesizing both fluorinated and nonfluorinated compounds, opening new departures in fluorine and gold chemistry. In this section, processes that involve the creation of a C−F bond are covered, whereas the combination of electrophilic fluorine sources with gold species in homo- and cross-coupling reactions will be discussed in detail in section 5.1. In addition, gold-catalyzed nucleophilic addition/nonmetal-catalyzed fluorination sequences have been reported as well, and they will be covered in section 4 too. It is commonly accepted that gold-catalyzed reactions involving alkynes start with the electronic activation of the alkyne by metal coordination, which enables the addition of a wide variety of nucleophiles both inter- and intramolecularly, rendering a vinyl gold intermediate. After evolution of this gold species, the catalytic cycle is commonly completed via protodeauration, which releases the product and regenerates

4.1. Gold-Catalyzed Electrophilic Fluorinations in O-Addition Processes

The mechanistic complexity of those processes is illustrated in the reaction of propargyl acetates 118 with gold complexes in the presence of Selectfluor as the electrophilic source of fluorine, depicted in Scheme 37. The initial purpose of both Gouverneur and Nevado was the preparation of α-fluoroenones via 1,3-acyloxy rearrangement of propargyl acetates 118 followed by C(sp2)−F bond formation. However, the final products detected were rather different. The reaction proved to be highly dependent on the gold source, the counterion, and the nature of the starting material. Thus, Gouverneur171 found that when propargyl acetate 118a was treated with in situ

Scheme 36. Gold-Catalyzed Alkoxyfluorination Reaction

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Scheme 37. Gold-Catalyzed Rearrangements of Propargyl Acetates

generated cationic Au(PPh3)OTf and Selecfluor in a mixture MeCN/H2O, the formation of fluoroenone 119 was observed in 45% yield, arising from the tandem [3,3]-sigmatropic rearrangement−fluorination sequence, together with 23% yield of conjugated ketone 120 (Scheme 37, eq 1). The formation of the desired product was improved up to 70% yield by using the NHC−gold complex Au(IPr)OTf [IPr = 1,3bis(2,6-diisopropylphenyl) imidazolin-2-ylidene] (Scheme 37, eq 2). In the absence of the gold catalyst, the reaction did not proceed at all, indicating the relevant role of gold in the process. In order to demonstrate the influence of gold, allene 121 was prepared and treated with Selectfluor in the absence of gold. After 72 h, 51% of fluoroenone 119 was isolated (Scheme 37, eq 3), thus suggesting a nongold-catalyzed fluorination pathway. On the other hand, Nevado172 found that tertiary acetate 118b gave fluoroenone 124 as the major product when Au(PPh3)NTf2 was used as the gold catalyst, together with small amounts of dimer 122 and enone 123 (Scheme 37, eq 4). Finally, on switching to the NHC−gold complex Au(IPr)NTf2 in the presence of NaHCO3 as a base, almost exclusive formation of fluoroenone 124 was observed (Scheme 37, eq 5). However, Gouverneur and Nevado uphold different mechanistic proposals. Whereas Nevado suggests that C−F bond formation arises from reductive elimination of a Au(III) fluoride (C), Gouverneur aims for an isomerization−nongoldcatalyzed fluorination cascade. Still, neither of them rule out fluorodeauration of a vinyl Au(I) species B (Scheme 38). Intriguingly, the formation of the C−F bond involved in both cases the use of a bulky N-heterocyclic ligand on the gold complex, which looks to play a key role in order to minimize competing homocoupling and protodeauration pathways.

Scheme 38. Mechanistic Proposals for the Gold-Catalyzed Rearrangement of Propargyl Acetates

Similarly, Hammond and Xu described the transformation of allenyl carbinol esters 125 into fluorinated enones 127 in a onepot procedure.173 After the initial gold-catalyzed isomerization of substrates 125 to intermediate dienes 126, treatment with Selectfluor afforded monofluoroalkyl ketones 127 in good yields and excellent E-diastereoselectivity. The low solubility of Selectfluor in CDCl3 seemed to be the main reason to perform this two-step reaction in a one-pot protocol, since the isomerization in MeCN was not effective (Scheme 39). The same authors recently reported the gold-catalyzed oxyfluorination of aromatic- and aliphatic-substituted alkynylic alcohols 128 and acids 130 in the presence of F-TEDA-PF6.174 R


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Scheme 39. Gold-Promoted Synthesis of Fluorinated Enones 127

Selectfluor (1.0 equiv) to render 3-fluorotetrahydropyran derivative 139 in 45% yield.175 After the initial 6-endo-dig attack, Petasis−Ferrier rearrangement would render nonfluorinated tetahydropyran 140 that, in the presence of Selecfluor, would afford product 139 (Scheme 42). This mechanism was based on the fact that a two-step procedure cyclization−fluorination afforded the desired product 139 in slightly better yield (58% combined yield). Therefore, fluorination seemed to take place after protodeauration. On the other hand, the process was highly substrate dependent, and only tertiary aryl homopropargyl acetals gave the desired products.

This protocol allowed the synthesis of difluorinated tetrahydrofurans 129 and monofluorolactones 131 in moderate to good yields (Scheme 40). Although a two-step cyclization− Scheme 40. Gold-Catalyzed Synthesis of Fluorinated Tetrahydrofurans 129 and Lactones 131 and 132

4.2. Gold-Catalyzed Electrophilic Fluorinations in N-Addition Processes

Gold-catalyzed aminofluorination of fluorinated N′-aryl-Npropargyl amidines 141 was disclosed by Wu and co-workers for the synthesis of fluorinated imidazoles 142.176 The tandem cyclization−fluorination process involved construction of a new C(sp3)−F bond. Thus, cyclization was accomplished by heating amidines 141 in the presence of Au(PPh3)Cl, Selectfluor, and sodium carbonate as a base, yielding imidazoles 142 in moderate to good yields (Scheme 43). The process was compatible with a wide range of aromatic substituents, but internal alkynes were inert under those conditions (R2 = Ph). In order to shed some light into the mechanistic outcome of the process, gold alkyl species 143 was prepared separately by treatment of amidine 141 with the gold catalyst. This compound remained unreactive when treated with Selectfluor. This result indicated that most likely fluorination takes place by fluorodeauration of the vinyl gold species 144 formed after the 5-exo-dig intramolecular attack over the activated triple bond, but prior to aromatization. Then, intermediate 145 would undergo isomerization to the final imidazol 142 (Scheme 44). Similarly, Liu and co-workers described the synthesis of fluorine-containing pyrazoles 147 from alkynyl hydrazones 146 through a gold-catalyzed aminofluorination reaction (Scheme 45).177 The reported one-pot protocol, which employs Selectfluor as the fluorine source, displayed a broad substrate scope under mild reaction conditions. Once again, addition of a base was critical to preserve the efficiency of the sequence. Protodeauration product 148, under optimized reaction conditions, rendered fluoropyrazole 147, even without the gold catalyst. Nevertheless, yields were higher when the gold complex was present in the reaction media. These results suggested several pathways coexisting in fluoropyrazole’s formation. Nonmetal-catalyzed fluorination of protodeaurated side-product 148, fluorodeauration, or reductive elimination from a high-valent Au(III) fluoride, may attest for the fluorination event. Mechanistic uncertainties arose again in the synthesis of a small family of fluorinated pyrrolidine and piperidine scaffolds 150 and 151 starting from alkynyl amines 149 (Scheme 46).178

nonmetal-catalyzed fluorination sequence was discarded, no further experimental evidence about the mechanistic outcome of the reaction was reported. In 2014, Ryu and co-workers developed an efficient one-pot gold-catalyzed oxyfluorination of alkynyl O-methyl oximes 133, leading to biologically valuable 4-fluoroisoxazoles 134 in good yields (Scheme 41). Remarkably, the use of stoichiometric Scheme 41. Gold-Catalyzed Preparation of Fluoroisoxazoles 134

amounts of base was critical for the success of the tandem protocol, since it helps to minimize an undesired protodeauration pathway (leading to compound 135). According to the authors’ proposal, C−F bond formation is accomplished through reductive elimination on a vinyl Au(III) fluoride species 136. In addition, the direct fluorination of protodeaurated side-product 135 was fully excluded. On the other hand, Fiksdahl and co-workers found that homopropargyl acetals 137 underwent a tandem Petasis− Ferrier rearrangement−cyclization−fluorination sequence in the presence of 5 mol % (acetonitrile)−[(2-biphenyl)di-tertbutylphosphine] Au(I) hexafluoroantimonate (138) and S


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Scheme 42. Gold-Catalyzed Synthesis of Fluorotetrahydropyranone Derivative 139

Scheme 43. Synthesis of Fluorinated Imidazoles 142 via Gold-Catalyzed Aminofluorination

