Hypervalent Iodine Reagents in High Valent Transition Metal Chemistry

molecules

Review Hypervalent Iodine Reagents in High Valent Transition Metal Chemistry

Felipe Cesar Sousa e Silva, Anthony F. Tierno and Sarah E. Wengryniuk * Department of Chemistry, Temple University, 1901 N. 13th St., Philadelphia, PA 19122, USA; [email protected] (F.C.S.S.); [email protected] (A.F.T.) * Correspondence: [email protected]; Tel.: +1-215-204-0360

Academic Editor: Margaret A. Brimble Received: 29 March 2017; Accepted: 8 May 2017; Published: 12 May 2017

Abstract: Over the last 20 years, high valent metal complexes have evolved from mere curiosities to being at the forefront of modern catalytic method development. This approach has enabled transformations complimentary to those possible via traditional manifolds, most prominently carbon-heteroatom bond formation. Key to the advancement of this chemistry has been the identiﬁcation of oxidants that are capable of accessing these high oxidation state complexes. The oxidant has to be both powerful enough to achieve the desired oxidation as well as provide heteroatom ligands for transfer to the metal center; these heteroatoms are often subsequently transferred to the substrate via reductive elimination. Herein we will review the central role that hypervalent iodine reagents have played in this aspect, providing an ideal balance of versatile reactivity, heteroatom ligands, and mild reaction conditions. Furthermore, these reagents are environmentally benign, non-toxic, and relatively inexpensive compared to other inorganic oxidants. We will cover advancements in both catalysis and high valent complex isolation with a key focus on the subtle effects that oxidant choice can have on reaction outcome, as well as limitations of current reagents.

Keywords: hypervalent iodine; oxidation; oxidant; redox; high valent; high oxidation state; catalysis

1. Introduction Over the last 20 years, high valent metal complexes have transitioned from mere curiosities to being at the forefront of modern catalytic method development. This approach has enabled transformations complimentary to those possible via traditional manifolds, most prominently carbon-heteroatom bond formation. Key to the advancement of this chemistry has been the identiﬁcation of oxidants that are capable of accessing these high oxidation state complexes. The oxidant has to be both powerful enough to achieve the desired oxidation as well as provide heteroatom ligands for transfer to the metal center; these heteroatoms are often subsequently transferred to the substrate via reductive elimination. The choice of heteroatom can be critical depending on the application. For example, chloride ligands can aide in the stabilization and isolation of high valent complexes whereas acetate ligands are often more successful in catalytic manifolds. Hypervalent iodine reagents have seen wide application in this ﬁeld as they are environmentally benign, non-toxic, and relatively inexpensive compared to other inorganic oxidants. Furthermore, they provide an excellent balance of versatile reactivity, heteroatom ligands, and mild reaction conditions. We will cover advancements in the use of hypervalent iodine reagents for both catalysis and high valent complex isolation with a key focus on the subtle effects that oxidant choice can have on reaction outcome, as well as limitations of current reagents. Many of these areas have been covered in the context of more broad reviews and in those cases the discussion will not be comprehensive but focus on the key aspects and most relevant elements for this review. The discussion is organized broadly

Molecules 2017, 22, 780; doi:10.3390/molecules22050780 www.mdpi.com/journal/molecules Molecules 2017, 22, 780 2 of 54

Molecules 2017, 22, 780 2 of 54 by the metal center being oxidized, including palladium, platinum, gold, nickel, copper, and ﬁnally oxidized, including palladium, platinum, gold, nickel, copper, and finally isolated examples with isolated examples with other transition metals. Below a summary graphic has been provided that other transition metals. Below a summary graphic has been provided that includes oxidants common includes oxidants common to high valent transition metal chemistry that will be discussed in this to high valent transition metal chemistry that will be discussed in this review as well as common review as well as common nomenclature and how they will be presented in the text (Figure1). nomenclature and how they will be presented in the text (Figure 1).

Hypervalent Iodine Reagents - Featured in blue throughout text Other Oxidants Commonly Utilized

General reactivity towards transition metals General reactivity towards transition metals - 2-e– inner sphere oxidants (1-e– is possible but rare) - 1e – or 2-e– inner sphere oxidants - Transfer of oxidant ligands to metal center (carbon or heteroatom) - Generation of electrophilic metal center - C–C or C–X reductive elimination pathways accessible - Can transfer functional groups to metal center (not always) - Re-establishment of active catalysts Advantages Advantages - Powerful oxidants - Powerful oxidants - Inexpensive - Non-toxic - Broad ligand scope for transference to metal center - Environmentally benign - Rapid synthesis - Transfer of ligands resistant to reductive elimination - Facile modulation of electronics and sterics Disadvantage Disadvantages - Expensive - Low atom economy - Harsh oxidantion conditions - Generate organic byproducts (ex- phenyl iodine, iodobenzoic acid) - Minimal modulation of electronic/steric effects - Limited by ligands available for transfer

Neutral, Acyclic λ3-Iodanes, Iodine(I) Reagents One-Electron Oxidants O O H R = Me; PhI(OAc) R = CF ; PhI(OTFA) , PhI(OCOCF ) O CuCl O O R 2 3 2 3 2 2 2 phenyliodine(III)diacetate phenyliodine(III) bis(trifluoroacetate) I t-butylhydrogenperoxide O Copper dichloride Oxygen R = Ph; PhI(O2CPh)2; PhI(OBz)2 R = tBu; PhI(O2CtBu)2, PhI(OPiv)2 tBuOOH, TBHP [bis-(benzoyloxy)iodo]benzene phenyliodine(III)dipivalate R O O

Cl OH I I O N O O N O Cl OTs Cl Br O Me OAc N-Chlorosuccinimide N-Bromosuccinimide Benzoquinone, I phenyliodine(III)dichloride Hydroxo-phenyliodine(III)tosylate NCS NBS BQ OAc PhI(Cl)2 PhI(OH)OTs, Koser's reagent Me Me Two-Electron Oxiants I NTs Iodomesitylene diacetate CH3 OTf MesI(OAc)2 IOAc Iodine monoacetate OTf

[N-(phenylsulfonyl)imino]phenyliodinane S H C N CH PhINTs 3 3 CF F 3 Neutral, Cyclic, λ3-Iodanes 1-Fluoro-2,4,6- S - (trifluoromethyl)- trimethylpyridinium triflate dibenzothiophenium triflate NFTPT TDTT F3C I O TIPS I O Me Me O 2BF SiH3 Cl 4 3,3 - Dimethyl-1-(trifluoromethyl)-1,2- N 1-[(triisopropylsilyl)ethynyl]-1,2- SiH benziodoxole; Togni's reagent benziodoxol-3(1H)-one;TIPS-EBX N 3 F 1,2 disilylbenzene (Poly)cationic, Acyclic λ3-Iodanes 1-Chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), R = H [(Py) IPh]2OTf– 2OTf 2 F-TEDA, SelectfluorR R R N,N dipyridinium phenyliodine(III) triflate NN I – R = CN, [(4CNPy)2IPh]2OTf PhO2S N,N [4- cyano]dipyridinium phenyliodine(III) triflate N F H3CI PhO2S R = NMe , [(DMAP) IPh]2OTf– 2 2 N-fluorobis(phenylsulfonyl)imide Methyliodide, N,N [4- dimethylamino]dipyridiniumphenyliodine(III) triflate NFSI MeI

Iodonium salts . . 2- 2KHSO5 KHSO4 K2SO4 PtCl6 OxoneR Hexachloroplatinum(IV) R BF R BF I+ 4 I+ C CR 4 R O N O O N O Diaryliodonium tetrafluoroborate Alkynylliodonium tetrafluoroborate Br [Ph I]BF [PhICCR]BF Cl 2 4 4 N-Chlorosuccinimide N-Bromosuccinimide NCS NBS Figure 1. Common oxidants utilized in high valent metal catalysis. Figure 1. Common oxidants utilized in high valent metal catalysis.

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2. Palladium Molecules 2017, 22, 780 3 of 54 2.1. Introduction 2. Palladium Palladium has a long and storied history in transition metal catalysis, facilitating such iconic cross2.1. coupling Introduction reactions as the Heck, Suzuki-Miyara, Negishi, Buchwald-Hartwig, Sonagashira, and others.Palladium Its ubiquity has a long stems and storied not only history from in itstransi excellenttion metal reactivity, catalysis, butfacilitating also from such iconic a detailed understandingcross coupling of reactions its underlying as the Heck, mechanisms Suzuki-Miyar anda, Negishi, predictable Buchwald-Hartwig, reactivity, which Sonagashira, facilitates and novel reactionothers. development. Its ubiquity stems For manynot only years, from palladiumits excellent reactivity, catalysis reliedbut also on from the a Pd(0)/Pd(II)detailed understanding redox couple, however,of its workunderlying in the 21stmechanisms century hasand shownpredictable the powerreactivity, and which promise facilitates of the highnovel oxidation reaction state Pd(II)/Pd(IV)development. manifold, For many as years, well palladium as the potential catalysis role relied of Pd(III)on the Pd(0)/Pd(II) species in redox catalysis couple, (Scheme however,1). This chemistrywork in has the enabled 21st century transformations has shown the previouslypower and promise inaccessible of the high via traditionaloxidation state catalytic Pd(II)/Pd(IV) manifolds, manifold, as well as the potential role of Pd(III) species in catalysis (Scheme 1). This chemistry has most notably carbon-heteroatom bond forming reductive eliminations, the microscopic reverse of the enabled transformations previously inaccessible via traditional catalytic manifolds, most notably oxidative addition pathways commonly encountered in low valent palladium catalysis. In this context, carbon-heteroatom bond forming reductive eliminations, the microscopic reverse of the oxidative hypervalentaddition iodinepathways reagents commonly have encountered emerged as in key low players, valent facilitatingpalladium catalysis. net two-electron In this context, oxidations at thehypervalent metal center iodine accompanied reagents have by emerged transfer as ofkey their players, heteroatom facilitating ligands, net two-electron most commonly oxidations acetateat or chloride.the metal Arguably center accompanied the rapid advancementsby transfer of thei andr heteroatom synthetic applicationsligands, most ofcommonly high valent acetate palladium or chemistrychloride. have Arguably spurred the investigations rapid advancements into more and obscure synthetic oxidation applications states of withhigh othervalent metals. palladium As both syntheticchemistry applications have spurred and investigations mechanistic into details more of obscure this area oxidation have been states comprehensively with other metals. discussedAs both in severalsynthetic excellent applications reviews and in recent mechanistic years details [1–8], thisof th sectionis area have will been discuss comprehensively the key role thatdiscussed hypervalent in iodineseveral reagents excellent have reviews played in in recent its development, years [1–8], this with section special will attentiondiscuss the paid key role to recent that hypervalent reports as well iodine reagents have played in its development, with special attention paid to recent reports as well as limitations of current methods that could be addressed through continued exploration of novel as limitations of current methods that could be addressed through continued exploration of novel oxidants.oxidants. As theAs the body body of of work work in in this this area area isis extensive,extensive, this this section section will will be beorganized organized based based on the on the typetype of bond of bond formation formation being being targeted, targeted, namely namely C–O,C–O, C–X, C–X, C–N, C–N, and and C–C C–C bonds, bonds, and andfinally ﬁnally studies studies focusingfocusing on Pd(III) on Pd(III) species. species.

Traditional: Pd(0)/Pd(II) Cross Coupling

Oxidative Addition Transmetallation 0 II II 1 Pd RPdX RPdR Suzuki, Heck, Negishi, RX [M] R1 Buchwald-Hartwig, Stille, Sonagashira, etc. C–C Reductive Elimination RR1

Last 20 years: Pd(II)/Pd(IV) Manifolds: C–H Functionalization, Alkene Difunctionalization, Allylic Oxidation

X X X [O] [O] = PhI(OR) , PhIX , [R I]X–, ArINTs, II IV III III 2 2 2 PdX2 RPdX RPd X RPd Pd R – [(Py)2IPh]2X X X X NCS, NBS, NFSI, TTDT, others

C–X Reductive Elimination

or SN2-Displacement R X Scheme 1. Manifolds for palladium catalysis. Traditional methods via Pd(0)/Pd(II) and recent Scheme 1. Manifolds for palladium catalysis. Traditional methods via Pd(0)/Pd(II) and recent advances advances in Pd(II)/Pd(IV) catalysis. in Pd(II)/Pd(IV) catalysis. 2.2. Palladium(IV) 2.2. Palladium(IV) 2.2.1. Introduction 2.2.1. Introduction Canty reported the first X-ray structure of an alkyl Pd(IV) organometallic complex in 1986, Cantyformed via reported the oxidative the ﬁrst addition X-ray of structureiodomethane of to an a alkyldimethyl Pd(IV) (bpy)Pd(II) organometallic complex (1, Scheme complex 2) [9]. in 1986, formedCanty’s via the work oxidative revealed addition the octahedr of iodomethaneal geometry of to Pd(IV) a dimethyl species (bpy)Pd(II) 1, as well complexas the clean (1, oxidative Scheme2 )[ 9]. Canty’saddition/reductive work revealed elimination the octahedral reactivity geometry and stability of Pd(IV) of these species complexes,1, as which well he as comments the clean could oxidative addition/reductive“suggest that development elimination of reactivity a rich organometall and stabilityic chemistry of these complexes,of palladium(IV) which may he be comments possible”. could “suggestThis thatreport development laid the foundation of a rich for organometallic the rich chemistry, chemistry mechanistic of palladium(IV) and structural may understanding be possible”. of This this high oxidation state redox couple that has emerged over the last 20 years. report laid the foundation for the rich chemistry, mechanistic and structural understanding of this high oxidation state redox couple that has emerged over the last 20 years. Molecules 2017, 22, 780 4 of 54 Molecules 2017, 22, 780 4 of 54

Me N Me MeI N Me - (CH3)2 N Me PdII PdIV PdII N Me Oxidation N Me C–C Reductive N I 1 I 2 Elimination Scheme 2. Canty’sScheme report 2. Canty’s resulting report in resulting the first in X-ray the first crystall X-ray crystallographicographic characterization characterization of ofa Pd(IV) a Pd(IV) alkyl species. alkyl species. Pd(II)/Pd(IV) chemistry has become as a powerful synthetic manifold to facilitate transformations Pd(II)/Pd(IV) chemistry has become as a powerful synthetic manifold to facilitate transformations not accessiblenot accessible via traditional via traditional Pd(0)/Pd(II) Pd(0)/Pd(II) catalysi catalysiss (Scheme (Scheme 11).). ThisThis field field has has been been pioneered pioneered by by the Sanford thegroup Sanford in groupthe area in the of area C–H of C–H acetoxylation acetoxylation and and halogenation.halogenation. There There have have been severalbeen several comprehensivecomprehensive reviews reviews written written on on this this topictopic in recentin recent years andyears the and reader the is directed reader there is directed for detailed there for detailed mechanisticmechanistic discussion discussion and anand exhaustive an exhaustive report of report applications of applications [1,4,5]. Building [1,4,5]. from Building this work, from this work, Pd(IV)Pd(IV) chemistry chemistry hashas been been applied applied to the to formationthe form ofation a diverse of a diverse array of C–N,array C–O, of C–N, C–X, andC–O, C–C C–X, and bond forming reactions. C–C bond forming reactions. 2.2.2. Carbon–Oxygen Bond Formation 2.2.2. Carbon–OxygenThere has been Bond extensive Formation work in the area of C–O bond formation via Pd(II)/Pd(IV) catalysis Therewith has hypervalent been extensive iodine reagents. work in This the application area of C–O is particularly bond formation well suited via as the Pd(II)/Pd(IV) most common catalysis hypervalent iodine oxidants, of the type PhI(OR)2, transfer carboxylate ligands to the metal center that with hypervalentare then engaged iodine in subsequentreagents. This C–O bondapplication forming reductiveis particularly elimination. well These suited carboxylate as the most ligands common hypervalentare also iodine highly oxidants, tunable, bothof the sterically type andPhI(OR) electronically,2, transfer allowing carboxylate for control ligands of complex to the stability, metal center that are reactionthen engaged pathway andin subsequent selectivity. Approaches C–O bond have forming expanded reductive to include C–H eliminat functionalization,ion. These allylic carboxylate ligands areoxidation, also highly as well astunable, alkene difunctionalization. both sterically and electronically, allowing for control of complex stability, 2.2.2.1.reaction C–H pathway Functionalization and selectivity. Approaches have expanded to include C–H functionalization, allylic oxidation, as well as alkene difunctionalization. The first report of Pd-catalyzed C–H acetoxylation using a hypervalent iodine oxidant was by Crabtree, who achieved the acetoxylation of benzene using Pd(OAc)2 with PhI(OAc)2 as the external 2.2.2.1. C–Hoxidant Functionalization and –OAc source (Scheme3)[ 10]. This built upon the work of Stock et al., which employed Thedichromate first report to performof Pd-catalyzed an analogous C–H transformation acetoxylation [11], using however a hypervalent PhI(OAc)2 offered iodine much oxidant higher was by selectivity and did not perform further product oxidations. In what has become a standard mechanistic Crabtree,proposal, who achieved Crabtree the proposed acetoxylation acetyl assisted of benzene C–H activation using Pd(OAc) at Pd(II) (intermediate2 with PhI(OAc)3) would2 as givethe external oxidant andintermediate –OAc source4, which (Scheme can then be3) diverted[10]. This down buil onet upon of two the pathways. work of Along Stock the et desired al., which pathway employed dichromate(Path to B) perform5 is then oxidizedan analogous by PhI(OAc) transformation2 to Pd(IV) species [11],5 howeverwith introduction PhI(OAc) of two2 offered acetyl groups. much higher selectivitySubsequent and did reductive not perform elimination further gives rise product to acetoxylated oxidations. product andIn regenerationwhat has ofbecome the Pd(OAc) a 2standard. mechanisticImportantly, proposal, Crabtree Crabtree noted proposed that competitive acetyl formation assisted of biphenylC–H activation (via Path A)at isPd(II) minimized (intermediate with 3) PhI(OAc)2, indicating that oxidation to Pd(IV) in this system is significantly faster than a second C–H would giveactivation intermediate step to give 4, which6. It was can also then found be diverted that in the down absence on ofe of oxidant, two pathways. biphenyl was Along the only the desired pathwayobservable (Path B) 5 product, is then thus oxidized indicating by thatPhI(OAc) Pd(II) intermediate2 to Pd(IV)4 specieswill not undergo5 with introduction direct C–X reductive of two acetyl groups. Subsequentelimination, and reductive emphasizing elimination the significance gives of rise Pd(IV) to pathwaysacetoxylated in facilitating product such and transformations. regeneration of the Pd(OAc)While2. Importantly, this system displayedCrabtree only noted moderate that catalyticcompetitiv activitye formation and required of solvent biphenyl quantities (via of Path the A) is arene, it laid the foundation for the development of directed C–H acetoxylation, which has relied on minimized with PhI(OAc)2, indicating that oxidation to Pd(IV) in this system is significantly faster hypervalent iodine oxidants to efficiently acetoxylate C(sp2)–H as well as C(sp3)–H bonds. than a second C–H activation step to give 6. It was also found that in the absence of oxidant, biphenyl was the only observable product, thus indicating that Pd(II) intermediate 4 will not undergo direct C–X reductive elimination, and emphasizing the significance of Pd(IV) pathways in facilitating such transformations. While this system displayed only moderate catalytic activity and required solvent quantities of the arene, it laid the foundation for the development of directed C–H acetoxylation, which has relied on hypervalent iodine oxidants to efficiently acetoxylate C(sp2)–H as well as C(sp3)– H bonds.

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Molecules 2017, 22, 780 + metallic palladium 5 of 54

PdII + metallic palladium C–C Reductive Elimination 6 PdII PhI(OAc)2

C–C Reductive Elimination Path A6 Ph–H minor PhI(OAc)2 H O H Path A Ph–PdH II(OAc) Pd(OAc)2 Pd minor H O O O O - AcOH 4 H 3 PdII(OAc) Pd(OAc)2 Pd O Path B O PhI(OAc)2 Assisted C-H Activation - AcOH major 4 O 3

Path B PhI(OAc) Assisted C-H Activation 2 C–X Reductive Elimination major OAc IV Pd OAc OAc C–X ReductiveOAc Elimination OAc 5 IV Pd OAc OAc OAc 5 Scheme 3. Pd(II)/Pd(IV) catalyzed acetoxylation of benzene with use of PhI(OAc)2 as external oxidant. Scheme 3. Pd(II)/Pd(IV) catalyzed acetoxylation of benzene with use of PhI(OAc)2 as external oxidant.

TheScheme Sanford 3. Pd(II)/Pd(IV) group’s contributionscatalyzed acetoxylation to this area of benzene began with in 2004 use of with PhI(OAc) their2 asseminal external report oxidant. on the Thedirected Sanford C–H acetoxylation group’s contributions of 2-phenylpyridine to this area using began Pd(OAc) in 20042/PhI(OAc) with their2 (Scheme seminal 4a) [12]. report Since on the 2 directedthen, C–HThe they Sanford acetoxylation have group’sextended ofcontributions 2-phenylpyridinethis method to tothis include area using began a Pd(OAc) range in 2004 of2/PhI(OAc) withdirecting their seminalgroups2 (Scheme forreport4 a)C(sp [on12 )–Hthe]. Since then,acetoxylationdirected they have C–H extended andacetoxylation a brief this overview method of 2-phenylpyridine tois includeincluded a in rangeusing Scheme ofPd(OAc) directing 4b [13].2/PhI(OAc) While groups other2 for(Scheme C(spoxidants 24a))–H [12].including acetoxylation Since 2 Mn(OAc)then, they2 andhave Oxone extended have beenthis usedmethod in thisto includechemistry, a rangePhI(OAc) of 2 directingis by far thegroups most forcommon C(sp )–H[2]. and a brief overview is included in Scheme4b [ 13]. While other oxidants including Mn(OAc)2 and Sanfordacetoxylation also demonstratedand a brief overview a polymer is includedsupported in variant Scheme of 4b this [13]. chemistry, While other which oxidants allows includingfor facile Oxone have been used in this chemistry, PhI(OAc)2 is by far the most common [2]. Sanford also recyclingMn(OAc) of2 and the hypervalentOxone have iodinebeen used reagent, in this addre chemistry,ssing the PhI(OAc)issue of iodobenzene2 is by far the byproducts most common produced [2]. demonstrated a polymer supported variant of this chemistry, which allows for facile recycling of inSanford these transformationsalso demonstrated (Scheme a polymer 4c) [14]. supported variant of this chemistry, which allows for facile the hypervalentrecycling of the iodine hypervalent reagent, iodine addressing reagent, addre the issuessing ofthe iodobenzene issue of iodobenzene byproducts byproducts produced produced in these transformationsin these transformationsa. (Scheme4c) (Scheme [14]. 4c) [14]. b. Directed C(sp2)–H acetoxylation Pd(OAc)2, a. N N b. PhI(OAc)2 N Ph Directed C(spN 2)–H acetoxylationN ° OAc R N MeCN,Pd(OAc) 1002, C R N R N OAc PhI(OAc)2 N Ph OAc N N N MeCN, 100 °C OAc R OAc Me R R OAc N OAc OMe N R R OAc O OAc Me N N OAc L [O] N II L OMe Pd PdIV N L L R O R N OAc L [O] N OAc OAc II L N Pd PdIV AcO L L c. OAc AcO OAc N I AcOI c. AcO OAc Pd(OAc)2 N I N I AcOH, 100 °C Pd(OAc)2 OAc N n N n AcOH, 100 °C 1. Precipitate with CH OH 3 OAc n n 2. Regenerate with AcO2H 1. Precipitate with CH3OH Scheme 4. (a) First report on the directed C(sp2)–H acetoxylation of 2-phenylpyridine with 2. Regenerate with AcO2H Pd(OAc)2/PhI(OAc)2; (b) General scope of directing groups used for C(sp2)–H acetoxylation; 3 2 Scheme(Schemec) Polymer-supported 4. (4.a )(a First) First report report λ -iodane on on the allowsthe directeddirected for facile C(spC(sp oxidant2)–H)–H recycling.acetoxylation acetoxylation of of2-phenylpyridine 2-phenylpyridine with with Pd(OAc)2/PhI(OAc)2; (b) General scope of directing groups used for C(sp2)–H2 acetoxylation; Pd(OAc)2/PhI(OAc)2;(b) General scope of directing groups used for C(sp )–H acetoxylation; The(c) Polymer-supported acetoxylation of λboth3-iodane benzylic allows and for facileunactivated oxidant recycling.C(sp3)–H bonds can also be accomplished (c) Polymer-supported λ3-iodane allows for facile oxidant recycling. with Pd(OAc)2 and PhI(OAc)2 (Scheme 5) [12,15,16]. In these reactions, sterics plays a large role in The acetoxylation of both benzylic and unactivated C(sp3)–H bonds can also be accomplished

3 Thewith acetoxylationPd(OAc)2 and PhI(OAc) of both benzylic2 (Scheme and 5) [12,15,16]. unactivated In these C(sp reac)–Htions, bonds sterics can plays also a be large accomplished role in with Pd(OAc)2 and PhI(OAc)2 (Scheme5)[ 12,15,16]. In these reactions, sterics plays a large role in Molecules 2017, 22, 780 6 of 54 Molecules 2017, 22, 780 6 of 54 dictatingdictatingMolecules regioselectivity, 2017 regioselectivity,, 22, 780 with with the the less less sterically sterically hindered hindered C–H C–H bond bond undergoing undergoing C–H C–H activation. activation.6 of While 54 3 theWhile C(sp the)–H C(sp variant3)–H often variant performs often mostperforms efﬁciently most withefficiently PhI(OAc) with2 asPhI(OAc) the oxidant,2 as the combinations oxidant, dictating regioselectivity, with the less sterically hindered C–H bond undergoing C–H activation. ofcombinations Oxone/Mn(OAc) of Oxone/Mn(OAc)2, molecular oxygen,2, molecular and peroxideoxygen, and oxidants peroxide have oxidants also been have used also effectively been used [2]. While the C(sp3)–H variant often performs most efficiently with PhI(OAc)2 as the oxidant, Anothereffectively interesting [2]. Another example interesting used iodine(I) example reagent used io IOAc,dine(I) whichreagent was IOAc, generated which was in situ generated from PhI(OAc) in situ 2 combinations of Oxone/Mn(OAc)2, molecular oxygen, and peroxide oxidants have also been used andfrom I ; PhI(OAc)PhI(OAc)2 andalone I2; wasPhI(OAc) ineffective2 alone inwas this ineffective case [17]. in this case [17]. effectively2 [2]. Another2 interesting example used iodine(I) reagent IOAc, which was generated in situ from PhI(OAc)2 anda. Benzylic I2; PhI(OAc) C–H acetoxylation2 alone was ineffective in this case [17].

Pd(OAc)2, a. BenzylicX C–H acetoxylation X PhI(OAc)2 R R Pd(OAc)2, ° NX AcOH/Ac2O, 100 C NX PhI(OAc)2 R R H ° OAc N AcOH/Ac2O, 100 C N b. Unactivated C(sp3)-H acetoxylation H OAc MeO Pd(OAc) , MeO 1 b. UnactivatedN C(sp3)-H acetoxylation2 N R = Me, R = Et PhI(OAc)2 PhI(OAc)2 75% MeOR H Pd(OAc)2, MeOR OAc KRS = OMe, R 1 =45% Et N AcOH/Ac2O, 100 °C N 2 2 8 R1 PhI(OAc)2 R1 PhI(OAc)2 75% R H R OAc K S O 45% AcOH/Ac2O, 100 °C 2 2 8 Scheme 5. (a) Directed acetoxylation1 of benzylic C(sp3)–H1 bonds; (b) Directed acetoxylation of Scheme 5. (a) DirectedR acetoxylation of benzylic C(sp3)–HR bonds; (b) Directed acetoxylation of 3 unactivated C(sp3 )–H bonds. unactivatedScheme 5. C(sp (a) Directed)–H bonds. acetoxylation of benzylic C(sp3)–H bonds; (b) Directed acetoxylation of 3 Theunactivated Sanford C(sp group)–H bonds.has conducted extensive mechanistic studies on these processes, and the readerThe is Sanford directed group to some has selected conducted full reports extensive for detailed mechanistic discussion studies [2,18–20]. on these Their processes, work has andbeen the The Sanford group has conducted extensive mechanistic studies on these processes, and the readeraccompanied is directed by that to some of Ritter selected and others, full reports with a forkey detailed point being discussion whether [Pd(IV)2,18–20 species]. Their or workPd(III) has reader is directed to some selected full reports for detailed discussion [2,18–20]. Their work has been beendimers accompanied are the active by that catalysts. of Ritter Key and reports others, detailing with athe key possibility point being of Pd(III) whether intermediates Pd(IV) species are or accompanied by that of Ritter and others, with a key point being whether Pd(IV) species or Pd(III) Pd(III)discussed dimers in aremore the detail active in catalysts.Section 1.3. Key Sanford’s reports seminal detailing report the possibilityin this area of outlines Pd(III) some intermediates of the key are dimers are the active catalysts. Key reports detailing the possibility of Pd(III) intermediates are discussedfeatures inof both more the detail ligand in Sectionscaffolds 2.3 and. Sanford’s hypervalent seminal iodine report oxidants in this that area allow outlines for study some of reactive of the key discussed in more detail in Section 1.3. Sanford’s seminal report in this area outlines some of the key featuresPd(IV) ofintermediates both the ligand as well scaffolds as mechanistic and hypervalent elucidation iodine (Scheme oxidants 6) [19]. that Two allow rigid for cyclometallated study of reactive features of both the ligand scaffolds and hypervalent iodine oxidants that allow for study of reactive Pd(IV)2-phenylpyridine intermediates ligands as well were as mechanistic incorporated elucidation to lend stability (Scheme to6)[ the19 ].resultant Two rigid complexes, cyclometallated and Pd(IV) intermediates as well as mechanistic elucidation (Scheme 6) [19]. Two rigid cyclometallated 2-phenylpyridinesuppress competing ligands ligand were exchange incorporated and side to lend reactions stability upon to theoxidation. resultant Additionally, complexes, andthe acetate suppress 2-phenylpyridine ligands were incorporated to lend stability to the resultant complexes, and competingligands of ligand PhI(OAc) exchange2 were exchanged and side reactionsfor aryl carboxylates upon oxidation. that could Additionally, be readily derivatized the acetate and ligands thus of suppress competing ligand exchange and side reactions upon oxidation. Additionally, the acetate PhI(OAc)used as facilewere handles exchanged to control for arylthe electronic carboxylates parameters that could at the be metal readily center. derivatized The Pd(IV) and complex thus ( used7) ligands 2of PhI(OAc)2 were exchanged for aryl carboxylates that could be readily derivatized and thus obtained upon oxidation with PhI(CO2p–XAr)2 where X=NO2 was able to characterized by X-ray asused facile as handles facile handles to control to control the electronicthe electronic parameters parameters at at the the metal metal center.center. The The Pd(IV) Pd(IV) complex complex (7) (7) crystallography, revealing cis addition of the two carboxylates ligands. Subsequent Hammett analysis obtainedobtained upon upon oxidation oxidation with with PhI(CO PhI(CO2p2p–XAr)–XAr)22 wherewhere XX=NO = NO2 was2 was able able to tocharacterized characterized by byX-ray X-ray revealed a clear correlation between carboxylate electronics and the rate of reductive elimination, crystallography,crystallography, revealing revealingcis cisaddition addition of ofthe the twotwo carboxylates ligands. ligands. Subs Subsequentequent Hammett Hammett analysis analysis indicating that the carboxylate acted in as a nucleophile in reductive elimination. revealedrevealed a cleara clear correlation correlation between between carboxylatecarboxylate el electronicsectronics and and the the rate rate of of reductive reductive elimination, elimination, indicatingindicating that that the the carboxylate carboxylate acted acted in in asas aa nucleophilenucleophile in reductive reductive elimination. elimination.

O C(p-XC H ) N N N 2 6 5 PdII I PdIV O C(p-XC H ) N N O C(p-XC H ) O22C(p-XC66H55) R 2 6 5 N N IV II R I OPd2C(p-XC6H5) Pd 7 X = H, OMe,O Me,C( pOPh,-XC HF, Cl,) Br, N O C(p-XC H ) 2 6 5 R 2 6 5 Ac, CF , CN, NO R 3 2 O2C(C-Op-XC6H5) X = H, OMe, Me, OPh, F, Cl, Br, 7 Reductive Hammett analysis shows correlation Ac, CF between, CN, NOcarboxylate ligand Elimination electronics and rate of reductive3 elimination2 C-O Reductive Hammett analysis shows correlation between carboxylate ligand Elimination electronics and rate of reductive elimination N (C6H5p-X)CO2 N Scheme 6. Seminal mechanistic investigation into Pd(IV)-mediated C–H acetoxylation. (C6H5p-X)CO2

The SchemeYuScheme group 6. 6. Seminalreported Seminal mechanistic mechanistican intramolecular investigationinvestigation C(sp into 2)–H Pd(IV)-mediated Pd(IV)-mediated acetoxylation C–Hthat C–H acetoxylation.could acetoxylation. also be rendered asymmetric using a Boc-Ile-OH chiral ligand (Scheme 7) [21]. This report was the first enantioselective The Yu group reported an intramolecular C(sp2)–H acetoxylation that could also be rendered application of Pd(II)/Pd(IV) catalysis and gave high yields2 and enantioselectivities of benzofuranones. asymmetricThe Yu group using reporteda Boc-Ile-OH an intramolecularchiral ligand (Scheme C(sp 7))–H [21]. acetoxylation This report was that the could first enantioselective also be rendered asymmetricapplication using of Pd(II)/Pd(IV) a Boc-Ile-OH catalysis chiral and ligand gave (Scheme high yields7)[ 21 and]. Thisenantioselectivi report wasties the of ﬁrst benzofuranones. enantioselective application of Pd(II)/Pd(IV) catalysis and gave high yields and enantioselectivities of benzofuranones.