Scheme 45. Synthesis of Fluoropyrazoles 147 by GoldCatalyzed Aminofluorination

Following the authors’ proposal, although a Au(I)/Au(III) redox couple is indeed operating, it is not clear if fluorination involved gold intermediacy. Early mechanistic studies pointed to a two-step one-pot procedure, where the cationic Au(III) fluoride 152 appeared as the actual catalytically active species (i.e., Selectfluor as preactivator) and a direct nonmetalcatalyzed fluorination would occur over pyrrolidine 155 after protodeauration of intermediate 153 (Scheme 47). A similar two-step one-pot procedure based on a goldcatalyzed aminocyclization−electrophilic fluorination sequence probably operates in the synthesis of 2-substituted fluoroindoles 157 and 158 from o-alkynylanilines 156, recently reported by Arcadi, Michelet, and co-workers (Scheme 48).179,180

The authors did not discard a Au(I)/Au(III) redox cycle, affording fluorination through a reductive elimination step on a Au(III) fluoride center. Alternatively, it might be suggested that Selectfluor, besides performing the electrophilic fluorination over protodeaurated species, would serve to generate a more active cationic Au(III) species for the hydroamination reaction. Nevertheless, the likeliness of this preactivator role or a Au(I)/ Au(III) redox cycle is seriously queried attending to the sequential addition of the reagents (Conditions A, Scheme 48). Anyway, the process gave rise to a wide range of 2-aryl-

Scheme 44. Mechanistic Studies on the Gold-Catalyzed Aminofluorination of Fluorinated N′-Aryl-N-propargyl Amidines 141

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Scheme 46. Gold-Mediated Synthesis of Fluorinated N-Heterocycles

Scheme 47. Mechanistic Proposal for the Aminofluorination Reaction on Compounds 149

Scheme 49. Gold-Catalyzed Tandem Hydroamination− Fluorination Sequence on Tosylamines 159

Likewise, this type of transformation may indeed operate as well without gold intermediacy, just in the presence of the electrophilic source of halogen, as it is shown in some examples. Even having demonstrated gold intermediacy, for example, through the observation of a kinetically faster reaction in the presence of a gold catalyst, this would not constitute an outright proof of an elementary fluorodeauration step since, for instance, gold intermediacy as a Lewis acid activating the electrophilic reagent and thus making it a more active “F+” donor should not be overlooked.

Scheme 48. Gold-Catalyzed Aminofluorination toward the Synthesis of Fluoroindoles

substituted-3,3-difluoroindoles 157 in an efficient manner in aqueous ethanol as solvent, without the need of any base or Nprotective group. Remarkably, reducing the amount of Selectfluor from 3.0 to 1.1 equiv and reaction temperature down to 0 °C gave access to 3-monofluoroindoles 158 (Conditions C, Scheme 48). Very recently, the preparation of enantioenriched 3fluoropyrrolidin-2-ols 160 was described by means of a goldcatalyzed tandem cycloisomerization−fluorination sequence from chiral homopropargyl tosylamines 159.181 The use of Au(BrettPhos)NTf2, Selectfluor as fluorine source, and Et3N in DCE at 60 °C, without exclusion of water, were found to be the optimum conditions to perform the tandem protocol, giving rise to the final pyrrolidines 160 in good yields and stereoselectivities (Scheme 49). The authors excluded the participation of a Au(III) species and postulated that the fluorination takes place over pyrroline 162 after initial 5-endodig cyclization of the activated alkyne and protodeauration. Final product 160 would be formed by the addition of water to the iminium intermediate 163, in turn generated by the reaction of nonfluorinated pyrroline 162 with Selectfluor (Scheme 49). Briefly, a general overview of the disclosed processes in this section and the performed mechanistic studies indicate that both types of reaction outcomes could operate at the same time, either by means of a fluorodeauration event or by taking advantage of the ability of Selectfluor to act as an external oxidant, allowing the redox couple Au(I)/Au(III) to perform in an analogous manner to other metals such as palladium.

5. FLUORINE IN OXIDATIVE GOLD-CATALYZED REACTIONS Early in the 21st century, the gold rush broke into synthetic organic chemistry. Since that time, homogeneous gold catalysis based on an overall redox-neutral gold activation of π−C−C bonds has almost exclusively dominated the literature. Unlike commonly observed in catalysis by late transition metals such as Pd, Pt, Ni, or Rh, gold tends to remain redox neutral throughout the course of the reaction, since the high redox potential exhibited by Au(I)/Au(III) redox couple (ε0 = +1.41 V) prevents changes in oxidation state. Instead, the Au(I)/ Au(III) manifold can be accessed through the use of a sacrificial two-electron exogenous oxidant, precluding the need for preactivation of the starting material as in a “classical” oxidative addition event. Stoichiometric two-electron oxidation of linear Au(I) species to the corresponding square planar Au(III) complexes is well precedented.182−185 Nevertheless, those initial procedures entailed harsh conditions using an excess of halogen or electron-deficient high-valent thallium(III) species as oxidants, addressing for their unsuitability in catalysis. Given the outstanding success achieved along the past few decades by late transition metal complexes in cross-coupling reactions, triggering feasible redox gold catalytic cycles in a “palladium-like” manifold becomes of practical interest from a reactivity standpoint, since the Au(I)/Au(III) redox pair is isoelectronic to the Pd(0)/Pd(II) redox couple.186 U


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One of the first homogeneous reactions involving a Au(I)/ Au(III) catalytic cycle was reported by Tse and co-workers in 2008.187 Previously, several reports of oxidative homocoupling reactions, using catalytic188 or stoichiometric80 amounts of gold complexes, hinted that Au(I)/Au(III) redox catalysis was feasible. Since Tse’s seminal report and important contributions by Zhang, Toste, Hashmi, Wegner, Hammond, Gouverneur, Nevado, Larrosa, and Nolan, among others, homogeneous gold catalysis involving Au(I)/Au(III) catalytic cycles ignited a second stage in the gold rush, adding a new dimension to gold chemistry beyond the well-established role of gold complexes as soft carbophilic π-Lewis acids. Among different oxidants, such as PhI(OAc)2 or tBuOOH,187−190 fluorine-containing [N−F]+ reagents introduced by Umemoto less than 30 years ago,191,192 commonly employed as sources of electrophilic fluorine, have met with great success as suitable versatile oxidants to overcome the aforementioned unfavorable oxidative addition step. It is worthy to note that the use of exogenous oxidants does not constitute the only approach, though gold may participate in coupling reactions. Several palladium-catalyzed crosscoupling reactions employing gold complexes as transmetalating reagents have been reported.193−198 The involvement of gold complexes as actual catalysts in a conventional crosscoupling manifold,199−202 i.e., involving aryl halide oxidation of Au(I) to Au(III), has raised some controversy as to whether trace contaminants of other transition metals can induce what appear to be a gold-catalyzed coupling.203 On the other hand, pioneering work by Larrosa and Nolan on the C(sp2)−H bond activation of electron-deficient fluoro(hetero)arenes set the landmark for an alternative goldcatalyzed oxidative coupling reaction manifold.

Besides the reluctance of gold species to undergo C−F reductive elimination, the effectiveness of fluorine-based oxidants in gold-catalyzed couplings may stem as well from the weakness of the Au−F bond139 and the strength of B−F or Si−F bonds, driving transmetalation. As we will discuss in the present section, beyond early dimerization processes, numerous transformations that involve C−C and C−X bond formation have also been devised, most of them exploiting the singular carbophilicity of gold complexes in a Au(I)/Au(III) redox catalytic cycle. Alkynylation reactions, difunctionalization of unactivated alkenes, and cross-coupling with boron and silicon reagents serve to illustrate the really amazing possibilities of the Au/[N−F]+ tandem. Scheme 50 depicts the plausible reactivity profiles of vinyl/alkyl Au(I/III) intermediates with electrophilic fluorinating reagents.