Molecules 2017, 22, 780 7 of 54 Molecules 2017, 22, 780 7 of 54

Molecules 2017, 22, 780 7 of 54 Ar R Pd(OAc) , Ar 2 R Molecules 2017, 22, 780 O Boc-Ile-OH 7 of 54 Ar R Pd(OAc) , Ar R1 2 R1 R O OHO PhI(OAc)Boc-Ile-OH2, Ar R Pd(OAc)2, AOr R1 O KOAc, tBuOH R1 R O OH PhI(OAc)Boc-Ile-OH2, up to 96% ee 1 1 O R KOAc, tBuOH R O OH PhI(OAc)2, up to 96% ee Scheme 7. Enantioselective intramolecular C(sp2)–H acetoxylation usingO chiral amino acid ligand. Scheme 7. Enantioselective intramolecularKOAc, C(sp )–H tBuOH acetoxylation using chiral amino acid ligand. up to 96% ee Scheme 7. Enantioselective intramolecular C(sp2)–H acetoxylation using chiral amino acid ligand. Sanford demonstrated an impressive example of non-directed C(sp2)–H acetoxylation through Scheme 7. Enantioselective intramolecular C(sp2)–H acetoxylation using chiral2 amino acid ligand. Sanford demonstrated an impressive example of non-directed C(sp )–H acetoxylation through the additionSanford of demonstrated pyridine to enhance an impressi catalyticve example activity ofof non-directedthe palladium C(sp catalyst2)–H (Schemeacetoxylation 8) [22]. throughIn this the addition of pyridine to enhance catalytic activity of the palladium catalyst (Scheme8)[ 22]. In this system,the additionSanford the ratioof demonstrated pyridine of [Pd]/pyridine to enhance an impressi catalyticprovedve example criticalactivity as ofof non-directedthewell palladium as the selection C(sp catalyst2)–H of (Schemeacetoxylation hypervalent 8) [22]. through iodineIn this system, the ratio of [Pd]/pyridine proved critical as well as the selection of hypervalent iodine oxidant.system,the addition theSwitching ratioof pyridine of to [Pd]/pyridinethe to more enhance sterically catalyticproved hindered critical activity MesI(OAc) as of wellthe palladium as2 fromthe selection PhI(OAc) catalyst of2(Scheme improved hypervalent 8) [22].both iodine In yield this oxidant.and regioselectivity. Switching to the more sterically hindered MesI(OAc)2 from PhI(OAc)2 improved both yield oxidant.system, Switchingthe ratio ofto [Pd]/pyridinethe more sterically proved hindered critical MesI(OAc) as well as2 fromthe selectionPhI(OAc) of2 improved hypervalent both iodine yield andand regioselectivity. regioselectivity. oxidant. Switching to theCl more sterically hindered MesI(OAc)Cl 2 from PhI(OAc)Cl 2 improved both yield and regioselectivity.Cl 2mol% [Pd] Cl OAc Cl Cl Cl + Cl Cl ArI(OAc)2mol%2, AcOH/Ac [Pd] 2O Cl OAc Cl Cl Cl 100 °C + Cl OAc Cl ArI(OAc)2mol%2, AcOH/Ac [Pd] 2O Cl α OAc Cl β 100 °C + OAc ArI(OAc)2, AcOH/Ac2O α β [O] [Pd] Yield α : β 100 °C OAc α β PhI(OAc)[O] 2 Pd(OAc)[Pd]2 Yield8 41α : 59β MesI(OAc)2 Pd(OAc)2 8 37 : 63 PhI(OAc)[O] 2 Pd(OAc)[Pd]2 Yield8 41α : : 59β PhI(OAc)2 Pd(OAc)2/pyr (1:0.9) 59 29 : 71 MesI(OAc)2 Pd(OAc)2 8 37 : 63 PhI(OAc)2 Pd(OAc)2 8 41 : 59 MesI(OAc)PhI(OAc) 2 Pd(OAc)2/pyr/pyr (1:0.9)(1:0.9) 6459 1129 :: 8971 MesI(OAc)2 2 Pd(OAc)2 2 8 37 : 63 MesI(OAc)PhI(OAc)22 Pd(OAc)Pd(OAc)22/pyr/pyr (1:0.9)(1:0.9) 6459 1129 : : 89 71 Scheme 8. Non-directed arene C–H acetoxylation. Effect of both catalyst and hypervalent iodine MesI(OAc)2 Pd(OAc)2/pyr (1:0.9) 64 11 : 89 oxidant on reactivity. SchemeScheme 8. 8.Non-directed Non-directedarene arene C–HC–H acetoxylation.acetoxylation. Effect Effect of of both both catalyst catalyst and and hypervalent hypervalent iodine iodine oxidantoxidantScheme on on reactivity.8. reactivity.Non-directed arene C–H acetoxylation. Effect of both catalyst and hypervalent iodine Chen reported C(sp3)–H and C(sp2)–H alkoxylation using a picolinamide directing group oxidant on reactivity. (Scheme 9) [23]. The reaction3 is proposed to2 proceed via displacement of acetate ligands by alkoxides Chen reported C(sp3 )–H and C(sp2)–H alkoxylation using a picolinamide directing group at aChen Pd(IV) reported intermediate C(sp (8)–H). The and authors C(sp rule)–H out alkoxylation an alternative using SN2-displacement a picolinamide of Pd(IV) directing by ROH group (SchemeChen 9) [23].reported The reactionC(sp3)–H is proposedand C(sp to2)–H proceed alkoxylation via displacement using a ofpicolinamide acetate ligands directing by alkoxides group (Schemesince t9-BuOH)[ 23]. also The participates reaction is proposedto give C–OR to proceed bond formation. via displacement This reactivity of acetate is divergent ligands byfrom alkoxides their at(Scheme a Pd(IV) 9) intermediate[23]. The reaction (8). The is proposed authors ruleto proceed out an alternativevia displacement SN2-displacement of acetate ligands of Pd(IV) by alkoxides by ROH atprevious a Pd(IV) intermediatereports on C–H (8 ).aminatio The authorsn using rule this out same an alternativesystem, where SN2-displacement 8 would undergo of selective Pd(IV) by C–N ROH sinceat a Pd(IV) t-BuOH intermediate also participates (8). The to authorsgive C–OR rule bond out an formation. alternative This SN2-displacement reactivity is divergent of Pd(IV) from by ROHtheir since t-BuOH also participates to give C–OR bond formation. This reactivity is divergent from their reductiveprevioussince t-BuOH reportselimination also on participates C–H in the aminatio absence to given of using an C–OR external this bond same nucleophile formation. system, where(for This discussion reactivity8 would of undergois C–N divergent bond selective formation,from C–Ntheir previousseereductiveprevious Section reports reportselimination 2.2.4.2, on on Scheme C–H C–H in the amination aminatio27b). absence It wasn of using using anfound external thisthis that samesame thenucleophile use system,system, of other where(for oxidants discussion 88 wouldwould including of undergo undergoC–N bondAgOAc, selective selective formation, Oxone, C–N C–N + reductiveCe(SOseereductive Section4) elimination2, K elimination 22.2.4.2,S2O8, “F Scheme in” insources, the the absence27b). absence as It well was of of an asfoundan hypervalent externalexternal that the nucleophile useiodine of other oxidants (for (for oxidants discussion discussion with includingother of of C–N carboxylate C–N AgOAc,bond bond formation, formation, ligandsOxone, 2 all gave inferior conversions.+ In C(sp )–H alkoxylation, either mono- or bisalkoxylation could be seeCe(SOsee Section Section4)2, 2.2.4.2K 22.2.4.2,S2O8,, Scheme“F Scheme” sources, 27b). 27b). as It It well was was foundasfound hypervalent thatthat the useiodine use of of other otheroxidants oxidants oxidants with includingother including carboxylate AgOAc, AgOAc, ligands Oxone, Oxone, achieved by altering+ the equivalents of2 PhI(OAc)2. Ce(SOallCe(SO gave4)24,K) 2,inferior 2KS22SO2O8,8 , “F conversions.“F+” sources, Inas wellC(sp as as)–H hypervalent hypervalent alkoxylation, iodine iodine either oxidants oxidants mono- with withor bisalkoxylationother other carboxylate carboxylate could ligands ligands be 2 allachievedall gave gave inferior inferiorby altering conversions. conversions. the equivalents In In C(sp C(sp of 2)–HPhI(OAc))–H alkoxylation,alkoxylation,2. either either mono- mono- or or bisalkoxylation bisalkoxylation could could be be C(sp3)–H alkoxylation achievedachieved by by altering altering the th equivalentse equivalents of of PhI(OAc) PhI(OAc)22.. C(sp3)–H alkoxylation OAc OR N 3 Pd(OAc) , N O O C(sp )–H alkoxylation 2 N N OAc OR C–OR RE N PhI(OAc)2 PdIV ROH PdIV H HN O Pd(OAc) , N O O 2 RO HN O NN NN ROH/xylenes (1:4) OAc OR C–OR RE N PhI(OAc)2 N OAcIV O ROH ORIV O R2 Pd(OAc) , 2 Pd Pd H HN O 2 RO HN R O N N 8 N N C–OR RE R1 ROHPhI(OAc)/xylenes (1:4)2 R1 OAcPdIV ROH ORPdIV H HN R2 O RO HN 2 O R 8 N N R1 ROH/xylenes (1:4) R1 OAc OR C(sp2)–H alkoxylationR2 2 R 8 R1 R1 C(sp2)–H alkoxylationO Pd(OAc)2, O OMe O PhI(OAc)2 2 C(sp )–H alkoxylationN O Pd(OAc)2, N O or OMe N O R H R H R H N MeOHPhI(OAc)/xylenes2 (1:4) N N N O Pd(OAc)2, OMeN O or OMeOMeN O R H R H R H N MeOHPhI(OAc)/xylenes2 (1:4) N N N PhI(OAc)OMe2N (1.5 equiv.) or PhI(OAc)OMe2 N(2.5 equiv.) R H R H R H N MeOH/xylenes (1:4) N N Scheme 9. C(sp3)–H alkoxylation using picolinamidePhI(OAc)OMe2 (1.5 directing equiv.) group PhI(OAc)via ligandOMe2 (2.5 exchange equiv.) at Pd(IV). PhI(OAc) (1.5 equiv.) PhI(OAc) (2.5 equiv.) Scheme 9. C(sp3)–H alkoxylation using picolinamide2 directing group via ligand2 exchange at Pd(IV).

A similar transformation3 has also been reported by Rao using an 8-aminoquinoline directing group SchemeScheme 9. C(sp9. C(sp3)–H)–H alkoxylation alkoxylation using using picolinamidepicolinamide directing group group via via ligand ligand exchange exchange at atPd(IV). Pd(IV). and theA similar unique transformation choice of λ5-iodane has also Dess-Martin been reported Periodinane by Rao using (DMP, an 9 8-aminoquinoline) as the oxidant (Scheme directing 10) group [24].

and theA similarunique transformation choice of λ5-iodane has also Dess-Martin been reported Periodinane by Rao using(DMP, an 9 )8-aminoquinoline as the oxidant (Scheme directing 10) group [24]. and the unique choice of λ5-iodane Dess-Martin Periodinane (DMP, 9) as the oxidant (Scheme 10) [24].

Molecules 2017, 22, 780 8 of 54

A similar transformation has also been reported by Rao using an 8-aminoquinoline directing group Molecules 2017, 22, 780 8 of 54 Moleculesand the 2017 unique, 22, 780 choice of λ5-iodane Dess-Martin Periodinane (DMP, 9) as the oxidant (Scheme 108)[ of24 54].

OtherOther oxidants including PhI(OAc) PhI(OAc)22, ,PhI(OTFA) PhI(OTFA)2,2 K,K2S22SO28O, NaIO8, NaIO4, NaIO4, NaIO3, and3, andSelectfluor Selectﬂuor all gave all gave little Other oxidants including PhI(OAc)2, PhI(OTFA)2, K2S2O8, NaIO4, NaIO3, and Selectfluor all gave little little or no conversion to desired products and competing functionalization of the 8-aminoquinoline oror nono conversionconversion toto desireddesired productsproducts andand compcompetingeting functionalizationfunctionalization ofof thethe 8-aminoquinoline8-aminoquinoline directingdirecting groupgroup waswas alsoalso observed.observed. TheThe authorsauthors proposepropose thatthat DMPDMP isis notnot thethe terminalterminal oxidantoxidant butbut directing group3 was also observed. The authors propose that DMP is not the terminal oxidant but rather cyclic λ 3-iodane 10, formed in situ by attack of the alcohol on DMP, which then transfers the ratherrather cycliccyclic λλ3-iodane-iodane 1010,, formedformed inin situsitu byby attackattack ofof thethe alcoholalcohol onon DMP,DMP, whichwhich thenthen transferstransfers thethe alkoxide to the palladium center upon oxidation. However, a similar ligand displacement at a Pd(IV) alkoxidealkoxide toto thethe palladiumpalladium centercenter uponupon oxidation.oxidation. However,However, aa similarsimilar ligandligand displacementdisplacement atat aa Pd(IV)Pd(IV) intermediate, analogous to Chen’s report, cannot be ruled out. intermediate,intermediate, analogousanalogous toto Chen’sChen’s report,report, cannotcannot bebe ruledruled out.out.

OAc O O AcO OAcOAc OR O O AcO I OAc OR 2 Pd(OAc)2 2 I ROH I R2 Pd(OAc) R2 O I R N 2 R N O ROH O NH DMP/ROH, 100 °C NH O H N DMP/ROH, 100 °C H N 1 N 1 N O R1 H R1 OR DMP (9) O 10 O R H R OR DMP (9) 10 O

Scheme 10. C(sp33)–H alkoxylation of methylene positions using an 8-aminoquinoline directing group Scheme 10. C(sp3)–H)–H alkoxylation alkoxylation of of methylene methylene positions positions us usinging an an 8-aminoquinoline 8-aminoquinoline directing directing group group and DMP as an oxidant. and DMP as an oxidant.

2.2.2.2.2.2.2.2. AlkeneAlkene Difunctionalization,Difunctionalization, AllylicAllylic OxidationOxidation TheThe difunctionalization difunctionalization difunctionalization of of alkenes ofalkenes alkenes is is also also is possible possible also possible employing employing employing Pd(II) Pd(II)/Pd(IV)/Pd(IV) Pd(II)/Pd(IV) catalysis catalysis and and catalysis hypervalent hypervalent and iodinehypervalentiodine reagents.reagents. iodine ThroughThrough reagents. thethe traditional Throughtraditional the Pd(0)/Pd(0)/ traditionalPd(II)Pd(II) catalysis,catalysis, Pd(0)/Pd(II) thethe Pd(II)Pd(II) catalysis, intermediateintermediate the Pd(II) ((1111 intermediate)) thatthat arisesarises (fromfrom11) that initialinitial arises heteropalladationheteropalladation from initial heteropalladation undergoesundergoes rapidrapid undergoes ββ-hydride-hydride rapid eliminationeliminationβ-hydride eliminationtoto regenerateregenerate to regenerateanan alkenealkene (Schemean(Scheme alkene 11).11). (Scheme ByBy introducingintroducing 11). By introducing anan appropriateappropriate an appropriate oxidant,oxidant, 11 oxidant,11 cancan insteadinstead11 can bebe instead oxidizedoxidized be oxidized toto aa Pd(IV)Pd(IV) to a speciesspecies Pd(IV) (species(1212),), whichwhich (12), isis which setset upup is forfor set subsequentsubsequent up for subsequent reductivereductive reductive elimination.elimination. elimination.

β-hydride X β-hydride X alkene products alkene products X R X R [PdII] R [PdII] R 1 11 X1 11 [O] X X C–X RE X difunctionalized [O] X C–X RE X difunctionalized [PdIV] X1 products R [PdIV] R X1 products R R 12 X1 12 X1 Scheme 11. Alkene difunctionalization enabled via Pd(II)/Pd(IV) catalysis. Scheme 11.11. Alkene difunctionalization enabledenabled viavia Pd(II)/Pd(IV)Pd(II)/Pd(IV) catalysis. catalysis.

ThereThere havehave beenbeen severalseveral reportsreports onon 1,2-aminoox1,2-aminooxygenationygenation ofof alkenesalkenes viviaa thisthis approachapproach thatthat There have been several reports on 1,2-aminooxygenation of alkenes via this approach that utilize utilizeutilize phthalimidephthalimide asas thethe nitrogennitrogen source.source. StahStahll reportedreported thethe useuse ofof allylicallylic ethersethers inin thethe phthalimide as the nitrogen source. Stahl reported the use of allylic ethers in the diastereoselective diastereoselectivediastereoselective aminoalkoxylationaminoalkoxylation ofof terminalterminal alkenesalkenes (Scheme(Scheme 12a)12a) [25].[25]. MechanisticMechanistic studiesstudies aminoalkoxylation of terminal alkenes (Scheme 12a) [25]. Mechanistic studies revealed that an revealedrevealed that that an an initial initial cis cis aminopalladation aminopalladation step step and and oxidation oxidation gave gave Pd(IV) Pd(IV) intermediate intermediate 13 13,, followed followed initialby C–Ocis bondaminopalladation formation via stepan intermolecular and oxidation SN gave2-displacement Pd(IV) intermediate by acetate.13 Using, followed a similar by C–O approach, bond by C–O bond formation via an intermolecular SN2-displacement by acetate. Using a similar approach, formation via an intermolecular S 2-displacement by acetate. Using a similar approach, Sanford SanfordSanford employedemployed homoallylichomoallylic Nalcoholsalcohols inin thethe diastereoselectivediastereoselective formformationation ofof substitutedsubstituted employed homoallylic alcohols in the diastereoselective formation of substituted tetrahydrofuran rings tetrahydrofurantetrahydrofuran ringsrings (Scheme(Scheme 12b)12b) [26].[26]. ConsisConsistenttent withwith Stahl’sStahl’s findings,findings, SanfordSanford reportsreports aa ciscis (Scheme 12b) [26]. Consistent with Stahl’s ﬁndings, Sanford reports a cis aminopalladation/oxidation aminopalladation/oxidationaminopalladation/oxidation sequencesequence however,however, inin ththisis case,case, thethe presencepresence ofof thethe homoallylichomoallylic alcoholalcohol sequence however, in this case, the presence of the homoallylic alcohol results in intramolecular resultsresults inin intramolecularintramolecular coorcoordinationdination toto givegive palladacyclepalladacycle 1414.. ThisThis leadsleads toto preferentialpreferential directdirect C–OC–O coordinationbond forming to reductive give palladacycle elimination14 .rather This leadsthan intermolecular to preferential S directN2 attack C–O on bond 14. Consistent forming reductive with the bond forming reductive elimination rather than intermolecular SN2 attack on 14. Consistent with the elimination rather than intermolecular S 2 attack on 14. Consistent with the necessary formation of necessarynecessary formationformation ofof thethe six-memberedsix-memberedN palladacycle,palladacycle, additionaladditional substitutionsubstitution onon thethe alcoholalcohol the six-membered palladacycle, additional substitution on the alcohol backbone results in signiﬁcantly backbonebackbone resultsresults inin significantlysignificantly higherhigher yields.yields. higher yields.

Molecules 2017, 22, 780 9 of 54 Molecules 2017, 22, 780 9 of 54

a. Stahl (2006)

PdCl2(CH3CN)2, NPhth NPhth Molecules 2017, 22, 780 9 of 54 RO phthalimide RO OAc RO [PdIV] SN2

1 PhI(OAc) 1 a.R Stahl (2006) 2 R1 R –OAc

PdCl2(CH3CN)2, NPhth NPhth13 IV S 2 RO phthalimide RO OAc viaRO cis-aminopalladation/[Pd ] N b. Sanford (2007)1 PhI(OAc) 1oxidation R 2 R1 R –OAc Pd(OAc)2, 13 AgBF4, via cis-aminopalladation/O phthalimide O b. Sanford (2007) IV C–O OH AcO oxidationPd Pd(OAc) , NPhth PhI(OAc)22 AcO reductive R AgBF , R 4 R NPhth O elmination phthalimide O 14 R= Ar, 54-80% AcO PdIV C–O OH NPhth alkyl,PhI(OAc) H <30% R 2 AcO reductive R NPhth R 14 elmination SchemeScheme 12. 12. TwoTwo approaches approaches to toR =alkene alkene Ar, 54-80% aminooxygenation aminooxygenation vi viaa Pd(II)/Pd(IV). Changes Changes in in substrate substrate lead lead alkyl, H <30% toto a a divergence divergence in in mechanism mechanism for for C–O C–O bond formation. Scheme 12. Two approaches to alkene aminooxygenation via Pd(II)/Pd(IV). Changes in substrate lead to a divergence in mechanism for C–O bond formation. Dong reported the dioxygenation of alkenes with [Pd(dppp)(H2O)2](OTf)2 and PhI(OAc)2, an Dong reported the dioxygenation of alkenes with [Pd(dppp)(H2O)2](OTf)2 and PhI(OAc)2, an attractive alternative to the use of toxic osmium-based reagents (Scheme 13) [27]. Based on labeling attractiveDong alternative reported to the the dioxygenatio use of toxicn osmium-based of alkenes with reagents[Pd(dppp)(H (Scheme2O)2](OTf) 13)[2 27and]. BasedPhI(OAc) on2, labelingan studies and the observed cis diastereoselectivity, they propose a mechanism involving a Pd(II)/Pd(IV) studiesattractive and the alternative observed tocis thediastereoselectivity, use of toxic osmium-b theyased propose reagents a (Scheme mechanism 13) [27]. involving Based on a Pd(II)/Pd(IV) labeling cycle and an SN2-type displacement of a Pd(IV) intermediate. Alkene coordination gives Pd(II) species cyclestudies and an and S Nthe2-type observed displacement cis diastereoselectivity, of a Pd(IV) they intermediate. propose a mechanism Alkene involving coordination a Pd(II)/Pd(IV) gives Pd(II) 15 andcycle promotes and an S intermolecularN2-type displacement attack of aby Pd(IV) AcOH intermediate to give 16. Alkene, which coordination is oxidized gives by PhI(OAc) Pd(II) species2 to give species 15 and promotes intermolecular attack by AcOH to give 16, which is oxidized by PhI(OAc)2 to Pd(IV)15 andspecies promotes 17. 17 intermolecular then undergoes attack byintramolecular AcOH to give 16SN, 2-diplacementwhich is oxidized by by acetate PhI(OAc) giving2 to give cyclic give Pd(IV) species 17. 17 then undergoes intramolecular SN2-diplacement by acetate giving cyclic oxoniumPd(IV) 18 speciesfollowed 17 . by17 openingthen undergoes with H intramolecular2O and acylation. SN2-diplacement This method by couldacetate also giving be appliedcyclic in oxonium 18 followed by opening with H2O and acylation. This method could also be applied in substratesoxonium possessing 18 followed tethered by opening alcohol with and H carboxy2O and acylation.lic acid nucleophiles This method tocould give also tetrahydrofuran be applied in and substrates possessing tethered alcohol and carboxylic acid nucleophiles to give tetrahydrofuran and lactonesubstrates products. possessing tethered alcohol and carboxylic acid nucleophiles to give tetrahydrofuran and lactonelactone products. products.

[Pd(dppp)(H2O)2](OTf)2 OAc R1 [Pd(dppp)(H2O)2](OTf)2 OAc R1 PhI(OAc)2, AcOH/H2O; R1 PhI(OAc)2, AcOH/H2O; R2 R1 R then Ac O R2 2 R 2 OAc 2 then Ac2O OAc

[Pd(dppp)(H[Pd(dppp)(H O)2O)](OTf)2](OTf)2 R R 2 2 2 1R R2 2 OAc OAc 1 H2O/AcH2O/Ac2O 2O - H O + H22OO - H2O2 R2 R2 O O OO+ + R1 R1 R2 R2 OAcOAc P OH MeMe P OH2 2 PdIIII R 18 Pd 1 R1 18 P

2+ OAc 2+ OAc P OH2 P OH2 II IV PPd OH2 P Pd OH H P II 2 R Pd R1 P PdIV H 2 R P R1 P R1 2 15 R2 RO R1 H 2 15 17 O HOAc H O 17 O HOAc

PhI

P OH2 PhI PdII H H PP OH PhI(OAc)2 R 2 R1 PdII 2 H H P H 16 PhI(OAc)2 OAc R R1 2 Scheme 13. Diastereoselective catalytic alkene dioxygenationH using16 Pd(II)/Pd(IV) catalysis. Scheme 13. Diastereoselective catalytic alkene dioxygenationOAc using Pd(II)/Pd(IV) catalysis.

SchemeUsing PhI(OBz) 13. Diastereoselective2 and PdCl2(PhCN) catalytic2, Sanford’s alkene di oxygenationgroup was alsousing able Pd(II)/Pd(IV) to perform catalysis. asymmetric Usingalkene PhI(OBz)dioxygenation2 and by PdCl tethering2(PhCN) of a2 chiral, Sanford’s oxime groupdirecting was group also (Scheme able to perform 14) [28]. They asymmetric were able alkene dioxygenationUsingto achieve PhI(OBz) bymoderate tethering2 and to PdClhigh of a 2levels(PhCN) chiral of oxime2 ,diastereos Sanford’s directingelectivity group group onwas (Schemea widealso ablera 14nge)[ toof28 perform].oxime They substrates wereasymmetric able to alkeneachievepossessing dioxygenation moderate different to high by chiral tethering levels elements. of diastereoselectivityof a Achiral control oxim experimente directing on a using wide group both range (Scheme a cis of oximeand 14)transsubstrates [28]. alkene They showed possessingwere able todifferent achievethat chiralboth moderate gave elements. rise to to Ahigh their control levels respective experiment of diastereos syn dioxygenated usingelectivity both a cisproducts, onand a transwide sheddingalkene range showedsome of oxime light that onsubstrates both the gave potential mechanism. While the exact pathway was not elucidated, they propose that an initial possessingrise to their different respective chiralsyn dioxygenatedelements. A control products, experiment shedding using some both light a cis on and the potentialtrans alkene mechanism. showed that both gave rise to their respective syn dioxygenated products, shedding some light on the potential mechanism. While the exact pathway was not elucidated, they propose that an initial

Molecules 2017, 22, 780 10 of 54

WhileMolecules the exact 2017,pathway 22, 780 was not elucidated, they propose that an initial oxypalladation could10 of occur 54 in eitheroxypalladation a trans or cis fashioncould occur to give in either19 or a trans20, each or cis of fashion which to can give converge 19 or 20, toeach the ofsyn whichproduct can converge by either an Molecules 2017, 22, 780 10 of 54 SN2-typeto the displacement syn product by or either direct an reductiveSN2-type displacement elimination or respectively. direct reductive elimination respectively.

oxypalladation could occur in either a trans or cis fashion to give 19OBz or 20, each of which can converge O PdCl2(PhCN)2, to the syn product by either an SN2-type displacement or directO reductiveOBz elimination respectively. N PhI(OBz)2 N * *Aux R dr up to 90:10 *Aux R 1 1 OBz PdCl (PhCN) O 2 2, O OBz N PhI(OBz) N * 2 R 1 OBz *Aux R dr up to 90:10 *Aux R 1trans oxypalladation/ IV 1 or [OBz] R2 N Pd OBz oxidation O OBz PhI(OBz)2 R1 OBz SN2-type O OBz O BzO 19 N II II trans oxypalladation/ or [OBz] IV N [Pd] Pd or [OBz] R2 N Pd OBz or L N O oxidation O Direct synOBz R1 R1 PhI(OBz)2 OBz reductive R2 PhI(OBz)2 SN2-type O OBz O BzO IV 19 elimination N N [Pd]II PdII R2or [OBz]N Pd OBz or L N O cis oxypalladation/ oxidation O Direct syn R R1 1 R PhI(OBz) OBz reductive 2 2 20 elimination R or [OBzN Pd] IV cis oxypalladation/ 2 OBz oxidation O Scheme 14. Asymmetric alkene dioxygenation using a chiral oxime directing group. Scheme 14. Asymmetric alkene dioxygenation using a chiral20 oxime directing group. or [OBz] Using a palladium NCN-pincer complex (21) or Pd(OAc)2, Szabo’s group was able to perform Scheme 14. Asymmetric alkene dioxygenation using a chiral oxime directing group. Usingallylic acetoxylation, a palladium benzoxylation, NCN-pincer or complex trifluoroacetoxylation (21) or Pd(OAc) using2, Szabo’sPhI(OAc)2 group, PhI(OBz) was2, ableor to performPhI(OTFA) allylic2 acetoxylation,(Scheme 15) [29,30]. benzoxylation, This offers ora complimentary triﬂuoroacetoxylation approach usingto traditional PhI(OAc) methods2, PhI(OBz) of 2, Using a palladium NCN-pincer complex (21) or Pd(OAc)2, Szabo’s group was able to perform allylic functionalization proceeding via Pd(0)/Pd(II) catalysis. Pd(0)/Pd(II) methods require or PhI(OTFA)allylic acetoxylation,2 (Scheme 15benzoxylation,)[29,30]. This or offers trifluoroacetoxylation a complimentary using approach PhI(OAc) to traditional2, PhI(OBz)2 methods, or stoichiometric benzoquinone as an essential additive to activate the allyl Pd(II) species for of allylicPhI(OTFA) functionalization2 (Scheme 15) proceeding[29,30]. This offers via Pd(0)/Pd(II) a complimentary catalysis. approach Pd(0)/Pd(II) to traditional methods methods requireof nucleophilic attack and the use of a more electrophilic Pd(IV) intermediate obviates the need for this stoichiometricallylic functionalization benzoquinone asproceeding an essential via additivePd(0)/Pd(II) to activate catalysis. the allylPd(0)/Pd(II) Pd(II) species methods for nucleophilicrequire activation. The proposed catalytic cycle is shown in the context of acetoxylation, beginning with attackstoichiometric and the use ofbenzoquinone a more electrophilic as an essential Pd(IV) intermediate additive to obviatesactivate the needallyl forPd(II) this species activation. for The oxidation of Pd(II) to Pd(IV) and subsequent alkene coordination to give complex 22. Pi-allyl proposednucleophilic catalytic attack cycle and is the shown use of in a themore context electrophi of acetoxylation,lic Pd(IV) intermediate beginning obviates with the oxidation need for this of Pd(II) formation gives 23, which can then undergo reductive elimination to give desired product 24. It to Pd(IV)activation. and subsequent The proposed alkene catalytic coordination cycle is shown to give in complexthe context22 of. Pi-allyl acetoxylation, formation beginning gives 23with, which should be noted that White has reported a Wacker oxidation employing a combination of Pd(OAc)2 oxidation of Pd(II) to Pd(IV) and subsequent alkene coordination to give complex 22. Pi-allyl can thenand undergocatalytic PhI(OAc) reductive2, eliminationhowever mechanistic to give desired studiesproduct indicate 24that. It this should does be not noted involve that direct White has formation gives 23, which can then undergo reductive elimination to give desired product 24. It reportedoxidation a Wacker to a Pd(IV) oxidation intermediate employing as no a combinationArI byproducts of were Pd(OAc) observed2 and [31]. catalytic PhI(OAc)2, however should be noted that White has reported a Wacker oxidation employing a combination of Pd(OAc)2 mechanistic studies indicate that this does not involve direct oxidation to a Pd(IV) intermediate as no and catalytic PhI(OAc)2, howeverPd(II) mechanistic catalyst 21 studies indicate that this does not involve direct ArI byproductsoxidation to werea Pd(IV) observed intermediate [31]. asor noPd(OAc) ArI2 byproducts were observed [31]. PhI(OR) R1 R2 2 R1 R2 Pd(II) basecatalyst 21 Me2N Pd NMe2 OR Br OR =or OAc, Pd(OAc) OBz,2 OTFA 21 PhI(OR) R1 R2 2 R1 R2 Me N Pd NMe R base 2 2 OR Br OR = OAc, OBz, OTFA 21 AcO COOMe PhI(OAc)2 [Pd]IIX L 24 2 2 R PhI

AcO COOMe PhI(OAc)2 L [Pd]IIX L 24 2 2

R COOMe X PhIIV AcO [Pd] X2L2 L AcO [Pd]IV LX OAc

R 23COOMe X IV AcO [Pd] X2L2

IV LX OAc COOMe AcOHAcO [Pd] 23 MeOOC R X R COOMe AcOH AcO [Pd]IVXL MeOOC 2 R X 22 OAc R IV Scheme 15. Allylic acetoxylation, benzoxylation,AcO [Pd] or trifluoroacetoxylationXL2 via Pd(II)/Pd(IV) catalysis. 22 OAc

Scheme Scheme 15. Allylic 15. Allylic acetoxylation, acetoxylation, benzoxylation, benzoxylation, oror triﬂuoroacetoxylationtrifluoroacetoxylation via via Pd(II)/Pd(IV) Pd(II)/Pd(IV) catalysis. catalysis.

Molecules 2017, 22, 780 11 of 54 Molecules 2017, 22, 780 11 of 54

2.2.3. Carbon-Halogen, Carbon-Boron Bond Formation 2.2.3.One Carbon-Halogen, of the most interesting Carbon-Boron transformations Bond Formation enabled by high valent palladium catalysis is in carbon-halogenOne of the and most carbon–boron interesting transformations bond formation. enabled In Pd(0)/Pd(II) by high catalysis, valent palladium these groups catalysis represent is in functionalcarbon-halogen handles and carbon–boronthat undergo bondfacile formation. oxidative Inaddition Pd(0)/Pd(II) and catalysis,the reverse these process groups is represent highly disfavored.functional handles Pd(II)/Pd(IV) that undergo manifolds facile offer oxidative the perfect addition compliment, and the reverse allowing process the installation is highly disfavored. of these valuablePd(II)/Pd(IV) atoms manifolds into carbon offer scaffolds the perfect via compliment, C–H functionalization. allowing the installation The application of these of valuable hypervalent atoms iodineinto carbon reagents scaffolds in this via area C–H is functionalization. limited by the relatively The application low stability of hypervalent and high iodine reactivity reagents of inthese this reagentsarea is limited that possess by the relativelyhalogen ligands. low stability PhICl and2 is highthe most reactivity common of these reagent reagents of this that type possess and has halogen seen theligands. most PhICl use,2 moreis the mostoften common in high reagentvalent ofcomplex this type isolation, and has seenwhereas the most N-halosuccinimides use, more often in have high dominatedvalent complex synthetic isolation, transformations whereas N-halosuccinimides [2]. have dominated synthetic transformations [2].

2.2.3.1. Carbon-Halogen Bond Formation In her 2004 report, Sanford shows that the use of N-chloro or N-bromosuccinimide-bromosuccinimide (NCS, (NCS, NBS) NBS) for the chlorination chlorination or bromination bromination of benzoquinoline benzoquinoline give rise rise to to the the directed directed halogenation halogenation products products in goodgood yieldyield (25(25, ,26 26,, Scheme Scheme 16 16))[12 [12].]. In In contrast, contrast, the the use use ofPhICl of PhICl2 gave2 gave C5-chlorinated C5-chlorinated products products both bothin the in presence the presence and absence and absence of palladium, of palladium, indicating indicating a direct electrophilic a direct electrophilic chlorination chlorination mechanism mechanismas opposed as to opposed a C–H activation to a C–H pathway.activation Thispathway. highlights This highlights the disadvantages the disadvantages of using suchof using a highly such areactive highly hypervalentreactive hypervalent iodine reagent iodine forreagent arene for halogenation. arene halogenation.

Pd(OAc)2, NXS via Pd(II)/Pd(IV) ° C–H Activation/Oxidation MeCN, 100 C N X = Br, Cl X 25

N Cl w/ or w/o Pd(OAc)2 via Electrophilic Chlorination PhICl2 N 26

Scheme 16. NN-halosuccinimide-halosuccinimide oxidants oxidants give give rise rise to directed directed C–H halogenation whereas PhICl2 gives product of direct electrophilic chlorination.

There have been several reports of C–I bond formation using the Suarez-type iodine reagent IOAc, There have been several reports of C–I bond formation using the Suarez-type iodine reagent often generated via reaction of PhI(OAc)2 and I2 in situ. Yu initially demonstrated this approach in the IOAc, often generated via reaction of PhI(OAc)2 and I2 in situ. Yu initially demonstrated this directed iodination of unactivated primary C(sp3)–H bonds using an oxazoline directing group (Scheme approach in the directed iodination of unactivated primary C(sp3)–H bonds using an oxazoline 17a) [32,33]. The use of a chiral oxazoline gave good to excellent levels of diastereoselectivity (91:9 to directing group (Scheme 17a) [32,33]. The use of a chiral oxazoline gave good to excellent levels 99:1) in prochiral substrates. A subsequent report from Yu showed the directed α-iodination of benzoic of diastereoselectivity (91:9 to 99:1) in prochiral substrates. A subsequent report from Yu showed acids under similar conditions giving rise to predominantly diiodinated products (Scheme 17b) [34]. It the directed α-iodination of benzoic acids under similar conditions giving rise to predominantly was found that DMF was essential for high conversion and the use of tetrabutylammonium iodide as diiodinated products (Scheme 17b) [34]. It was found that DMF was essential for high conversion an additive could help control mono- vs. bisiodination products. While the mechanism of Pd(II) and the use of tetrabutylammonium iodide as an additive could help control mono- vs. bisiodination oxidation with IOAc has not been fully elucidated, KIE indicate that C–H bond cleavage is proceeding products. While the mechanism of Pd(II) oxidation with IOAc has not been fully elucidated, KIE via an electrophilic mechanism in these cases and thus a Pd(II)/Pd(IV) catalytic cycle is proposed. indicate that C–H bond cleavage is proceeding via an electrophilic mechanism in these cases and thus Kraft demonstrated the use of a Pd(II)-NHC complex for stoichiometric dichlorination of linear a Pd(II)/Pd(IV) catalytic cycle is proposed. alkenes and monochlorination of benzylic C–H bonds (Scheme 18) [35]. PhICl2 oxidizes Pd(II) species Kraft demonstrated the use of a Pd(II)-NHC complex for stoichiometric dichlorination of linear 27 to Pd(IV) (28), and subsequent loss of chloride generates a cationic, pentacoordinated Pd(IV) alkenes and monochlorination of benzylic C–H bonds (Scheme 18)[35]. PhICl2 oxidizes Pd(II) species species that is active for C–H chlorination. 27 to Pd(IV) (28), and subsequent loss of chloride generates a cationic, pentacoordinated Pd(IV) species that is active for C–H chlorination.

Molecules 2017, 22, 780 12 of 54 Molecules 2017, 22, 780 12 of 54 Molecules 2017, 22, 780 12 of 54 a. Yu (2005) a. Yu (2005)

I Me Pd(OAc)2, I R Me Pd(OAc)2, R R N PhI(OAc)2/I2 R N R N PhI(OAc)2/I2 R N R tBu R tBu O tBu O tBu O O PhI(OAc)2/I2 IOAc b. Yu (2008) PhI(OAc)2/I2 IOAc b. Yu (2008) I Pd(OAc)2, I Pd(OAc)2, Me CO2H PhI(OAc)2/I2 Me CO2H Me CO2H Me CO2H PhI(OAc)2/I2 Me CO2H Me CO2H DMF, additive + DMF, additive I + I I I major w/ NBu I major w/o NBu4I major w/ NBu4I major w/o NBu4I (15:1 mono:bis)4 (15:1 mono:bis) Scheme 17. Directed iodination of (a) C(sp3)–H and (b) C(sp2)–H bonds using in situ generated IOAc. SchemeScheme 17. 17. DirectedDirected iodination of (a) C(sp3)–H)–H and ( b) C(sp 2)–H)–H bonds bonds using in situ generated IOAc.IOAc.