5.1. Fluorine-Based Oxidants in Gold-Catalyzed Coupling Reactions

As regards to path a, which was discussed in section 4, some authors defend that C−F bond formation stands on a Au(III)− F reductive elimination rather than an electrophilic trapping of an organogold intermediate. The first step within the fruitful Au/fluorine-based oxidants tandem was hinted at by Hashmi and co-workers in 2009.215 In this report, beyond demonstrating the feasibility of Au(I) chloride complexes to undergo transmetalation in the presence of arylboronic acids, they studied the electrophilic halogen transfer event onto vinyl gold species 164. In stark contrast to what was observed with other electrophilic halogen sources, in which the trapping of the intermediate vinyl gold species 164 rendered vinyl halides, with NFSI, product 165 was isolated in high yield (Scheme 51). On the basis of previously reported

Scheme 50. Plausible Reactivity Profiles of Vinyl/Alkyl Au(I/III) Species

In agreement with the widespread significance of fluorocompounds in synthetic, pharmaceutical, and material sciences, many efforts have been focused on the synthesis of fluorinecontaining compounds via gold catalysis, as depicted in sections 2−4. Within this context, in 2008, Gouverneur explored for the first time the chemistry of Au(I) complexes with [N−F]+ reagents.54 Besides their original role as electrophilic fluorinating reagents (or as Lewis acids), [N−F]+ species can participate in an electron-transfer event to increase the oxidation state of a transition metal species without being necessarily incorporated into the final product during the subsequent reductive elimination. Indeed, the use of [N−F]+ species as an additive in transition metal-catalyzed reactions is widespread in the literature. Several examples have been recently described with Ag, Pd, Ir, Fe, or Cu being the oxidant of choice in transitionmetal-catalyzed C−H activations, fluorinations, oxidations, and coupling reactions, as demonstrated by Ritter,204−206 Sanford,207−209 Michael,210 Yu,211 and Liu,212,213 among others. In a similar way, gold chemistry has found in electrophilic fluorinating reagents an excellent partnership to exploit the fruitful Au(I)/Au(III) redox catalysis in several “fluorine-free” functionalizations of organic compounds due, in part, to the reluctance of fluorine to engage in C−F bond-forming reductive elimination.214 This is presumably because fluorine is highly electronegative and forms a highly polarized bond with the metal center. Moreover, fluoride anions possess exceptionally low polarizability and thus low nucleophilicity.

Scheme 51. Preliminary Results by Hashmi

transformations involving Au(I)/Au(III) cycles, which employed powerful oxidants such as PhI(OAc)2 or t-BuOOH, the formation of 165 could be explained through an oxidative coupling, ascribing to NFSI the role of oxidant. For the first time, suitability of fluorine-based oxidants in oxidative goldcatalyzed transformations was demonstrated. The same group registered the same reactivity pattern in further studies,216 proving that fluorine-based electrophilic V


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accessing homocoupling enones 170 in a highly efficient manner (Scheme 53).219 In the presence of stoichiometric amounts of Selectfluor, vinyl Au(I) enone 171 was readily oxidized to cationic Au(III) fluoride complex 172. Then C−C bond formation could be explained by reductive elimination from 173, after transmetalation between 172 and 171 (Scheme 53). Remarkably, the lack of enone formation arising from protodeauration, which is observed in the absence of Selectfluor, reveals that oxidation is favored over protodeauration. Later, Nevado and Gouverneur, independently, found conditions to carry out the fluorodeauration event originally attempted by Zhang (see section 4.1, Scheme 37). Even though homocoupling processes may be less synthetically useful, the study of such kind of transformations provided interesting insights into gold’s duality as either a classical transition metal center or a transmetalating agent. Precisely this dichotomy on gold’s character underlies the idea to access cross-coupling reaction manifolds comparable to those displayed by other late transition metals. Assuming the role of vinyl Au(I) species 171, not just as a precursor of Au(III)−fluoride complex 172 but as a transmetalating agent as well, its replacement by an external organometallic reagent ready to compete in that step would address the whole process toward the cross-coupled product (see Scheme 50, path c). Among different tested transmetalating reagents, arylboronic acids ArB(OH)2 were found as suitable partners in order to drive the process in the desired way.220 Highly reactive ArBF3K rendered homocoupling biaryls predominantly, while arylboronic esters ArB(OR)2 were not active enough to outcompete vinyl Au(I) species 171, rendering lower yields. Cross-coupling proceeded with excellent E selectivity, accessing (E)-α-arylenones 174 in moderate to good yields (Scheme 54). This reaction was applicable to a wide range of propargyl acetates 169 bearing functionalized and nonfunctionalized alkyl and aryl substituents at both ends of the propargyl moiety, whereas arylboronic acid scope was limited by steric bulk in ortho-substituted ones, as shown by the reported common incompatibility between electron-rich boronic acids and the strongly oxidative Selectfluor. Noteworthy, besides not observing precipitate formation, light scattering experiments over prefiltered reaction solutions

reagents stand in the midpoint between halodeauration and coupling pathways. Further evidence for fluorine-based mediated Au(I)/Au(III) oxidations has been reported. For instance, in 2012 Nevado and co-workers reported the unexpected formation of the bimetallic Au(I)−Au(III) complex [Au(PPh3)2]−[Au(C6F5)4] 168,217 albeit in low 25% yield, when electron-deficient Au(I) complex [Au(C6F5)(PPh3)] 167 was treated with Selectfluor in 1,2dichloroethane at 93 °C for 64 h (Scheme 52). Complex 168 Scheme 52. Au(I)/Au(III) Oxidation by a Fluorine-Based Oxidant

arises from the oxidation of 167 and subsequent ligand exchange, underlining the lability of the Au(III)−F bond, especially in the absence of electron-donor ligands. In the wake of Gouverneur’s54 and Hashmi’s215 early results, it was not long until the Zhang group reported the first examples of homogeneous gold-catalyzed oxidative coupling reactions. In these studies, Selectfluor was found as the unique suitable oxidant for promoting this transformation. In a parallel way to Gouverneur’s seminal work and given the growing demand for new methods to introduce fluorine into organic molecules, Zhang’s original goal was to study the feasibility of a fluorodeauration event over propargyl esters as a model system (see Scheme 50, path a) in an attempt to extend the scope of a previously described gold-catalyzed rearrangement−iodination sequence.218 In this manner, this methodology would have provided easy access to α-fluoroenones. In agreement with previously reported reactivity for propargyl esters 169, under gold catalysis, these systems evolved according to a [3,3]-sigmatropic rearrangement, rendering vinyl Au(I) intermediate 171. In the presence of an electrophilic source of fluorine such as Selectfluor, homodimer (E,E)-enone 170 was detected besides protodeauration monomer as the major products (see Scheme 50, path b), whereas the target α-fluoroenone was observed as a minor side product. Optimization of the reaction conditions upgraded oxidation of Au(I) to Au(III) over protodeauration, thus

Scheme 53. Gold-Catalyzed Oxidative Dimerization of Propargyl Acetates

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formed prior to C−B breakup. Fluorine departure from the gold center was then completed readily in a three-centered reductive elimination step (via transition state 176), triggering C−C bond formation (Scheme 54). In agreement with Zhang’s experimental results, with other halogen-based oxidants, higher reaction profiles arose, since larger Au−X bonds altered the four-centered transition state. In the absence of an exogenous transmetalating reagent, a similar mechanism was calculated with the early appearance of a F−Au interaction parallel to the above-described F−B one. In this case, reductive elimination appeared as the rate-limiting step, and remarkably, no aurophilic interactions were observed but could not be discarded at all. In 2014, Nevado and co-workers illustrated, for the first time, the feasibility of a direct Au(III)−B transmetalation between boron reagents and the proposed Au(III) intermediates in goldcatalyzed coupling reactions.222 They studied the reaction between electronically biased boronic acids and aryl Au(III) dichlorides 177, which were generated by oxidation of the corresponding aryl Au(I) chloride with PhICl2. Under neutral conditions, Au(III) dichloride 177 remained unreactive toward phenylboronic acid (Scheme 55, eq 1), but transmetalates with electron-deficient pentafluorophenylboronic acid providing the corresponding diaryl Au(III) species 178 in 73% yield after 2 h at 150 °C in 1,2-dichloroethane. Longer reaction times yielded the homocoupling compound decafluorobiphenyl 179, likely resulting from reductive elimination on 178, which also gave rise to 179 just by heating it in 1,2-dichloroethane (Scheme 55, eq 2). An alternative pathway entailing transmetalation between two Au(III) species instead of reductive elimination could be discarded when reacting trifluoroaryl Au(III) dichloride 177a with pentafluorophenylboronic acid. As expected, heterocoupling product octafluorobiphenyl 179a was obtained in 94% yield, besides Au(PPh3)Cl in 92% yield (Scheme 55, eq 3).

Scheme 54. Gold-Catalyzed Oxidative Cross-Coupling of Propargyl Acetates with Arylboronic Acids

further supported the homogeneous nature of this transformation. Additionally, despite other oxidants being tested, they were less effective, highlighting the suitability of merging gold with fluorine-based oxidants. A recent in-depth mechanistic study on Zhang’s goldcatalyzed homo- and cross-coupling reactions221 helps to shed some light onto the reaction outcome once Au(I) species 171 is oxidized to Au(III) fluoride 172 (see Scheme 53), focusing on transmetalation and reductive elimination steps. Largely based on DFT calculations, this study brought out the role displayed by fluorine as a gold ligand, not as a mere consequence of using Selectfluor as oxidant but as a pivotal component for the success of the overall process, providing a low-energy barrier for rate-limiting transmetalation. The fluorine atom on gold’s coordination sphere was assisting through a F−B interaction (via transition state 175), a stepwise nonconcerted transmetalation, where the new Au−C bond is Scheme 55. Neutral Au(III)−B Transmetalation

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steric interaction with ligands on the tetracoordinated Au(III) center 184. On the other hand, exogenous carboxylic acids did not incorporate to the final product, depicting the intramolecular character of the [3,3]-carboxy migration. Likewise, no cross-over products were detected. Liu and co-workers recently revised the role displayed by Selectfluor in this oxidative C−O bond-forming reaction.225 A theoretical study based on DFT calculations concluded that Selectfluor did not function as an oxidant but instead did operate as an electrophilic source of fluorine. A novel electrophilic fluorination−defluorination mechanism, which did not involve a Au(I)/Au(III) redox cycle, displayed the lowest activation barriers. According to the proposed mechanism, once [3,3]sigmatropic rearrangement triggered by the Au(I) complex takes place, the resulting vinyl Au(I) complex 183 would undergo a 5-exo-trig cyclization to render intermediate 186. Then electrophilic attack on the double bond by Selectfluor would give rise to species 187. This was established as the ratelimiting step, with an energy barrier much lower than either alternative pathway involving a Au(I)/Au(III) redox cycle, in which Selectfluor would operate as an oxidant. Barrierless hydrolysis and defluorination steps would yield final 1benzoxyvinyl ketone 182 (Scheme 57).