Cl Cl Cl Cl N N N N N N Cl N N N N PhICl2 N Cl N PhICl N IV N N II N 2 N IV N Pd N Pd N N Pd N N IV N R II R IV R Pd R Cl Pd R Pd R R C4H9 R Cl Cl R R Cl Cl R Cl R C H Cl Cl Cl Cl Cl Cl Cl 4 9 Cl 27 Cl 28 Cl Cl C H 27 Cl 28 4 9 C4H9 Scheme 18. Stoichiometric chlorination of linear alkenes or benzylic positions with a cationic Pd(IV) Scheme 18. Stoichiometric chlorination of linear alkenes or benzylic po positionssitions with a cationic Pd(IV) generated upon oxidation with PhICl2. generated upon oxidation with PhICl2. generated upon oxidation with PhICl2. Direct C–H fluorination is challenging for transition metal catalysis due to the low reactivity of Direct C–H fluorination is challenging for transition metal catalysis due to the low reactivity of metal-fluorineDirect C–H bonds fluorination towards is challengingreductive elimination. for transition Several metal attempts catalysis duehave to been the low made reactivity using metal-fluorine bonds towards reductive elimination. Several attempts have been made using ofPd(II)/Pd(IV) metal-fluorine catalysi bondss, however towards the reductive use of hypervalent elimination. iodine Several oxidants attempts has been have met been with made challenges. using Pd(II)/Pd(IV) catalysis, however the use of hypervalent iodine oxidants has been met with challenges. Pd(II)/Pd(IV)This is due to catalysis, the high however reactivity the of use the of hypervalentmost common iodine λ3-iodane oxidants X-ligands, has been metnamely with acetates challenges. or This is due to the high reactivity of the most common λ3-iodane X-ligands, namely acetates or Thishalogens, is due to undergo to the high competitive reactivity reductive of the most elimination. common Inλ this3-iodane area, Ritter X-ligands, has been namely successful acetates in the or halogens, to undergo competitive reductive elimination. In this area, Ritter has been successful in the halogens,radiofluorination to undergo of C(sp competitive2)–H bonds reductive using stoichiometric elimination. Pd(II) In this complexes area, Ritter as fluorinating has been successful agents and in radiofluorination of C(sp2)–H bonds using stoichiometric Pd(II) complexes as fluorinating agents and thea (poly)cationic radiofluorination λ3-iodane of C(sp (292))–H as the bonds oxidant using (Scheme stoichiometric 19) [36]. These Pd(II) (poly)cationic complexes as fluorinatingλ3-iodane reagents agents a (poly)cationic λ3-iodane (29) as the oxidant (Scheme 19) [36]. These (poly)cationic λ3-iodane reagents andare relatively a (poly)cationic underutilizedλ3-iodane in the (29 synthetic) as the oxidant literature, (Scheme however 19 )[Dutton36]. These has also (poly)cationic used these complexesλ3-iodane are relatively underutilized in the synthetic literature, however Dutton has also used these complexes reagentsto study arehigh relatively valent palladium underutilized and platinum in the synthetic comple literature,xes and this however work Duttonis discussed has also in Section used these 2.1. to study high valent palladium and platinum complexes and this work is discussed in Section 2.1. complexesRitter’s report to studyis an extension high valent of his palladium prior work and which platinum utilized complexes the “F+” and source this Selectfluor work is discussed in the two in Ritter’s report is an extension of his prior work which utilized the “F+” source Selectfluor in the two Sectionstep fluorination 2.1. Ritter’s of report arylboronic is an extension acids with of his a prior similar work complex, which utilized however the “Fthe+” use source of Selectfluorelectrophilic in step fluorination of arylboronic acids with a similar complex, however the use of electrophilic thefluorinating two step fluorinationagents are not of arylboronic readily translatable acids with to a similarradiolabeling complex, applications however the [37]. use They of electrophilic therefore fluorinating agents are not readily translatable to radiolabeling applications [37]. They therefore fluorinatingdesigned a system agents employing are not readily a highly translatable electrophilic to radiolabelingPd(IV) complex applications (30), could [then37]. undergo They therefore ligand designed a system employing a highly electrophilic Pd(IV) complex (30), could then undergo ligand designedexchange awith system a source employing of nucleophilic a highly electrophilic18F−. Pd(IV) complex Pd(IV) complex30 was accessed (30), could via thenoxidation undergo of 31 ligand with exchange with a source of nucleophilic 18F−. Pd(IV) complex 30 was accessed via oxidation of 31 with exchange(poly)cationic with λ a3-iodane source of29; nucleophilic the key feature18F− of. Pd(IV)this oxidant complex is th30e wasdonation accessed of a vialabile oxidation heterocyclic of 31 (poly)cationic λ3-iodane 29; the key feature of this oxidant is the donation of a labile heterocyclic withligand (poly)cationic which can undergoλ3-iodane facile29; theligand key ex featurechange, of thisfirst oxidantwith 4-picoline is the donation to give of32 a, and labile subsequently heterocyclic ligand which can undergo facile ligand exchange, first with 4-picoline to give 32, and subsequently ligandwith fluoride which canupon undergo exposure facile to a ligand nucleophilic exchange, 18F-source first with in 4-picolinethe reaction to giveconditions.32, and This subsequently complex with fluoride upon exposure to a nucleophilic 18F-source in the reaction conditions. This complex withthen serves fluoride as upon a highly exposure electrophilic to a nucleophilic source of 1818FF-source for a second in the Pd(II) reaction species conditions. (33) which This then complex undergoes then then serves as a highly electrophilic source of 18F for a second Pd(II) species (33) which then undergoes servesC–F bond as a reductive highly electrophilic elimination source to give of 18desiredF for a produc secondt. Pd(II) In a later species report (33) whichthey also then report undergoes the use C–F of C–F bond reductive elimination to give desired product. In a later report they also report the use of bondan analogous reductive nickel-mediated elimination to process give desired under product. similar conditions In a later report(see Section they also5.2). report the use of an an analogous nickel-mediated process under similar conditions (see Section 5.2). analogous nickel-mediated process under similar conditions (see Section 5.2).

Molecules 2017, 22, 780 13 of 54 Molecules 2017, 22, 780 13 of 54

Molecules 2017, 22, 780 2OTf 13 of 54

NC CN N N 2OTf Me N I 2OTf 2OTf N N NC CN Me N I N 2OTf N 29 2OTf N N N N N IV IV Pd N Pd N N N PdII N N 29 N N N N IV N IV 30 NPd 32 31 N Pd N N N PdII N N N N 32 31 N N 30 CN Me N N N B N = N Me N N N N CN N N N F BN N O = N Ar N N N N S N F N O O N Ar N PdIISPy Ar OTf N 2OTf O O 33 N S II Reductive O N Pd RPy Ar OTf 2OTf F Elimination ON Py N N S PdIV 33 IV N O R Pd N Reductive S 2-type N N Py N F Elimination N F IV N Pd fluoride transfer FPdIV N N N N SN2-type F fluoride transfer18 3 SchemeScheme 19. 19.Ritter’s Ritter’s approachapproach toto radioﬂuorinationradiofluorination using nucleophilic 18FF and and a a (poly)cationic (poly)cationicF λλ-iodane.3-iodane.

18 3 SchemeIn catalytic 19. Ritter’s Pd(II)/Pd(IV) approach toapproaches radiofluorination to C–H using fluorination, nucleophilic electrophilicF and a (poly)cationic N-fluoropyridinium λ -iodane. reagentsIn catalytic (35, 36 Pd(II)/Pd(IV)) have been much approaches more successful to C–H than fluorination, the analogous electrophilic hypervalentN-fluoropyridinium iodine reagent In catalytic Pd(II)/Pd(IV) approaches to C–H fluorination, electrophilic N-fluoropyridinium reagentsPhIF2 ( (3435),, 36as )both have the been oxidant much and more fluoride successful source than (Scheme the analogous 20a) [38,39]. hypervalent Sanford iodine has attempted reagent PhIF to 2 reagents (35, 36) have been much more successful than the analogous hypervalent iodine reagent (34utilize), as both a nucleophilic the oxidant fluoride and fluoride source source in combin (Schemeation 20witha) [ 38a ,hypervalent39]. Sanford iodine has attempted oxidant achieve to utilize PhIF2 (34), as both the oxidant and fluoride source (Scheme 20a) [38,39]. Sanford has attempted to a nucleophiliccatalytic benzylic fluoride fluorination source in (Scheme combination 20b) [40]. with This a hypervalent is a much iodinemore economical oxidant achieve approach catalytic as utilize a nucleophilic fluoride source in combination with a hypervalent iodine oxidant achieve benzylicnucleophilic fluorination fluoride (Scheme sources are20b) considerably [40]. This is less a much expensive more than economical electrophilic approach reagents as nucleophilic(e.g., 36— catalytic benzylic fluorination (Scheme 20b) [40]. This is a much more economical approach as fluoride$88,295/mol sources vs. areKF $3.95/mol). considerably A critical less expensive challenge thanto this electrophilic approach is the reagents relative (e.g., rates36 of—$88,295/mol competitive nucleophilic fluoride sources are considerably less expensive than electrophilic reagents (e.g., 36— vs.C–O KF $3.95/mol).bond forming A reductive critical challenge elimination to this at Pd(IV) approach (39) isrelative the relative to displacement rates of competitive of the carboxylate C–O bond $88,295/mol vs. KF $3.95/mol). A critical challenge to this approach is the relative rates of competitive formingligands reductive by F− to give elimination 40. The use at Pd(IV) of AgF ( 39as )the relative nucleophilic to displacement fluoride source of the proved carboxylate critical ligands as well by as F − C–O bond forming reductive elimination at Pd(IV) (39) relative to displacement of the carboxylate the use of a sterically hindered oxidant PhI(OPiv)2 to suppress C–O bond formation, however this to giveligands40 .by The F− useto give of AgF40. The as theuse nucleophilicof AgF as the fluoridenucleophilic source fluoride proved source critical proved as well critical as theas well use as of a stericallypathway hindered could never oxidant be completely PhI(OPiv) eliminated.to suppress Therefore, C–O bond while formation, the combination however this of pathwayoxidant and could the use of a sterically hindered oxidant2 PhI(OPiv)2 to suppress C–O bond formation, however this nucleophilic fluoride source is certainly attractive, the choice of oxidant remains challenging and neverpathway be completely could never eliminated. be completely Therefore, eliminated. while the Therefore, combination while of the oxidant combination and nucleophilic of oxidant fluoride and continued research in this area is required. sourcenucleophilic is certainly fluoride attractive, source the is choicecertainly of oxidantattractive, remains the choice challenging of oxidant and remains continued challenging research inand this area is required. continueda. C–H fluorination research with in Fthis+ oxidants area is required.

+ a. C–H fluorinationPd(OAc) with F+ 2oxidants, "F " sources Me + "F " source F Pd(OAc) , + BF – BF – C H , μwave2 "F " sourcesI 4 Me 4 N "F6 +"6 source N F F N+ Me N+ Me Me BF – BF – C H , μwave F I 4 4 N 6 6 N 34F F 35F 36 + + Me 3% 15%N Me 75%N Me F 34F 35F 36 3% 15% 75% b. C–H fluorination with oxidant/F– combination

Pd(OAc) , b. C–H fluorination with oxidant/F2 – combination OPiv F PhI(OR)2, AgF C–O L F– L Pd(OAc) , + 38 PdIV PdIV 2° C OPiv C F N MgSO4, 60 C N N RE PhI(OR)2, AgF C–O L F– L Me 37+ 38 38 39PdIV 40PdIV ° C C N MgSO4, 60 C N F N OR RE Me 3762:18 (37:38) 38 39 40 F OR Scheme 20. Complimentary approaches62:18 (37:38) to C–H fluorination with Pd(II)/Pd(IV) catalysis via (a) electrophilic fluorine sources and (b) nucleophilic fluorine sources. SchemeScheme 20. 20.Complimentary Complimentary approachesapproaches toto C–HC–H fluorinationfluorination with with Pd(II)/Pd(IV) Pd(II)/Pd(IV) catalysis catalysis via via (a)( a) electrophilicelectrophilic fluorine fluorine sources sources and and (b (b)) nucleophilic nucleophilic fluorinefluorine sources.sources.

Molecules 2017, 22, 780 14 of 54

Molecules 2017, 22, 780 14 of 54 2.2.3.2. Carbon-Boron Bond Formation 2.2.3.2. Carbon-Boron Bond Formation The selectiveThe selective C–H C–H borylation borylation of alkenesof alkenes under under oxidative oxidative conditions conditions was was reported reported byby SzaboSzabo inin 2010, giving2010, rise giving to valuable rise to valuable alkenyl alkenyl boronates boronates (Scheme (Scheme 21)[ 4121)]. [41]. Using Using an an NCN-pincer NCN-pincer Pd(II) Pd(II) catalystcatalyst (21), PhI(OTFA)(21), PhI(OTFA)2 as an oxidant,2 as an oxidant, and B2pin and2, theB2pin borylation2, the borylation of simple of simple alkenes alkenes could could be accomplished be accomplished in good yield.in It good is noted yield. that It is a noted particular that a advantageparticular advantage of this method of this method is that theis that oxidizing the oxidizing conditions conditions produce TFAO-BPinproduce upon TFAO-BPin transmetallation upon transmet ratherallation than borohydrides,rather than borohydrides, which avoids which competitive avoids competitive hydroboration of thehydroboration resultant alkene of the products. resultant Whilealkene theproducts. authors While could the not authors fully elucidatecould not thefully mechanism elucidate the of this process,mechanism they propose of this that process, initial they oxidation propose of catalystthat initial21 oxidationgenerates of a highlycatalyst electrophilic 21 generates Pd(IV) a highly species electrophilic Pd(IV) species 41 which then undergoes facile transmetallation with B2pin2 to give 42. 41 which then undergoes facile transmetallation with B pin to give 42. Alkene coordination, insertion, Alkene coordination, insertion, and finally elimination 2and decomplexation2 give the desired products and ﬁnallyand regenerate elimination 21. The and method decomplexation is limited giveby the the need desired to use products solvent quantities and regenerate of the 21alkene,. The and method is limitedinternal by alkenes the need react to usevery solvent poorly. quantities of the alkene, and internal alkenes react very poorly.

Pd(II) 21, B2Pin2, H PhI(OTFA)2 R Bpin II R Me2N Pd NMe2 neat 51-86% Br 21

TFAO OTFA I Bpin R + TFA-H II Me2N Pd NMe2 Br PhI 21 TFA

Br IV Br Me2N Pd NMe2 IV Me2N Pd NMe2 R Bpin TFAO OTFA 41 H B2pin2

TFA TFA - Bpin

Br IV Br Me2N Pd NMe2 IV Me2N Pd NMe2 Bpin Bpin OTFA 42 R

Scheme 21. C–H borylation of olefins under oxidative conditions with PhI(OTFA)2. Scheme 21. C–H borylation of oleﬁns under oxidative conditions with PhI(OTFA)2. 2.2.4. Carbon-Nitrogen Bond Formation 2.2.4. Carbon-Nitrogen Bond Formation Carbon–nitrogen (C–N) bond formation is a valuable synthetic transformation as nitrogen atoms Carbon–nitrogenare ubiquitous is bioactive (C–N) bondmolecules. formation Pd(0)/Pd(II) is a valuable catalysis synthetic has served transformation as a valuable approach as nitrogen for the atoms are ubiquitousformation of is bioactiveC(sp2)–N bonds molecules. via the Pd(0)/Pd(II) venerable Buchwald-Hartwig catalysis has served amination as a valuable of aryl approachhalides. for the formationUnfortunately of C(sp wide2 )–Nspread bonds approaches via the to venerable C–N bond Buchwald-Hartwig formation, via either aminationC–H activation, of aryl alkene halides. Unfortunatelyfunctionalization, wide spreador others, approaches remains a challenge to C–N bondin palladium formation, catalysis. via eitherThis is due C–H both activation, to the high alkene activation barrier for C–N bond reductive elimination from Pd(II) species and the fact that many functionalization, or others, remains a challenge in palladium catalysis. This is due both to the high amine substrates will coordinate to palladium, leading to rapid catalyst deactivation. Innovative activation barrier for C–N bond reductive elimination from Pd(II) species and the fact that many amine approaches relying on Pd(II)/Pd(IV) catalysis have emerged to address these challenges and this area substrateshas been will recently coordinate reviewed to palladium, by Muniz [42]. leading Hypervalen to rapidt iodine catalyst reagents deactivation. have played Innovative a key role approaches in this relyingarea, on with Pd(II)/Pd(IV) careful tuning catalysis of oxidant have sterics emerged and toelectronics address theseplaying challenges a role in the and success this area a given has been recentlymethod. reviewed by Muniz [42]. Hypervalent iodine reagents have played a key role in this area, with careful tuning of oxidant sterics and electronics playing a role in the success a given method. Molecules 2017,, 22,, 780780 15 of 54

2.2.4.1. Alkene Diamination 2.2.4.1. Alkene Diamination The Muniz group has been a leader in the development of both intra- and intermolecular approachesThe Muniz to alkene group diamination has been a via leader Pd(II)/Pd(IV) in the development catalysis [42]. of both Their intra- first andreport intermolecular in this area approachesinvolved the to intramolecular alkene diamination diamination via Pd(II)/Pd(IV) of terminal alkenes catalysis with [42]. urea Their derivatives, ﬁrst report a particularly in this area involvedchallenging the transformation intramolecular due diamination to the high of terminalcoordinating alkenes ability with of urea these derivatives, substrates ato particularly palladium challenging(Scheme 22) transformation[43]. Their method due tohad the broad high scope coordinating and gave ability the ofbicyclic these 1,2-diamine substrates to products palladium in (Schemeexcellent 22 yields.)[43]. TheirThey methodnote that had the broad choice scope of oxidant and gave was the critical bicyclic and 1,2-diamine only PhI(OAc) products2 was in excellent able to yields.promote They the notereaction that thewith choice high of efficiency. oxidant was A criticalsubsequent and onlymechanistic PhI(OAc) investigation2 was able to promoteshowed the reaction withproceeds high efﬁciency.via rate Alimiting subsequent aminopalladation, mechanistic investigation followed by showed oxidation the reaction to give proceeds Pd(IV) viaintermediate rate limiting 43, aminopalladation, which then undergoes followed SN by2-type oxidation displacement to give Pd(IV) by th intermediatee second amine43, which [44]. thenThis undergoescatalytic cycle SN 2-typeis supported displacement by stoichiometric by the second studies amine conducted [44]. in This their catalytic group (employing cycle is supported PhI(OAc) by2 stoichiometricas the oxidant), studies which conducted showed inthat their C–N group bond (employing formation PhI(OAc) proceeded2 as thevia oxidant),ligand ionization which showed and thatsubsequent C–N bond SN2-displacement formation proceeded rather viathan ligand a concerted ionization redu andctive subsequent elimination SN from2-displacement Pd(IV) [45]. rather This thangeneral a concerted catalytic cycle reductive is invoked elimination for their from subsequent Pd(IV) [45 applications]. This general in both catalytic intra- cycleand intermolecular is invoked for theiramination subsequent reactions. applications in both intra- and intermolecular amination reactions.

O O Ts Pd(OAc) , HN N 2 PhI(OAc) , CH Cl H 2 2 2 R N N Ts R 78-95% R n R n

O H N O N N Ts N Ts

Pd(OAc)2 SN2 - type cyclization O Ts N N OAc PdIV H OAc N O Amide PdII N Dissociation Ts OAc O Ts N N OAc PdIV Rate-limiting OAc O syn-aminopalladation 43 Ts N N PhI II [Pd ] AcOH Oxidation PhI(OAc)2

Scheme 22. Intramolecular diamination of alkenes via a SN2-type displacement of a Pd(IV) intermediate. Scheme 22. Intramolecular diamination of alkenes via a SN2-type displacement of a Pd(IV) intermediate.

Muniz extended this approach to Boc-protected guanidine substrates, which required a change Muniz extended this approach to Boc-protected guanidine substrates, which required a change in in oxidant from PhI(OAc)2 to stoichiometric CuCl2 (Scheme 23a) [46]. In this case, the use of PhI(OAc)2, oxidant from PhI(OAc)2 to stoichiometric CuCl2 (Scheme 23a) [46]. In this case, the use of PhI(OAc)2, a more powerful oxidant than CuCl2, gives rise to exclusively the aminoacetoxylated product as a a more powerful oxidant than CuCl , gives rise to exclusively the aminoacetoxylated product as a result result of competitive C–O reductive2 elimination (Scheme 23b). Furthermore, reducing the of competitive C–O reductive elimination (Scheme 23b). Furthermore, reducing the nucleophilicity of nucleophilicity of the terminal amine in the presence of CuCl2 led to aminochlorinated products the terminal amine in the presence of CuCl2 led to aminochlorinated products (Scheme 23c). This SN2 (Scheme 23c). This SN2 cyclization mechanism is also analogous to Sanford’s Pd(IV) mediated cyclization mechanism is also analogous to Sanford’s Pd(IV) mediated cyclopropanation and these cyclopropanation and these results clearly indicate that the further development of SN2 based results clearly indicate that the further development of S 2 based methods with Pd(IV) will depend on methods with Pd(IV) will depend on careful tuning ofN both oxidant and nucleophile [47]. A final careful tuning of both oxidant and nucleophile [47]. A ﬁnal report of intramolecular diamination from report of intramolecular diamination from Muniz involved the intramolecular diamination of stilbene Muniz involved the intramolecular diamination of stilbene derivatives to yield bisindoline substrates derivatives to yield bisindoline substrates employing Pd(OAc)2 and PhI(OAc)2 (not shown) [48]. employing Pd(OAc)2 and PhI(OAc)2 (not shown) [48].

Molecules 2017, 22, 780 16 of 54 Molecules 2017, 22, 780 16 of 54

Molecules 2017a. Standard, 22, 780 conditions 16 of 54

NBoc a. Standard conditions NBoc Pd(OAc) , HN NHBoc 2 NBoc CuCl N 2 Ph NBocN Boc Fate of Pd(IV) intermediate sensitive Pd(OAc)2, to choice of substrate and oxidant Ph HN NHBoc K2CO3, DMF Ph CuCl2 Ph N Fate of Pd(IV) intermediate sensitive Ph 99% N Boc NR to choice of substrate and oxidant Ph K2CO3, DMF Ph R N NRN b. UsePh of PhI(OAc)2 99% X IV NBoc PdR b. Use of PhI(OAc) NBoc N N 2 Pd(OAc)2, X X HN NHBoc PdIV NBoc PhI(OAc)2 N Boc SN2-type C–X Ph NBocN X Pd(OAc)2, H Ph HN NHBoc K2CO3, DMF Ph CuCl2 PhI(OAc)2 PhI(OAc)2 N Boc SN2-type C–X Ph 90% Ph N OAcH Ph K2CO3, DMF Ph CuCl2 PhI(OAc)2 c. ReducedPh nucleophilicity of terminal90% amine OAc NR NR

NBoc NBoc N N c. Reduced nucleophilicity of terminalPd(OAc) amine2, NRN R NRNHR HN NH CuCl2 N NBoc 2 Ph NBocNH2 N Pd(OAc)2, N R N NHR K2CO3, DMF Ph X Ph HN NH CuCl2 N 2 85% Ph NH2 Ph Cl K2CO3, DMF Ph X Ph 85% Scheme Ph23. Intramolecular alkene diamination with guanCl idines. Reactivity of Pd(IV) intermediate Scheme 23. Intramolecular alkene diamination with guanidines. Reactivity of Pd(IV) intermediate sensitive to both substrate and oxidant selection. (a) Standard conditions with CuCl2 as oxidant (b) sensitiveScheme to 23. both Intramolecular substrate and alkene oxidant diamination selection. with (a) Standardguanidines. conditions Reactivity with of Pd(IV) CuCl 2intermediateas oxidant (b) Use of PhI(OAc)2 as oxidant (c) Terminal amine with CuCl2. Usesensitive of PhI(OAc) to both2 as substrate oxidant and (c) Terminaloxidant selection. amine with (a) CuClStandard2. conditions with CuCl2 as oxidant (b) Use of PhI(OAc)2 as oxidant (c) Terminal amine with CuCl2. Extending this approach to intermolecular diamination was challenging as C–O bond forming reductiveExtending elimination this approach formation to intermolecular would be more diamination competitive relative was challenging to a slower as intermolecular C–O bond forming SN2 Extending this approach to intermolecular diamination was challenging as C–O bond forming reductiveamine displacement. elimination formation In three reports, would the be Muniz more competitivegroup succeeded relative in addressing to a slower this intermolecular challenge in the SN 2 reductive elimination formation would be more competitive relative to a slower intermolecular SN2 amineintermolecular displacement. diamination In three reports,of terminal the alkenes, Muniz groupallyl ethers, succeeded and finally in addressing internal styrene this challenge derivatives in the amine displacement. In three reports, the Muniz group succeeded in addressing this challenge in the intermolecularwith phthalimide, diamination saccharide of terminal or N-fluoro-bis(phenylsulf alkenes, allyl ethers,onyl)imide and ﬁnally (NFSI) internal as the styrene amine derivatives sources intermolecular diamination of terminal alkenes, allyl ethers, and finally internal styrene derivatives (Scheme 24) [49–51]. In all cases,N PhI(OPiv)2 was employed as the hypervalent iodine oxidant as withwith phthalimide, phthalimide, saccharide saccharide oror N-ﬂuoro-bis(phenylsulfonyl)imide-fluoro-bis(phenylsulfonyl)imide (NFSI) (NFSI) as as the the amine amine sources sources (SchemePhI(OAc) 24)[2 gave49–51 very]. In low all yields cases, with PhI(OPiv) a range wasof palladium employed catalysts. as the hypervalentThe use of the iodine more sterically oxidant as (Scheme 24) [49–51]. In all cases, PhI(OPiv)2 was employed as the hypervalent iodine oxidant as encumbered PhI(OPiv)2 is presumably critical to address the issue of competitive C–O reductive PhI(OAc)PhI(OAc)2 gave2 gave very very low low yields yields withwith aa rangerange of palladium catalysts. catalysts. The The use use of of the the more more sterically sterically elimination as the –OPiv group will undergo this process much slower than the corresponding –OAc, encumberedencumbered PhI(OPiv) PhI(OPiv)2 2 isis presumablypresumably criticalcritical to to address address the the issue issue of of competitive competitive C–O C–O reductive reductive allowing intermolecular SN2 displacement to occur. It is noteworthy than a similar approach from eliminationelimination as as the the –OPiv –OPiv group group will will undergoundergo this process process much much slower slower than than the the corresponding corresponding –OAc, –OAc, Michael utilized NFSI as both the amine source and external oxidant, circumventing competitive C– allowingallowing intermolecular intermolecular S SNN22 displacementdisplacement to occur. occur. It It is is noteworthy noteworthy than than a asimilar similar approach approach from from X reductive elimination [52,53]. MichaelMichael utilized utilized NFSI NFSI as as both both the the amine amine source source and and externalexternal oxidant,oxidant, circumventing competitive competitive C– C–X reductiveXa. reductive Muniz elimination(2010 elimination) [52 ,[52,53].53]. b. Muniz (2011)

a. Muniz (2010) b. Muniz (2011) Pd(NCPh)2Cl2, saccharin, Pd(hfacac) , phthalimide, R2 2 HNTs, PhI(OPiv)2 O2S FN(SO2Ph)2, PhI(OPiv)2 N O O O O R Pd(NCPh)2Cl2, saccharin, Pd(hfacac) , phthalimide, N 35-90% R R2 2 HNTs, PhI(OPiv) O S NTs 40-72% O NHTs 2 2 R O R1 FN(SO2Ph)2, PhI(OPiv)2 O N O R O N 2 R R 1R 35-90% NTs 40-72% O R NHTs R R1 R c. Muniz (2012) R2 R1 2 O (R O2S)2N c. Muniz (2012) Pd(NCPh)2Cl2, phthalimide, 2 (R SO2)2NH, PhI(OPiv)2 2 O N (R O2S)2N R Pd(NCPh)2Cl2, phthalimide, R 1 1 R 2 40-93% R O (R SO2)2NH, PhI(OPiv)2 N R R R1 1 O Scheme 24. Reports from the Muniz group40-93% on intermolecular alkeneR diamination with PhI(OPiv)2 as the oxidant. (a) Diamination of terminal alkenes (b) Diamination of allyl ethers (c) Diamination of Scheme 24. Reports from the Muniz group on intermolecular alkene diamination with PhI(OPiv)2 as Schemestyrene 24. derivatives.Reports from the Muniz group on intermolecular alkene diamination with PhI(OPiv)2 as the oxidant. (a) Diamination of terminal alkenes (b) Diamination of allyl ethers (c) Diamination of the oxidant. (a) Diamination of terminal alkenes (b) Diamination of allyl ethers (c) Diamination of styrene derivatives. 2.2.4.2.styrene C–H derivatives. Amination

2.2.4.2.Sanford C–H Amination reported a study of C(sp2) and C(sp3)–H bond amination using Pd(II) catalysts and 2.2.4.2. C–H Amination PhI=NTs as the oxidant in a stoichiometric context (Scheme 25) [54]. Using various palladacyclic Sanford reported a study of C(sp2) and C(sp3)–H bond amination using Pd(II) catalysts and species 44, 45, generated via directed C–H2 activation,3 they found that C–H insertion happens readily PhI=NTsSanford as reportedthe oxidant a study in a stoichiometric of C(sp ) and context C(sp )–H (Scheme bond 25) amination [54]. Using using various Pd(II) palladacyclic catalysts and PhI=NTs as the oxidant in a stoichiometric context (Scheme 25)[54]. Using various palladacyclic species 44, 45, generated via directed C–H activation, they found that C–H insertion happens readily

Molecules 2017, 22, 780 17 of 54

Molecules 2017, 22, 780 17 of 54 species 44, 45, generated via directed C–H activation, they found that C–H insertion happens readily upon oxidation with PhI=NTs. In both cases, bypr byproductsoducts arising from competitive C–X bond forming reductive elimination were observed in up to 18% yield (compounds 46, 47), and this was highly dependent on reaction conditions. Oxidant electronic electronicss were were found to play a role in the rate of C–H insertion;insertion; alteringaltering thethe substituentssubstituents on on the the benzylsulfonamide benzylsulfonamide PhINSO PhINSO2C2C5H5H44XX (X(X == OMe/NOOMe/NO22) led to prolonged reactionreaction times. times. The The authors authors refrain refrain from from drawing drawing mechanistic mechanistic conclusions conclusions from from this this data data due todue the to highlythe highly varied varied solubility solubility and and hydrolytic hydrolytic instability instability of the of hypervalentthe hypervalent iodine iodine reagents reagents under under the reactionthe reaction conditions. conditions. A general A general mechanism mechanism is shown is shown in Schemein Scheme 25c, 25c, and and the the intermediacy intermediacy of of Pd(IV) Pd(IV) is supportedis supported by the by observation the observation of C–X reductive of C–X elimination reductive products. elimination Direct C–Hproducts. activation/amination Direct C–H couldactivation/amination also be achieved could at sp3 C–Halso bonds,be achieved however at isolatedsp3 C–H yields bonds, upon however protolysis isolated were loweryields relative upon toprotolysis sp2 analogues. were lower It should relative be noted to sp that2 analogues. a catalytic It approach should be to noted C–Hbond that a amination catalytic hasapproach been reported to C–H usingbond amination K2S2O8 as has a stoichiometric been reported oxidant using K [552S].2O8 as a stoichiometric oxidant [55].

a. C(sp2 ) C-N amination

Py PhINTs NTs Protolysis NHTs PdII N N X Pd Py N X N 46 44 (X=Cl/OAc) X observed in b. C(sp3) C-N amination up to 18% yield

Py NTs Py NHTs II PhINTs Protolysis Pd Pd Cl N N N Cl N 45 X 47 c. Proposed general mechanism

NTs N N Cl N Cl Cl PhINTs IV Insertion II Protolysis PdII Pd Pd Pd (II) + C N C Py C Py CN Py TsN Ts H

Scheme 25. Stoichiometric study of directed C–H bond amination with Pd(II) and PhI=NTs as oxidant and N-source. Insert:: Byproducts observed asas aa resultresult ofof competitivecompetitive C–XC–X bondbond formation.formation.

Daugulis provided the first report of catalytic alkyl-nitrogen coupling via C–H activation with Daugulis provided the first report of catalytic alkyl-nitrogen coupling via C–H activation with Pd(II)/Pd(IV), which relied on oxidation with PhI(OAc)2 (Scheme 26a) [56]. Other oxidants screened Pd(II)/Pd(IV), which relied on oxidation with PhI(OAc)2 (Scheme 26a) [56]. Other oxidants screened included more electron-deficient λ3-iodanes PhI(OTFA)2, PhI(p-NO2C6H4O2C)2, as well as AgOAc, all included more electron-deficient λ3-iodanes PhI(OTFA) , PhI(p-NO C H O C) , as well as AgOAc, of which gave very low or no conversion. The net intramolecular2 2 C–H6 4 amination2 2 proceeded via all of which gave very low or no conversion. The net intramolecular C–H amination proceeded via consecutive N–H/C–H activation, oxidation of complex 48 to give Pd(IV) intermediate 49, and final consecutive N–H/C–H activation, oxidation of complex 48 to give Pd(IV) intermediate 49, and final C–N bond forming reductive elimination. Mechanistic insights into the C–N bond forming step were C–N bond forming reductive elimination. Mechanistic insights into the C–N bond forming step were not provided. This work was followed closely by that of Chen who used the picolinamide directing not provided. This work was followed closely by that of Chen who used the picolinamide directing group for the construction of diverse 4- and 5-membered nitrogen heterocycles via C(sp3)–H group for the construction of diverse 4- and 5-membered nitrogen heterocycles via C(sp3)–H amination amination (Scheme 26b) [57]. (Scheme 26b) [57].

Molecules 2017, 22, 780 18 of 54 Molecules 2017, 22, 780 18 of 54 Molecules 2017, 22, 780 18 of 54 a. Daugulis (2012) a. Daugulis (2012) Pd(OAc) O 2 O Pd(OAc)2 O PhI(OAc)2 O N PhI(OAc)2 N HN toluene, 80 °C N N H toluene, 80 °C N N N

N–H/C–H activationN–H/C–H O O O activation O [O] N [O] N N IV N II N Pd N Pd IV N PdII AcON PdOAc AcO OAc 48 49 48 49 b. Chen (2012) b. Chen (2012)

N PA N N PA N N C–N Reductive N C–N Reductive H PA Elimination via H HN O H HN O R1 R2 Elimination via HN O 1 2 PA OAc H HN O Pd(OAc)2, R R N 1 3 OAc O 2 R R Pd(OAc)2, N 3 R 1 3 PhI(OAc)2 R N O 2 R 2 R 1 3 1 R R PhI(OAc)2 R R PdIVN R 2 1 R1 R AcOH, toluene, 110 °C R R2 PdIVN AcOH, toluene, 110 °C R2 OAc N R OAc R N R HN N N R HN NPA O PA O Scheme 26. Intramolecular C–H amination via Pd(II)/Pd(IV) catalysis with PhI(OAc)2. (a) Daugulis SchemeScheme 26. 26.Intramolecular Intramolecular C–H C–H amination amination via via Pd(II)/Pd(IV) Pd(II)/Pd(IV) catalysis with with PhI(OAc) PhI(OAc)2.2 (.(a)a Daugulis) Daugulis report on direct C(sp3)-amination (b) Chen’s C(sp3) and C(sp2)–H amination. reportreport on on direct direct C(sp C(sp3)-amination3)-amination ( b(b)) Chen’s Chen’s C(sp C(sp33)) and C(sp 22)–H)–H amination. amination. The Muniz group reported a benzylic C–H amidation via a directed C–H bond activation and The Muniz group reported a benzylic C–H amidation via a directed C–H bond activation and subsequentThe Muniz SN2-type group displacement reported a benzylic at Pd(IV) C–H (Scheme amidation 27) [58]. via In a this directed reaction C–H it was bond more activation effective and subsequent SN2-type displacement at Pd(IV) (Scheme 27) [58]. In this reaction it was more effective subsequentto have the SN 2-typeoxidant displacement also serve the at source Pd(IV) of (Scheme nitrogen 27 )[and58 ].hypervalent In this reaction iodine it wasreagents more therefore effective to to have the oxidant also serve the source of nitrogen and hypervalent iodine reagents therefore haveproved the oxidant to be less also efficient serve than the source NFSI. A of more nitrogen electron and deficient hypervalent bidentate iodine hexafluoroacetylacetonate reagents therefore proved proved to be less efficient than NFSI. A more electron deficient bidentate hexafluoroacetylacetonate to be(hfacac) less efficient ligand on than palladium NFSI. Aalso more improved electron efficien deficientcy. This bidentate reaction hexafluoroacetylacetonate could be extended to anisole (hfacac) and (hfacac) ligand on palladium also improved efficiency. This reaction could be extended to anisole and ligandpyridine on palladium directing alsogroups, improved giving efficiency.a rather versatile This reaction method could for beC–H extended bond amidation. to anisole andDespite pyridine its pyridine directing groups, giving a rather versatile method for C–H bond amidation. Despite its directingutility, groups,the use givingof NFSI a ratheras the versatileoxidant does method lead for to C–Hgeneration bond amidation. of an equivalent Despite of its HF, utility, and thethus use utility, the use of NFSI as the oxidant does lead to generation of an equivalent of HF, and thus discovery of more environmentally friendly alternatives would be a significant advancement for of NFSIdiscovery as the of oxidantmore environmentally does lead to generation friendly alte ofrnatives an equivalent would ofbe HF, a significant and thus discoveryadvancement of morefor large-scale applications. environmentallylarge-scale applications. friendly alternatives would be a significant advancement for large-scale applications.

Pd(X)2, oxidantPd(X)2, oxidant N 1,4-dioxane N via: N 1,4-dioxane100 °C N via: N(SO Me) ° 2 2 100 C NTos2 N(SO2Me)2 NTos2 Cat Oxidant Yield OR Cat Oxidant Yield IVOR SN2-type N Pd S 2-type Pd(OAc)2 PhI(OAc)NTs2 54% N PdIV displacementN Pd(OAc)2 PhI(OAc)NTs2 54% OR displacement X OR Pd(OAc)2 PhI(OAc)2/HNTs2 69% X Pd(OAc)2 PhI(OAc)2/HNTs2 69% Pd(hfacac)2 NFSI 95% Pd(hfacac)2 NFSI 95% Scheme 27. Directed C(sp3)-amidation of benzylic C–H bonds via SN2-displacement of Pd(IV). Scheme 27. Directed C(sp3 3)-amidation of benzylic C–H bonds via SN2-displacement of Pd(IV). Scheme 27. Directed C(sp )-amidation of benzylic C–H bonds via SN2-displacement of Pd(IV). Li reported the synthesis of oxindole derivatives via a intermolecular aminopalladation/C–H Li reported the synthesis of oxindole derivatives via a intermolecular aminopalladation/C–H activation cascade employing Pd(OAc)2 and PhI(OAc)2 (Scheme 28) [59]. In this case, other oxidants activationLi reported cascade the synthesisemploying of Pd(OAc) oxindole2 and derivatives PhI(OAc)2via (Scheme a intermolecular 28) [59]. In this aminopalladation/C–H case, other oxidants such as oxone, K2S2O8, Cu(OAc)2, benzoquinone, and O2 were ineffective, giving little or no activationsuch as cascadeoxone, employingK2S2O8, Cu(OAc) Pd(OAc)2, benzoquinone,2 and PhI(OAc) and2 (Scheme O2 were 28 )[ineffective,59]. In this giving case, otherlittle oxidantsor no conversion to products. The authors propose either terminal C–N reductive elimination from Pd(IV) suchconversion as oxone, to K 2products.S2O8, Cu(OAc) The authors2, benzoquinone, propose either and terminal O2 were C–N ineffective, reductive giving elimination little or nofrom conversion Pd(IV) or Pd(IV) C–H activation, however further mechanistic investigation is required. to products.or Pd(IV) C–H The activation, authors propose however either further terminal mechanistic C–N reductiveinvestigation elimination is required. from Pd(IV) or Pd(IV) C–H activation, however further mechanistic investigation is required.

Molecules 2017, 22, 780 19 of 54 Molecules 2017, 22, 780 19 of 54 Molecules 2017, 22, 780 19 of 54 Molecules 2017, 22, 780 19 of 54

O O R1 O O O N N 1 O O Pd(OAc)2, PhI(OAc)2 O OAr ineffective oxidants screened: R N 1 N Ar + ONH benzoquinone, O , Cu(OAc) , R Pd(OAc)2, PhI(OAc)° 2 O N Ar ineffective oxidants2 screened:2 N Ar Pd(OAc)DCE,, 100PhI(OAc) C ineffectiveK S oxidantsO , oxone screened: + NH 2 2 O ArO benzoquinone,2 2 8 O2, Cu(OAc)2, Ar DCE, 100 °C + ONH benzoquinone,K S O ,O oxone2, Cu(OAc)2, R DCE, 100 °C N O 2 2 8 R 1 K S O , oxone R O NR O 2 2 8 O R R NR1 R 1 SchemeScheme 28.28. SynthesisSynthesis ofof substitutedsubstituted oxindolesoxindoles viavia sequentialsequential aminopalladation/C–HaminopalladaR tion/C–H activation. Scheme 28. Synthesis of substituted oxindoles via sequential aminopalladation/C–H activation. Scheme 28. Synthesis of substituted oxindoles via sequential aminopalladation/C–H activation. The synthesis of carbazole derivatives via an oxidative C–H amidation procedure with Pd(OAc)2 The synthesis of carbazole derivatives via an oxidative C–H amidation procedure with Pd(OAc)2 and PhI(OAc)The synthesis2 at ambient of carbazole temperature derivatives was viareported an oxidative by Gaun C–Ht in amidation2008 (Scheme procedure 29) [60]. with This Pd(OAc) protocol2 and PhI(OAc)The synthesisat ambient of carbazole temperature derivatives was via reported an oxidative by Gaunt C–H in amidation 2008 (Scheme procedure 29)[60]. with This Pd(OAc) protocol2 offersand PhI(OAc) an alternative22 at ambient to Ulmann temperature and Buchwald-Hartwig was reported by Gauncouplingt in 2008reactions (Scheme and 29)obviates [60]. This the needprotocol for offersand PhI(OAc) an alternative2 at ambient to Ulmann temperature and Buchwald-Hartwig was reported by Gaun couplingt in 2008 reactions (Scheme and 29) obviates [60]. This the needprotocol for prefunctionalization.offers an alternative to The Ulmann reaction and mechanism Buchwald-Hartwig should proceed coupling as reactionsthe other and examples obviates demonstrated the need for offers an alternative to Ulmann and Buchwald-Hartwig coupling reactions and obviates the need for prefunctionalization.inprefunctionalization. this review. The TheTheisolation reactionreaction of mechanism mechanisma trinuclear should should Pd(II) proceed proceedcomplex as asthe (the50 other) otherhaving examples examples two demonstratedcy demonstratedclopalladated in prefunctionalization. The reaction mechanism should 50proceed as the other examples demonstrated thisaminobiphenylin this review. review. The isolation connectedThe isolation of athrough trinuclear of a bridgingtrinuclear Pd(II) complex acetat Pd(II) (es complex)to having a third two(50 )Pd(II) cyclopalladated having suggests two cy aminobiphenyltheclopalladated oxidation in this review. The isolation of a trinuclear Pd(II) complex (50) having two cyclopalladated connectedpathwaysaminobiphenyl leads through toconnected a bridgingPd(IV) thatthrough acetates promotes bridging to a the third reductive acetat Pd(II)es suggests elimination.to a third the However oxidationPd(II) suggests it pathways is also the possible leadsoxidation tothat a aminobiphenyl connected through bridging acetates to a third Pd(II) suggests the oxidation Pd(IV)thepathways trimeric that leadspromotes complex to a Pd(IV) dissociates the reductive that promotesinto elimination. monomeric the reductive However species elimination.prior it isalso to the possible oxidation.However that it the is also trimeric possible complex that pathways leads to a Pd(IV) that promotes the reductive elimination. However it is also possible that dissociatesthe trimeric into complex monomeric dissociates species into prior monomeric to the oxidation. species prior to the oxidation. the trimeric complex dissociates into monomeric species prior to the oxidation.

Pd(OAc)2 (5-10 mol%) Pd(OAc)PhI(OAc) (5-102, PhMe, mol%) rt H 2 N R Me HN N Pd(OAc)PhI(OAc)2 (5-10, PhMe, mol%) rt H R 2 N R O HN PhI(OAc)2, PhMe, rt Me Pd II HN R N R Me O HN N O II O O R O PdII Me OO PdPd II O Me II O OO Directed C–H C–N Reductive Me OO PdII O MeO Me O II Me DirectedActivation C–H C–NElimination Reductive O PdPd O MeO Me O II O Directed C–H C–N Reductive MePh N Pd O Activation OAcElimination O II 50 ActivationOAc EliminationOAc Ph N Pd II PhI(OAc) OAc Ph 50 PdOAc 2 IV N OAc OAcPd OAc 50 OAcII PhI(OAc) OAc Pd 2 IVOAc N II OAc PhI(OAc) Pd RPd 2 NR OAcIV OAc N OAc Pd OAc Isolated trimetallic Pd(II) complex N R NR OAc R NR OAc Isolated trimetallic Pd(II) complex Isolated trimetallic Pd(II) complex Scheme 29. Direct C(sp2)-amination at ambient temperature via Pd(II)/Pd(IV). SchemeScheme 29. 29.Direct DirectC(sp C(sp22)-amination)-amination atat ambientambient temperaturetemperature viavia Pd(II)/Pd(IV).Pd(II)/Pd(IV). Scheme 29. Direct C(sp2)-amination at ambient temperature via Pd(II)/Pd(IV). Gaunt also reported the synthesis of aziridines through C–H activation with Pd(OAc)2 and PhI(OAc)Gaunt2 (Scheme also reported 30). Mechanistic the synthesis experiments of aziridines demons throughtrated C–H that theactivation reaction with proceeds Pd(OAc) through2 and Gaunt alsoalso reportedreported thethe synthesissynthesis ofof aziridinesaziridines throughthrough C–HC–H activationactivation withwith Pd(OAc)Pd(OAc)22 andand formationPhI(OAc)2 of(Scheme a relatively 30). Mechanisticrare four-membered experiments palladacycle demons trated(51), which that thefurther reaction reductively proceeds eliminates through PhI(OAc)2 (Scheme 30).30). Mechanistic experiments demons demonstratedtrated that the reaction proceedsproceeds throughthrough toformation generate of thea relatively C–N bond. rare four-memberedThose experiments palladacycle also suggest (51), which that cyclopalladationfurther reductively is eliminatesthe rate- formationformation ofof aa relativelyrelatively rare rare four-membered four-membered palladacycle palladacycle (51 (51),), which which further further reductively reductively eliminates eliminates to determiningto generate step,the C–N followed bond. by Those fast oxidation experiments by PhI(OAc) also suggest2. They that subsequently cyclopalladation translated is thethis rate-to a generateto generate the C–Nthe C–N bond. bond. Those Those experiments experiments also suggest also thatsuggest cyclopalladation that cyclopalladation is the rate-determining is the rate- flowdetermining process step,providing followed an elegantby fast andoxidation efficient by aPhI(OAc)pproach 2to. They the synthesissubsequently of challenging translated thisstrained to a step,determining followed step, by fastfollowed oxidation by fast by PhI(OAc)oxidation2 by. They PhI(OAc) subsequently2. They subsequently translated this translated to a ﬂow this process to a nitrogenflow process heterocycles providing [61]. an elegant and efficient approach to the synthesis of challenging strained providingflow process an providing elegant and an elegant efﬁcient and approach efficient to approach the synthesis to the ofsynthesis challenging of challenging strained nitrogenstrained nitrogen heterocycles [61]. heterocyclesnitrogen heterocycles [61]. [61]. H OAc H OAcOAc H N NH PdOAcIV N 5mol% Pd(OAc)2 OAcL H O N O N PdIV OAc O N HCH3 5mol% Pd(OAc)2 N N IV L PhI(OAc)2, Ac2O R O PdOAc NR 5mol% Pd(OAc)2 O 1 R1 L O 1CH3 70 - 80 °C O O O O OAc51 O O CH PhI(OAc)2, Ac2O R1 R R1 3 O 1 OAc 51 PhI(OAc)7040-81% - 802, °AcC 2O O R1 ProposedR four-membered O R1 ° O O 1 51 O 7040-81% - 80 C highProposed oxidation four-memberedstate palladacycle 40-81% highProposed oxidation four-membered state palladacycle high oxidation state palladacycle Scheme 30. C–H activation approach to aziridines through high oxidation Pd(IV). Scheme 30. C–H activation approach to aziridines through high oxidation Pd(IV). Scheme 30. C–H activation approach to aziridinesaziridines through highhigh oxidationoxidation Pd(IV).Pd(IV).

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2.2.5.Molecules C–C bond 2017, 22 Formation, 780 20 of 54 Molecules 2017, 22, 780 20 of 54 2.2.5.1.2.2.5. Diaryliodonium C–C bond Formation Salts 2.2.5. C–C bond Formation − For2.2.5.1. many Diaryliodonium years, diorganoiodine Salts (III) compounds, represented [Ar–I–R]X , have been utilized for catalytic2.2.5.1. Diaryliodonium C–C bond formation Salts via oxidative transfer of “R+” to a Pd(0) catalyst and subsequent For many years, diorganoiodine (III) compounds, represented [Ar–I–R]X−, have been utilized for reductive elimination [62]. In recent years, these reagents have been extended− to Pd(II) catalysis, catalyticFor many C–C years,bond diorganoiodineformation via oxidative (III) compounds, transfer represented of “R+” to [Ar–I–R]Xa Pd(0) catalyst, have beenand utilizedsubsequent for + in bothcatalyticreductive stoichiometric C–C elimination bond and formation [62]. catalytic In recent via studies, oxidative years, proceeding these transfer reag ents viaof “R eitherhave” to been Pd(III)a Pd(0) extended or catalyst Pd(IV) to Pd(II) and intermediates. subsequentcatalysis, in From 2 2 3 2 this work,reductiveboth stoichiometric a variety elimination of C(spand [62]. catalytic–sp In recent) and studies, years, C(sp proceeding these–sp ) reag bond viaents formations either have Pd(III)been haveextended or Pd(IV) been to intermediates. reported. Pd(II) catalysis, From in boththis work,stoichiometric a variety and of C(sp catalytic2–sp2 )studies, and C(sp proceeding3–sp2) bond via formations either Pd(III) have or been Pd(IV) reported. intermediates. From Stoichiometricthis work, a Studies variety of C(sp2–sp2) and C(sp3–sp2) bond formations have been reported. Canty2.2.5.1.1. has Stoichiometric conducted manyStudies of the seminal reports on the isolation of various Pd(IV) and Pt(IV) 2.2.5.1.1. Stoichiometric Studies complexesCanty via oxidation has conducted with many both arylof the and seminal alkynyliodonium reports on the saltsisolation (Scheme of various 31)[63 Pd(IV)–66]. and The Pt(IV) iodonium saltscomplexes wereCanty able has tovia cleanly conductedoxidation oxidize manywith Pd(II)ofboth the arylseminal complexes and reports alkynyliodonium with on athe variety isolation salts of of ligand (Schemevarious scaffolds, Pd(IV)31) [63–66]. and giving Pt(IV) The rise to varyingcomplexesiodonium degrees saltsvia of wereoxidationcis/trans able toisomerswith cleanly both (oxidize52 -arylcis or Pd(II)and52 -alkynyliodonium transcomplexes) and with a Pd(III) a varietysalts dimer (Scheme of ligand (53 ),31) scaffolds, at low[63–66]. temperature. giving The For characterizationiodoniumrise to varying salts were degrees purposes able toof cleanly cis/trans these oxidize isomers complexes Pd(II) (52 complexes-cis were or 52- then transwith treated a) varietyand a with Pd(III)of ligand NaI dimer scaffolds, resulting (53), givingat in low triﬂate rise to varying degrees of cis/trans isomers (52-cis or 52-trans) and a Pd(III) dimer (53), at low displacementtemperature. or For addition characterization into the cationicpurposes Pd(III)these complexes species were (54-cis thenor treated54-trans with), andNaI resulting a summary in of temperature. For characterization purposes these complexes were then treated with NaI resulting in the complexestriflate displacement synthesized or addition via this approachinto the cationic is provided Pd(III) species below ((5554-–cis59 ,or Scheme 54-trans 32), ).and Throughout a summary these triflateof the complexesdisplacement synthesized or addition via into this the approach cationic isPd(III) provided species below (54- cis(55 –or59 54-, Schemetrans), 32).and Throughouta summary reports, Canty notes that the palladium complexes are signiﬁcantly less stable than the corresponding ofthese the complexesreports, Canty synthesized notes that via thisthe approachpalladium is complexesprovided below are significantly (55–59, Scheme less 32).stable Throughout than the platinum species meaning isolation and characterization were much more challenging. For a further thesecorresponding reports, Cantyplatinum notes species that me theaning palladium isolation complexes and characterizatio are significantlyn were much less morestable challenging. than the discussioncorrespondingFor a further of the discussionanalogous platinum ofspecies platinumthe analogous meaning components platinumisolation andcomponents to Canty’scharacterizatio studies,to Canty’sn were see stud much Sectionies, see more 3.1Section .challenging. 3.1. For a further discussion of the analogous platinum components to Canty’s studies, see Section 3.1.

[IAr2]OTf R2 = –Ph, CCR [IAr2or]OTf R2 = –Ph, CCR [PhICor CR]OTf R2 R NaI R2 R R ° R R2 R 25 °C R R2 R R PdII [PhIC–60 CR]OTf C PdIV or RPdIV NaI PdIV or PdIV RR II –60 °C RR IV RR2 IV 25 °C RR IV RR2 IV Pd PdOTf or PdOTf PdI or PdI R R R2 R R2 OTf52-trans OTf52-cis I54-trans I54-cis 52-trans 52-cis 54-trans 54-cis R 2 OTf R R Pd2 III OTf RR PdIII RR PdIII RR PdIII R 53 53 CR CO2R CR Ph Ph CR CONMeR 2 CR 2 Me2 Ph Ph N Me N IV R IV N PdIV PdIV PdNMeI2 P Pd Me PdIV Me2 RR N IV NN MeMe IV NN IV P PdIV N Pd Pd NMePd I MeMe IV I I N Me I N 2 Pd P R N C Me I Me2 I I NMe2 P 55I R = Ph, Me 56 57 58 59 I CCR Me2 55 R = Ph, Me 56 57 58 59 All complexes detected by 1H-NMR CR All complexes detected by 1H-NMR

SchemeScheme 31. 31. Synthesis of Pd(IV) species upon oxidation with diaryl- and alkynyl iodonium salts. Scheme 31.Synthesis Synthesis of of Pd(IV) Pd(IV) species species uponupon oxidatio oxidationn with with diaryl- diaryl- and and alkynyl alkynyl iodonium iodonium salts. salts. a. a. - reaction also applicable to R Pd(OAc)2 (5 mol%) R R [Mes-I-Ar]BF R1 - reactionpyrrolidinone, also applicable quinoline, to R 1 Pd(OAc)2 (5 mol%)4 R N N R and oxazolidinone directing groups R1 [Mes-I-Ar]BF 1 pyrrolidinone, quinoline, N solvent, 100 °4C, N Ar and- Benzylic oxazolidinone sp3 bonds directing also reactive groups solvent,8-24 100 hr °C, Ar 3 8-24 hr - Benzylic sp bonds also reactive b. Ac Pd(OAc) (5 mol%) <1% b. O [Mes-I-Ar]BF 2 N Ac 4 Pd(OAc)Ph–I or (5Ph–OTf mol%) <1% PdII N N 2 N N O [Mes-I-Ar]BF4 Ph–I or Ph–OTf PdII 2 N N solvent, 100 °C, N Ar Ph 2 solvent,8-24 100 hr °C, Ar Ph 8-24 hr rate identical to use of Pd(OAc)2 no reaction with substrates for Pd(0) oxidative addition no reaction with substrates for Pd(0) oxidative addition rate identical to use of Pd(OAc)2 Scheme 32. (a) Directed C–H arylation with diaryliodonium salts and Pd(OAc)2; (b) Evidence for Scheme 32. (a) Directed C–H arylation with diaryliodonium salts and Pd(OAc)2; (b) Evidence for SchemePd(II)/Pd(IV) 32. (a) Directed pathway. C–H arylation with diaryliodonium salts and Pd(OAc)2;(b) Evidence for Pd(II)/Pd(IV) pathway. Pd(II)/Pd(IV) pathway.

Molecules 2017, 22, 780 21 of 54

Catalytic Applications

Molecules 2017, 22, 780 21 of 54 In 2005, Sanford reported a directed C–H arylation using diaryliodonium salts and Pd(OAc)2, the first report of C–H arylation invoking a Pd(II)/Pd(IV) catalytic manifold (Scheme 32a) [67]. 2.2.5.1.2. Catalytic Applications The reaction was applicable to a wide range of heterocyclic directing groups and a range of electron-deficientIn 2005, Sanford and electron-rich reported a directed aryl rings C–H could arylation be transferred using diaryliodonium in good yields. salts and This Pd(OAc) method2, was the first report of C–H arylation invoking a Pd(II)/Pd(IV) catalytic manifold (Scheme 32a) [67]. The further extended to benzylic C(sp3)–H arylation on C8-methylquinoline as well as the regioselective reaction was applicable to a wide range of heterocyclic directing groups and a range of electron- arylation of 2,5-disubstituted pyrroles (not shown) [68]. This group subsequently reported a variant deficient and electron-rich aryl rings could be transferred in good yields. This method was further usingextended polymer-supported to benzylic C(sp iodonium3)–H arylation salts on that C8-methylquinoline gave equally high as well yields as the and regioselective the hypervalent arylation iodine reagentof 2,5-disubstituted could be readily pyrroles recycled (not [shown)14]. The [68]. reactionThis group was subsequently proposed reported to proceeded a variant via using a Pd(IV) intermediatepolymer-supported by analogy iodonium to their salts work that with gave C–H equally acetoxylation high yields (seeand the Section hypervalent 2.2.2.1 ),iodine and preliminaryreagent mechanisticcould be investigationsreadily recycled supported[14]. The reaction this hypothesis was proposed (Scheme to proceeded 32b). via A subsequenta Pd(IV) intermediate study revealed by furtheranalogy mechanistic to their work insights, with includingC–H acetoxylation that oxidation (see Section by the2.2.2.1), diaryliodonium and preliminary salt mechanistic was turnover investigations supported this hypothesis (Scheme 32b). A subsequent study revealed further limiting [69]. This is particularly interesting since analogous acetoxylation reaction with PhI(OAc)2 mechanistic insights, including that oxidation by the diaryliodonium salt was turnover limiting [69]. are found to be zero-order in PhI(OAc)2 and that cyclopalladation is turnover limiting. This implies This is particularly interesting since analogous acetoxylation reaction with PhI(OAc)2 are found to be that oxidation by diaryliodonium salts is much slower than by PhI(OAc)2 and this could be significant zero-order in PhI(OAc)2 and that cyclopalladation is turnover limiting. This implies that oxidation by in the further development of this chemistry as undesirable side reactions could begin to compete diaryliodonium salts is much slower than by PhI(OAc)2 and this could be significant in the further withdevelopment oxidation. A of complete, this chemistry detailed as undesirable mechanistic side study reactions was could later begin conducted to compete between with oxidation. the groups of Sanford,A complete, Canty, and detailed Yates, mechanistic incorporating study computational was later conducted studies, between and readers the groups are directedof Sanford, to Canty, that report for furtherand Yates, discussion incorporating [70]. computational studies, and readers are directed to that report for further Indiscussion 2006, [70]. Sanford reported of the C2-arylation of indoles using diaryliodonium salts (Scheme In33 )[2006,71 ].Sanford The reported proposed of the mechanism C2-arylation invoked of indoles a Pd(II)/Pd(IV)using diaryliodonium catalytic salts cycle(Scheme beginning 33) with[71]. rate-determining The proposed mechanism cyclopalladation, invoked a followedPd(II)/Pd(IV by) catalytic oxidative cycle addition beginning to with give rate-determining Pd(IV) species 60 and subsequentcyclopalladation, C–C followed reductive by elimination.oxidative addition This to approach give Pd(IV) improved species 60 upon and priorsubsequent reports C–C using reductive elimination. This approach improved upon prior reports using Pd(0)/Pd(II), which required Pd(0)/Pd(II), which required long reaction times and high temperatures (12–24 h, >125 ◦C), by long reaction times and high temperatures (12–24 h, >125 °C), by accelerating rate-determining accelerating rate-determining cyclopalladation through use of a Pd(II) catalyst. The use of IMes (61) as cyclopalladation through use of a Pd(II) catalyst. The use of IMes (61) as an ancillary ligand improved an ancillaryconversion ligand by improvedstabilizing conversionthe Pd(IV) byintermed stabilizingiate, but the Pd(IV)slowed intermediate,reaction times, but supporting slowed reaction a times,mechanism supporting wherein a mechanism electrophilic wherein palladation electrophilic is rate-limiting. palladation is rate-limiting.

IMesPd(OAc)2 R [Ar2I]BF4 Prior reports: Pd(0)/Pd(II) R R H 12-24hr, >125 °C N AcOH, 25 °C-60 °C N

H OAc N OAc Reductive [Ar2I]BF4 IV II MesI Pd Elimination MesI Pd(OAc) MesI Pd Ph 2 N - AcOH Oxidation N N Electrophilic Pd(II) cyclopalladation 60

Me Me Me Me IMes = N N 61 Me Me

SchemeScheme 33. 33. FacileFacile C2-arylation C2-arylation of indoles of indoles with diaryliodonium with diaryliodonium salts through salts Pd(II)/Pd(IV) through catalytic Pd(II)/Pd(IV) cycle. catalytic cycle. In a systematic study of ligand effects on regiocontrol in non-directed C–H activation, Sanford examined the C–H arylation of naphthalene with Pd(II) and diaryliodonium salts (Scheme 34) [72]. It Inwas a systematicfound that studysubtle ofchanges ligand to effects ligand on sterics regiocontrol had dramatic in non-directed effects on the C–H regioselectivity activation, Sanford of examinedarylation the using C–H arylationa range of of bidentate naphthalene diamine with ligands. Pd(II) andSimilar diaryliodonium to previous reports, salts (Schememechanistic 34)[ 72]. It wasinvestigations found that subtle revealed changes oxidation to ligand was rate-limiting, sterics had dramatichowever in effects this case on the it precedes regioselectivity C–H activation, of arylation usingwhich a range then of occurs bidentate at a Pd(IV) diamine center. ligands. Similar to previous reports, mechanistic investigations revealed oxidation was rate-limiting, however in this case it precedes C–H activation, which then occurs at a Pd(IV) center.

Molecules 2017, 22, 780 22 of 54 Molecules 2017, 22, 780 22 of 54 Molecules 2017, 22, 780 22 of 54

[Pd]II [Pd]II Ph [Pd]II Ph [Pd]II Ph tBu [Ar2I]BF4 tBu [Ar I]BF + Ph Cl Cl 2 4 Cl Cl N NO Ph, + Me N Me N Cl 2 Me Cl Me Cl N Pd 130NO °C,2Ph, 16 hr N Pd Cl N Pd Cl Cl Cl Cl Pd Cl 130 °C, 16 hr N Pd N Pd N Cl Ligand 62 63 Me Cl Me Cl Me N Me N N Ligand 62 63 Cl Cl 66 Cl Cl tBu 64 91 tBu 66 64 91 64 65 65 27 1 64 65 65 27 1 Ligand sterics greatly influences regioselectivity 66 71 1 Ligand sterics greatly influences regioselectivity 66 71 1

Scheme 34. Ligand-controlled regioselectivity in non-directed C–H arylation with diaryliodonium salts. SchemeScheme 34. 34. Ligand-controlledLigand-controlled regioselectivity regioselectivity in in non-directed C–HC–H arylationarylation with with diaryliodonium diaryliodonium salts. salts. 2.2.5.2. Benzoiodoxolones 2.2.5.2. Benzoiodoxolones In 2013, Waser reported the direct C2-alkynylation of indoles using 1-[(triisopropylsilyl)ethynyl]- In 2013, 2013, Waser Waser reported reported the thedirect direct C2-alkynylatio C2-alkynylationn of indoles of indoles using 1-[(triisopropylsilyl)ethynyl]- using 1-[(triisopropylsilyl) 1λ3,2-benziodoxol-3(1H)-one (TIPS-EBX, 67) as both an alkynyl transfer reagent and oxidant (Scheme ethynyl]-11λ3,2-benziodoxol-3(1λ3,2-benziodoxol-3(1H)-one (TIPS-EBX,H)-one (TIPS-EBX, 67) as both67 )an as alkynyl both an transfer alkynyl reagent transfer and reagent oxidant and (Scheme oxidant 35) [73]. The authors have worked extensively with this reagent with further applications in (Scheme35) [73]. 35The)[73 authors]. The authors have worked have worked extensively extensively with with this this reagent reagent with with further further applications applications in Au(I)/Au(III) catalysis (see Section 4.3). This method is proposed to proceed through a Pd(II)/Pd(IV) Au(I)/Au(III) catalysis catalysis (see (see Sectio Sectionn 4.3).4.3). This This method is proposed to proceed throughthrough aa Pd(II)/Pd(IV)Pd(II)/Pd(IV) catalytic cycle highly analogous to that proposed for C–H arylation (see previous discussion). This catalytic cycle cycle highly highly analogous analogous to tothat that proposed proposed for forC–H C–H arylation arylation (see (seeprevious previous discussion). discussion). This approach addresses issues of C2/C3 selectivity in prior methods and products are obtained in Thisapproach approach addresses addresses issues issues of C2/C3 of C2/C3 selectivity selectivity in prior in prior methods methods and andproducts products are areobtained obtained in moderate to good yield. inmoderate moderate to togood good yield. yield.

Pd(MeCN)4(BF4)2 (2 mol%) Pd(MeCN)4(BF4)2 (2 mol%) O I TIPS TIPS-EBX (3 equiv.) O I TIPS R H TIPS-EBX (3 equiv.) R TIPS R H R TIPS O N CH2Cl2/H2O, rt N O TIPS-EBX CH Cl /H O, rt TIPS-EBX NR1 41–72%2 2 2yield NR1 67 R1 41–72% yield R1 67

Scheme 35. Direct C2-alkynylation of indoles via Pd(II)/Pd(IV) using alkynyl benzoiodoxolone 67. Scheme 35.35. Direct C2-alkynylation ofof indolesindoles viavia Pd(II)/Pd(IV)Pd(II)/Pd(IV) using using alkynyl benzoiodoxolone 67.. 2.2.5.3. Trifluoromethylation 2.2.5.3. Trifluoromethylation Trifluoromethylation Palladium-catalyzed approaches to arene trifluoromethylation are rare, largely because most Palladium-catalyzed approaches to arene trifluoromethylation are rare, largely because most palladiumPalladium-catalyzed (II) species are approachesinert to Ar-CF to3 arene bonding trifluoromethylation forming reductive are elimination rare, largely [74–76]. because Methods most palladium (II) species are inert to Ar-CF3 bonding forming reductive elimination [74–76]. Methods palladiuminvolving a (II) Pd(II)/Pd(IV) species are cycle inert are toAr-CF an attractive3 bonding alternative forming due reductive to more elimination facile reductive [74–76 eliminations]. Methods involving a Pd(II)/Pd(IV) cycle are an attractive alternative due to more facile reductive eliminations involvingfrom high aoxidation Pd(II)/Pd(IV) state cyclePd(IV). are Unfortunately, an attractive alternative a limiting duefactor to of more most facile common reductive Pd(IV) eliminations oxidants, from high oxidation state Pd(IV). Unfortunately, a limiting factor of most common Pd(IV) oxidants, fromincluding high hypervalent oxidation state iodine Pd(IV). reagents, Unfortunately, is the transfer a limiting of X-groups factor to of the most metal common center Pd(IV)that will oxidants, readily including hypervalent iodine reagents, is the transfer of X-groups to the metal center that will readily includingoutcompete hypervalent a –CF3 group iodine for reagents, reductive is theelimination. transfer of This X-groups problem to the was metal exemplified center that in willstudies readily by outcompete a –CF3 group for reductive elimination. This problem was exemplified in studies by outcompeteSanford, wherein a –CF the3 group synthesis for reductiveand stoichiometric elimination. reactivity This problemof a Pd(IV)–CF was exemplified3 complex was instudies examined by Sanford, wherein the synthesis and stoichiometric reactivity of a Pd(IV)–CF3 complex was examined Sanford,with a range wherein of common the synthesis oxidants and (Scheme stoichiometric 36) [77,78]. reactivity Upon ofoxidation a Pd(IV)–CF of complex3 complex 68, high was examinedoxidation with a range of common oxidants (Scheme 36) [77,78]. Upon oxidation of complex 68, high oxidation withstate aPd(IV) range ofintermediate common oxidants 69 could (Scheme undergo 36 )[two77, 78possible]. Upon reductive oxidation elimination of complex pathways68, high oxidation to form state Pd(IV) intermediate 69 could undergo two possible reductive elimination pathways to form statewith Pd(IV)an Ar–CF intermediate3 or Ar–X69 bond.could Employing undergo two PhI(OAc) possible2 or reductive N-halosuccinimides elimination pathways exclusive to C–X form bond with with an Ar–CF3 or Ar–X bond. Employing PhI(OAc)2 or N-halosuccinimides exclusive C–X bond anformation Ar–CF3 wasor Ar–X observed, bond. in Employing varying yields. PhI(OAc) Only2 or uponN-halosuccinimides use of a “F+” source exclusive as an oxidant, C–X bond the formation optimal formation was observed, in varying yields. Only upon use+ of a “F+” source as an oxidant, the optimal wasbeing observed, NFTPT ( in70), varying was Ar–CF yields.3 bond Only formation upon use observed of a “F ” in source high asyield an oxidant,(71). This the landmark optimal beingstudy being NFTPT (70), was Ar–CF3 bond formation observed in high yield (71). This landmark study NFTPTshows the (70 ),feasibility was Ar–CF of 3Ar–CFbond formation3 bond formation observed via in a high Pd(IV) yield intermediate, (71). This landmark however study it also shows exposes the shows the feasibility of Ar–CF3 bond formation via a Pd(IV) intermediate, however it also exposes feasibilitythe limitations of Ar–CF of current3 bond oxidants. formation Common via a Pd(IV) “F+” intermediate,sources are expensive however relative it also exposes to hypervalent the limitations iodine the limitations of current oxidants. Common “F+” sources are expensive relative to hypervalent iodine ofreagents current or oxidants. N-halosuccinimides Common “F and+” sourcestheir use are in catalytic expensive reaction relative manifolds to hypervalent of this type iodine is not reagents proven. or reagents or N-halosuccinimides and their use in catalytic reaction manifolds of this type is not proven. NTherefore,-halosuccinimides the identification and their of use suitable in catalytic oxidant/liga reactionnd manifolds combinations of this that type will is facilitate not proven. selective Therefore, –CF3 Therefore, the identification of suitable oxidant/ligand combinations that will facilitate selective –CF3 thereductive identification elimination of suitable from Pd(IV) oxidant/ligand is of critical combinations importance thatto the will advancement facilitate selective of this –CF area.3 reductive reductive elimination from Pd(IV) is of critical importance to the advancement of this area. elimination from Pd(IV) is of critical importance to the advancement of this area.