These experimental results were against the expected reactivity trend in a classical transmetalation outcome, where the aryl fragment on boron acts as a nucleophile when transferred onto the gold center. Alternatively, a stepwise mechanistic outcome via intermediate 180 was devised by the authors based on DFT calculations (Figure 1). They proposed

Figure 1. Proposed intermediate for the Au(III)−B transmetalation.

gold activation by chloride abstraction as the first step, prior to the migration of the aryl moiety from boron to gold. That would explain why just electrophilic boron species transmetalate. Analogously, under Zhang’s reaction conditions, the presence of fluoride ions in the media derived from Selectfluor could be expected to aid the transmetalation of preactivated boronate complexes. This hypothesis is supported by the strong B−F bond. The use of nonsubstituted propargyl benzoates 181 led the Zhang group to further report the first homogeneous goldcatalyzed oxidative C−O bond-forming reaction (Scheme 56).223,224

Scheme 57. Revised Role of Selectfluor in Gold-Catalyzed Oxidative C−O Bond Formation

Scheme 56. Gold-Catalyzed Oxidative C−O Bond Formation

Oxidative gold catalysis was further extended to C(sp3)− C(sp2) bond formation from Au(III)−C(sp3) species. These types of couplings have been traditionally challenging with palladium species given the undesired β-hydride elimination side reaction. However, this competitive pathway is not favored in gold species, facilitating cross-coupling reactions. In 2010, the Zhang group disclosed the intramolecular 1,2amino- and oxyarylation of terminal olefins 188 with arylboronic acids in the presence of Selectfluor as the stoichiometric oxidant once again.226 This method provided straightforward access to various substituted N- and Ocontaining heterocycles 189 in good yields (Scheme 58). Interestingly, Zhang revised his earlier mechanistic assumptions, coming up with the initial oxidation of Au(I) complex to a Au(III) fluoride by Selectfluor, prior to nucleophilic attack. Even transmetalation was proposed to precede intramolecular attack but without further evidence. This hypothesis came up from the unlikeliness of a neutral Au(I) complex promoting nucleophilic attack. The cationic Au(III) complex 190 arising from Au(PPh3)Cl oxidation looks more likely as the active catalytic species.

In the presence of low water concentration, oxidation would take place over oxocarbenium species 183 (Scheme 56). After hydrolysis, the benzoyl group would remain attached to the Au(III) center in 185, opening up a chance for the reductive elimination that triggers the new C−O bond. This strategy enabled the synthesis of 1-benzoxyvinyl ketones 182 in good yields starting from various substituted internal propargyl benzoates 181. Whereas the acetate group was optimal for the α-arylation, the benzoate worked better for the α-esterification. In stark contrast with the above-described transformations, substitution at the propargylic position was critical in the outcome of the oxidative C−O bond-forming reaction, not being tolerated at all. On the basis of previously observed Eselectivity, any propargylic substituent would have a detrimental Y


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oxyarylation, presented comparable broad arylboronic acid scope. Hindered and electron-poor ones provided diminished yields but were still synthetically useful, while electron-rich arylboronic acids met with competing oxidation by Selectfluor. The use of bimetallic gold complexes had a deep mechanistic impact in the outcome of transmetalation and reductive elimination steps but did as well in oxidation and nucleophilic attack steps, lowering energy barriers of the whole catalytic cycle, as it was further demonstrated based on DFT calculations and experimental observations.229 On one hand, preformed alkyl Au(I) complex 197 and phenylboronic acid in the presence of Selectfluor failed to produce pyrrolidine 193a (Scheme 60, eq 1), attesting for

Scheme 58. Gold-Catalyzed Oxidative Heteroarylation of Alkenes (Zhang)

Scheme 60. Mechanistic Insights on the Gold-Catalyzed Oxidative Heteroarylation of Alkenes Indeed, early oxidation of Au(I) to Au(III) prior to π activation was originally considered and subsequently discarded by Zhang himself in his pioneering work with propargyl esters 181, arguing that oxidation over Au(I) vinyl intermediate 183 (see Scheme 56), with a 1-acylalkenyl ligand anchirally attached, was more likely rather than the oxidation over cationic Au(PPh3)NTf2 species, readily amenable for π activation, unlike Au(PPh3)Cl. Simultaneously, the Toste group independently reported analogous gold-catalyzed carboamination227 and carbooxylation228 reactions of terminal olefins 192 and 194 with arylboronic acids and Selectfluor (Scheme 59). Nonetheless, they required the use of a bimetallic gold complex such as [dppm(AuBr)2] in order to avoid the formation of catalytically inactive bisphosphine−Au(I) species [Au(PPh3)2]+. Aminoarylation was efficiently applied in an intramolecular pathway starting from several types of sulfonamides (Scheme 59, eq 1). When alcoholic cosolvents were used in an attempt to improve the solubility of the arylboronic acids, intermolecular incorporation of alcohol occurred (Scheme 59, eq 2). Thus, oxyarylation could be further extended to various oxygen nucleophiles, including primary and secondary alcohols, carboxylic acids, and water. Both reactions, amino- and

oxidation preceding nucleophilic attack, as Zhang suggested but did not further demonstrate. Additionally, DFT calculations illustrated the benefit of using a bimetallic complex over monogold species, prompting facile oxidation to a bridged Au(II)−Au(II) species. Cyclic voltammetry data revealed that this bimetallic oxidation pathway was driven by the establishment of a σ-Au(II)−Au(II) aurophilic interaction, with milder redox potentials on gold centers. On the other hand, no transmetalation of arylboronic acids was observed with Au(PPh3)Cl under stoichiometric reaction conditions. Thus, transmetalation did not precede oxidation. Moreover, treatment of starting sulfonamide 192a with different arylboronic acids in the presence of preformed

Scheme 59. Gold-Catalyzed Oxidative Heteroarylation of Alkenes (Toste)

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alkenes.232 In the presence of Selectfluor, Au(SIMes)Cl complex worked as well as an efficient catalytic system for the intramolecular oxy- and aminoarylation of terminal alkenes 204, providing access to a wide variety of heterocyclic scaffolds 205, including tetrahydrofurans, lactones, pyrrolidines, or cyclic ureas, in general good yields (Scheme 62). As it is well known,

Au(PPh3)Ph gave rise to products 193a derived from aryl transfer from the boronic acid but not from phenylgold species, regardless of the electronics of the boronic acid (Scheme 60, eq 2). Given this perspective, a transmetalation−reductive elimination sequence looks unlikely. Alternatively, they hypothesized both transmetalation and reductive elimination occurred simultaneously via a concerted, but asynchronous, five-centered transition state 196 (see Scheme 59) in a likely intramolecular electrophilic aromatic substitution mechanism, which they coined as a bimolecular reductive elimination. As depicted in Scheme 59 (transition state 196), this mechanism entailed the attack of a nucleophilic Au(III) fluoride species onto the boron center of the boronic acid, as it transfers the aryl group directly to the α-carbon of the alkyl Au(III) intermediate. Once again, the aforementioned aurophilic interaction was not innocent. DFT calculations predicted about a 15 kcal/mol advantage for bimetallic reductive elimination over the monometallic pathway. Computational studies also illustrated that fluorine intermediacy was critical, presumably by increasing not only the nucleophilicity of the arylboronic acid but also the electrophilicity of the organic residue on the Au(III) complex. Further experiments supported the proposed concerted bimolecular reductive elimination pathway. In 2010, the Toste group reported for the first time isolable Au(III) fluoride complexes by oxidation of different NHC-derived methyl Au(I) complexes 198 with XeF2.230 X-ray analysis in the solid state, besides NMR experiments in solution, confirmed the formation of these Au(III) fluoride complexes 199, which coexist in differently shifted, nearly thermoneutral equilibriums with their dinuclear species 200 (Scheme 61). Outstandingly, this work was the first unambiguous evidence for the formation of these key intermediates in gold-catalyzed oxidative transformations.

Scheme 62. Gold-Catalyzed Oxidative Heteroarylation of Alkenes (Zhu)

NHC ligands show improved stability toward air and moisture in comparison to phosphine-type ligands. Likewise, based on their stronger electron-donating character, the authors assumed that NHC ligands would make Au(I) complexes easier to oxidize, aiding Au(I)/Au(III) redox cycles to operate. Alternatively, the Toste233 and Russell234 research groups independently illustrated the suitability of arylsilanes as aryl sources in the oxidative gold-catalyzed cross-couplings of alcohols 206 (Scheme 63). Competency of arylsilanes relied Scheme 63. Gold-Catalyzed Oxidative Heteroarylation of Alkenes with Arylsilanes

Scheme 61. First Isolable Au(III) Fluoride Complexes

on the use of fluorine-based oxidants, which also operate as silicon center activators, providing a fluoride anion, thus avoiding the use of stoichiometric amounts of exogenous base additives typically required in related palladium-catalyzed transformations. The high fluoride affinity for silicon is assumed as the thermodynamic driving force of the whole process (see transition state 208), as attested by the mild reaction conditions required. The use of arylsilanes provided further potential benefits over arylboronic acids. Arylsilanes are readily accessible species with improved stability. Such stability resulted in a broader aryl scope, since competing reactions when using highly reactive arylboronic acids in the presence of Selectfluor, especially with nitrogen- and oxygen-containing species, are circumvented. Products arising from protodesilylation or oxidation were not observed. Likewise, a detrimental biaryl homocoupling side pathway was significantly diminished. Gold-catalyzed cross-couplings were not only restricted to preactivated arenes, such as boronic acids or silanes. Alternatively to aryl groups, Nevado and co-workers demonstrated that water, alcohols, ethers, and esters were also suitable

Reported species were postulated as feasible intermediates in oxidative gold-catalyzed coupling reactions because they proved to be proficient at performing C−C couplings (yielding compounds 201) in the presence of arylboronic acids. Kinetics on this reaction was insensitive to the electronics of the arylboronic acid, while bulky alkyl Au(III) fluorides remained unreactive. These experimental results supported a bimolecular reductive elimination mechanism rather than a transmetalation−reductive elimination sequence. Whereas reductive elimination is often sensitive to electronics, conceptually related concerted σ-bond metathesis processes are not rate dependent on electronics.231 Bulkier substituents would accelerate reductive elimination after transmetalation. Likewise, they would encumber direct attack of the boronic acid on a sterically hindered carbon center. Later, Zhu and co-workers found a complementary catalytic system to the phosphine-based Au(I) complexes employed by the Zhang and Toste groups for the heteroarylation of AA


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Scheme 64. Gold-Catalyzed Oxidative Aminofunctionalization of Alkenes

Scheme 65. Gold-Catalyzed Oxidative Intramolecular Cross-Coupling of Nonactivated Arenes (Gouverneur)

C−C bond formation would result from an inner-sphere reductive elimination on the Au(III) center of intermediate 217. This pathway is supported on the long-established ability of electron-deficient Au(III) species to insert into C(sp2)−H bonds of electron-rich arenes.237 Alternatively, arylation might resemble a conjugate addition-type process to render 218, accomplishing C−C bond formation prior to reductive elimination. Even though no further experimental evidence was given in order to differentiate between both pathways, control experiments rejected a mechanism based on a fluorodeauration event through intermediate 219, followed by conjugate addition and subsequent HF elimination. Similarly, Liu and co-workers disclosed a closely related work using allene esters 220 as starting materials as well but not derived from tert-butyl esters.238 Likewise, a pendant aryl substituent, placed at the γ position in Gouverneur’s report, was attached to the α position. Liu’s work showcased how subtle structural modifications may have deep impacts in the reaction outcome. Under similar reaction conditions, Liu’s transformation led to a family of fluorinated indenes 221 in moderate to good yields (Scheme 66). The use of alternative alkyl-derived allene esters 220 instead of tert-butylallenoates prompted intermolecular nucleophilic addition of H2O on a gold-activated allene moiety over intramolecular O-carbonyl addition. This addition took place regioselectively over the terminal allenoate position. Oxidation by Selectfluor might happen prior to nucleophilic attack over the Au(PPh3)NTf2 complex or later over the vinyl Au(I)

nucleophiles in the oxidative difunctionalization of unactivated alkenes. They developed a gold-catalyzed endo-selective aminooxygenation of terminal alkenes 209 in the presence of Selectfluor.235 Aminoalcohols 210 were obtained as the major products, together with variable amounts of regioisomers 211. Furthermore, when reducing the amount of water in the reaction, a novel aminoamidation process was observed by in situ gold activation of the nitrile solvent, rendering aminoamides 212 (Scheme 64). Even though several mechanistic outcomes may be outlined, the authors considered that the oxidation of Au(I) to Au(III) takes place after the cyclization. Furthermore, Gouverneur and co-workers showed how gold catalysts can insert into nonactivated aryl C−H bonds. They reported an O-addition-cross-coupling cascade over benzylsubstituted tert-butyl-allenoates 213, yielding tricyclic dihydroindene derivatives 214 in moderate to high yields.236 Once again, Selectfluor acted as a highly efficient oxidant over other fluorine-based reagents such as NFSI and alternative oxidants such as t-BuOOH, PhI(OAc)2, or Ph2SO. The higher efficiency achieved by electron-rich aryl-substituted allenoates over electron-poor ones was indicative of a Friedel−Crafts arylation (Scheme 65). Thus, following the proposed mechanism, the cascade starts with the O-addition over the allene moiety activated by the gold complex, with concomitant loss of isobutene. Then, oxidation of the vinyl Au(I) species 215 by Selectfluor to Au(III) fluoride complex 216 followed by Friedel−Crafts arylation, i.e., an electrophilic aromatic auration with or without fluoride displacement ought take place. Thus, AB


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arylation event over an in situ generated alkyl gold species.240 The process, which resembled a formal [3 + 2] annulation, led to tricyclic indolines 230 in generally good yields, starting from N-allyl-N′-arylureas 229, using preformed Au[P(4-CF 3C6H4)3]NTf2 as the catalyst and Selectfluor as exogenous oxidant, in aqueous THF (Scheme 68). Water was found to

Scheme 66. Gold-Catalyzed Oxidative Intramolecular CrossCoupling of Nonactivated Arenes (Liu)

Scheme 68. Gold-Catalyzed Oxidative Intramolecular CrossCoupling of Nonactivated Arenes (Zhang)

intermediate. Resulting vinyl Au(III) fluoride species 222 would undergo C−H gold insertion to intermediate 223, followed by reductive elimination, which would complete the catalytic cycle and render intermediate 224, and then prone to undergo successive 1,3-proton shift, alcohol oxidation, and final fluorination. Notably, the proposed mechanism ascribed multiple roles to Selectfluor. Very recently, You and co-workers reported the goldcatalyzed C−H bond ortho-arylation of (oxy)pyridine, quinoline, and pyrimidine-substituted arenes 225 to forge biaryl scaffolds 226 based on a chelation-assisted strategy (Scheme 67).239 The use of NFSI as an external oxidant enabled the

increase the reaction yields significantly, presumably by improving Selectfluor’s solubility. The reaction was sensitive to sterics and highly biased electronics on the aryl ring. Whereas substitution at the allylic position (R2) was well tolerated, substituents on the double bond had a detrimental impact. The proposed mechanism was closely related with that previously reported by Gouverneur (see Scheme 65), but they provided further experimental results, which clarified the main uncertainties in Gouverneur’s seminal proposal. Deuterium labeling and kinetic isotope effect studies, along with the isolation of alkyl Au(I) intermediates, supported that (1) oxidation to Au(III) fluoride occurred after amination and (2) a Friedel−Crafts-type electrophilic arylation was indeed operating. Thereby, a final reductive elimination step was responsible for the C−C bond formation. This process has been recently theoretically investigated by DFT calculations,241 considering four alternative pathways, whether oxidation takes place over an alkyl−Au(I) species (after amination, as Zhang proposed), the Au(I) precatalyst, the Au(I) π-alkene intermediate complex (prior to amination), or an aryl−Au(I) intermediate (assuming Au(I) salts are capable to insert into C−H bond). The last two options were lightly discarded by computational results, since they showcased the higher free energy profiles. Thus, the former two pathways, with similar barrier heights and late reductive elimination as the rate-limiting step, might be operating, as was further confirmed by stereochemical outcome analysis, in agreement with experimentally observed cis diastereoselectivity. Alternative mechanistic manifolds not involving a Au(I)/Au(III) redox cycle were ruled out, since energy profiles were higher than any of those entailing a redox pair as considered above. Additionally, this theoretical study revealed an alternative role for water, not only increasing Selectfluor’s solubility but also reducing the activation barrier of rate-limiting reductive elimination, thus enhancing catalytic efficiency. However, no meaningful water effect was observed on the oxidation step. On the basis of their previous work with tert-butyl allenoates, the Gouverneur group further exploited the gold-mediated C− H functionalization strategy to effect an O-addition− intermolecular alkynylation cascade reaction for the preparation of β-alkynyl-γ-butenolides 232 (Scheme 69).242 This transformation proceeded smoothly with a wide range of terminal alkyl- and aryl-acetylenes, regardless of sterics or electronics. Likewise, a substitution effect on the starting allenoate 231 was not too severe.