Molecules 2017, 22, 780 23 of 54 Molecules 2017, 22, 780 23 of 54 Molecules 2017, 22, 780 23 of 54 Me F TfO Me F TfO

N CF3 Me N Me PdII CF3 N CF3 [Oxidant]–XY Me 70 NF Me N PdII N IV CF3 CF3 Aryl - CF3 [Oxidant]–XY Pd 70 F bond formation N F N IV CFY 3 F Aryl - CF3 68 Pd bond formation F N X Y F 68 69 70%, 71 X 69 70%, 71

Traditional oxidants for Pd(IV) transfer ligands X Aryl - X thatTraditional will outcompete oxidants –CF for 3Pd(IV) for reductive transfer elimination ligands X bondAryl formation - X that will outcompete –CF3 for reductive elimination F bond formation PhI(OAc)2 20F % (X= OAc) PhI(OAc)2 20 % (X= OAc) NBS 75 % (X= Br) NBS 75 % (X= Br) NCS 70 % (X= Cl) NCS 70 % (X= Cl) Scheme 36. Isolation and study of –CF3 reductive elmination from Pd(IV) complexes . Scheme 36. Isolation and study of –CF3 reductive elmination from Pd(IV) complexes. Scheme 36. Isolation and study of –CF3 reductive elmination from Pd(IV) complexes . In a significant report, the catalytic trifluoromethylation of indoles was reported by Liu, utilizing In a significant report, the catalytic trifluoromethylation of indoles was reported by Liu, utilizing TMSCFIn a3 significantas the trifluoromethyl report, the catalytic source andtrifluoromethylation PhI(OAc)2 as a stoichiometric of indoles was oxidant reported (Scheme by Liu, utilizing37) [79]. TMSCF as the trifluoromethyl source and PhI(OAc) as a stoichiometric oxidant (Scheme 37)[79]. TMSCFThe authors3 as the propose trifluoromethyl a Pd(II)/Pd(IV) source catalyticand PhI(OAc) cycle,22 involvingas a stoichiometric electrophilic oxidant palladation (Scheme at 37) Pd(II), [79]. The authors propose a Pd(II)/Pd(IV) catalytic cycle, involving electrophilic palladation at Pd(II), Thefollowed authors by proposeoxidation a Pd(II)/Pd(IV)by PhI(OAc) catalytic2/TMSCF cycle,3 and involvingreductive electrophilic elimination. palladation However, atdetailed Pd(II), followed by oxidation by PhI(OAc) /TMSCF and reductive elimination. However, detailed followedmechanistic by support oxidation is not by provided PhI(OAc) and2 2/TMSCF this result3 and is perhapsreductive surprising elimination. given However, Sanford’s previousdetailed mechanistic support is not provided and this result is perhaps surprising given Sanford’s previous mechanisticreports detailing support competitive is not provided –OAc andvs. this–CF 3result reductive is perhaps elimination surprising at Pd(IV) given Sanford’s[77,78]. Given previous the reports detailing competitive –OAc vs. –CF reductive elimination at Pd(IV) [77,78]. Given the complex reportscomplex detailing set of reaction competitive conditions –OAc employed,vs. –CF3 3 reductive a more detailedelimination mechanistic at Pd(IV) study [77,78]. is required Given the to set of reaction conditions employed, a more detailed mechanistic study is required to definitively prove complexdefinitively set prove of reaction the intermediacy conditions ofemployed, Pd(IV), and a moresuch adetailed study could mechanistic provide studyvaluable is requiredinsights forto the intermediacy of Pd(IV), and such a study could provide valuable insights for further development definitivelyfurther development prove the of intermediacy Pd(IV) trifluoromethylation of Pd(IV), and such with a PhI(OAc) study could2 as providean oxidant. valuable insights for furtherof Pd(IV) development trifluoromethylation of Pd(IV) withtrifluoromethylation PhI(OAc)2 as an with oxidant. PhI(OAc)2 as an oxidant.

2 2 R Pd(OAc)2 (10 mol%), 72 R O O R2 Pd(OAc)PhI(OAc) (10 mol%),(2 equiv.) 72 R2 O O 2 2 N N R H PhI(OAc) (2 equiv.) R CF3 CsF (42 equiv.) N N R N H R N CF3 NR1 TMSCsFCF (43 (4equiv.) equiv) NR1 72 R1 TEMPOTMSCF3 (50 (4 equiv)mol%) 33–75% yieldR1 72 TEMPOCH3 (50CN, mol%) rt 33–75% yield CH3CN, rt Scheme 37. Catalytic trifluoromethylation of indoles with PhI(OAc)2 as the oxidant and TMSCF3 as Schemethe trifluoromethyl 37. Catalytic source. trifluoromethylationtrifluoromethylation of indoles with PhI(OAc)PhI(OAc)2 as the oxidant and TMSCFTMSCF3 as the trifluoromethyl trifluoromethyl source. Due to the low reactivity towards reductive elimination, trifluoromethyl palladium complexes Due to the low reactivity towards reductive elimination, trifluoromethyl palladium complexes haveDue been to used the low as reactivitytools to probe towards mechanistic reductive de elimination,tails and oxidation trifluoromethyl states palladiumof proposed complexes catalytic have been used as tools to probe mechanistic details and oxidation states of proposed catalytic haveintermediates. been used There as tools is an toongoing probe discussion mechanistic in detailsthe literature and oxidation whether Pd(IV) states ofmonomeric proposed species catalytic or intermediates. There is an ongoing discussion in the literature whether Pd(IV) monomeric species or intermediates.Pd(III)–Pd(III) dimers There is are an the ongoing intermediates discussion arising in the from literature hypervalen whethert iodine Pd(IV) oxidation monomeric of a species Pd(II) Pd(III)–Pd(III) dimers are the intermediates arising from hypervalent iodine oxidation of a Pd(II) orspecies Pd(III)–Pd(III) (see Section dimers 2.3.2 are for the further intermediates discussion). arising Ritter from has hypervalent reported that iodine oxidation oxidation of palladium of a Pd(II) species (see Section 2.3.2 for further discussion). Ritter has reported that oxidation of palladium speciescomplex (see 73 with Section PhI(OAc) 2.3.2 for2 and further PhICl discussion).2 results in the Ritter formation has reported of Pd(III) that dimers oxidation [80] of. In palladium contrast, complex 73 with PhI(OAc)2 and PhICl2 results in the formation of Pd(III) dimers [80]. In contrast, complexSanford showed73 with that PhI(OAc) oxidation2 and of PhICl73 with2 results Togni’s in reagent the formation (74) gave of rise Pd(III) to an dimers isolable [80 Pd(IV)]. In contrast, species Sanford showed that oxidation of 73 with Togni’s reagent (74) gave rise to an isolable Pd(IV) species Sanford(76) (Scheme showed 38) that[81]. oxidationIn this study, of 73 Togni’with Togni’ss reagent reagent gave the (74 )best gave yield rise toof ancomplex isolable 76 Pd(IV), as compared species (76) (Scheme 38) [81]. In this+ study, Togni’s reagent gave the best yield of complex 76, as compared (to76 other) (Scheme electrophilic 38)[81]. “CF In this3 ” sources. study, Togni’s A subsequent reagent study gave between the best yieldthe groups of complex of Ritter,76, Yates, as compared Canty, + to other electrophilic “CF3 +” sources. A subsequent study between the groups of Ritter, Yates, Canty, toin othercollaboration electrophilic with “CFSanford,3 ” sources. showed A that subsequent monomeric study Pd(IV) between complex the groups76 is likely of Ritter, formed Yates, through Canty, a in collaboration with Sanford, showed that monomeric Pd(IV) complex 76 is likely formed through a intwo-step collaboration oxidation/disproportionation with Sanford, showed that sequence, monomeric through Pd(IV) complex the intermediacy76 is likely formed of bimetallic through a two-step oxidation/disproportionation sequence, through the intermediacy of bimetallic two-stepintermediate oxidation/disproportionation 75 [82]. It is suggested that sequence, formation through of the the Pd–Pd intermediacy bond that of bimetallic occurs during intermediate initial intermediate 75 [82]. It is suggested that formation of the Pd–Pd bond that occurs during initial 75oxidation[82]. It isto suggestedPd(III) lowers that formationthe activation of the barrier Pd–Pd to bondoxidation that occursen route during to 76. initial oxidation to Pd(III) oxidation to Pd(III) lowers the activation barrier to oxidation en route to 76. lowers the activation barrier to oxidation en route to 76.

Molecules 2017, 22, 780 24 of 54 Molecules 2017, 22, 780 24 of 54

F C I O 3 Me Molecules 2017, 22, 780 Me 24 of 54 N CF O 74 N 3 PdII F C I O III O CF 3 Me Pd 3 O Me AcOH, CH Cl O Me Disproportionation OH2 2 2Me PdIV O Me O N N II Bimetallic Oxidation N CF3 Me OAc Pd O II O 74 PdIII Pd III O CF3 OAc N Pd O Me AcOH, CH Cl N O Me Disproportionation OH2 73 2 2 75 PdIV 76 O N II Me Bimetallic Oxidation O Me OAc Pd O III Pd O OAc SchemeN 38. Evidence for intermediacy of bimetallicN Pd(III) species en route to monomeric Pd(IV) Scheme 38. Evidence73 for intermediacy of bimetallic Pd(III)75 species en route to monomeric Pd(IV)76 upon upon oxidation with Togni’s reagent. oxidation with Togni’s reagent. Scheme 38. Evidence for intermediacy of bimetallic Pd(III) species en route to monomeric Pd(IV) 2.2.6. Miscellaneousupon oxidation with Togni’s reagent. 2.2.6. Miscellaneous Sanford2.2.6. Miscellaneous has reported an interesting transformation wherein enynes are converted to highly Sanford has reported an interesting transformation wherein enynes are converted to substituted cyclopropanes via a cyclization cascade employing Pd(OAc)2 and PhI(OAc)2 (Scheme 39) highly substitutedSanford has cyclopropanes reported an interesting via a cyclization transformation cascade wherein employing enynes are Pd(OAc) convertedand to highly PhI(OAc) [47]. In this case, the high-oxidation state of Pd(IV) intermediate (77) undergoes2 nucleophilic2 (Schemesubstituted 39)[47 cyclopropanes]. In this case, via a thecyclization high-oxidation cascade employing state of Pd(OAc) Pd(IV)2 intermediateand PhI(OAc)2 (Scheme (77) undergoes 39) displacement by an internal enol ether to generate the cyclopropane moiety via an SN2-type pathway, nucleophilic[47]. In this displacement case, the high-oxidation by an internal state enol of etherPd(IV) to intermediate generate the (77 cyclopropane) undergoes nucleophilic moiety via an analogousdisplacement to Muniz’s by an reportsinternal enolon Pd(IV)-mediated ether to generate the am cyclopropaneination (see moiety Section via 2.2.4.1). an SN2-type Key pathway, to success is S 2-type pathway, analogous to Muniz’s reports on Pd(IV)-mediated amination (see Section 2.2.4.1). thatN theanalogous rate ofto Muniz’sintramolecular reports oncyclization Pd(IV)-mediated is faster am inationthan that(see Sectionof C–O 2.2.4.1). bond Key forming to success reductive is Key to success is that the rate of intramolecular cyclization is faster than that of C–O bond forming eliminationthat the from rate 77of andintramolecular trace amounts cyclization of C–O is products faster than (78 )that are ofobserved. C–O bond forming reductive reductiveelimination elimination from 77 from and trace77 and amounts trace amountsof C–O products of C–O (78 products) are observed. (78) are observed. 1 R R R1 1 R R R1 H Pd(OAc)2 (5 mol%) H Pd(OAc) (5 mol%) O R H PhI(OAc)2 (1.12 - 4 equiv.) H R PhI(OAc) (1.1 - 4 equiv.) O 2 O X O 44-79% X O X O 44-79% X X = O, N X = O, N

Ph Ph MeMe PhPh H H H H OO MeMe Pd(OAc)Pd(OAc)2 O 2 X O XX O X O

OAc Me OAc O Me Ph O Pd II O Ph O Pd II H Me O H O O Me O Competitive X O X O CompetitiveC–O Reductive O X O Elimination X C–O Reductive O EliminationPh Me H O Ph O O MeAcOH AcO Ph O PdII O AcO O O H O X Me H Ph AcO Ph Me PdII 78O O H O X Me H Ph O IV Me X 78 AcO Pd O O O OAc X X AcOPdIV O AcO 77 Me Ph OAc X O H AcO O O II 77 PhI(OAc)2 Pd Ph Me H OAc O O X II PhI(OAc)2 Pd Scheme 39. Cyclopropane synthesis via Pd(II)/Pd(IV) catalysisOAc with SON2-type displacement of Pd(IV). Scheme 39. Cyclopropane synthesis via Pd(II)/Pd(IV) catalysisX with SN2-type displacement of Pd(IV).

2.3.Scheme Palladium(III) 39. Cyclopropane synthesis via Pd(II)/Pd(IV) catalysis with SN2-type displacement of Pd(IV). 2.3. Palladium(III) 2.3.1. Introduction 2.3.2.3.1. Palladium(III) Introduction In contrast to reactions with palladium in its 0, +1, +2, and +4 oxidation states, little is known 2.3.1.In aboutIntroduction contrast the chemistry to reactions of Pd(III) with dimers palladium or their in potentia its 0, +1,l role +2, in andcatalysis. +4 oxidation This has been states, duelittle to the is low known aboutstability the chemistry of these ofcompounds, Pd(III) dimers hindering or their their potential isolation and role characterization, in catalysis. This and has a lack been ofdue examples to the low In contrast to reactions with palladium in its 0, +1, +2, and +4 oxidation states, little is known stability of these compounds, hindering their isolation and characterization, and a lack of examples about the chemistry of Pd(III) dimers or their potential role in catalysis. This has been due to the low stability of these compounds, hindering their isolation and characterization, and a lack of examples

Molecules 2017, 22, 780 25 of 54 Molecules 2017, 22, 780 25 of 54 employing Pd(III) organometallic species in catalyticcatalytic manifolds. Over the last 10 years, hypervalent iodine reagentsreagents have have emerged emerged as as excellent excellent oxidants oxidan forts thefor isolationthe isolation of Pd(III) of Pd(III) dimers dimers and these and studies these havestudies provided have provided key insights key into insights the role into that the Pd(III) role intermediates that Pd(III) couldintermediates play in carbo-heteroatom could play in carbo- bond formingheteroatom transformations. bond forming In transformations. this section we will In highlightthis section some we of will the more highlight signiﬁcant some studies of the inmore this area,significant with anstudies emphasis in this on thosearea, thatwith relatean emphasis to the previously on those discussedthat relate Pd(II)/Pd(IV) to the previously carbon-halogen discussed andPd(II)/Pd(IV) carbon-oxygen carbon-halogen bond forming and reactions.carbon-oxygen bond forming reactions.

2.3.2. Complex Isolation Cotton reported the isolation and characterization of several dimeric Pd(III) species possessing a Pd–Pd single bond, all accessed via two, one-electron oxidations of dimeric Pd(II) precursors with PhICl (Scheme 40)[83,84]. In their initial report, cyclic voltammetry measurements revealed that PhICl2 (Scheme 40) [83,84]. In their initial report, cyclic voltammetry measurements revealed that Pd(II) species 79, with a bridging hpp (1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2–α]pyrimidine)]pyrimidine) ligand, ligand, possessed aa quasi-reversiblequasi-reversible oxidation oxidation at at –0.12 –0.12 V V and and an an irreversible irreversible oxidation oxidation at +0.82at +0.82 V hinting V hinting at the at lowthe low stability stability of the of products. the products. Indeed, Indeed, while theywhile were they able were to achieveable to oxidationachieve oxidation with PhICl with2, products PhICl2, wereproducts isolated were in lowisolated yield viain manuallow yield selection via ofmanual crystals selection amongst numerousof crystals decomposition amongst numerous products. Adecomposition subsequent study products. improved A subsequent on the oxidation study improved by exploring on the other oxidation bridging by exploring ligands and other found bridging that whileligands it and was found possible that to while oxidize it was Pd(II) possible dimers to with oxidize a variety Pd(II)of dimers electron-rich with a variety and electron-deficient of electron-rich carboxylateand electron-deficient ligands (80 carboxylate); oxidation ligands became (80 inaccessible); oxidation upon became introduction inaccessible of upon an electron-deficient introduction of perfluorinatedan electron-deficient aryl backbone perfluorinated on the aryl phosphine backbone ligand. on the phosphine ligand.

a. Cotton (1998) Cl N N N N PdII PdII N N N N N PhICl2 = NN N N N N N N PdII -PhI PdII N N N N (hpp) 79 Cl

b. Cotton (2006) Cl C O C O R PdII PdIII OO P O PhICl2 P O = O O P O -PhI P O PdII PdIII PPh2 C O C O = CP 80 Cl

Scheme 40. Formation of Pd(III) dimers upon oxidation withwith PhIClPhICl22.(. (a) Use of an hpp hpp bridging ligand ((b)) UseUse ofof bridgingbridging carboxylatecarboxylate andand arylphosphinearylphosphine ligands.ligands.

Ritter has conducted extensive studies on the potential role that bimetallic Pd(III) dimers could Ritter has conducted extensive studies on the potential role that bimetallic Pd(III) dimers could play in what had been widely proposed to be Pd(II)/Pd(IV) catalytic cycles (Scheme 41) [80,82,85]. play in what had been widely proposed to be Pd(II)/Pd(IV) catalytic cycles (Scheme 41)[80,82,85]. The first definitive report for the presence of Pd(III) intermediates was in 2009. The oxidation of a The ﬁrst deﬁnitive report for the presence of Pd(III) intermediates was in 2009. The oxidation of a dimeric Pd(II) complex (81) was examined employing oxidants common to Pd(II)/Pd(IV) C–X bond dimeric Pd(II) complex (81) was examined employing oxidants common to Pd(II)/Pd(IV) C–X bond forming reactions, including PhI(OAc)2, PhICl2, or N-halosuccinimides. Oxidation of 81 with PhICl2 forming reactions, including PhI(OAc)2, PhICl2, or N-halosuccinimides. Oxidation of 81 with PhICl2 gave rise to Pd(III) intermediate 82, which was characterized by X-ray crystallography. The Pd–Pd gave rise to Pd(III) intermediate 82, which was characterized by X-ray crystallography. The Pd–Pd bond length in 82 is 2.84 Å, which strongly suggests a metal-metal single bond and bond order of bond length in 82 is 2.84 Å, which strongly suggests a metal-metal single bond and bond order zero. Therefore, in a net two-electron oxidation, PhICl2 oxidizes each palladium center by one electron of zero. Therefore, in a net two-electron oxidation, PhICl2 oxidizes each palladium center by one (d8 -> d7), which results in formation of a metal-metal single bond. Detailed mechanistic and electron (d8 -> d7), which results in formation of a metal-metal single bond. Detailed mechanistic and computational studies support that 82 is then able to undergo a concerted reductive elimination event computational studies support that 82 is then able to undergo a concerted reductive elimination event wherein both components of the new C–X bond arise from a single palladium center. A subsequent wherein both components of the new C–X bond arise from a single palladium center. A subsequent report from Ritter provides additional evidence that a Pd (III) dimer is the kinetically competent report from Ritter provides additional evidence that a Pd (III) dimer is the kinetically competent species in the acetoxylation of 2-phenylpyridine with Pd(OAc)2/PhI(OAc)2 [85]. species in the acetoxylation of 2-phenylpyridine with Pd(OAc)2/PhI(OAc)2 [85].

Molecules 2017, 22, 780 26 of 54 Molecules 2017, 22, 780 26 of 54

Bimetallic Oxidative PhI PhICl2 Addition

Cl Cl Fast N N N Pd O PdII O III O Equilibrium 2 Pd O Me N O Me O Me - 2L O Pd(OAc)L O Me II Me O Me Pd O Pd O PdIIIO + 2L N N N Cl 81 Cl 82 L

Bimetallic HCl Reductive Elimination H Cl N N

SchemeScheme 41. 41.First First evidence evidence forfor thethe rolerole of bimetallic Pd(III) Pd(III) dimers dimers in in catalysis. catalysis.

Together, these reports are the first to show the catalytic competence of Pd(III) dimers in C–X bondTogether, forming these reactions reports and arecould the fuel first further to show investigations the catalytic in the competence area of bimetallic of Pd(III) Pd(III) dimers catalysis. in C–X bondFurthermore forming reactions it supports and the could consideration fuel further of investigations Pd(III) dimers in thealong area Pd(II)/P of bimetallicd(IV) catalytic Pd(III) catalysis.cycles Furthermoreemploying hypervalent it supports iodine the consideration oxidants. of Pd(III) dimers along Pd(II)/Pd(IV) catalytic cycles employing hypervalent iodine oxidants. 2.3.3. Conclusions 2.3.3. Conclusions High valent palladium chemistry represents one of the most well developed areas of high oxidationHigh valent state metal palladium catalysis. chemistry Advancements represents in the oneformation of the of most a wide well range developed of carbon-heteroatom areas of high oxidationbonds including state metal C–O, catalysis. C–X, AdvancementsC–N, as well as in C–C the formationbonds via ofthis a widemanifold range have of carbon-heteroatom been reported. bondsPhI(OAc) including2 andC–O, diaryliodonium C–X, C–N, assalts well have as C–Cbeenbonds the most via widely this manifold applied have hypervalent been reported. iodine reagents PhI(OAc) 2 andin diaryliodoniumcatalytic method salts development have been and the mostPhICl widely2 has been applied successfully hypervalent used iodinefor high reagents valent incomplex catalytic methodisolation. development Detailed mechanistic and PhICl2 studieshas been have successfully revealed usedclear forevidence high valent for Pd(II)/Pd(IV) complex isolation. redox couples Detailed mechanisticin these processes, studies have however revealed the role clear of evidence Pd(III)-dim forers Pd(II)/Pd(IV) along the catalytic redox couplescycles is inbecoming these processes, more howeverevident. the Current role of limitations Pd(III)-dimers remain along in the the reduct catalyticive elimination cycles is becoming of challenging more evident.groups such Current as limitationsfluoride remainor trifluoromethyl in the reductive groups, elimination and developmen of challengingt of oxidants groups that such do as fluoridenot possess or trifluoromethyl competitive groups,ligands and for development reductive elimination of oxidants would that significantly do not possess contribute competitive to this ligands area. for reductive elimination would significantly contribute to this area. 3. Platinum 3. PlatinumPlatinum has played a pivotal role in the evolution of oxidative couplings. Arguably, the “Shilov system”Platinum was hasthe first played significant a pivotal example role of in an the intermolecular evolution ofC–H oxidative functionalization, couplings. wherein Arguably, the oxidation of alkanes to a mixture alcohols and alkyl chlorides was mediated by an aqueous solution the “Shilov system” was the first significant example of an intermolecular C–H functionalization, of [PtCl42−] and [PtCl62−] (Scheme 42a) [86]. Since this seminal discovery, extensive studies have been wherein the oxidation of alkanes to a mixture alcohols and alkyl chlorides was mediated by an aqueous conducted on the Pt(II)/Pt(IV) redox couple, as well as the potential formation of Pt(III) dimeric solution of [PtCl 2−] and [PtCl 2−] (Scheme 42a) [86]. Since this seminal discovery, extensive studies species. Oxidation4 of square6 planar Pt(II) to octahedral Pt(IV) is significantly more facile than have been conducted on the Pt(II)/Pt(IV) redox couple, as well as the potential formation of Pt(III) palladium (standard reduction potentials of [PtCl62−] and [PdCl62−] are +0.68 V and +1.29 V, dimeric species. Oxidation of square planar Pt(II) to octahedral Pt(IV) is significantly more facile respectively) [86], however, Pt(II)/Pt(IV) mediated oxidative couplings are comparatively rare. This 2− 2− thanis due palladium to the significantly (standard higher reduction barrier potentials to reductiv of [PtCle elimination6 ] and for [PdCl Pt(IV)6 relative] are +0.68 to Pd(IV) V and [87]. +1.29 The V, respectively)enhanced stability [86], however, of Pt(IV) Pt(II)/Pt(IV) complexes has mediated been exploited oxidative in their couplings use as areisolable comparatively model systems rare. for This is duethe study to the of significantly more elusive higher Pd(II)/Pd(IV) barrier redox to reductive couples elimination[88]. Mechanistic for Pt(IV) insights relative provided to Pd(IV) by these [87 ]. Thestudies enhanced have stabilitybeen recently of Pt(IV) reviewed complexes [88,89] has and been this section exploited will in cover their recent use as advancements isolable model in Pt(IV) systems forchemistry the study as of they more relate elusive to hypervalent Pd(II)/Pd(IV) iodine redox reagents. couples [88]. Mechanistic insights provided by these studies have been recently reviewed [88,89] and this section will cover recent advancements in Pt(IV) chemistry as they relate to hypervalent iodine reagents.

Molecules 2017, 22, 780 27 of 54 Molecules 2017, 22, 780 27 of 54 Molecules 2017, 22, 780 27 of 54 a. Shilov (1976) Cl NH a. Shilov (1976) 4 a. TFA/H2O H3N Cl IV ClIV NH4 H2Pt Cl6 Pt b.a. NHTFA/H3 2O HCl3N Cl IV PtIV H2Pt Cl6 Cl b. NH3 Cl Stoichiometric C-H activation at Pt(IV)Cl Stoichiometric C-H activation at Pt(IV) b. Modern studies on Pt(IV) – [O] = PhI(OAc)2, PhICl2, Ar2I[X], [(Py)2IPh]2OTf b. UseModern as a studies model system on Pt(IV) for Pd(IV) – [O] = PhI(OAc)2, PhICl2, Ar2I[X], [(Py)2IPh]2OTf Use as a model system for Pd(IV)R R - common in catalysis - relatively unreactive R R R R R R - unstable PdIV PtIV - relatively stable -- challengingcommon in tocatalysis isolate RR R RR R - relatively- often isolable unreactive PdIV PtIV - unstable R R - relatively stable - challenging to isolate R R R R - often isolable R R Development of Pt(II)/Pt(IV) C–H activation Development of Pt(II)/Pt(IV) C–H activation C–H X activation [O] C–H II IV PtX2 RPt X RPtX X has displayed divergent activation–HX [O] II IV reactivity and selectivity to Pd(IV) PtX2 RPt X RPtX X has displayed divergent –HX reactivity and selectivity to Pd(IV) C–X reductive elimination X R X C–X reductive elimination R X SchemeScheme 42. 42.(a )(a Stoichiometric) Stoichiometric C–H C–H functionalization functionalization of of naphthalene naphthalene by by Shilov; Shilov; ( b(b)) General General scheme scheme for for modern applications Pt(II)/Pt(IV) redox couples with hypervalent iodine oxidants. modernScheme applications 42. (a) Stoichiometric Pt(II)/Pt(IV) C–H redox functionalization couples with hypervalentof naphthalene iodine by Shilov; oxidants. (b) General scheme for modern applications Pt(II)/Pt(IV) redox couples with hypervalent iodine oxidants. 3.1. Complex Isolation 3.1. Complex Isolation 3.1. Complex Isolation Canty has conducted many of the seminal reports on the isolation of various Pt(IV) and Pd(IV) Canty has conducted many of the seminal reports on the isolation of various Pt(IV) and Pd(IV) complexesCanty hasvia conductedoxidation manywith bothof the aryl seminal and reportsalkynyliodonium on the isolation salts of (Scheme various Pt(IV)43) [63–66]. and Pd(IV) The complexes via oxidation with both aryl and alkynyliodonium salts (Scheme 43)[63–66]. The iodonium iodoniumcomplexes salts via wereoxidation able to with cleanly both oxidize aryl Pt(II)and complexesalkynyliodonium with a varietysalts (Scheme of ligand 43) scaffolds, [63–66]. giving The saltsriseiodonium were to varying able salts todegrees were cleanly able of cis/transto oxidize cleanly isomers Pt(II) oxidize complexes(83- Pt(II)cis or complexes 83- withtrans), a with at variety low a varietytemperature. of ligand of ligand scaffolds,For scaffolds,characterization giving giving rise topurposesrise varying to varying degreesthese degrees complexes of cis/trans of cis/trans wereisomers isomersthen (83-treated (83-ciscisor with or83- 83-trans NaItrans ),resulting), at at low low temperature. temperature.in triflate displacement, For For characterization characterization and a purposessummarypurposes these theseof complexesthe complexescomplexes were weresynthesized then then treated treated via with this with NaI approach resultingNaI resulting is inprovided triﬂate in triflate displacement,below displacement,(compounds and a summary84and–88 ).a ofThroughoutsummary the complexes of thesethe synthesized complexes reports, Cantysynthesized via this notes approach thevia thishigher is approach provided stability is below ofprovided the (compounds resultant below platinum(compounds84–88). complexes Throughout 84–88). theserelativeThroughout reports, to palladium, Canty these notesreports, facilitating the higherCanty isolation notes stability the and of higher thestru resultantctural stability characterization platinum of the resultant complexes that was platinum relative not possible tocomplexes palladium, with facilitatingtherelative corresponding to isolation palladium, palladium and facilitating structural species. isolation characterization For a furtherand stru discussionctural that characterization was of the not analogous possible that palladium withwas not the possible corresponding components with palladiumtothe Canty’s corresponding species. studies, For palladiumsee a Section further species. 2.2.5.1. discussion For a offurther the analogous discussion palladium of the analogous components palladium to Canty’s components studies, seeto Section Canty’s 2.2.5.1 studies,. see Section 2.2.5.1. R2 = –Ph, CCR [IAr2]OTf or R R2 = –Ph, CCR R [IAr2]OTf 2 R 2 R [PhIC CR]OTf R II or R IV R IV NaI R IV R IV Pt PtR2 or PtR PtR2 or PtR R ° R R ° R R [PhIC–60 CR]OTfC 2 25NaI C R R2 R PtII R OTfPtIV or R OTfPtIV PtI IV or PtI IV R –60 °C R 83-trans R2 83-cis 25 °C R R2 OTf OTf I I 83-trans 83-cis CR CO2R CR Ph Ph CR NMe2 CO R CR Me2 N Me N IV2 R PhIV N PtPhIV PtIV Pt I Me P Pt NMe2 IV Me Pt Me2 R Me Me R IV N PtIV N PtIV N NMePt2IV I P PtI I I Me PtIV Me C I Me2 R R = Ph, Me 85 86 87 Me 88 84 I I NMe2 P I CR I 87 C Me2 84 R = Ph, Me 85 86 88 CR Scheme 43. Characterization of Pt(IV) upon oxidation with diaryl and alkynyliodonium salts. SchemeScheme 43. 43.Characterization Characterization ofof Pt(IV)Pt(IV) uponupon oxidation with with diaryl diaryl and and alkynyliodonium alkynyliodonium salts. salts. In 2005, Sanford reported the oxidation of benzo[h]quinoline supported Pt(II)acac complex 89 with InPhI(OAc) 2005, Sanford2 in an reportedeffort to thegain oxidation mechanistic of benzo[ insighhts]quinoline into the supportedanalogous Pt(II)acacPd(II)/Pd(IV) complex system 89 In 2005, Sanford reported the oxidation of benzo[h]quinoline supported Pt(II)acac complex 89 (Schemewith PhI(OAc) 44) [90].2 in Interestingly,an effort to gain it was mechanistic found that insigh solventts into had the a analogouspronounced Pd(II)/Pd(IV) effect on product system with PhI(OAc) in an effort to gain mechanistic insights into the analogous Pd(II)/Pd(IV) system distribution.(Scheme 44) In 2[90]. AcOH, Interestingly, Pt(III)–Pt(III) it dimerwas found 90 was that obtained, solvent while had a mixturea pronounced of Pt(IV) effect alkoxides on product (91, 92) (Schemeweredistribution. obtained 44)[ 90In ].AcOH,in Interestingly,the Pt(III)–Pt(III)alcoholic solvents, it dimer was found90with was ratios thatobtained, solventdependent while had a onmixture a the pronounced steric of Pt(IV) bulk alkoxides effect of the on alcohol. (91 product, 92) distribution.Alcoholicwere obtained solvents In AcOH,in theare alcoholicnot Pt(III)–Pt(III) able to solvents, serve dimer as withbridging90 ratioswas ligands, obtained,dependent thus while resultingon the a mixturesteric in preferential bulk of Pt(IV)of the formation alcohol. alkoxides (91, 92) were obtained in the alcoholic solvents, with ratios dependent on the steric bulk of the Alcoholic solvents are not able to serve as bridging ligands, thus resulting in preferential formation

Molecules 2017, 22, 780 28 of 54

Molecules 2017, 22, 780 28 of 54 alcohol. Alcoholic solvents are not able to serve as bridging ligands, thus resulting in preferential formationof the monomeric of the monomeric species ( species91, 92) (and91, 92 such) and complexes such complexes were werehypothesized hypothesized to be to analogous be analogous to tointermediates intermediates in inPd(II) Pd(II)/Pd(IV)/Pd(IV) C–H C–H oxygenations. oxygenations. In Incont contrast,rast, isolation isolation of of Pt(III)–Pt(III) Pt(III)–Pt(III) 9090 was surprising asas these these intermediates intermediates had had not beennot invokedbeen invoked in Pd(II)/Pd(IV)-catalyzed in Pd(II)/Pd(IV)-catalyzed processes, processes, however subsequenthowever subsequent studies from studies Ritter, from Sanford, Ritter, andSanford, others and have others shown have the shown viability the of viability Pd(III) dimersof Pd(III) in thesedimers processes in these (seeprocesses Section (see 2.3 Section). Only 2. 0.53.1.2). equivalents Only 0.5 of equivalents PhI(OAc)2 ofwere PhI(OAc) needed2 were for formation needed for of eitherformation themonomeric of either the or bimetallic monomeric species, or bimetallic providing species, strong evidence providing that strong both pathways evidence proceed that both via two-electronpathways proceed oxidation. via two-electron oxidation.

Me O O 0.5 equiv. PtIII Me Me N O N O PhI(OAc)2 Me PtII O AcOH N O 89 Me PtIII Me O O 0.5 equiv. 90 PhI(OAc)2 Me ROH

OR O Me ROH Ratio (91:92) Me N O N MeOH 2.0:1.0 IV IV O Pt Pt EtOH 1.6:1.0 O OR Me iPrOH 0.4:1.0 OR OAc 91 92 Scheme 44. Benzo[h]quinoline Pt(II) oxidation studies. Effect of solvent on oxidation product ratios.ratios.