Scheme 67. Gold-Catalyzed Oxidative C−H Bond OrthoArylation

development of a catalytic version, whereas other oxidants such as PhI(OAc)2 failed to promote the coupling reaction. Mechanistic studies revealed that NFSI’s role is not just limited as the stoichiometric oxidant, since it operates as well as a fluoride source, once Au(I) oxidation takes place, promoting transmetalation through C−B bond activation. Both an innersphere (transition state 227) and an outer-sphere (transition state 228) activation by fluoride could be considered. In stark contrast to the concerted bimolecular reductive elimination proposed by Toste, experimentally observable transmetalation and reductive elimination operated as discrete steps in this example. Beyond the construction of C(sp2)−C(sp2) bonds, this strategy was further extended by Zhang and co-workers to C(sp3)−C(sp2) bond formation. They reported a similar C−H AC


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Scheme 69. Gold-Catalyzed Cyclization−Oxidative Alkynylation Cascade Reaction

Detection of varying amounts of the diyne resulting from oxidative homocoupling of the terminal alkyne hinted at the feasibility of a gold-mediated C(sp)−H activation, which would require stoichiometric amounts of base. Two pathways were proposed for the formation of intermediate 233 (the precursor of final product 232 by means of a reductive elimination) as to whether C−H gold insertion takes place prior to (via species 234 or 235) or after (via species 236 or 237) O-addition on a Au(I) (234 or 236) or Au(III) (235 or 237) center, respectively (Scheme 70).

Scheme 71. Gold-Catalyzed Oxidative Homocoupling of Alkynes

Scheme 70. Plausible Mechanistic Outcomes for the Formation of Intermediate 233 two acetylene molecules, since comparable yields were obtained when using one or one-half equivalents of Selectfluor. Additionally, no crossover products were detected when mixing phenylacetylene with a preformed Au(I) acetylide derived from a different aryl acetylene. With these data in hand, a transmetalation−inner-sphere reductive elimination sequence on a monometallic Au(III) center was fully discarded. Instead, supported by cyclic voltammetry data, a bimolecular reductive elimination event between Au(I) acetylide 241 and its oxidized Au(III) fluoride species 242 was expected (Scheme 71). Further experimental results sustained gold acetylide formation preceding oxidation. σ-Bond formation was presumably favored by initial π coordination of Au(PPh3)NTf2 catalyst to the triple bond (240), increasing the acidity of the acetylenic proton. In the presence of arylboronic acids, gold acetylides would be prone to be trapped in a gold-catalyzed Sonogashira-type fashion, opening up a new avenue beyond the plethora of metal-based (Cu, Pd, Co, ...) catalytic and noncatalytic systems already developed for this type of transformations. Qian and Zhang illustrated this strategy employing a fluorine-based oxidant.244 The developed transformation tolerated the presence of several potentially reactive functionalities such as carbamates, esters, ethers, sulfonamides, alkenes, or internal alkynes. Nevertheless, both electron-rich and electron-deficient boronic acids rendered diminished yields. In agreement with the proposed mechanism (Scheme 72), cationic Au(III) fluoride species [alkyne−Au(PPh3)F]+, resulting from gold preactivation by chloride abstraction and Selectfluor-prompted oxidation, would insert into the C(sp)− H bond in the presence of stoichiometric amounts of Et3N (complex 244). Even though prior insertion followed by oxidation was not considered by the authors, this mechanistic

Although mechanistic studies pointed to initial gold acetylide formation (via 234 or 235), those were not still conclusive. For instance, a Au(I) acetylide acting as a transmetalating agent could not be ruled out. This mechanistic uncertainty, besides diyne byproducts detection, inspired the gold-catalyzed oxidative coupling of alkynes in both homo- and cross-coupling variants in an oxidative dimerization event or in the presence of arylboronic acids. In 2012, Corma and co-workers reported a gold-catalyzed oxidative homocoupling reaction applicable over both alkyl and aryl terminal alkynes 238.243 This process afforded final diynes 239 in an efficient manner under mild reaction conditions using Au(PPh3)NTf2 as catalyst, Selectfluor as oxidant, Na2CO3 as base, and wet acetonitrile as solvent (Scheme 71). Noteworthy, the reaction proceeded in air at room temperature, without the need of any protecting inert atmosphere. Mechanistic studies indicated that just one oxidation from Au(I) to Au(III) species occurred per coupling of each of the AD


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rendering biaryl homocoupling side product. Additionally, through high-resolution ESI-MS (electrospray ionization-mass spectrometry) analysis of those samples, several Au(III) species were detected. However, none of them corresponded to a Au(III) fluoride, likely due to the labile character of the Au−F bond. In agreement with the experimental data, the reaction was proposed to be initiated by catalyst preactivation via oxidation with Selectfluor to a cationic Au(III) fluoride species, which then bends the substrate, prompting intermolecular nucleophilic attack by water and rendering a vinyl Au(III) fluoride species. After transmetalation with the arylboronic acid present in the media, resulting species would be then be prone to undergo several pathways until final α-fluoroketone. Both reductive elimination−fluorination and inversed fluorination− reductive elimination sequences may be considered. Independently, Nevado and co-workers reported a closely related alkoxylation/hydration−fluorination protocol of alkynes 246 under similar reaction conditions (Scheme 74).247 This method led to α-fluoro acetals 249 and ketones 250, respectively, in good yields and with high levels of both chemo- and regioselectivity, especially when dealing with terminal alkynes. Mechanistic studies suggested that this transformation proceeded through two cooperative pathways. After initial addition of the alcohol (to species 251) and subsequent protodeauration (252), either gold species, in a Au(I)/Au(III) redox cycle (via species 254−256) or Selectfluor (via species 253), may activate enol ether intermediate 252 mediating fluorination. Under similar reaction conditions, Liu and co-workers did not observe any fluorine incorporation when using o-alkynyl benzoates 257 as starting materials. Instead, unexpected oxidative diketonization of the triple bond by water in the presence of Selectfluor was detected.248 Mechanistic studies revealed that fluorine was indeed incorporated into the substrate along the catalytic cycle, since α,α-difluoro-ketone 262 was confirmed as an intermediate in the overall process. Nevertheless, under the reaction conditions, compound 262 was hydrolyzed yielding diketone 258 (Scheme 75). Noteworthy, the ester moiety at the ortho position did not play an innocent role, since the efficiency of the process was harshly affected when moving to meta or para positions. Presumably, it facilitates nucleophilic attack by assisting Au(I) complexation onto the triple bond, and in turn, it stabilizes Au(III) complexes with the substrate along the catalytic cycle (via species 259−261). An optimized protocol provided access to 1,2-dicarbonyl compounds 258 in moderate to good yields, displaying higher efficiency with electron-deficient o-alkynyl benzoates. Resulting 1,2-diketones could be further functionalized as biologically attractive quinoxaline derivatives 263 in a one-pot procedure in the presence of o-phenylenediamines 264. Results from Hammond and Xu inspired an alternate mode of catalyst preactivation, not limited to gold-catalyzed oxidative couplings but further operative in contemporary gold catalysis, i.e., as soft carbophilic π-Lewis acids. Beyond the use of either silver salts for chloride abstraction or strong acids for protonolysis of a Au−Me bond, combination with substoichiometric amounts of fluorine-based oxidants emerged as an alternative strategy. It would be expected that resulting cationic Au(III) species, arising from the fluorination of a low-valence Au(I) complex, would have an increased Lewis acidity.

Scheme 72. Gold-Catalyzed Sonogashira-Type Reaction

alternative should not be overlooked due to the unlikeness of oxidation of cationic Au(PPh3)BF4 species after chloride abstraction. The weakness of the Au−F bond together with the establishment of a stronger B−F bond would drive transmetalation over intermediate 245. Final reductive elimination would yield the C(sp)−C(sp2) bond in final compounds 243. As noted before, other authors queried the feasibility of goldcatalyzed Sonogashira-type couplings. In 2010, Echavarren reported a mechanistic study about the unlikeliness of Sonogashira reactions catalyzed by gold complexes.203 5.2. Fluorine-Based Oxidants in Other Gold-Catalyzed Oxidative Reactions

Along with the presented examples within the last section, initial oxidation/preactivation of a Au(I) catalyst by the corresponding fluorine-based oxidant has been considered. Nevertheless, further experimental evidence was not often provided, and it was just postulated as a plausible mechanistic pathway. Even though Zhang and Toste were the first authors coming up with this idea, to the best of our knowledge, Hammond and Xu first confirmed this hypothesis through what they coined a gold-catalyzed “functionalized” hydrofluorination of alkynes in the presence of stoichiometric amounts of Selectfluor.245,246 The reported one-pot tandem procedure provided access to α-substituted fluoroketones 247 and 248 in very good yields, albeit with moderate regioselectivity (Scheme 73). Reaction conditions were applicable over a wide range of internal alkynes 246 and nonelectronically biased arylboronic acids. Scheme 73. Gold-Catalyzed Hydrofluorination of Alkynes (Hammond and Xu)

X-ray photoelectron spectroscopy (XPS) studies of different mixtures of Au(I) species with Selectfluor revealed the formation of Au(III) species, afterward confirmed as the catalytically active species. Likewise, 19F NMR monitoring of these samples resulted in the appearance of a down-shifted new peak, which was tentatively assigned to [AuIIIClFLn]+ species and that disappeared by the addition of an arylboronic acid, AE


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Scheme 74. Gold-Catalyzed Hydrofluorination of Alkynes (Nevado)

Scheme 75. Gold-Catalyzed Diketonization of Alkynes

Hammond and Xu reported illustrative examples showcasing the potential of this new strategy.245 Combination of catalytic amounts of Au(PPh3)Cl and Selectfluor worked efficiently in both the hydration of internal alkynes 265 and the cyclization of alkynoic acids 267 (Scheme 76). This synergic effect was further extended, for instance, to the gold-catalyzed reaction of enynals and enynones 269 with

alkenes 270 and 271, recently reported by Zhu, Jiang, and coworkers.249,250 Once O-addition takes place, the reaction proceeded through a well-known pyrylium intermediate 273 in successive Diels−Alder reactions.251 The tandem protocol gave access to a wide variety of symmetrical and nonsymmetrical propeller-like skeletons 272 (Scheme 77). Combination of a Au(NHC)Cl species with Selectfluor performed as a superior catalytic system over other gold salts or complexes and conventional strategies to generate more active species. The authors assumed that Au(NHC)Cl was oxidized to a cationic [AuIIIClF(NHC)]+ species. This protocol was further extended to the formation of 1,3cyclohexadienes 276, which could be generated through the gold-catalyzed reaction of enynals 274 and alkenes 275, utilizing again a NHC−Au(I) species in combination with Selectfluor (Scheme 78).252 Notably, the process was metal dependent, and when using a Cu(II) salt instead of Au(I) or In(III), the 2,4-isomer was furnished. On the other hand, when they employed 1,3-dienes 278 instead of monoalkenes, they gained access into highly strained cyclopropane-fused polycyclic skeletons 279 with a broad substrate scope and high-functional-group tolerance (Scheme 79).253 The reaction was proposed to proceed via an intramolecular Diels−Alder reaction over intermediate species

Scheme 76. Selectfluor as Gold Complex Preactivator

AF


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Scheme 77. Gold-Catalyzed Tandem Reaction of Enynals and Enynones with Alkenes (I)

Scheme 78. Gold-Catalyzed Tandem Reaction of Enynals with Alkenes (II)

Scheme 80. Gold-Catalyzed Tandem Reaction of Enynones with Alkenes (III)

280, formed as well from a pyrylium intermediate 273 (see Scheme 77). Scheme 79. Gold-Catalyzed Tandem Reaction of Enynals and Enynones 277 with Dienes 278

Scheme 81. Gold-Catalyzed Tandem Reaction of Enynones with Alkenes (IV)

Very recently, Wang, Shi, and co-workers presented a new catalytic system for a mechanistically related cycloaddition−airprompted oxidation cascade reaction of substrates 277 to render naphthalene derivatives 283 (Scheme 80).254 This system consisted of the combination of a newly designed family of NHC−oxazoline Au(I) iodides 281 with catalytic amounts of Selectfluor. Though closely related to those previously utilized by Zhu, Selectfluor displayed an innovative role oxidizing preferably the iodine atom instead of the metal gold center, thus rendering cationic bis-chelated NHC−oxazoline diAu(I) complexes 282 as the actual catalytic species, as supported by NMR and ESI-mass spectroscopic studies. The Zhu group further illustrated the efficiency of combining the NHC−Au(I)/[N−F]+ catalytic system in carbene transfer reactions.255 Combination of Au(IPr)Cl complex and Selectfluor was highly efficient, with TONs (turnover number) up to 990 000, in trapping gold−carbene intermediates 287, which were in situ generated starting from enynones 284 in a 5-exodig cyclization mode. Cyclopropanation reaction in the presence of alkenes (yielding compound 285) and X−H (X = Si, N, O) insertion reactions (giving furans 286) were employed in carbene transfer (Scheme 81).

5.3. Fluorinated Building Blocks in Gold-Catalyzed Coupling Reactions

As discussed in section 2.3, Larrosa and Nolan showcased that Au(I) complexes bearing strong donor ligands can perform the activation of C−H bonds in electron-deficient fluoro(hetero)arenes. This discovery opened the door for the design of new AG


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Importantly, the intermediacy of an aryl−Au(III) species was proved. Likewise, alternative roles of I(III) species, beyond acting as the exogenous oxidant, mediating a hypothetical transmetalation, were fully discarded. Instead, an aromatic electrophilic substitution SEAr-type mechanism was likely operating after oxidation of aryl−Au(I) complex 68 by the I(III) reagent. The resulting biaryl−Au(III) complex 292 would yield, upon reductive elimination, the final coupling product 290. The development of mutually compatible conditions for both C−H bond activation steps, besides an oxidant that selectively oxidizes aryl−Au(I) intermediate 68 in the presence of other Au(I) species, finally allowed the successful development of the first gold-catalyzed dehydrogenative coupling of (hetero)arenes (Scheme 84).258 As in previous Au(I)-mediated C−H bond activations of electron-poor arenes, the presence of two fluorine substituents ortho to the position being activated as well as a silver additive were essential for catalytic turnover. The introduction of gold in such type of processes showed multiple advantages compared to Pd-catalyzed protocols, namely, (a) high cross-selectivity versus homocoupling, (b) high regioselectivity, and (c) milder reaction conditions. Actually, the ability of gold species to catalyze the crosscoupling of aryl derivatives to yield biaryl motifs was previously stated by Lloyd-Jones and Russell but in a different reaction manifold.45 In the presence of small gold catalyst loadings (1−2 mol %) and a mild I(III) oxidant, electron-rich (hetero)arenes undergo site-selective C−H arylation by electron-deficient fluoroarylsilanes 293, yielding biaryls 290 in good to excellent yields (Scheme 85). Notably, the reaction proceeds under open air mild reaction conditions and displays a broad functionalgroup tolerance. Halogens, esters, amides, alcohols, and sulfonates were well tolerated. Stoichiometric experiments and kinetic isotope effects support a Au(III) species as the actual active catalytic species prompting sequential SEAr of both the arylsilane and the electron-rich arene. Final biaryl 290 would be rendered upon reductive elimination, while the exogenous I(III) oxidant would regenerate the Au(III) active species.259 Consistent with a SEAr-type reactivity, electron-deficient arenes and electron-rich arylsilanes were unsuitable substrates. Control experiments proved the essential role played by gold in the process, discarding the involvement of alternative mediators. Bronsted acid catalysis and I(III)-mediated coupling were fully discarded. Additionally, gold’s role as a mere activator of the oxidant was rejected as well.

gold-mediated transformations, since accessed Au(I)−(hetero)arenes appeared as potential intermediates of a catalytic cycle. The first contribution in this sense was due to Nolan and coworkers, who demonstrated that NHC−Au(I) hydroxide 65 mediates the carboxylation of fluoroarenes with high Scheme 82. Gold-Catalyzed Carboxylation of Fluoroarenes

regioselectivity in a redox-neutral catalytic cycle (Scheme 82).256 As in their seminal contribution, regioselectivity was dictated by the acid−base principle and carboxylation took place at the most acidic C(sp 2)−H bond. Under CO2 atmosphere and after C−H bond activation by Au(I) hydroxide 65, a small CO2 molecule inserts onto the Au(I)−C(sp2) bond, affording intermediate 288. Finally, in the presence of an alkali hydroxide, catalytically active NHC−Au(I) hydroxide 65 is released besides final carboxylic acid 289. Besides the Au(I) ability to perform C−H activation on electron-poor arenes, Au(III) species display a long-established selectivity for C−H bond activation on electron-rich arenes, even at room temperature.237 Thereby, the selectivity of C−H bond activation between electron-poor and electron-rich arenes can be controlled just by switching the oxidation state on the Au metal center. This singular redox-controlled selectivity imparted by gold provided the basis for the dehydrogenative cross-coupling of arenes via a double C−H bond activation. The feasibility of such an oxidative coupling was first supported on a stoichiometric variant.257 Oxidation of preformed fluoroaryl Au(I) complexes 68 with a I(III) reagent afforded the direct C−H arylation of a wide range of electron-rich (hetero)arenes 289 at close to stoichiometric ratios compared to other metals (Scheme 83). Nevertheless, optimized conditions were quite different relative to those previously reported for the C−H bond activation of electron-poor arenes with Au(I) species.