A subsequent study by Sanford examined the oxidation of 2-phenylpyridine Pt(II) complex 93 with A subsequent study by Sanford examined the oxidation of 2-phenylpyridine Pt(II) complex 93 PhICl2, which led to a mixture of cis and trans Pt(IV) complexes (94-cis 94-trans, Scheme 45a) [91]. This with PhICl2, which led to a mixture of cis and trans Pt(IV) complexes (94-cis 94-trans, Scheme 45a) [91]. was particularly interesting as the analogous Pd(II) complex has been found to give exclusive This was particularly interesting as the analogous Pd(II) complex has been found to give exclusive formation of the cis isomer (95) upon oxidation with PhICl2. Pt(II) complex 93 was also subject to a formation of the cis isomer (95) upon oxidation with PhICl2. Pt(II) complex 93 was also subject to delicate interplay between Pt(IV) and Pt(III)–Pt(III) dimer formation upon oxidation, similar to their a delicate interplay between Pt(IV) and Pt(III)–Pt(III) dimer formation upon oxidation, similar to previous report [90], however in this case product ratios were contingent on choice of external their previous report [90], however in this case product ratios were contingent on choice of external oxidant. Whereas PhICl2 gave exclusively Pd(IV) monomers, altering the oxidant to NCS provided a oxidant. Whereas PhICl2 gave exclusively Pd(IV) monomers, altering the oxidant to NCS provided a Pt(III)–Pt(III) dimer as the major product (not shown). Rourke and co-workers showed that treatment Pt(III)–Pt(III) dimer as the major product (not shown). Rourke and co-workers showed that treatment of Pt(II) complex 96 with PhICl2 resulted in two-electron oxidation with concomitant C–H activation of Pt(II) complex 96 with PhICl2 resulted in two-electron oxidation with concomitant C–H activation to provide Pt(IV) dichloride 98 even at temperatures as low as −40 °C (Scheme 46b) [92]. This result to provide Pt(IV) dichloride 98 even at temperatures as low as −40 ◦C (Scheme 46b) [92]. This is notable as previous studies employing other oxidants (peroxides and molecular oxygen) produced result is notable as previous studies employing other oxidants (peroxides and molecular oxygen) complex mixtures. It is proposed that oxidation proceeds via a five-coordinate, cationic Pt(IV) produced complex mixtures. It is proposed that oxidation proceeds via a five-coordinate, cationic intermediate (97) that is highly active towards arene functionalization. Pt(IV) intermediate (97) that is highly active towards arene functionalization. Building on Ritter’s use of poly(cationic) λ3-iodanes in high oxidation state nickel and Building on Ritter’s use of poly(cationic) λ3-iodanes in high oxidation state nickel and palladium-mediated fluorination (see Sections 2.2.3.1 and 5.3), Dutton investigated the potential of palladium-mediated fluorination (see Section 2.2.3.1 and Section 5.3), Dutton investigated the potential poly(cationic) λ3-iodanes to access a range of dicationic Pd(IV) and Pt(IV) complexes through the of poly(cationic) λ3-iodanes to access a range of dicationic Pd(IV) and Pt(IV) complexes through delivery of neutral heterocyclic ligands to the metal center (Scheme 46) [93]. They found that 2- the delivery of neutral heterocyclic ligands to the metal center (Scheme 46)[93]. They found phenylpyridine Pt(II) complex 93 could be cleanly oxidized to Pt(IV) complex 100 with a DMAP- that 2-phenylpyridine Pt(II) complex 93 could be cleanly oxidized to Pt(IV) complex 100 with a derived poly(cationic) λ3-iodane 99 (Scheme 46a). However, oxidation of dimethyl Pt(II) 101 led to a DMAP-derived poly(cationic) λ3-iodane 99 (Scheme 46a). However, oxidation of dimethyl Pt(II) 101 led less defined product distribution (Scheme 46b), possibly arising from oxidative disproportionation. to a less defined product distribution (Scheme 46b), possibly arising from oxidative disproportionation. This reactivity has been documented in similar Pt(II)/Pt(IV) redox couples, however the intermediacy This reactivity has been documented in similar Pt(II)/Pt(IV) redox couples, however the intermediacy of Pt(III) intermediates cannot be ruled out in this case [94]. These oxidations were also performed on of Pt(III) intermediates cannot be ruled out in this case [94]. These oxidations were also performed on the analogous palladium complexes, which were found to be too unstable for isolation and the analogous palladium complexes, which were found to be too unstable for isolation and underwent underwent rapid disproportionation. While the Pt(IV) species 100 and 102 were isolable, it is notable that they are considerably less stable than complexes possessing anionic chloride or acetate ligands, and similar stability trends were observed for the palladium complexes. While this is detrimental in

Molecules 2017, 22, 780 29 of 54 rapid disproportionation. While the Pt(IV) species 100 and 102 were isolable, it is notable that they are considerably less stable than complexes possessing anionic chloride or acetate ligands, and similar stabilityMolecules trends 2017 were, 22, 780 observed for the palladium complexes. While this is detrimental in the29 context of 54 of Molecules 2017, 22, 780 29 of 54 complex isolation, it could be adventitious for enhancing the reactivity of both high-oxidation state the context of complex isolation, it could be adventitious for enhancing the reactivity of both high- palladiumtheoxidation context and state platinumof complex palladium species isolation, and inplatinum catalysis.it could species be advent in catalysis.itious for enhancing the reactivity of both high- oxidation state palladium and platinum species in catalysis. a. Sanford (2008) Cl Cl a. Sanford (2008) N Cl Cl Cl Cl IV N Cl N Pd N N PhICl PtIV N Cl N IV Cl II 2 N Cl IV Pd N Pt IV N Pt II N PhICl2 Pt IV N N Pt N Pt Cl 95 N 93 N Cl 95 93 Pd(IV)- cis 94-cis (64%) 94-trans (29%) formedPd(IV)- exclusively cis 94-cis (64%) 94-trans (29%) formed exclusively b. Rourke (2008) b. Rourke (2008)

N Cl N N N PtII Arene C–H Cl N Cl N Cl PtII N PhICl2 F IV AreneActivation C–H F IV Pt Cl Pt Cl N PhICl2 F IV Activation F IV Pt Cl Pt Cl F 84% F Cl Cl F N 84% N F F N N F 96 97 98 96proposed 97 intermediate 98 proposed intermediate SchemeScheme 45. ( a45.) Oxidation (a) Oxidation of 2-phenylpryidine of 2-phenylpryidine Pt(II) Pt(II) complex complex with PhIClwith PhICl. Divergent2. Divergent complex complex geometry Scheme 45. (a) Oxidation of 2-phenylpryidine Pt(II) complex with 2PhICl2. Divergent complex geometry from Pd(II); (b) Pt(II) oxidation with PhICl2 resulting in arene C–H activation. fromgeometry Pd(II); (b from) Pt(II) Pd(II); oxidation (b) Pt(II) with oxidation PhICl 2withresulting PhICl2 inresulting arene C–Hin arene activation. C–H activation. a. a. 2 OTf– NMe2 NMe 2 2 OTf– 2 NMe2 NMe2 2

NMe2 N N NMe2 N N N PtII I N N N N N + PtIV PtII NI - PhI N N + PtIV N - PhI 93 N 93 N NMe2 99NMe2 100 99 100 b. b. NMe2 NMe 2 2 NMe2 2 N N NMe2 II Me N N N Pt + 99 PtII N II MeMe N N Me N Pt + 99 IV PtII Me N Pt Me N PtIV Me N 101 NMe Me Me 103 2 101 NMe 102 Me 103 2 102

NMe2 NMe Products Detected N N 2 II Productsby Mass Detected N Pt N PtII Me Spectrometryby Mass Me 104 Spectrometry 104

Scheme 46. Dicationic [PhI(4-DMAP)2][OTf] mediated oxidation of (a) 2-Phenylpyridine Pt(II) complex Scheme 46. Dicationic [PhI(4-DMAP)2][OTf] mediated oxidation of (a) 2-Phenylpyridine Pt(II) complex Scheme93; ( 46.b) DimethylDicationic Pt(II) [PhI(4-DMAP) complex 101. ][OTf] mediated oxidation of (a) 2-Phenylpyridine Pt(II) complex 93; (b) Dimethyl Pt(II) complex 101.2 93;(b) Dimethyl Pt(II) complex 101. 3.2. Catalytic Applications 3.2. Catalytic Applications 3.2. CatalyticWhile Applications platinum is most commonly employed as a model system, recent advancements have shown its viabilityWhile platinumin catalytic is manifolds. most commonly Particularly employed intere assting a model is the system,finding thatrecent platinum-catalyzed advancements have processes shown Whileitsoften viability display platinum in catalytic divergent is mostmanifolds. reactivity commonly Particularly and sele employedctivity intere tosting those as is athe mediated model finding system, thatby palladium. platinum-catalyzed recent advancements processes have often display divergent reactivity and selectivity to those mediated by palladium. shown itsSuna viability reported in catalytic that PtCl manifolds.2 with PhI(OAc) Particularly2 cleanly acetoxylated interesting is the the C-3 ﬁnding position that onplatinum-catalyzed various indoles Suna reported that PtCl2 with PhI(OAc)2 cleanly acetoxylated the C-3 position on various indoles processes(Scheme often 47) display [95]. Pd(OAc) divergent2 was reactivity also a competent and selectivity catalyst, to however those mediated PtCl2 was by found palladium. to be more (Scheme 47) [95]. Pd(OAc)2 was also a competent catalyst, however PtCl2 was found to be more

Molecules 2017, 22, 780 30 of 54

Suna reported that PtCl with PhI(OAc) cleanly acetoxylated the C-3 position on various Molecules 2017, 22, 780 2 2 30 of 54 indoles (Scheme 47)[95]. Pd(OAc)2 was also a competent catalyst, however PtCl2 was found to beMolecules more efﬁcient, 2017, 22, 780 giving cleaner reactions and higher isolated yields. Other oxidants including30 of 54 efficient, giving cleaner reactions and higher isolated yields. Other oxidants including K2S2O8, m-CPBA, K S O , m-CPBA, t-BuOOH, and Cu(OAc) were all completely ineffective (0% conversion) and Mg t-BuOOH,2 2 8 and Cu(OAc)2 were all completely2 ineffective (0% conversion) and Mg peroxyphthalate efficient, giving cleaner reactions and higher isolated yields. Other oxidants including K2S2O8, m-CPBA, peroxyphthalategave a complex mixture gave a complex of products. mixture While of products. not reported, While oxidation not reported, to the oxidation active Pt(IV) to the species active would Pt(IV) speciest-BuOOH, would and likely Cu(OAc) proceed2 were through all completely intermediates ineffective similar (0% to thoseconversion) shown and in SchemeMg peroxyphthalate 43. likelygave proceed a complex through mixture intermediates of products. similarWhile not to reported,those shown oxidation in Scheme to the 43.active Pt(IV) species would

likely proceed through intermediates similar to those shownOAc in Scheme 43. 5 mol% PtCl2, PhI(OAc)2 OAc R1 = CO2R, Me, Ar R3 R2 5 mol% PtCl2, R3 R2 R = Me, Ar AcOH 2 N PhI(OAc) N R1 = CO2R, Me, Ar R R 2 R R R3 = Br, I, OMe, CN, NO2 3 2 3 2 R2 = Me, Ar RN1 AcOH NR1 R3 = Br, I, OMe, CN, NO2 R1 R1 Scheme 47. PtCl2/PhI(OAc)2 mediated C-3 acetoxylation of indoles. Scheme 47. PtCl2/PhI(OAc)2 mediated C-3 acetoxylation of indoles. Scheme 47. PtCl2/PhI(OAc)2 mediated C-3 acetoxylation of indoles. In 2013, Sanford provided the first example of an intermolecular C(sp2)–H arylation enabled by In 2013, Sanford provided the ﬁrst example of an intermolecular C(sp2)–H arylation enabled by a Pt(II)/Pt(IV)In 2013, manifold Sanford provided(Scheme 48a)the first [96]. example The reacti of onan intermolecularwas found to have C(sp a2)–H much arylation broader enabled scope bythan a Pt(II)/Pt(IV) manifold (Scheme 48a) [96]. The reaction was found to have a much broader scope thea analogous Pt(II)/Pt(IV) palladium-catalyzed manifold (Scheme 48a) transformations, [96]. The reaction being was foundtolerant to haveof a widea much range broader of both scope electron than than the analogous palladium-catalyzed transformations, being tolerant of a wide range of both richthe and analogous electron palladium-catalyzed deficient arenes, andtransformations, furthermor e,being a complete tolerant of reversal a wide rangein site-selectivity of both electron was electron rich and electron deﬁcient arenes, and furthermore, a complete reversal in site-selectivity was observedrich and when electron using deficient Na2PtCl arenes,4 versus and Na 2furthermorPdCl4 (Schemee, a complete48b). The reversalproposed in mechanismsite-selectivity proceeds was observed when using Na PtCl versus Na PdCl (Scheme 48b). The proposed mechanism proceeds viaobserved a Pt(II)/Pt(IV) when redoxusing cycleNa2 2PtCl with4 4 versus two-electron Na22PdCl C–C44 (Scheme bond 48b).forming The reductive proposed elimination,mechanism proceedsanalogous via a Pt(II)/Pt(IV) redox cycle with two-electron C–C bond forming reductive elimination, analogous to previousvia a Pt(II)/Pt(IV) work on redox Pd(IV) cycle (see with Section two-electron 2.2.5) [72]. C–C bond forming reductive elimination, analogous to previousto previous work work on on Pd(IV) Pd(IV) (see (see Section Section 2.2.5 2.2.5))[ 72[72].]. a. b. Ph a. b. [M]IV Na2PtCl4 (2.5–5 mol %) IV Ph Na PtCl (2.5–5 mol %) [M] Ph 2[Ar24I]TFA [Ph2I]TFA Ph R [Ar2I]TFA [Ph2I]TFA + R Ar + R AcOH or TFA R Ar Bu4NOTf AcOH or TFA Bu4NOTf Bu NOTf 4 42-85% IV Bu4NOTf [M] 105 106 42-85% [M]IV 105 106

Tolerant of both electron-rich and Na2PdCl4 25 1 Tolerant of both electron-rich and Na2PdCl4 25 1 electron-deficient arenes electron-deficient arenes Na2PtCl4 110 Na2PtCl4 110 Optimized Na PtCl - 1:35 with 65% yield Optimized Na2PtCl2 4 4- 1:35 with 65% yield

Scheme 48. (a) Intermolecular C–H arylation with Pt(II) and diaryliodonium salts; (b) Reversal of site SchemeScheme 48. 48.(a )(a Intermolecular) Intermolecular C–H C–H arylation arylation with with Pt(II)Pt(II) andand diaryliodonium salts; salts; (b (b) )Reversal Reversal of of site site selectivity for Pt(II) vs. Pd(II) in arene C–H activation. selectivityselectivity for for Pt(II) Pt(II) vs. vs. Pd(II) Pd(II) in in arene arene C–H C–H activation. activation.

3.3.3.3. Conclusion Conclusion 3.3. Conclusions TheThe true true strength strength of of the the Pt(II)/Pt(IV) Pt(II)/Pt(IV) redox redox couple couple remains inin itsits use use as as a a model model complex complex for for more more The true strength of the Pt(II)/Pt(IV) redox couple remains in its use as a model complex for reactivereactive Pd(II)/Pd(IV) Pd(II)/Pd(IV) species species due due to to their their increased increased stability.stability. However,However, the the potential potential synthetic synthetic utility utility more reactive Pd(II)/Pd(IV) species due to their increased stability. However, the potential synthetic of platinumof platinum catalyzed catalyzed reactions reactions is is evident, evident, having having displayed displayed enhanced reactivity, reactivity, and and divergent divergent selectivity selectivity utility of platinum catalyzed reactions is evident, having displayed enhanced reactivity,3 and divergent relativerelative to palladium.to palladium. Dutton’s Dutton’s findings findings that that oxidation oxidation employingemploying poly(cationic)poly(cationic) λ λ-iodanes3-iodanes produce produce less less selectivity relative to palladium. Dutton’s ﬁndings that oxidation employing poly(cationic) λ3-iodanes stablestable Pt(IV) Pt(IV) centers centers relative relative to to traditional traditional oxidan oxidantsts maymay lead toto moremore reactive reactive Pt(IV) Pt(IV) intermediates intermediates produceand expand less stable their applications Pt(IV) centers in oxidative relative tocouplings. traditional oxidants may lead to more reactive Pt(IV) and expand their applications in oxidative couplings. intermediates and expand their applications in oxidative couplings. 4. Gold 4. Gold 4.1. Introduction 4.1. Introduction Gold catalysis has historically proceeded through redox neutral pathways relying on its high efficiencyGold catalysiscatalysis as a carbophilic has historicallyhistorically pi acid. proceededThis has seen through wide application redox neutral in the pathways activation relying of alkynes on itsits and highhigh efﬁciencyefficiencyalkenes asasfor aa nucleophilic carbophiliccarbophilic attack pipi acid.acid. and This cycloisomerizati has seen wideon cascades, application and in synthetic the activationactivation applications of alkynesalkynes of these andand alkenespathways forfor nucleophilicnucleophilic have been recently attackattack andreviewedand cycloisomerizationcycloisomerizati [97–100]. Reactionson cascades, containing and syntheticsyntheticAu(I)/Au(III) applicationsapplications redox cycles of thesetheseare pathwayspathwaysrare by have havecomparison, beenbeen recentlyrecently a consequence reviewedreviewed of [[97–100].97 the–100 high]. ReactionsRe baactionsrrier for containingcontaining oxidation Au(I)/Au(III)Au(I)/Au(III) of Au(I) to redoxAu(III) cycles (redox are rarerarepotential byby comparison, comparison, +1.41 V). a consequenceaTypical consequence oxidative of theof hightheaddition/red high barrier ba forrrieructive oxidation for elimination, oxidation of Au(I) whichof to Au Au(III) (I)are to (redoxubiquitous Au(III) potential (redox in +1.41potentialPd(0)/Pd(II) V). Typical+1.41 chemistry, V). oxidative Typical are addition/reductive therebyoxidative cha llengingaddition/red with elimination, Au(I)/Au(III)uctive elimination, which (Scheme are ubiquitouswhich 49a, 107 are to in109ubiquitous Pd(0)/Pd(II)) [101,102] in Pd(0)/Pd(II)and examples chemistry, of such arereactivity thereby are cha scarcellenging [103–105]. with Au(I)/Au(III) Instead, Au(III) (Scheme complexes 49a, can107 beto accessed109) [101,102] via andexposure examples of of an such Au(I) reactivity species, are L nscarce–Au–X, [103–105]. to a powerful Instead, external Au(III) oxidant,complexes and can in be this accessed context via exposurehypervalent of an iodine Au(I) reagents species, have L nfound–Au–X, widespread to a powerful use, along external with hydroperoxides, oxidant, and Selectfluor, in this context and hypervalent iodine reagents have found widespread use, along with hydroperoxides, Selectfluor, and

Molecules 2017, 22, 780 31 of 54 chemistry, are thereby challenging with Au(I)/Au(III) (Scheme 49a, 107 to 109)[101,102] and examples of such reactivity are scarce [103–105]. Instead, Au(III) complexes can be accessed via exposure of an Au(I) species, Ln–Au–X, to a powerful external oxidant, and in this context hypervalent iodine reagentsMolecules have 2017 found, 22, 780 widespread use, along with hydroperoxides, Selectﬂuor, and others. A31 of catalytic 54 cycle based on this approach is shown in Scheme 49a; oxidation of Ln–Au–X gives Au(III) species 107, others. A catalytic cycle based on this approach is shown in Scheme 49a; oxidation of Ln–Au–X gives followed by two subsequent ligand exchanges to access 109, which would then undergo rapid reductive Au(III) species 107, followed by two subsequent ligand exchanges to access 109, which would then eliminationundergo [ 102rapid]. Thisreductive strategy elimination has led [102]. to developments This strategy has in led alkynylation, to developments oleﬁn in functionalization, alkynylation, cross-couplingsolefin functionalization, and dimerization/homo-coupling cross-couplings and dimerization/homo-coupling reactions using a wide reactions range of using oxidants a wide beyond hypervalentrange of iodineoxidants species beyond and hypervalent these reports iodine have specie beens and recently these reports reviewed have bybeen Gouverneur recently reviewed [102]. Unfortunately,by Gouverneur [102]. advancements in reaction development centered on Au(I)/Au(III) have not coincidedUnfortunately, with equivalent advancements mechanistic in reaction understanding development of thecentered oxidation/reduction on Au(I)/Au(III) have pathways not or speciationcoincided of thewith organometallic equivalent mechanistic gold complexes understanding involved. of the Oxidationoxidation/reduction potentials pathways of active or Au(I) speciesspeciation are varied, of the andorganometallic can depend gold on complexes both the involved. counterion Oxidation and the potentials ligand of sphere, active Au(I) making species proper are varied, and can depend on both the counterion and the ligand sphere, making proper oxidant oxidant selection delicate and the generation of isolable Au(III) species challenging and unpredictable. selection delicate and the generation of isolable Au(III) species challenging and unpredictable. However, pioneering studies by Hashmi [106,107], along with the synthesis and characterization of However, pioneering studies by Hashmi [106,107], along with the synthesis and characterization of stoichiometricstoichiometric Au(III) Au(III) complexes complexes by by Bennett Bennett [[108],108], Lippert [1 [10909], ],Fuchita Fuchita [110], [110 and], and Constable Constable [111], [ 111], havehave laid thelaid foundationsthe foundations for for a morea more in in depth depth understandingunderstanding of of the the chemistry chemistry of these of these highly highly reactive reactive intermediatesintermediates (Scheme (Scheme 49b). 49b).

a. Au(I)/Au(III) catalytic cycle b. Stoichiometric Au(III) complexes

R Cl R L AuI X III S Au Reductive [O] N N Cl O Elimination NC III Cl RX Me Au Cl N N CN N III X Au S L X L X O N III III Cl Au Au Me R R Direct X X 109 107 Lippert (1999) Oxidative Constable (1992) Addition R Me X Me PPh2 L X Ligand I III Cl N Ligand AuIII Exchange Au Au AuIII Exchange R X R X Me Cl 108 Ph2P Me [O] = hypervalent iodine, Selectfluor, peroxide

Bennett (2001) Fuchita (2001)

Scheme 49. (a) Plausible Au(I)/Au(III) catalytic cycle based on use of an external oxidant; (b) Pioneering Scheme 49. (a) Plausible Au(I)/Au(III) catalytic cycle based on use of an external oxidant; examples of stoichiometric Au(III) complexes. (b) Pioneering examples of stoichiometric Au(III) complexes. 4.2. Complex Synthesis and Characterization 4.2. Complex Synthesis and Characterization Au(I) cationic salts, along with phosphine and N-heterocyclic carbene (NHC) supported Au(I) Au(I)complexes, cationic are the salts, most along utilized with in phosphine Au(I)/Au(III) and catalysis. N-heterocyclic NHC–Au(I) carbene chemistry (NHC) in particular supported has Au(I) complexes,gained immense are the most popularity utilized in the in Au(I)/Au(III)last decade, making catalysis. them arguably NHC–Au(I) the most chemistry well studied in particular of Au(I) has gainedcomplexes. immense The popularity strong σ–donation in the last of decade, the NHC making ligand themaides arguablyin stabilization the most of both well the studied Au(I) and of Au(I) complexes.Au(III) Thespecies, strong makingσ–donation these ofcomplexes the NHC ideal ligand candidates aides in stabilizationfor the synthesi of boths of theisolable Au(I) Au(III) and Au(III) complexes [112]. species, making these complexes ideal candidates for the synthesis of isolable Au(III) complexes [112]. Limbach and Nolan reported the synthesis of a range of NHC-Au(III) complexes via oxidation Limbach and Nolan reported the synthesis of a range of NHC-Au(III) complexes via oxidation of of an NHC–Au(I)–Cl with PhICl2 (Scheme 50, 110 → 113) [113,114]. The oxidation could also be an NHC–Au(I)–Cl with PhICl (Scheme 50, 110 → 113)[113,114]. The oxidation could also be carried carried out with Cl2(g) at cryogenic2 temperatures, however the oxidation with PhICl2 proceeded more out withcleanly, Cl2 (g)in higherat cryogenic yield, and temperatures, at room temperature, however making the oxidation it far more with advantageous. PhICl2 proceeded This advantage more cleanly, in higherwas attributed yield, and to at the room relatively temperature, milder oxidizing making itconditions far more when advantageous. using PhICl This2 versus advantage Cl2(g). was 3 attributedInterestingly, to the relatively attempted milder oxidations oxidizing with other conditions λ -iodanes when such using as Ph2 PhIClIBr, PhI(OAc)2 versus2, Cland2(g) PhI(OTFA). Interestingly,2 3 attemptedeither oxidationsfailed to oxidize with otherthe Au(I)λ -iodanes complexes such or asgave Ph complex2IBr, PhI(OAc) product2, mixtures. and PhI(OTFA) The authors2 either assert failed to oxidizethat the chlorine Au(I) complexesligands are orcrucial gave to complex stabilize productthe Au(III) mixtures. center and The thus authors PhICl assert2 is optimal that chlorineas it acts ligandsas both an oxidant and chlorinating agent. NHC–Au(I)–Ph complex 112 was also readily oxidized in are crucial to stabilize the Au(III) center and thus PhICl2 is optimal as it acts as both an oxidant and high yield with PhICl2 to give 113, which the authors state is the first reported Au(III) complex of the chlorinating agent. NHC–Au(I)–Ph complex 112 was also readily oxidized in high yield with PhICl2 to type [AuArCl2L] [113]. It is worth noting that trichloride Au(III) complex 111 could not be converted

Molecules 2017, 22, 780 32 of 54

give 113, which the authors state is the ﬁrst reported Au(III) complex of the type [AuArCl2L] [113]. It is worthMolecules noting 2017 that, 22, trichloride780 Au(III) complex 111 could not be converted to 113 via transmetalation32 of 54 with p-methoxyphenylmagnesium bromide, instead giving rise to 4,40-bismethoxybiphenyl via either Moleculesto 113 via 2017 transmetalation, 22, 780 with p-methoxyphenylmagnesium bromide, instead giving rise to32 4,4of 54′- a radicalbismethoxybiphenyl coupling or inner-sphere via either a reductiveradical coupling elimination or inner-sphere pathway. reductive elimination pathway. to 113 via transmetalation with p-methoxyphenylmagnesium bromide, instead giving rise to 4,4′- bismethoxybiphenylMes via either a radical couplingMes or inner-sphere reductive elimination Opathway.Me N N PhICl (p-OMeC H )MgBr AuI Cl 2 Cl 6 4 Mes N MesAuIII OMe N 92-94% N 81% N R Cl Cl R PhICl (p-OMeC H )MgBrMeO AuI Cl 2 111 Cl 6 4 N AuIII 110N PhMgBr 92-94% R Cl Cl 81% R 96% MeO 111 110 PhMgBr R = Mes, Mes 96% Mes N N AuI Ph PhICl2 R = Mes,N N III Cl NMes MesAu 93% R ClN Ph NR AuI Ph PhICl2 N N 113 III Cl 112N Au 93% R Cl Ph R Scheme 50. Clean oxidation of NHC Au(I)113 complexes with PhICl2 by Nolan and Limbach. Scheme112 50. Clean oxidation of NHC Au(I) complexes with PhICl2 by Nolan and Limbach.

It hasScheme also been 50. shown Clean oxidation by Nevado of NHCthat Au(III) Au(I) complexes diacetate complexeswith PhICl2 areby Nolanless stable and Limbach.than the analogous ItAu(III) has alsodichloride been complexes shown by (Schem Nevadoe 51). that Upon Au(III) oxidation diacetate with PhICl complexes2, Au(III) are dichloride less stable complex than the analogous115 isIt has Au(III)isolated also been dichloridein high shown yields by complexes Nevado(Scheme that (Scheme51a), Au(III) however diacetate51). Uponuse complexesof oxidationPhI(OAc) are2 withlessleads stable PhIClto isolation than2, Au(III)the analogousof Au(III) dichloride Au(III) dichloride complexes (Scheme 51). Upon oxidation with PhICl2, Au(III) dichloride complex complexbispentafluorophenyl115 is isolated in complex high yields 119, via (Scheme Au(I) mediated 51a), however transmetalation use of PhI(OAc) (Scheme 51b)2 leads [115]. to Ligand isolation of Au(III)115exchange bispentaﬂuorophenyl is isolated is proposed in high toyields occur complex (Scheme through 11951a), two, via possiblhowever Au(I)e pathways, use mediated of PhI(OAc) either transmetalation via2 leads oxidation to isolation (Schemeof Au(I) of Au(III)species 51b) [ 115]. bispentafluorophenyl complex 119, via Au(I) mediated+ transmetalation (Scheme 51b) [115]. Ligand Ligand116exchange to give 117 is or proposed of a dissociated to occur [Au(PPh through3)2] twospecies possible to give pathways, 118. Both of either these viacomplexes oxidation would ofAu(I) exchangethen converge is proposed to give to119 occur, where through the chloride two possibl atome (observed pathways,+ in either X-ray via crystallography) oxidation of Au(I) is proposed species species 116 to give 117 or of a dissociated [Au(PPh3)2] species to give 118. Both of these complexes 116to come to give from 117 solvent or of aactivation. dissociated [Au(PPh3)2]+ species to give 118. Both of these complexes would wouldthen then converge converge to give to 119 give, where119, wherethe chloride the chlorideatom (observed atom (observedin X-ray crystallography) in X-ray crystallography) is proposed is proposedto come to from come solvent from solventactivation.a. activation. PhICl2 Ph3P Cl I AuIII C6F5 Au PPh3 a. 93% C6F5 Cl

114PhICl2 Ph3P 115 Cl I AuIII C6F5 Au PPh3 93% C6F5 Cl b. 114 115 PhI(OAc) Ph3P Cl I 2 III C6F5 Au PPh3 Au b. 39% C6F5 C6F5 116 119 PhI(OAc) Ph3P Cl I 2 III C6F5 Au PPh3 Au 39% C6F5 C6F5 Ph3P OAc 119 116 AuIII III or [Au (OAc)4] C6F5 OAc 117 118 Ph3P OAc directAu oxidationIII oxidationIII after or [Audissociation(OAc)4] C6F5 OAc 117 118 Scheme 51. (a) Oxidation of [Au(I)(C6F5direct)PPh oxidation3] with PhICloxidation2; (b) Oxidation after of [Au(I)(C6F5)PPh3] with PhI(OAc)2. dissociation

SchemeBased 51. (ona) Oxidationthese findings, of [Au(I)(C PhICl6F52)PPh has3 ]become with PhICl the2 ; reagent(b) Oxidation of choice of [Au(I)(C for the6F 5generation)PPh3] with PhI(OAc)of isolable2. Scheme 51. (a) Oxidation of [Au(I)(C6F5)PPh3] with PhICl2;(b) Oxidation of [Au(I)(C6F5)PPh3] Au(III) complexes, particularly in the context of NHC complexes [112,116,117]. A noteworthy report with PhI(OAc)2. fromBased Huynh on andthese co-workers findings, PhICl utilized2 has PhICl become2 as thethe reagent oxidant of in choice a thorough for the investigationgeneration of intoisolable the Au(III)structural complexes, and electrochemical particularly inproperties the context of of a NHCrange complexes of mono- [112,116,117]. and bis-NHC A noteworthyAu(I) and Au(III)report fromBasedcomplexes. Huynh on theseThis and report findings, co-workers is an PhIClexce utilizedllent2 has source PhICl become for2 as data the on oxidant reagent how oxidation in of a choice thorough state, for NHC, theinvestigation generationand halide into ligands of the isolable Au(III)structuraleffect complexes, the propertiesand particularlyelectrochemical of NHC-Au in the properties species, context and ofof NHC thea rangereader complexes of is directedmono- [112 and there,116 bis-NHC,117 for]. a Adetailed noteworthyAu(I) discussionand Au(III) report of from complexes. This report is an excellent source for data on how oxidation state, NHC, and halide ligands Huynhtheir and findings co-workers [112]. utilized PhICl2 as the oxidant in a thorough investigation into the structural and electrochemicaleffectDutton the properties propertiesand co-workers of NHC-Au of a range recently species, of mono- utilized and the and (poly)cationicre bis-NHCader is directed Au(I) λ3-iodanes there and Au(III)for as a detailedneutral complexes. ligand-donordiscussion This of report their findings [112]. is anoxidants excellent to source access fortricationic data on Au(III) how complexes oxidation state,[118]. The NHC, same and group halide has ligands used these effect oxidants the properties for the of Dutton and co-workers recently utilized (poly)cationic λ3-iodanes as neutral ligand-donor NHC-Austudy species, of Pd(IV) and and the Pt(IV) reader complexes is directed (see there Section for a3.1) detailed and Ritter discussion also employed of their findingsthese reagents [112]. as oxidants toin accessa high tricationicprofile study Au(III) on Pd(IV)-catalyz complexes [118].ed C–H The samefluorination group has(see used Section these 2.2.3.1). oxidants Oxidation for the Dutton and co-workers recently utilized (poly)cationic λ3-iodanes as neutral ligand-donor studyof Au(I) of Pd(IV)complex and 120 Pt(IV) with complexes three different (see Section (poly)cationic 3.1) and λRitter3-iodanes also employedpossessing these varied reagents pyridine as oxidantsoxidantsligands to resulted accessin a high tricationicin profile complexes study Au(III) 121 on– Pd(IV)-catalyz123 complexes (Scheme 52)ed [.118 C–HThis]. discoveryfluorination The same is significant(see group Section has as 2.2.3.1). usedprior attempts theseOxidation oxidants to for theofaccess Au(I) study similar complex of Pd(IV)complexes 120 andwith via Pt(IV) threesalt metathesisdifferent complexes (poly)cationicon (seehalogenated Section λ3 -iodanesAu(III) 3.1) and intermediates possessing Ritter also varied led employed to pyridinecomplex these reagentsligands as oxidantsresulted in in complexes a high proﬁle 121–123 study (Scheme on Pd(IV)-catalyzed 52). This discovery C–H is significant ﬂuorination as prior (see attempts Section 2.2.3.1to ). access similar complexes via salt metathesis on halogenated Au(III) intermediates led to complex

Molecules 2017, 22, 780 33 of 54

Oxidation of Au(I) complex 120 with three different (poly)cationic λ3-iodanes possessing varied pyridine ligands resulted in complexes 121–123 (Scheme 52). This discovery is signiﬁcant as prior attempts to access similar complexes via salt metathesis on halogenated Au(III) intermediates led to complexMolecules decomposition, 2017, 22, 780 emphasizing the power of halide-free external oxidants in Au(I)/Au(III)33 of 54 redox − chemistrydecomposition, [117]. Cyclic emphasizing voltammetry the revealspower of Au(III)/Au(I) halide-free external reduction oxidants potentials in Au(I)/Au(III) ranging from redox0.41 to + + −0.04chemistry V vs. [Fc\Fc [117]. ]Cyclic for 121 voltammetry–123 (reference reveals 0.069 Au(III)/Au(I) V vs. [Fc\Fc reduction] for [Au(III)/Au(I)][(dppe)potentials ranging from 2−]),0.41 showing to a trend−0.04 that V mirrorsvs. [Fc\Fc the+] electronfor 121–123 donating (reference ability 0.069 of V the vs. different [Fc\Fc+] for pyridine [Au(III)/Au(I)][(dppe) ligands ((121)NMe2]), showing2 > (122 )H > (123)CN)a trend and that highlighting mirrors the electron the potential donating to tune ability the of reactivity the different of tricationicpyridine ligands Au(III) ((121 complexes)NMe2 > ( by122 varying)H the heterocyclic> (123)CN) and ligands. highlighting Facile the ligand potential exchange to tune from the reactivity123 was demonstratedof tricationic Au(III) with complexes 2,2,2-tripyridine by varying the heterocyclic ligands. Facile ligand exchange from 123 was demonstrated with 2,2,2- to give 124, which could undergo subsequent exchange with H2O to give Au(III)–OH complex 125. The synthesistripyridine of to terminal give 124, Au(III)–OH which could complexesundergo subsequent is rare and exchange previous with complexes H2O to give were Au(III)–OH accessed via complex 125. The synthesis of terminal Au(III)–OH complexes is rare and previous complexes were salt metathesis with AgClO4 [119]. Intriguingly, homoleptic Au(III) complex (121) is stable to aqueous accessed via salt metathesis with AgClO4 [119]. Intriguingly, homoleptic Au(III) complex (121) is conditions, unlike Au(III) complexes (122 and 123). This distinction in reactivity also indicates that stable to aqueous conditions, unlike Au(III) complexes (122 and 123). This distinction in reactivity chemoselectivealso indicates ligand that chemoselective exchange could ligand be possibleexchange in could these be Au(III) possible trications. in these Au(III) trications.

NMe 2OTf 2 R 2 OTf 3 3OTf

R NMe2 N N N N I Au + I AuIII - PhI N N N N Potential vs Fc/Fc+ Me2N R III/I R Ep,red (Au ) R see table NMe2 (121) –NMe2 –0.41 V 120 (122) –H –0.22 V (123) –CN –0.04 V R = CN 125 0.21 V NMe2 3 3 3OTf 3OTf N N N OH N H O AuIII 2 AuIII N N N N N N

125 124

SchemeScheme 52. 52. Dutton’sDutton’s synthesis synthesis of tricationic of Au(III) tricationic complexes Au(III) and evaluation complexes of their and electrochemical evaluation properties. of their electrochemical properties. 4.3. Synthetic Applications

4.3. SyntheticIn 2008, Applications Beller and Tse developed the first gold catalyzed homo-coupling of arenes using HAuCl4 with PhI(OAc)2 as the external oxidant (Scheme 53a) [120,121]. Mechanistic insights hint that Au(III) is Inthe 2008,active C–H Beller functionalization and Tse developed catalyst and the th firstat a free gold radical catalyzed cation homo-couplingis not likely. PhI(OAc) of arenes2 showed using HAuClthe4 highestwith PhI(OAc) conversion2 as compared the external to other oxidant oxidants (Scheme including 53a) [PhI(OTFA)120,121].2 Mechanistic, IBX and Oxone insights and hint that Au(III)subsequent is thestudies active found C–H it was functionalization essential that the ex catalystternal oxidant and that be hypervalent a free radical iodine cation derived is not[121]. likely. More recently, Larrosa and co-workers demonstrated that electron deficient arene-Au(I) species are PhI(OAc)2 showed the highest conversion compared to other oxidants including PhI(OTFA)2, IBX and Oxonecapable andof mediating subsequent hetero-coupl studies founding reactions it was essentialwith unactivated, that the externalelectron-rich oxidant arenes be utilizing hypervalent Koser’s reagent, PhI(OH)OTs, as the external oxidant (Scheme 53b) [122]. PhI(OPiv)2 also gave very iodine derived [121]. More recently, Larrosa and co-workers demonstrated that electron deficient high yields in this transformation, however “F+” based oxidants Selectfluor and XeF2, as well as other arene-Au(I) species are capable of mediating hetero-coupling reactions with unactivated, electron-rich acetate-ligated hypervalent iodine reagents (PhI(OAc)2, PhI(OTFA)2), were ineffective, again emphasizing arenesthe utilizing delicate Koser’snature of reagent, oxidant PhI(OH)OTs,selection in high-valent as the external metal catalysis. oxidant It (Scheme has also 53demonstratedb) [122]. PhI(OPiv) that 2 + also gavesilylated very arenes high are yields capable in of this undergoing transformation, arylation with however a range “F of” electron-deficient based oxidants and Selectfluor electron- and XeF2,rich as wellarenes as under other Au(I)/Au(III) acetate-ligated redox hypervalent conditions, using iodine an reagentsin situ formed (PhI(OAc) oxidant2, PhI(OTFA)from PhI(OAc)2),2 were ineffective,and camphor again emphasizingsulphonic acid the(CSA) delicate (Scheme nature 53c) [123]. of oxidant Other selectioncarboxylate in ligands high-valent of the PhI(O metal2CR) catalysis.2 It hastype also were demonstrated also effective, that however, silylated λ3-iodane arenes iodosylbenzoic are capable ofacid undergoing and the “F+” arylation oxidant Selectfluor with a range of electron-deficientwere completely ineffective, and electron-rich producing arenes none of under the desired Au(I)/Au(III) product. redox conditions, using an in situ formed oxidant from PhI(OAc)2 and camphor sulphonic acid (CSA) (Scheme 53c) [123]. Other 3 carboxylate ligands of the PhI(O2CR)2 type were also effective, however, λ -iodane iodosylbenzoic acid and the “F+” oxidant Selectfluor were completely ineffective, producing none of the desired product.

Molecules 2017, 22, 780 34 of 54 Molecules 2017, 22, 780 34 of 54

a. Beller, Tse (2008) Me Me Me [O] 2 mol% HAuCl4 Yield PhI(OAc)2 PhI(OTFA)2 69% 81% IBX 1% Me Me Me Oxone 0%

b. Larrosa (2012) OMe F F I Au PHPh3 OMe PhI(OH)OTs I 85% NO2 I NO2

c. Russell (2012) 1 mol% R TMS PPh3AuOTs PhI(OAc)2, CSA R R R 29-97%

SchemeScheme 53.53. ((aa)) FirstFirst exampleexample ofof aa goldgold catalyzed homo-couplinghomo-coupling byby TseTse andand Beller;Beller; ((bb)) StoichiometricStoichiometric Au(I)-areneAu(I)-arene hetero-couplinghetero-coupling ofof unactivatedunactivated arenesarenes usingusing Koser’sKoser’s reagent;reagent; ((cc)) GoldGold catalyzedcatalyzed arylationarylation ofof silylatedsilylated arenesarenes withwith electron-richelectron-rich andand electron-poorelectron-poor arenesarenesby byLloyd-Jones Lloyd-Jones and and Russell. Russell.

Nevado recently provided mechanistic insights into the role of various oxidants in Au(I)/Au(III) Nevado recently provided mechanistic insights into the role of various oxidants in Au(I)/Au(III) oxidative couplings (Scheme 54) [124]. Oxidation of Au(I) complex with PhI(OAc)2 in the presence of oxidative couplings (Scheme 54)[124]. Oxidation of Au(I) complex with PhI(OAc) in the presence of N-methylindole cleanly gave the hetero-coupling product (126) in 80% yield; this transformation2 was N-methylindole cleanly gave the hetero-coupling product (126) in 80% yield; this transformation was also successful using electron-rich arenes 1,3,5- and 1,2,5-trimethoxybenzene. Interestingly, the same also successful using electron-rich arenes 1,3,5- and 1,2,5-trimethoxybenzene. Interestingly, the same transformation using PhICl2 as the external oxidant was only applicable to N-methylindole as a transformation using PhICl as the external oxidant was only applicable to N-methylindole as a substrate. Upon oxidation to 2Au(III) 127, arene-auration can occur through two modes: (1) electrophilic substrate. Upon oxidation to Au(III) 127, arene-auration can occur through two modes: (1) electrophilic aromatic substitution to give 128 or (2) concerted C-H activation via 129, both of which converge to aromatic substitution to give 128 or (2) concerted C-H activation via 129, both of which converge give intermediate 130, which undergoes C–C bond-forming reductive elimination. The reactivity to give intermediate 130, which undergoes C–C bond-forming reductive elimination. The reactivity difference between PhI(OAc)2 and PhICl2 indicate that the basicity of the in-situ generated counterion difference between PhI(OAc)2 and PhICl2 indicate that the basicity of the in-situ generated counterion may play a key role and, analogous to Sanford’s work in Pd(II)/PhI(OAc)2 C–H activation [2], the may play a key role and, analogous to Sanford’s work in Pd(II)/PhI(OAc) C–H activation [2], acetate group may assist in the key activation step (129). This would account2 for the diminished the acetate group may assist in the key activation step (129). This would account for the diminished reactivity seen with PhICl2 in the case of substrates possessing less acidic C–H bonds such as 1,3,5- reactivity seen with PhICl2 in the case of substrates possessing less acidic C–H bonds such as 1,3,5- and and 1,2,5-trimethoxybenzene, and suggest that PhI(OAc)2 may be superior to PhICl2 for Au(III)- 1,2,5-trimethoxybenzene, and suggest that PhI(OAc) may be superior to PhICl for Au(III)-mediated mediated C–H activation. 2 2 C–H activation. Au(III)-catalyzed arene alkynylations have been reported by both Nevado [125] and Waser [126], Au(III)-catalyzed arene alkynylations have been reported by both Nevado [125] and Waser [126], employing PhI(OAc)2 and an alkynyl benziodoxolone respectively (Scheme 55). The development of employing PhI(OAc) and an alkynyl benziodoxolone respectively (Scheme 55). The development gold-mediated alkynylations2 of this type has been recently reviewed [127]. Nevado’s work used of gold-mediated alkynylations of this type has been recently reviewed [127]. Nevado’s work used PhI(OAc)2 as an oxidant to couple electron-withdrawn alkynes and unactivated, electron-rich arenes; PhI(OAc) as an oxidant to couple electron-withdrawn alkynes and unactivated, electron-rich arenes; oxidants 2including PhIO, Selectfluor, and TBHP gave significantly lower yields. Waser utilized a oxidants including PhIO, Selectﬂuor, and TBHP gave signiﬁcantly lower yields. Waser utilized slightly different approach wherein 1-[(triisopropylsilyl)ethynyl]-1λ3,2-benziodoxol-3(1H)-one (TIPS- a slightly different approach wherein 1-[(triisopropylsilyl)ethynyl]-1λ3,2-benziodoxol-3(1H)-one EBX) served as both the oxidant and alkyne source, in the direct C3-alkynylation of indoles. Waser later (TIPS-EBX) served as both the oxidant and alkyne source, in the direct C3-alkynylation of indoles. extended this method to the alkynylation of other electron-rich heterocycles including thiophenes, Waser later extended this method to the alkynylation of other electron-rich heterocycles including anilines, and furans [128–130]. Although Au(I)/Au(III) redox couples are proposed in these cases via thiophenes, anilines, and furans [128–130]. Although Au(I)/Au(III) redox couples are proposed in these intermediates such as 132, Au(I) carbophilic pi activation cannot dismissed as subsequent α- or cases via intermediates such as 132, Au(I) carbophilic pi activation cannot dismissed as subsequent α- β-elimination could provide the desired products via iodo-Au(I) intermediate 131. or β-elimination could provide the desired products via iodo-Au(I) intermediate 131.

Molecules 2017, 22, 780 35 of 54 Molecules 2017, 22, 780 35 of 54 Molecules 2017, 22, 780 35 of 54

C6F5 I C6F5 Ph3P Au C6F5 I Ph3P Au C6F5 N PhI(OAc)2 N N PhI(OAc) N Me 80% 2 126 Me Me 80% 126 Me

Ph3P OAc Ph P AuIII 3 III OAc C6F5 Au N Me H C6F5 N Me H N OAc HOAc NMe OAc HOAc Me 128 C6F5 128 C6F5 PhI(OAc)2 Ph P Ph3P OAc I 3 III OAc III Au PhI(OAc)2 Ph P Au OAc Ph3P Au OAc I 3 III III Me Au C6F5 Au OAc C6F5 Au N C F Me PPh3 C6F5 OAc 6 5 N 126 PPh 127 Me 130 126 3 127 Me O 130 O O H HOAc N O H Ph P Au HOAc NMe 3 Au PhC 3FP Me 6 5 OAc N C6F5 OAc MeN Me 129 129 Scheme 54. Proposed mechanism of Au(I)/Au(III) catalyzed catalyzed hetero-coupling hetero-coupling of electron rich arenes. Scheme 54. Proposed mechanism of Au(I)/Au(III) catalyzed hetero-coupling of electron rich arenes. Nevado (2010) Nevado (2010) OMe 5.0 mol% OMe R Possible Intermediates OMe [Au(PPh5.0 mol%3)Cl] OMe R Possible IntermediatesI [Au(PPhPhI(OAc)3)Cl]2 Au I PhI(OAc)2 [I] Au [I] MeO OMe R MeO OMe R MeO OMe R MeO OMe R 131 131 via pi activation/elimination Si(iPr)3 Waser (2009) Si(iPr) via pi activation/elimination Waser (2009) 3 AuIII Si(iPr) III 3 5.0 mol% AuCl Au Si(iPr)3 5.0 mol% AuCl 132 N N 132 HN (iPr)3Si I O via Au(I)/Au(III) redox cycle H O HN (iPr)3Si I O H via Au(I)/Au(III) redox cycle O

Scheme 55. Oxidative alkynylation reactions by Nevado and Waser. Two potential pathways for Scheme 55. Oxidative alkynylation reactions by Nevado and Waser. Two potential pathways for Schemealkynylation 55. Oxidativebased upon alkynylation Au(I) oxidation reactions or Au(I) by pi Nevado activation. and Waser. Two potential pathways for alkynylationalkynylation basedbased uponupon Au(I)Au(I) oxidationoxidation oror Au(I)Au(I) pipi activation.activation. In 2009, Muñiz and Iglesias took advantage of highly reactive Au(III) complexes to develop a In 2009, Muñiz and Iglesias took advantage of highly reactive Au(III) complexes to develop a gold-catalyzedIn 2009, Muñiz alkene and diamination Iglesias tookreaction advantage (Scheme of56), highly analogous reactive to their Au(III) previous complexes report toemploying develop gold-catalyzed alkene diamination reaction (Scheme 56), analogous to their previous report employing aPd(II)/Pd(IV) gold-catalyzed (see alkeneSection diamination2.2.4.1) [131]. reactionAlkenes (Schemeunderwent 56 ),intramolecular analogous to diamination their previous with reporttosyl- Pd(II)/Pd(IV) (see Section 2.2.4.1) [131]. Alkenes underwent intramolecular diamination with tosyl- employingprotected ureas Pd(II)/Pd(IV) 133 under (see basic Section conditions 2.2.4.1 using)[131 [Au(OAc)PPh]. Alkenes underwent3] to give intramolecular bicyclic ureas ( diamination136) in high protected ureas 133 under basic conditions using [Au(OAc)PPh3] to give bicyclic ureas (136) in high withyield. tosyl-protected Redox neutral ureasanti-aminoauration133 under basic gives conditions Au(I) usingintermediate [Au(OAc)PPh 134, followed] to give by bicyclic irreversible ureas yield. Redox neutral anti-aminoauration gives Au(I) intermediate 134, followed3 by irreversible (oxidation136) in high by PhI(OAc) yield. Redox2 to Au(III) neutral diacetate anti-aminoauration 135. Following gives deprotonation, Au(I) intermediate SN2-type134 intramolecular, followed by oxidation by PhI(OAc)2 to Au(III) diacetate 135. Following deprotonation, SN2-type intramolecular irreversiblecyclization provides oxidation the by desired PhI(OAc) cyclicto urea Au(III) 136 diacetate and regenerates135. Following the Au(I) deprotonation, catalyst. Although S 2-type the cyclization provides the desired cyclic2 urea 136 and regenerates the Au(I) catalyst. AlthoughN the intramolecularproposed Au(III) cyclization intermediates provides were the too desired reactive cyclic to be ureaisolated136, andmechanistic regenerates studies the Au(I)using catalyst.a PPh3– proposed Au(III) intermediates were too reactive to be isolated, mechanistic studies using a PPh3– AlthoughAu(I)–Me thecomplex proposed 137 Au(III)gave an intermediates isomeric mixtures were too of reactiveAu(III) tointermediates be isolated, mechanistic138 and 139 studies upon Au(I)–Me complex 137 gave an isomeric mixtures of Au(III) intermediates 138 and 139 upon oxidation with PhI(OAc)2, which were detectable by 31P-NMR. using a PPh3–Au(I)–Me complex 137 gave an isomeric31 mixtures of Au(III) intermediates 138 and 139 oxidation with PhI(OAc)2, which were detectable by P-NMR.31 upon oxidation with PhI(OAc)2, which were detectable by P-NMR.

Molecules 2017, 22, 780 36 of 54 Molecules 2017, 22, 780 36 of 54 Molecules 2017, 22, 780 36 of 54 H O N O H Ts 7.5 mol% O N [Au(OAc)PPh ] O Ts NH Ts 7.5 mol% 3 N PhI(OAc)[Au(OAc)PPh2, NaOAc3] N Ts NH PhI(OAc) , NaOAc N N R 62-93%2 R RR 133 62-93% RR 136 R 133 R 136

136 133 136 133 LAuIOAc LAuIOAc AcOH Ph3PAu(I)Me AcOH Ph3PAu(I)137 Me 137 Ts PhI(OAc)2 Ts N Ts O PhI(OAc)2 L OAc III O I O N LAu TsHN Au L Ph3P Me OAc N I AuIII N IIIOAc HN Au L Ph P Me 138 O Au AcO3 III OAc N N Au 138 OAc AcO OAc 134 Ph3P OAc 134 AuIII Ph P OAc139 Ts AcO3 III Me Au 139 Ts NH L PhI(OAc) AcO Me AcOH OAc 2 Detected by 31P NMR O NH L AuIII PhI(OAc) AcOH OAc 2 Detected by 31P NMR O N AuIII OAc N OAc OAc 135 OAc 135 Scheme 56. Au(I)/Au(III) catalytic catalytic cycle cycle for for intr intramolecularamolecular diaminat diaminationion of of olefins. oleﬁns. Scheme 56. Au(I)/Au(III) catalytic cycle for intramolecular diamination of olefins. An interesting example of C–C bond cleavage was demonstrated by Shi and co-workers with An interesting example of C–C bond cleavage was demonstrated by Shi and co-workers with Au(I)/Au(III)An interesting catalysis example and methylenecyclopropanes of C–C bond cleavage (Schemewas demonstrated 57) [132]. Precom by Shi plexationand co-workers of alkene with to Au(I)/Au(III)Au(I)/Au(III) catalysis and methylenecyclopropanes (Scheme 5757))[ [132].132]. PrecomplexationPrecomplexation of alkene to Au(I) leads to a redox neutral allylic rearrangement to give 140, which is oxidized with PhI(OAc)2 to Au(I) leads to a redox neutral allylic rearrangement to give 140, which is oxidized with PhI(OAc) to giveAu(I) Au(III) leads todiacetate a redox 141 neutral. Reductive allylic eliminationrearrangement from to 141give would 140, which give the is oxidized desired diacetatewith PhI(OAc) 142 with22 to givegive Au(III)Au(III) diacetatediacetate 141141.. ReductiveReductive eliminationelimination fromfrom 141 would give the desired diacetate 142142 withwith regeneration of a [Au(I)(PMe3)OAc] catalyst. regenerationregeneration ofof aa [Au(I)(PMe[Au(I)(PMe33)OAc] catalyst.catalyst. 5.0 mol% Ar [Au(PMe5.0 mol%3)Cl] Ar OAc PhI(OAc) Ar [Au(PMe3)Cl]2 Ar OAc PhI(OAc) Ar 40-99% 2 Ar OAc Ar 40-99% Ar 142 OAc 142 Ar OAc AuClL Ar Ar OAc AuClL Ar Ar OAc Ar 142 OAc Ar 142 Ar LAuIOAc LAuIOAc HCl HCl

Ph OAc Ph OAc Ph L OAc Ph OAc Ph AuIII OAc Ph L AuI Ph AuIIIOAcOAc Ph AuI 141 OAc 141

Ph OAc PhI(OAc) 2 Ph OAc PhI(OAc) 2 Ph AuI L Ph 140 AuI L 140 Scheme 57. Au(I)/Au(III) catalyzed diacetoxylation of methylenecyclopropanes via C–C bond cleavage. SchemeScheme 57. 57. Au(I)/Au(III)Au(I)/Au(III) catalyzed catalyzed diacetoxylation diacetoxylation of methylenecyclopropanes of methylenecyclopropanes via C–C bond via cleavage. C–C bond cleavage.

Molecules 2017, 22, 780 37 of 54 Molecules 2017, 22, 780 37 of 54 4.4. Conclusions 4.4. ConclusionsAlthough advancements have been made toward mechanistic understanding of Au(I)/Au(III)- mediatedAlthough oxidative advancements couplings, it is have clear that been synthe madetic applications toward mechanistic of gold redox understanding chemistry are still of inAu(I)/Au(III)-mediated their infancy. As methods oxidative development couplings, and it mechanistic is clear that elucidation synthetic applicationsin this field continues, of gold redox the choicechemistry of external are still inoxidant their infancy.play a Ascrucial methods role as development it affects both and the mechanistic stability elucidationof the reactive in this Au(III) field intermediatescontinues, the and choice their of subsequent external oxidant reactivity play in a organic crucial transformations. role as it affects bothThus thefar, stabilityPhICl2 has of emerged the reactive as a leader for the isolation of Au(III) complexes, due the mild reaction conditions and stabilization Au(III) intermediates and their subsequent reactivity in organic transformations. Thus far, PhICl2 impartedhas emerged by the as a transfer leader for of thechloride isolation ligands. of Au(III) Conversely, complexes, PhI(OAc) due the2 is mild more reaction efficient conditions in catalytic and manifolds as the resultant complexes are more reactive and acetate ligands can assist in key C–H stabilization imparted by the transfer of chloride ligands. Conversely, PhI(OAc)2 is more efficient 3 activationin catalytic steps. manifolds The work as the of resultantDutton in complexes the use of (poly)cationic are more reactive λ -iodanes and acetate has laid ligands the groundwork can assist in forkey the C–H exploration activation steps.of highly The tunable work of Au(III) Dutton co inmplexes the use ofand (poly)cationic this discoveryλ3-iodanes could lead has laidto new the developmentsgroundwork for in thethe explorationchemistry of of cationic highly tunableAu(III) intermediates. Au(III) complexes and this discovery could lead to new developments in the chemistry of cationic Au(III) intermediates. 5. Nickel 5. Nickel 5.1. Introduction 5.1. Introduction Nickel is a group 10 metal, the first-row counterpart of palladium. Low oxidation state nickel redoxNickel couples, is a groupsuch as 10 Ni(0)//Ni(I)/Ni(II), metal, the first-row have counterpart seen significant of palladium. applications Low oxidation in catalysis, state nickel including redox Suzuki,couples, Negishi, such as Ni(0)//Ni(I)/Ni(II),and Kumada couplings, have as seen well significant as recent applicationsadvancements in catalysis,in radical including mediated Suzuki, cross- couplingNegishi, andreactions Kumada [133]. couplings, A recent asresurgence well as recent in nickel-catalyzed advancements processes in radical has mediated been fueled cross-coupling not only byreactions its greater [133 sustainability]. A recent resurgence and economic in nickel-catalyzed advantages, but processes also by its has unique been fueled electronic not onlyproperties by its thatgreater facilitate sustainability reactivity and inaccessible economic to advantages, its palladium but counterpart. also by its unique Unlike electronic palladium, properties which relies that almostfacilitate exclusively reactivity inaccessibleon two-electron to its redox palladium cycles, counterpart. nickel can undergo Unlike palladium, facile one- which and two-electron relies almost redoxexclusively events, on providing two-electron access redox to cycles,Ni(0), Ni(I), nickel Ni(I canI), undergo Ni(III), facile and in one- rare and examples, two-electron Ni(IV) redox oxidation events, statesproviding (Scheme access 58). to Ni(0),While Ni(I),these Ni(II), numerous Ni(III), pathways and in rare expand examples, the scope Ni(IV) of oxidation reactivity, states they (Scheme also make 58). characterizationWhile these numerous and mechanistic pathways investigations expand the scope difficult of reactivity, due to the they wide also range make of characterization redox couples that and couldmechanistic be invoked. investigations Recent advancements difficult due toin thehigh wide oxidation range state of redox palladium couples chemistry that could has be sparked invoked. a renewedRecent advancements investigation in into high the oxidation synthesis state and palladium characterization chemistry Ni(III) has and sparked Ni(IV) a renewed species, investigationwhich could greatlyinto the expand synthesis the andcurrent characterization scope of nickel-catalyzed Ni(III) and Ni(IV) reactions. species, In this which section, could we greatly will highlight expand the the keycurrent role scopethat both of nickel-catalyzed ligand scaffold and reactions. oxidant In can this serve section, in the we selection will highlight between the either key role one- that or two- both electronligand scaffold pathways and as oxidant well as can the serve stability in the of selectionthe resultant between high eithervalent one- complexes. or two-electron Hypervalent pathways iodine as oxidantswell as the have stability played of a the key resultant role in the high advancement valent complexes. of this Hypervalent field, analogous iodine to oxidantstheir prominent have played role ina keythe roledevelopment in the advancement of Pd(II)/Pd(IV) of this catalysis field, analogous (see Section to their 2.1). prominent In order to role put in modern the development approaches of intoPd(II)/Pd(IV) context, we catalysis will begin (see with Section a brief 2.1). history In order of to isolated put modern Ni(IV) approaches complexes into accessed context, via we a variety will begin of methods.with a brief history of isolated Ni(IV) complexes accessed via a variety of methods.

Traditional Modes of Ni catalysis: Ni(0)/Ni(I)/Ni(II) Emerging area of research: Ni(II)/Ni(III)/Ni(IV)

1 e– 1 e– 1 e– 2 e– Ni 0 Ni I Ni II Ni III Ni II Ni IV

direct 2 e– Common Oxidants: HVI: PIDA, PhICl2 2 e– Non-HVI: TDTT, NFTPT, Br2 Ni I Ni III

SchemeScheme 58. TraditionalTraditional and and emerging emerging nickel nickel oxidation oxidation states states invoked invoked in in catalysis, and common oxidantsoxidants reported reported in the literature.

Reports on the isolation of Ni(IV) complexes date back to the mid 1970’s, and these species were Reports on the isolation of Ni(IV) complexes date back to the mid 1970’s, and these species even proposed as intermediates in some of the first Ni(0) catalyzed cross coupling reactions. The first were even proposed as intermediates in some of the ﬁrst Ni(0) catalyzed cross coupling reactions. diorganonickel (IV) complex was synthesized and isolated by Cordier in 1994 through oxidative The ﬁrst diorganonickel (IV) complex was synthesized and isolated by Cordier in 1994 through addition of methyl iodide to a Ni(II) precursor with acylphenolato and trimethylphosphine ligands oxidative addition of methyl iodide to a Ni(II) precursor with acylphenolato and trimethylphosphine (Scheme 59) [134]. In this case, the rigid chelate ring contains a hard base and powerful σ-donating ligands (Scheme 59)[134]. In this case, the rigid chelate ring contains a hard base and powerful phosphine ligands that provide substantial stability to the high-oxidation nickel complex. In 1999,

Molecules 2017, 22, 780 38 of 54

σ-donating phosphine ligands that provide substantial stability to the high-oxidation nickel complex. In 1999, Tanaka et al reported the ﬁrst silylnickel(IV) complex (Scheme 59) through a proposed Molecules 2017, 22, 780 38 of 54 oxidative addition of 1,2-disilylbenzene to a Ni(dmpe)2 and subsequent elimination of H2 [135]. Again, this complex was stabilized by strong σ-donor ligands and a rigid chelate similar to Tanaka et al reported the first silylnickel(IV) complex (Scheme 59) through a proposed oxidative that of Cordier, and in both reports, X-ray crystallographic analysis conﬁrmed an octahedral addition of 1,2-disilylbenzene to a Ni(dmpe)2 and subsequent elimination of H2 [135]. Again, this geometry.complex In was 2003, stabilized Linden by reportedstrong σ-donor an isolable ligands Ni(IV)and a rigid complex chelate containingsimilar to that three of Cordier, sigma and bonded norbonylin both ligands reports, in X-ray a pseudo-tetrahedral crystallographic analysis geometry confirmed (Scheme an octahedral 59)[136 ].geometry. This species In 2003, was Linden accessed ◦ via oxidationreported an of isolable a tris(1-norbornyl)nickel(II) Ni(IV) complex containing complex three sigma anion bonded with Onorbonyl2 at −60 ligandsC. Along in a pseudo- with being strongtetrahedralσ-donor geometry ligands, (Scheme the steric 59) [136]. bulk This of thespecies 1-norbonyl was accessed ligands via oxidation provides of a shielding tris(1-norbornyl) necessary for stabilizationnickel(II) complex of the anion trialkylnickel(IV) with O2 at −60 °C. Along species. with Most being recently,strong σ-donor the Steigerwaldligands, the steric group bulk isolatedof the a tetraalkyl1-norbonyl aspirocyclononane ligands provides Ni(IV) shieldin complexg necessary that for is remarkably stabilization stableof the trialkylnickel(IV) to oxygen and high species. temperatures Most recently, the Steigerwald group isolated a tetraalkyl aspirocyclononane Ni(IV) complex that is (Scheme 59)[137]. The complex was isolated as an intermediate in a Ni(0) catalyzed strain release remarkably stable to oxygen and high temperatures (Scheme 59) [137]. The complex was isolated as an ring-opening polymerization, formed via the combination of two molecules of substrate into a dimeric intermediate in a Ni(0) catalyzed strain release ring-opening polymerization, formed via the bismetallocyclopentanecombination of two molecules nickel species. of substrate The remarkable into a dimeric stability bismetallocyclopentane of this complex is nickel attributed species. to The the high degreeremarkable of steric stability shielding of affordedthis complex by theis attributed large alkyl to the ligands. high degree From of these steric reports, shielding common afforded features by emergethe whichlarge alkyl stabilize ligands. high From oxidation these reports, state nickel common complexes: features emerge strong whichσ-donor stabilize ligands, high rigid oxidation chelation, and stericstate shieldingnickel complexes: of the metal strong center. σ-donor Additionally, ligands, rigid these chelation, examples and highlight steric shielding the unusual of the stabilitymetal of the nickel–alkylcenter. Additionally, bond, a featurethese examples not common highlight in latethe unusual transition stability metal of organometallic the nickel–alkyl complexes.bond, a feature Finally, a widenot range common of oxidants, in late transition varied metal in mechanism organometallic and strength,complexes. were Finally, utilized a wide to range access of these oxidants, systems, varied in mechanism and strength, were utilized to access these systems, ranging from C–X oxidative ranging from C–X oxidative addition to O2 oxidation at low temperature. While these studies provide addition to O2 oxidation at low temperature. While these studies provide valuable evidence for the valuable evidence for the viability of Ni(IV) species and the oxidants capable of accessing them, they viability of Ni(IV) species and the oxidants capable of accessing them, they are not readily translatable are not readily translatable to catalytic manifolds. to catalytic manifolds.

O PMe 3 SiH2 Me [O] Me 2 II IV IV H2Si P Ni Ni Ni NiIV O I H2Si P PMe Me2 [O] = MeI, RSi–H, O2 XX 3 SiH2 Cordier (1994) Tanaka (1999)

NiIV R IV Br Ni R

Steingerwald (2009) R = Linden (2003)

SchemeScheme 59. Examples 59. Examples of isolated of isolated organonickel organonickel (IV) (IV) complexes. complexes. Highly Highly rigid rigid ligand ligand scaffolds scaffolds and and strong σ-donorstrong ligands σ-donor are ligands common are featurescommon thatfeatures aid that in stabilization aid in stabilization of these of these species. species.

Over the last 10 years, a renewed interest in this has focused on the subsequent reactivity and Overpossible the synthetic last 10 years,utility aof renewed Ni(IV) species, interest along in thiswith has ligand focused scaffolds on theand subsequentoxidants that reactivity could be and possibledeveloped synthetic into utilityviable catalytic of Ni(IV) systems. species, In alongthis effort, with hypervalent ligand scaffolds iodine reagents and oxidants have emerged that could as be developedpromising into candidates viable catalytic for both systems. species isolation In this effort,and catalysis. hypervalent iodine reagents have emerged as promising candidates for both species isolation and catalysis. 5.2. Stoichiometric Studies 5.2. StoichiometricContinued Studies efforts in the stoichiometric synthesis and characterization of Ni(IV) complexes have Continuedexpanded to effortsinclude in their the subseque stoichiometricnt reactivity, synthesis particularly and characterization in C–C and C–X bond of Ni(IV) forming complexes reductive have expandedeliminations. to include The theirmost challenging subsequent element reactivity, of this particularly work has been in C–C species and isolation C–X bond and formingproof of either reductive Ni(II)/Ni(III) or Ni(II)/Ni(IV) redox couples, as these intermediates are highly reactive and short lived. eliminations. The most challenging element of this work has been species isolation and proof of either The Sanford group has spearheaded these efforts, building on their extensive work in high Ni(II)/Ni(III)oxidation orstate Ni(II)/Ni(IV) palladium chemistry. redox couples, They ashave these explored intermediates the viability are highlyof both reactive Ni(III) and Ni(IV) short lived.

Molecules 2017, 22, 780 39 of 54

The Sanford group has spearheaded these efforts, building on their extensive work in high oxidation state palladium chemistry. They have explored the viability of both Ni(III) and Ni(IV) manifolds as inexpensive analogues to Pd(IV) in C–X reductive eliminations. A 2010 report studied Molecules 2017, 22, 780 39 of 54 the oxidation of complex 143 with an excess of PhICl2, which yielded an approximately 2:1 mixture of C–Clmanifolds and C-Br as reductive inexpensive elimination analogues products to Pd(IV) (Schemein C–X reductive 60a) [138 eliminations.]. This represented A 2010 report the ﬁrst studied example of C–Xthe bondoxidation forming of complex reductive 143 with elimination an excess fromof PhICl nickel.2, which They yielded propose an approximately the likely intermediacy 2:1 mixture of a Ni(III)of speciesC–Cl and (144 C-Br), however reductive note elimination that two-electron products oxidation(Scheme 60a) to Ni(IV)[138]. This (145 )represented cannot be ruledthe first out due to anexample inability of to isolateC–X bond the reactiveforming intermediates.reductive elimin Itation is also from noteworthy nickel. thatThey bothpropose the chlorinethe likely ligands introducedintermediacy upon oxidation,of a Ni(III) andspecies the bromine(144), however ligand note present that intwo-electron complexes oxidation144 and to145 Ni(IV), were (145 available) for C–Xcannot reductive be ruled elimination. out due to an inability to isolate the reactive intermediates. It is also noteworthy that both the chlorine ligands introduced upon oxidation, and the bromine ligand present in complexes A subsequent study by Sanford examined the oxidation of a Ni(PhPy) complex (146), which 144 and 145, were available for C–X reductive elimination. 2 can then undergo competitive C–X or C–C reductive elimination (Scheme 60b) [139]. The analogous A subsequent study by Sanford examined the oxidation of a Ni(PhPy)2 complex (146), which can palladiumthen undergo complex competitive had previously C–X or beenC–C shownreductive to elimination undergo preferential (Scheme 60b) C–X [139]. reductive The analogous elimination whenpalladium exposed complex to a variety had previously of oxidants, been including shown to hypervalentundergo preferential iodine reagentsC–X reductive (see elimination Section 2.2.3.1 ), and thuswhen this exposed study to provideda variety of an oxidants, excellent including comparison hypervalent of the iodine reactivity reagents of these (see Section two metals. 2.2.3.1), It was shownand that thus upon this study oxidation provided with an PhICl excellent2, complex comparis146ongave of the only reactivity trace C–Clof these bond two formation metals. It (3%,was 147) and theshown major that productupon oxidation148 was with that PhICl of2,C–C complex reductive 146 gave elimination. only trace C–Cl Interestingly, bond formation oxidation (3%, 147 of) 146 and the major+ product 148 was that of C–C reductive elimination. Interestingly, oxidation of 146 with with other Cl sources, NCS or CuCl2, provided no observable C–Cl products, showing a slight but other Cl+ sources, NCS or CuCl2, provided no observable C–Cl products, showing a slight but signiﬁcant divergence in reactivity of the hypervalent iodine oxidant. Again, in this study, no high significant divergence in reactivity of the hypervalent iodine oxidant. Again, in this study, no high oxidation state intermediates could be isolated or observed in situ, although the divergent reactivity oxidation state intermediates could be isolated or observed in situ, although the divergent reactivity fromfrom that that of palladium of palladium may may suggest suggest a a difference difference inin mechanism.

a. Sanford (2009) Me Cl Path A: 1 e– N NiIII Ni (III) N Br 53% Me 4 equiv. 144 N N PhICl2 Cl NiII 12 hr, 25 °C + N Br Me 143 Cl 25% Path B: 2 e– N NiIV N Ni (IV) N Cl Br Br 145

b. Sanford (2010) via

II [O] N Ni NiIII or NiIV + N N N C6H6, N rt No isolable Cl 146 intermediates 147 148

[O] yield C–X (147) (%) yield C–C (148) (%)

PhICl2 369 NCS nda 68

a CuCl2 nd 79 a nd = not detected Scheme 60. C–X versus C–C bond forming reductive elimination from high oxidation state nickel. Scheme 60. C–X versus C–C bond forming reductive elimination from high oxidation state nickel. (a) Competitive C–Br vs. C–Cl bond formation; (b) Competitive C–Cl vs. C–C bond formation. (a) Competitive C–Br vs. C–Cl bond formation; (b) Competitive C–Cl vs. C–C bond formation. Recently, in a high-profile report, the same group succeeded in the isolation and characterization Recently,of a Ni(IV) inintermediate a high-proﬁle upon report, oxidation the of same a diorganonickel(II) group succeeded complex in the 149 isolation (Scheme and 61) [140]. characterization At the of a Ni(IV)outset intermediateof their study, upon key insights oxidation into of the a diorganonickel(II) stability of 149 to complexoxidation 149were(Scheme obtained 61 via)[140 cyclic]. At the outsetvoltammetry. of their study, Observation key insights of two intoquasi-reversible the stability oxidation of 149 peaksto oxidation at −0.61 V were and +0.27 obtained vs. Fc/Fc via+, cyclic voltammetry.representative Observation of Ni(II)/Ni(III) of two and quasi-reversible Ni(III)/Ni(IV) redox oxidation couples, peaks is noteworthy at −0.61 as V these and potentials +0.27 vs. are Fc/Fc +, relatively low and hints that catalytic cycles with interchange between these redox states could be representative of Ni(II)/Ni(III) and Ni(III)/Ni(IV) redox couples, is noteworthy as these potentials plausible. Initially, oxidation of 149 with hypervalent iodine reagents PhI(OAc)2, PhICl2, or F+ source

Molecules 2017, 22, 780 40 of 54

areMolecules relatively 2017, 22 low, 780and hints that catalytic cycles with interchange between these redox states could40 of be54 + plausible. Initially, oxidation of 149 with hypervalent iodine reagents PhI(OAc)2, PhICl2, or F source NFTPT resulted in rapidrapid C(spC(sp33)–C(sp2)) reductive reductive elimination elimination to to give cyclobutane 151, notnot allowingallowing for studystudy ofof anyany intermediates.intermediates. However, useuse ofof TDTTTDTT resultedresulted inin formationformation ofof aa stablestable Ni(IV)–CFNi(IV)–CF33 intermediate 152152 thatthat waswas detectabledetectable byby 11H- and 19F-NMR,F-NMR, before before giving rise to the same cyclobutane product 151.. Further evidence for the intermediacy of a Ni(IV) species was provided through X-ray crystallographic characterization of a complex posses possessingsing a tridentate tris(2-pyridyl) methane ligand, ligand, again upon oxidationoxidation with TDTTTDTT (not(not shown).shown). AlthoughAlthough products of oxidationoxidation with hypervalenthypervalent iodine reagents were not directly observed in this case,case, the analogous reactivity of complex 150 to that of hypervalent iodine-mediated oxidation providesprovides strong evidence that those reactions are also proceeding viavia aa Ni(II)/Ni(IV)Ni(II)/Ni(IV) redoxredox couple.couple. This This study study provides provides clear clear evidence evidence for for the the accessibility accessibility of Ni(II)/Ni(IV)of Ni(II)/Ni(IV) catalysis catalysis manifolds manifolds and and supports supports further further efforts efforts for developingfor developing reactions reactions that that invoke invoke this pathway.this pathway. It also It showsalso shows that thethat development the development of novel of novel C–X bond-formingC–X bond-forming reactions, reactions, analogous analogous to those to withthose Pd(II)/Pd(IV), with Pd(II)/Pd(IV), will likely will require likely ligandrequire scaffolds ligand scaffolds that are not that capable are not of undergoingcapable of undergoing competitive C–Ccompetitive reductive C–C elimination. reductive elimination.