Scheme 83. Stoichiometric Gold-Prompted Oxidative Cross-Coupling of Arenes

AH


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Scheme 84. Gold-Catalyzed Oxidative Cross-Coupling of Arenes via Double C−H Bond Activation

Scheme 85. Gold-Catalyzed Oxidative C−H Arylation by Arylsilanes

One of the latest contributions on gold-catalyzed oxidative coupling reactions showed that digold species such as [AuI2(μdppm)2]2+ can work as efficient photocatalysts for the generation of reactive carbon-centered radicals from organohalides. On the basis of this principle, the Hashmi research group reported the radical C(sp2)−H di- and perfluoroalkylation of (hetero)aromatic aldehyde-derived hydrazones 294 with

Scheme 87. Mechanistic Proposal for the Gold-Catalyzed Photoredox C(sp2)−H (Di/per)fluoroalkylation

Scheme 86. Gold-Catalyzed Photoredox C(sp2)−H (Di/ per)fluoroalkylation

bonding aminyl radical intermediate 300. After oxidation by 299 and further deprotonation, 300 would finally render fluorinated hydrazone 295 (Scheme 87). The radical nature of this protocol, also supported by DFT calculations, could be confirmed by the addition of radical scavengers, which inhibited the process. Moreover, EPR spingtrapping experiments allowed intercepting radical intermediate 300. In conclusion, this section perfectly illustrates the arrival of a new era in gold catalysis toward the establishment of new paradigms and major breakthroughs and where fluorine chemistry may still play a fruitful role.

fluoroalkyl bromides in the presence of [Au2(μ-dppm)2](OTf)2 (296) as a photoredox catalyst under UVA light irradiation (Scheme 86).260 Stoichiometric amounts of a base were also required to neutralize released HBr. Mild reaction conditions attested for a broad substrate scope and high functional-group tolerance (e.g., halogens, boronic esters, alkynes, alcohols). Moreover, fluorinated hydrazones 295 could be further derivatized into attractive fluorinated β-aminophosphonic acids and β-amino acid derivatives. The authors’ proposed mechanism is depicted in Scheme 87. As we pointed out above, light-excited gold photocatalyst 297 would readily generate the carbon-centered radical 298 from perfluoroalkyl bromide. Attending to its electrophilic character, imparted by fluorine substitution, radical intermediate 298 would attack hydrazone 294, rendering the three-electron π-

6. SUMMARY AND OUTLOOK It is well known that the reactivity and properties of molecules could change dramatically in the presence of fluorinated moieties. On the other hand, the unique ability exhibited by gold salts to activate multiple bonds, promoting the addition of a wide variety of nucleophiles, converted gold catalysis into a AI


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Notes

fundamental synthetic tool for the generation of C−C and C− heteroatom bonds. However, very few reports concerning the use of fluorinated starting materials have been devised. The examples shown herein indicate that the combination of gold salts with fluorinated building blocks leads to unusual behavior in the reactivity and selectivity in comparison with that of their nonfluorinated counterparts, allowing for the generation of new fluorinated chemical entities. The introduction of transition metal-catalyzed fluorinations was essential to overcome the high electronegativity of fluorine and the dual reactivity profile exhibited by fluoride anions as bases and nucleophiles. However, the use of gold complexes in these types of processes lagged behind other metals such as Pd, Cu, Ag, or Ru. This was probably due to the highly reactive nature of Au−F bonds. The use of NHC ligands to stabilize those complexes was a breakthrough in this area, allowing for the preparation of air-stable complexes that found applications in organic synthesis, opening new perspectives in this emerging area of research. Recent discoveries in this context indicated that the use of nucleophilic fluoride sources in combination with gold salts was a good strategy for the development of novel fluorination and trifluoromethylation reactions taking advantage of the redox properties of the gold(I)−gold(III) couple. This knowledge was also driven by the application of fluorine in PET, since nucleophilic fluorination methods were more favorable due to the direct availability of fluoride ion from cyclotron synthesis, which made the preparation of those fluorine-derived radiotracers more convenient. In the context of the redox properties of gold salts, their combination with electrophilic fluorine sources constituted a new departure in fluorine chemistry. The addition of Selectfluor as external oxidant enabled new cationic gold catalysis, expanding the utility of gold beyond the carbophilic activation on unsaturated moieties. Following the elementary steps of organometallic chemistry, gold species undergo oxidative addition, reductive elimination, transmetalation, and migratory insertion. However, it is important to state that the factors that govern these processes are very different from those controlling the reactivity of analogous Pd complexes. Thus, gold complexes are reluctant to undergo classical oxidative addition or reductive elimination. Significant mechanistic insights gained in the past few years gave a better understanding of those events, allowing for the generation of C−F bonds by means of a reductive elimination from a gold(III) species or, alternatively, in the presence of boronic acids or other nucleophiles the crosscoupling products with the formation of C−C and C− heteroatom bonds, respectively. Nevertheless, our knowledge of the electronic and structural parameters that delineate the reactivity of gold complexes is still in its infancy, and additional studies are clearly needed to gain a more comprehensive mechanistic picture, such us that of the Group 10 metals. Due to the critical role of the ligands in the reactivity of gold complexes, the design of new complexes will be crucial for the selective generation of new C−F bonds and cross-coupling reactions. In the near future, we will witness a growing number of new methodologies based on the combination of gold and fluorine.

The authors declare no competing financial interest. Biographies Javier Miró was born in Valencia (Spain) in 1988. He graduated in Chemistry in 2011 at the University of Valencia, Spain. In 2013, he was awarded with the Master in Experimental and Industrial Organic Chemistry Prize granted by University of Valencia, Polytechnic University of Valencia, University of Barcelona, University of Illes Balears, and University Cardenal-Herrera CEU. Since that year he has been carrying out his Ph.D. studies within the area of transition-metal catalysis at the University of Valencia (Spain) under the supervision of Prof. Santos Fustero and Dr. Carlos del Pozo. Carlos del Pozo was born in Palacios del Sil, León (Spain), in 1965. He studied Chemistry at the University of Oviedo, where he obtained his B.Sc. degree in 1988. He received his Ph.D. degree in Organic Chemistry in 1995, performed under the supervision of Prof. Barluenga, working in the field of heterocyclic chemistry. He then carried out postdoctoral studies for 27 months at the University of Colorado at Boulder under the supervision of Prof. Gary A. Molander, working in samarium iodide chemistry. He joined then the group of Dr. Francisco Javier González at the University of Oviedo until the end of 2001, focusing on β-lactam chemistry and protease inhibitors synthesis. In 2005, after working for 3 years in the pharmaceutical industry (total synthesis of natural products with antitumoral activity), he joined the group of Prof. Santos Fustero at the University of Valencia. Currently, he holds an Associate Professor position. His research interests are organofluorine chemistry, natural product synthesis, organometallic chemistry, and organocatalysis.

ACKNOWLEDGMENTS We thank the Spanish Ministerio de Ciencia e Innovación (CTQ2013-43310-P) and Generalitat Valenciana (GV/PrometeoII/2014/073) for their generous financial support. J.M. thanks the University of Valencia for a predoctoral fellowship. REFERENCES (1) Heidelberger, C.; Chaudhuri, N. K.; Danneberg, P.; Mooren, D.; Griesbach, L.; Duschinsky, R.; Schnitzer, R. J.; Pleven, E.; Scheiner, J. Fluorinated Pyrimidines, a New Class of Tumour-Inhibitory Compounds. Nature 1957, 179, 663−666. (2) Longley, D. B.; Harkin, D. P.; Johnston, P. G. 5-Fluorouracil: Mechanisms of Action and Clinical Strategies. Nat. Rev. Cancer 2003, 3, 330−338. (3) See, for example: Müller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881− 1886. (4) See, for example: Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev. 2008, 37, 320−330. (5) O’Hagan, D. Understanding Organofluorine Chemistry. An Introduction to the C−F Bond. Chem. Soc. Rev. 2008, 37, 308−319. (6) Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001−2011). Chem. Rev. 2014, 114, 2432−2506. (7) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of FluorineContaining Pharmaceuticals, Compounds Currently in Phase II−III Clinical Trials of Major Pharmaceutical Companies: New Structural Trends and Therapeutic Areas. Chem. Rev. 2016, 116, 422−518.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. AJ


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