Me Me C–C Me Me N reductive NiII Me [O] N Me NiIV elimination N 2 N X II 1 -[Ni ] 149 X 150 151 + 3 2 E1/2 = –0.61V, +0.27V vs Fc/Fc X = F/OTf, OAc, Cl C(sp ) – C(sp ) bond formation [O] X1, X2 Me Me PhI(OAc) OAc, OAc 2 rapid RE PhICl Cl, Cl no isolable N 2 NiIV intermediates S – N CF OTf NFTPT F, OTf 3 TDTT CF3 OTf 152 TDTT OTf, CF3 characterized in situ

Scheme 61.61. OxidationOxidation and and reductive reductive elimination elimination from from a Ni(IV) a Ni(IV) intermediate intermediate using hypervalentusing hypervalent iodine, + + + + Fiodine,, and F CF, and3 sources.CF3 sources. Rapid Rapid and and selective selective C–C C–C bond bond formation formation was was observed observed in in the thecase case ofof all hypervalent iodine oxidants.

Sanford’s group has recently utilized tripyrazoylborate (Tp) as a supporting ligand to isolate Ni(IV) Sanford’s group has recently utilized tripyrazoylborate (Tp) as a supporting ligand to isolate Ni(IV) 2 complex 153 and examine its competency in C(sp2)–CF3 reductive eliminations (Scheme 62a) [141]. complex 153 and examine its competency in C(sp )–CF3 reductive eliminations (Scheme 62a) [141]. Oxidation was examined with a variety of Ar–X species and it was found that only aryldiazonium Oxidation was examined with a variety of Ar–X species and it was found that only aryldiazonium salts salts and diaryliodonium salts were competent oxidants, with diaryliodonium salts giving superior and diaryliodonium salts were competent oxidants, with diaryliodonium salts giving superior yields yields of complex 154. This represents the first evidence of the accessibility of the Ni(II)/Ni(IV) of complex 154. This represents the ﬁrst evidence of the accessibility of the Ni(II)/Ni(IV) manifold manifold under mild conditions with diaryliodonium salts. 154 was further shown to undergo clean under mild conditions with diaryliodonium salts. 154 was further shown to undergo clean C–CF3 bond C–CF3 bond formation upon heating and results suggest a two-electron reductive elimination formation upon heating and results suggest a two-electron reductive elimination pathway. Sanford pathway. Sanford also recently reported the oxidation of a TpNi(II)biphenyl complex 155 and its also recently reported the oxidation of a TpNi(II)biphenyl complex 155 and its subsequent reactivity in subsequent reactivity in C–O bond reductive elimination (Scheme 62b) [142]. Oxidation with C–O bond reductive elimination (Scheme 62b) [142]. Oxidation with PhI(OTFA)2 for just 10 min at PhI(OTFA)2 for just 10 min at 25 °C cleanly produced 156 in 50% isolated yield. In line with their 25 ◦C cleanly produced 156 in 50% isolated yield. In line with their previous studies, intramolecular previous studies, intramolecular C(sp2)–O coupling from 156 was slow, however 157 could be C(sp2)–O coupling from 156 was slow, however 157 could be detected upon heating, the result of C–O detected upon heating, the result of C–O bond-forming reductive elimination followed by cyclization bond-forming reductive elimination followed by cyclization and hemiketalization. It was also found and hemiketalization. It was also found that the –OTFA ligand could under rapid displacement with that the –OTFA ligand could under rapid displacement with a nucleophilic source of –CF3, which a nucleophilic source of –CF3, which would then undergo slow C–CF3 reductive elimination (not would then undergo slow C–CF3 reductive elimination (not shown). Taken together, these two reports shown). Taken together, these two reports show the relatively facile access of the Ni(II)/Ni(IV) show the relatively facile access of the Ni(II)/Ni(IV) manifold with hypervalent iodine reagents and manifold with hypervalent iodine reagents and lend strong support for the development of diverse lend strong support for the development of diverse catalytic reactions via this pathway. Furthermore, catalytic reactions via this pathway. Furthermore, the tripyrazoylborate ligand is emerging as an the tripyrazoylborate ligand is emerging as an excellent choice for stabilization and isolation of high excellent choice for stabilization and isolation of high oxidation state nickel complexes. oxidation state nickel complexes.

Molecules 2017, 22, 780 41 of 54 Molecules 2017, 22, 780 41 of 54 Molecules 2017, 22, 780 41 of 54 a. Sanford (2015) a. Sanford (2015) I BF4 H N NBu I BF H N N 4 4 N H B N NBu4 H B N B N N B N N NN CF3 NN CF3 ° CF3 II IV 55 C CF N Ni CF3 N Ni CF3 55 °C 3 N II ° N IV Ni CF3 –35 C, 10 min N Ni CF3 –Ni(II) N N ° N N CF3 –35 C,77% 10 min N CF3 –Ni(II) 153 77% 154 153 154 Use of other Ar–X oxidants characterized by 1H, 13C, 11 B, 19F NMR Use of other Ar–X oxidants 1 13 11 19 characterizedand x-ray by crystallographyH, C, B, F NMR X N2 BF4 and x-ray crystallography X X= Br, I, OTf N2 BF4 X= Br,<1% I, OTf 42% <1% 42%

b. Sanford (2017) b. Sanford (2017) F3C O O CF3 F C O I O CF 3 I 3 H N K O O H N O H B N N K O O H B N N O N N N N CF3 B B O CF3 ° CFOH NN NN O CF 70 C, 6 h O 3 N NiII N NiIV 3 70 °C, 6 h O OH N NiII 10 min, 25 °C N NiIV –Ni(II) N N 10 min, 25 °C N N –Ni(II) N 50 % N 155 50 % 155 156 157 156 157 Scheme 62. Use of tripyrazoylborate (Tp) ligand in the synthesis and characterization of Ni(IV) SchemeScheme 62. 62.Use Use of tripyrazoylborateof tripyrazoylborate (Tp) (Tp) ligand ligand in the in synthesisthe synthesis and characterizationand characterization of Ni(IV) of Ni(IV) species species via oxidation with hypervalent iodine reagents. (a) Use of diaryliodonium salts; (b) Use of viaspecies oxidation via withoxidation hypervalent with hy iodinepervalent reagents. iodine (reagents.a) Use of diaryliodonium(a) Use of diaryliodonium salts; (b) Use salts; of PhI(OTFA)(b) Use of 2. PhI(OTFA)2. PhI(OTFA)2. TakingTaking advantage advantage of of the the excellentexcellent σσ-donor-donor ability of of NN-heterocyclic-heterocyclic carbenes carbenes (NHCs), (NHCs), Alison Alison Taking advantage of the excellent σ-donor ability of N-heterocyclic carbenes (NHCs), Alison Fout’sFout’s group group reported reported the the isolation isolation of Ni(IV)of Ni(IV) complex complex159 and159 itsand reactivity its reactivity has an has electrophilic an electrophilic halogen Fout’s group reported the isolation of Ni(IV) complex 159 and its reactivity has an electrophilic surrogatehalogen surrogate (Scheme (Scheme63)[143 63)]. Initial[143]. Initial characterization characterization of Ni(II)of Ni(II) species species 158158 via cyclic cyclic voltammetry voltammetry halogen surrogate (Scheme 63) [143]. Initial characterization of Ni(II) species 158 via cyclic voltammetry revealedrevealed only only a a single single reversiblereversible oxidation wave wave at at +0.57 +0.57 V Vvs. vs. Fc/Fc Fc/Fc+, which+, which was attributed was attributed to the to revealed only a single reversible oxidation wave at +0.57 V vs. Fc/Fc+, which was attributed to the theNi(II)/Ni(III) Ni(II)/Ni(III) couple. couple. Thus, it Thus, was so itmewhat was somewhat surprising surprising that treatment that of treatment158 with common of 158 outer-spherewith common Ni(II)/Ni(III) couple. Thus, it was so+ mewhat+ surprising+ + +that treatment+ of 158 with common outer-sphere outer-sphereone-electron one-electron oxidants such oxidants as Ag , such Ph3C as, or Ag Fc, Ph, was3C unsuccessful., or Fc , was Howe unsuccessful.ver, treatment However, of 158 treatment with one-electron oxidants such as Ag+, Ph3C+, or Fc+, was unsuccessful. However, treatment of 158 with ofPhICl158 with2 resulted PhICl 2inresulted clean two-electron in clean two-electron oxidation oxidationto give 159 to, givewhich159 was, which characterized was characterized by X-ray by PhICl2 resulted in clean two-electron oxidation to give 159, which was characterized by X-ray X-raycrystallography. crystallography. This result This result was the was first the definitive first definitive evidence evidence that hypervalent that hypervalent iodine reagents iodine reagents were crystallography. This result was the first definitive evidence that hypervalent iodine reagents were competent oxidants in the Ni(II)/Ni(IV) redox couple. Also notable is the significantly higher werecompetent competent oxidants oxidants in the in the Ni(II)/Ni(IV) Ni(II)/Ni(IV) redox redox couple. couple. Also Also notable notable is the is the significantly significantly higher higher oxidationoxidation potential potential of of158 158relative relative toto thatthat ofof 149 (see Scheme Scheme 61) 61 )and and yet yet PhICl PhICl2 waswas still still a competent a competent oxidation potential of 158 relative to that of 149 (see Scheme 61) and yet PhICl2 2was still a competent oxidant. In the continued development of this field, it will likely be important to continue to obtain oxidant.oxidant. In In the the continued continued development development ofof thisthis field,field, it will likely likely be be important important to to continue continue to toobtain obtain electrochemical measurements of both hypervalent iodine reagents and metal complexes, which electrochemicalelectrochemical measurements measurements of of both both hypervalent hypervalen iodinet iodine reagents reagents and and metal metal complexes, complexes, which which could could then be used as a predictive tool for the success of the subsequent oxidation. thencould be usedthen be as aused predictive as a predictive tool for tool the fo successr the success of the subsequentof the subsequent oxidation. oxidation.

N N N N PhICl N N 2 NCl N PhICl IV N NiII N 2 N Cl Ni N II iPr IV Cl iPr iPr N Ni N iPr N NiCl N Cl iPr iPr iPr Cl iPr iPr iPr Cl iPr Cl iPr iPr iPr iPr iPr 158 159 158 + 159 Ni(II) / Ni(III) --> E1/2 = +0.57 V vs Fc/Fc + Ni(II) / Ni(III) --> E1/2 = +0.57 V vs Fc/Fc Scheme 63. Two electron oxidation of Ni(II) monoanionic bis(carbene) pincer complex with PhICl2 Scheme 63. Two electron oxidation of Ni(II) monoanionic bis(carbene) pincer complex with PhICl2 Schemeand characterization 63. Two electron of stable oxidation Ni(IV) of intermediate Ni(II) monoanionic 159. bis(carbene) pincer complex with PhICl2 and characterization of stable Ni(IV) intermediate 159. and characterization of stable Ni(IV) intermediate 159. 5.3. Synthetic Applications 5.3. Synthetic Applications 5.3. SyntheticCatalytic Applications cycles, and thus also synthetic applications, invoking high oxidation state nickel Catalytic cycles, and thus also synthetic applications, invoking high oxidation state nickel intermediates remain quite rare. However, building on the body of work in stoichiometric complex intermediatesCatalytic cycles, remain and quite thus rare. also However, synthetic building applications, on the body invoking of work high in stoichiometric oxidation state complex nickel synthesis, such reports are beginning to emerge, but the oxidation states in play are difficult to intermediatessynthesis, such remain reports quite are rare. beginning However, to emerge, building bu ont the the oxidation body of work states in in stoichiometric play are difficult complex to

Molecules 2017, 22, 780 42 of 54 synthesis,Molecules 2017 such, 22, 780 reports are beginning to emerge, but the oxidation states in play are difﬁcult42 of 54 to discern.Molecules Below 2017, 22 we, 780 outline recent catalytic reports invoking both Ni(III) and Ni(IV) intermediates42 of 54 via discern. Below we outline recent catalytic reports invoking both Ni(III) and Ni(IV) intermediates via oxidation with hypervalent iodine reagents as well as synthetically relevant applications involving oxidation with hypervalent iodine reagents as well as synthetically relevant applications involving stoichiometricdiscern. Below complexes. we outline recent catalytic reports invoking both Ni(III) and Ni(IV) intermediates via stoichiometricoxidation with complexes. hypervalent iodine reagents as well as synthetically relevant applications involving The Nocera group reported the catalytic photoelimination of Cl2 from a Ni(III) intermediate, stoichiometricThe Nocera complexes. group reported the catalytic photoelimination of Cl2 from a Ni(III) intermediate, accessed via one-electron oxidation of a Ni(II) species with PhICl2 (Scheme 64)[144]. In this case, accessedThe viaNocera one-electron group reported oxidatio nthe of catalytic a Ni(II) photoeliminationspecies with PhICl of2 (SchemeCl2 from 64)a Ni(III) [144]. intermediate,In this case, careful control of the equivalents of PhICl2 allows for selective transfer of a single chlorine atom. carefulaccessed control via one-electron of the equivalents oxidatio of nPhICl of a 2 Ni(II)allows species for selective with PhICltransfer2 (Scheme of a single 64) chlorine [144]. In atom. this case,It is It is also possible that the ligand scaffold does not lower the oxidation potential far enough to make a alsocareful possible control that of the equivalentsligand scaffold of PhICl does2 notallows lower for theselective oxidation transfer potential of a single far enough chlorine to atom. make It ais subsequentsubsequentalso possible Ni(III)/Ni(IV) Ni(III)/Ni(IV) that the ligand oxidation oxidat scaffoldion accessible accessible does not inin lo thisthiswercase, case,the howeveroxidation however electrochemicalpotentialelectrochemical far enough measurementsmeasurements to make a on thisonsubsequent complex this complex were Ni(III)/Ni(IV) were not provided.not provided. oxidation accessible in this case, however electrochemical measurements on this complex were not provided. 0.5 PhICl2 0.5 PhI

0.5 PhICl2 0.5 PhI Cl

P P P ClP Δ -1 NiII H = + 23.7kcal.mol NiIII Cl P P P P Cl Δ -1 Cl Cl NiII H = + 23.7kcal.mol NiIII Cl Cl Cl Cl

hν 0.5 Cl 2 hν 0.5 Cl2 Cl

Cl Cl P P P ClP NiIII III P P Ni Cl Cl P P III Cl Cl Ni NiIII Cl Cl Cl Cl

Scheme 64. Photoelimination of Cl2 via single electron Ni(II)/Ni(III) cycle mediated by PhICl2. Scheme 64. Photoelimination of Cl2 via single electron Ni(II)/Ni(III) cycle mediated by PhICl2. Scheme 64. Photoelimination of Cl2 via single electron Ni(II)/Ni(III) cycle mediated by PhICl2. Chatani’s group invoked a Ni(II)/Ni(IV) catalytic cycle in their development of a directed C(sp3)– Chatani’s group invoked a Ni(II)/Ni(IV) catalytic cycle in their development of a directed H arylationChatani’s with group diaryliodonium invoked a Ni(II)/Ni(IV) salts (Scheme catalytic 65) [145]. cycle A in variety their development of diaryliodonium of a directed salts bearing C(sp3)– C(sp3)–H arylation with diaryliodonium salts (Scheme 65)[145]. A variety of diaryliodonium salts differentH arylation counter with ions diaryliodonium such were exam saltsined, (Scheme however 65) high [145]. yields A werevariety only of obtaineddiaryliodonium in the case salts of triflate,bearing bearing different counter ions such were examined, however high yields were only obtained in the presumablydifferent counter due to ions the such necessary were examregenerationined, however of the Ni(OTf)high yields2 catalyst. were only Although obtained no inintermediates the case of triflate, were case of triﬂate, presumably due to the necessary regeneration of the Ni(OTf) catalyst. Although isolated,presumably radical due trap to theexperiments necessary withregeneration TEMPO gaveof the no Ni(OTf) TEMPO-adducts,2 catalyst. Although providing no 2at intermediates least preliminary were noevidenceisolated, intermediates radicalagainst trap wereone-electron experiments isolated, pathways. radicalwith TEMPO trap experimentsgave no TEMPO-adducts, with TEMPO providing gave no at least TEMPO-adducts, preliminary providingevidence at against least preliminary one-electron evidence pathways. against one-electron pathways. O Ph O Ni(OTf)2, Na2CO3 O R R Ph ON MesCO2H O Ph R ON Ni(OTf)2, Na2CO3 R N Ni N R H R H Ph N N MesCO H N R N Ar I 2 R Ar N ArNi N H OTf H OTf H N N ArPh I Possible Ni(IV) intermediate H Ar Ar OTf 21-72% yieldOTf Ph Possible Ni(IV) intermediate 21-72% yield Scheme 65. C(sp3)–H arylation with diaryliodonium salts through a proposed Ni(II)/Ni(IV) catalytic cycle.

3 Scheme 65. 65. C(spC(sp)–H3 )–Harylation arylation with diaryliodonium with diaryliodonium salts throug saltsh a throughproposed aNi(II)/Ni(IV) proposed Ni(II)/Ni(IV)catalytic cycle. Continuing their work in oxidative fluorination chemistry (for palladium analogue see Section catalytic cycle. 2.2.3.1),Continuing the Ritter grouptheir work reported in oxidative the development fluorination of a chemistry one-step oxidative (for palladium radiofluorination analogue see of arenesSection employing2.2.3.1), the Ni(II) Ritter complexgroup reported 160 with the aqueous development 18F, and of a poly(cationic) one-step oxidative N-ligated radiofluorination λ3-iodane 161 of asarenes the oxidantemployingContinuing (Scheme Ni(II) their66) complex [146]. work This 160 in one-step with oxidative aqueous oxidatio ﬂuorination 18F,n/C–F and bondpoly(cationic) chemistry formation N proceeds (for-ligated palladium λvia3-iodane the two-electron analogue 161 as the see Sectionoxidationoxidant 2.2.3.1 (Scheme of), 160 the 66) Ritterby [146]. cationic group This hypervalentone-step reported oxidatio the iodine developmentn/C–F 161 bond, which of formation a one-stepundergoes proceeds oxidative ligand via theexchange radioﬂuorination two-electron with 18 3 ofnucleophilic arenesoxidation employing of fluoride 160 by Ni(II) and cationic subsequent complex hypervalent160 reductivewith iodine aqueous elimination. 161, whichF, The and useundergoes poly(cationic) of (poly)cationic ligandN-ligated exchange λ3-iodaneλ -iodane with161 161isnucleophilic ascritical the oxidant in this fluoride case (Scheme as and the 66subsequent desired)[146]. 18F This reductive one-step elimination.elimination oxidation/C–F couldThe use easily bond of (poly)cationic be formation outcompeted proceeds λ3-iodane by the via –X161 the two-electronligandsis critical transferred in oxidation this case to theas of the 160metal desiredby center cationic 18 Fwith reductive hypervalent traditio eliminationnal hypervalent iodine could161, whichiodine easily complexes undergoesbe outcompeted (i.e., ligand –Cl, by exchange –OAc,the –X –OTFA)ligands transferred[40]. Instead to complexthe metal 161 center transfers with traditio two “innocent”nal hypervalent hetero iodinecyclic complexesligands, allowing (i.e., –Cl, for –OAc, the –OTFA) [40]. Instead complex 161 transfers two “innocent” heterocyclic ligands, allowing for the

Molecules 2017, 22, 780 43 of 54 with nucleophilic ﬂuoride and subsequent reductive elimination. The use of (poly)cationic λ3-iodane 161 is critical in this case as the desired 18F reductive elimination could easily be outcompeted by the –X ligands transferred to the metal center with traditional hypervalent iodine complexes (i.e., –Cl, Molecules 2017, 22, 780 43 of 54 –OAc, –OTFA) [40]. Instead complex 161 transfers two “innocent” heterocyclic ligands, allowing for the challengingchallenging C–FC–F reductivereductive eliminationelimination toto proceedproceed inin highhigh yield.yield. EvenEven though the detailed mechanistic studiesstudies werewere notnot reported,reported, thethe formationformation ofof Ni(IV)Ni(IV) intermediateintermediate 162162 isis reasonablereasonable byby analogyanalogy toto theirtheir λ3 priorprior reports,reports, as as well well as workas work by Dutton by Dutton employing employing (poly)cationic (poly)cationic-iodanes λ3-iodanes as two-electron as two-electron oxidants inoxidants the generation in the generation of Pd(IV) of and Pd(IV) Pt(IV) and species Pt(IV) (seespecies Section (see Section3.1). This 3.1). work This shows work theshows promise the promise of the λ3 relativelyof the relatively unexplored unexplored class of (poly)cationicclass of (poly)cationic-iodanes λ3 as-iodanes powerful as oxidantspowerful that oxidants allow for that challenging allow for reductivechallenging eliminations reductive eliminations that would be that precluded would be with precluded the use with of more the commonuse of more oxidants. common oxidants.

2 OTf– O O S S N O NO2 O NO2 1.5 equiv N-HVI (161) Ph N Py 18 – N NiII N aqueous F , 18-cr-6 OMe N NiIV N MeCN F Ar 23 oC, <1min 65% Py = 160 Py 162 N Ph 2 Possible Ni(IV) intermediate analogous MeO OMe 2 OTf to Pd(IV)-mediated transformation N N I N-HVI 161 Ph

SchemeScheme 66.66. Ritter’s nickel-mediated radioﬂuorinationradiofluorination via oxidation of Ni(II)Ni(II) withwith (poly)cationic(poly)cationic λλ33-iodane-iodane 161161,, possessingpossessing neutralneutral heterocycleheterocycle ligands.ligands.

5.4.5.4. ConclusionsConclusions HighHigh valentvalent nickelnickel catalysis,catalysis, speciﬁcallyspecifically viavia thethe Ni(II)/Ni(IV)Ni(II)/Ni(IV) redox couple is an emergingemerging areaarea ofof researchresearch thatthat hashas thethe potentialpotential toto offeroffer novelnovel andand powerfulpowerful reactivity.reactivity. TheThe continuedcontinued growthgrowth andand maturationmaturation of this this area area will will rely rely on on continued continued effo effortsrts to tounderstand understand the the role role that that ligand ligand scaffold scaffold and andoxidant oxidant can canplay play in the in theoxidation oxidation states states accessible, accessible, as aswell well as as studies studies aimed aimed at at the isolation andand characterizationcharacterization ofof thesethese highhigh oxidationoxidation statestate complexes.complexes. Furthermore,Furthermore, aa moremore detaileddetailed mechanisticmechanistic understandingunderstanding ofof reportedreported syntheticsynthetic methodsmethods willwill educateeducate furtherfurther reactionreaction development.development.

6.6. Copper

6.1.6.1. Introduction AsAs recentlyrecently asas thethe yearyear 2000,2000, reportsreports ofof isolableisolable high-valenthigh-valent organometallicorganometallic Cu(III)Cu(III) speciesspecies werewere extremelyextremely rarerare (Scheme(Scheme 6767aa)) [[147–149]147–149] andand littlelittle waswas knownknown aboutabout thethe potentialpotential rolerole of of Cu(I)/Cu(III) Cu(I)/Cu(III) cyclescycles inin catalysis.catalysis. However, signiﬁcantsignificant progressprogress hashas beenbeen mademade inin thisthis areaarea overover thethe lastlast 1515 yearsyears andand modernmodern analyticalanalytical techniquestechniques such such as as rapid-injection rapid-injection NMR NMR (RI-NMR) (RI-NMR) have have provided provided clear clear evidence evidence of Cu(III)of Cu(III) intermediates intermediates in carbon-carbon, in carbon-carbon, carbon-halogen, carbon-halogen, and carbon-nitrogen and carbon-nitrogen bond forming bond reactionsforming (Schemereactions 67 (Schemeb) [1]. Applications 67b) [1]. Applications of hypervalent of iodine hypervalent reagents iodine in this areareagents are scarce in this however area are one scarce could imaginehowever that one this could will imagine be a fruitful that area this of will research be a fruitful in the coming area of years. research In this in sectionthe coming recent years. examples In this of proposedsection recent Cu(I)/Cu(III) examples redoxof proposed cycles involvingCu(I)/Cu(III) hypervalent redox cycles iodine involving reagents hypervalent will be presented, iodine reagents though thewill underlying be presented, mechanisms though the of underlying these transformations mechanisms are of stillthese the transformations subject of debate are in still the the literature. subject of debate in the literature.

Molecules 2017, 22, 780 44 of 54 Molecules 2017, 22, 780 44 of 54 Molecules 2017, 22, 780 44 of 54

a. EtO a. EtO N C F N C F C 6F 5 C 6F 5 6 5 6 5 Cl Cl N CF N S III CF 3 III NH III Me S CuIII 3 N CuIII NH NCuIII Me S Cu CF N Cu NCuS N S CF 3 S N 3 N N S S Burton (1989) S S Burton (1989) C6F5 C6F5 C6F5 C6F5 Santo (2006) Santo (2006) Osuka (2000) Osuka (2000) b. b. Br OTMS Me Br OTMS CN Me Me Li Me Li Li CN Li Li III Li Br CuIII Me Me Br III CuIII Me CuIII Me Cu Me Me CuIII Me HN CuIII NH CuIII Me CuIII Me Me CuIII HN Cu NH Me Me Me Me Me Me MeMe Me N Me Me Me N Conjugate addition S 2 alklyation S 2 and S 2' allylic alklyation C–N, C–X, C–O Conjugate addition S N2 alklyation S N2 and S N2' allylic alklyation C–N, C–X, C–O N N N bond formation bond formation Scheme 67. ((aa)) ExamplesExamples Examples ofof isolableisolable isolable Cu(III)Cu(III) Cu(III) complexes;complexes; complexes; (( bb)) ObservedObserved Observed Cu(III)Cu(III) speciesspecies byby rapid-injectionrapid-injection (RI)(RI) NMRNMR spectroscopy.spectroscopy.

6.2. Synthetic Applications Gaunt andand co-workersco-workers havehave reportedreported landmarklandmark examplesexamples ofof Cu(I)/Cu(III)Cu(I)/Cu(III) catalysis through C–H arylation of indoles and benzene derivatives with with diaryliodonium diaryliodonium salts salts (Scheme (Scheme 68)68)[ [150,151].150,151]. Remarkably, these arylations proceeded with extremely high C3C3-- and and metameta-selectivity-selectivity respectively,respectively, respectively, complimentarycomplimentary to to the the analogousanalogous Pd(II)-catalyzedPd(II)-catalyzed transformations transformations which which give give exclusivelyexclusively productsproducts arising from directed C–H activation.activation. Shown Shown in in the context of aren arenee functionalization (Scheme (Scheme 69),69), the authors propose a catalytic cycle involving Ph2IBF4-mediated oxidation of Cu(I) to a highly the authors propose a catalyticcatalytic cyclecycle involvinginvolving PhPh22IBF4-mediated-mediated oxidation oxidation of of Cu(I) Cu(I) to to a a highly electrophilic Cu(III) Cu(III) complex complex 163163,, accompaniedaccompanied, accompanied byby byarylaryl aryl transfer.transfer. transfer. ThisThis Thisspeciesspecies species thenthen thenundergoesundergoes undergoes meta-- selectivemetaselective-selective Friedel-Crafts-typeFriedel-Crafts-type Friedel-Crafts-type metalation,metalation, metalation, facilitatedfacilitated byby facilitated thethe pendantpendant by amide,amide, the pendant followedfollowed amide, byby rearomatizationrearomatization followed by toto giverearomatization Cu(III) complex to give 164 Cu(III).. C–CC–C complex bondbond formingforming164. C–C reductivereductive bond forming eliminationelimination reductive wouldwould elimination provideprovide would thethe providedesireddesired arylatedthe desired product arylated and product regenerate and Cu(I)OTf. regenerate While Cu(I)OTf. this mechanism While this mechanismexplains the explains observed the selectivity, observed theselectivity,the intermediacyintermediacy the intermediacy ofof Cu(III)Cu(III) inin of thesethese Cu(III) processesprocesses in these haha processesss notnot beenbeen has confirmedconfirmed not been expeexpe conﬁrmedrimentally.rimentally. experimentally. TheThe authorsauthors noteThe authorsthat the addition note that of the a radical addition inhibitor, of a radical 1,1-diphenylethylene, inhibitor, 1,1-diphenylethylene, does not inhibit product does notformation, inhibit suggestingproductsuggesting formation, aa radicalradical suggesting mechanismmechanism aradical isis unlikely.unlikely. mechanism InIn cocontrast, is unlikely. Buchwald In contrast, has shown Buchwald that Cu(I)-catalyzed has shown that processesCu(I)-catalyzed involving processes Togni’s involving reagent Togni’sproceed reagent via one-electron proceed via radical one-electron cascades radical [152]. cascades [152].

Previous Reports Gaunt (2009) Previous Reports Gaunt (2009) Pd(II) catalysis 10 mol% Cu(OTf) Ph Pd(II) catalysis 10 mol% Cu(OTf) Ph Ph2I(BF4) Ph2I(OTf) Ph Ph2I(BF4) Ph2I(OTf) Ph 74% N N 74% N NH NH NH H H H

R tBu tBu R tBu Gaunt (2009) tBu Gaunt (2009) O NH HN O HN O O NH Pd(II) Catalysis HN O 10 mol% Cu(OTf) HN O Ph Pd(II) Catalysis Me 10 mol% Cu(OTf) Me Ph Ph2I(PF6) Me Ph2I(BF4) Me Ph2I(PF6) Ph2I(BF4) 79% 79% Ph Ph Scheme 68. Copper-catalyzedCopper-catalyzed oxidativeoxidative arylationarylation reacreactionstions withwith diaryliodoniumdiaryliodonium saltssalts showshow Scheme 68. Copper-catalyzed oxidative arylation reactions with diaryliodonium salts show complimentarycomplimentary regioselectivityregioselectivity toto ananalogousalogous palladium-catalyzedpalladium-catalyzed systems.systems. complimentary regioselectivity to analogous palladium-catalyzed systems.

Molecules 2017, 22, 780 45 of 54 Molecules 2017, 22, 780 45 of 54

Me H N tBu

O Ph2I(BF4) I Ph Cu (OTf)

PhI

Me III [PhCu (OTf)]BF4 NH CuIII Me TfO tBu O Ph NH 164 tBu Me O HOTf H N OTf III O Cu H tBu TfO Ph 163

Scheme 69. Proposed Cu(I)/Cu(III) catalytic catalytic cycle cycle for for C–H C–H functionalization functionalization of benzene derivatives.

6.3. Conclusions 6.3. Conclusions The past 15 years have provided critical experimental evidence for the intermediacy of Cu(III) The past 15 years have provided critical experimental evidence for the intermediacy of Cu(III) in a in a variety of catalytic transformations. Hypervalent iodine reagents have been applied in seminal variety of catalytic transformations. Hypervalent iodine reagents have been applied in seminal reports reports by Gaunt using diaryliodonium salts in C–H arylation, however experimental evidence by Gaunt using diaryliodonium salts in C–H arylation, however experimental evidence supporting a supporting a Cu(I)/Cu(III) pathway is still lacking. Therefore, while the potential of hypervalent Cu(I)/Cu(III) pathway is still lacking. Therefore, while the potential of hypervalent iodine reagents in iodine reagents in high-valent copper catalysis is immense, the continued development of this area high-valent copper catalysis is immense, the continued development of this area will require a more will require a more detailed mechanistic understanding of the pathways involved. detailed mechanistic understanding of the pathways involved.

7. Miscellaneous High Valent Metal ComplexesComplexes In addition to the applications applications discussed discussed thus far, far, hypervalent iodine reagents have been utilized as oxidants for a wide range of metals less prevalent in traditional catalysis. These include oxidations of Mo, W, V, Ce,Ce, Ir,Ir, FeFe andand Rh,Rh, withwith aa largelarge focusfocus onon highhigh valentvalent complexcomplex isolation but a few recent examples also include catalytic reaction development. In this area, PhICl2 and PhI(OAc)2 have been examples also include catalytic reaction development. In this area, PhICl2 and PhI(OAc)2 have been the mostmost widelywidely appliedapplied due due to to their their well-studied well-studied reactivity reactivity and and their their inherent inherent transfer transfer of chloride of chloride and acetateand acetate ligands ligands capable capable of stabilizing of stabilizing high high oxidation oxidation state state species. species.

7.1. Complex Synthesis and Isolation Scheme 70 summarizes the diverse metal complexes that have been accessed via hypervalenthypervalent iodine oxidants.oxidants. TheseThese complexes complexes vary vary in in their their oxidation oxidation states, states, geometries, geometries, ligand ligand scaffolds, scaffolds, and were and accessedwere accessed through through both one-both andone- two-electronand two-electr oxidationon oxidation pathways. pathways. Filippou Filippou utilized utilized PhICl PhICl2 in2 anin oxidativean oxidative decarbonylation decarbonylation approach approach to accessing to accessing Mo(IV) Mo(IV) and W(IV) and complexesW(IV) complexes en route en to studyingroute to trichlorogermylstudying trichlorogermyl compounds compou [153].nds Legzdins [153]. Legzdins synthesized synthesized a V(II) nitrosyl a V(II) complex nitrosyl usingcomplex PhICl using2 in orderPhICl2 to in study order the to nitrosylstudy the ligand nitrosyl effects ligand on early effects transition on early metals transition [154 ].metals In an effort[154]. toIn improvean effort the to synthesesimprove the of syntheses Ce(IV) amides, of Ce(IV) Andwander amides, Andwan and Edelmannder and synthesized Edelmann synthesized a Ce(IV) complex a Ce(IV) with complex use of PhIClwith use2 as of a one-electron PhICl2 as a oxidantone-electron [155]. oxidant Neve used [155]. PhICl Neve2 to used study PhICl the structure2 to study and the properties structure of and an Ir(III)properties dimer of [ 156an Ir(III)]. A report dimer from [156]. Nocera A report synthesized from Nocera Rh(III) synthe complexessized Rh(III) with PhICl complexes2 as part with of a PhICl study2 toas understandpart of a study the to role understand of Rh(III) the hydride role of complexes Rh(III) hydride in the reductioncomplexes of in oxygen the reduction to H2O of in oxygen reactions to withH2O HClin reactions [157]. Periana with HCl demonstrated [157]. Periana functionalization demonstrated of functionalization an Ir(V) complex of with an bothIr(V) PhI(OAc)complex2 withand PhI(OTFA)both PhI(OAc)2 in2 orderand PhI(OTFA) study oxy-functionalization2 in order study oxy-functionalizat reactions from highion reactions oxidation from state high iridium oxidation [158]. Althoughstate iridium not [158]. shown Although in Scheme not 70 shown, PhI(OAc) in Scheme2 and PhICl 70, PhI(OAc)2 also have2 and rich PhICl histories2 also as have co-oxidants rich histories in the studyas co-oxidants of metalloporphyrins in the study of [159 metalloporphyrins–161]. [159–161].

Molecules 2017, 22, 780 46 of 54 Molecules 2017, 22, 780 46 of 54 Molecules 2017, 22, 780 46 of 54 Me Me Me Me Me Cl Si Me Cl IV Cl M PMe2 Cl IV Me2P Si Ce OC PMe PMe N(TMS)2 Cl IV Cl 3 VII 2 (TMS) N MCl PMe2 2 IVN(TMS) Me2ClP NO Ce 2 OC PMe3 Cl II PMe2 N(TMS)2 [M = MoCl or W] V (TMS)2N NO N(TMS)2 ClCl Filippou[M = Mo (or1999 W]) Legzdins (2002) Andwander/Edelmann (2010) PhICl2 PhICl2 PhICl2 Filippou (1999) Legzdins (2002) Andwander/Edelmann (2010) PhICl2 PhICl2 PhICl2 Cl Ph2P PPh2 Ph N Cl N Et3P CO CO Cl III PhI 2IrPIII IrPPhIII I2 Rh Ph N X Cl N III Cl Cl Et3P Ir CO CO Cl III PEt3 PhI IrPIII IrPPhIII I Rh X Cl 2 2 CO N III X Cl Cl PEt3 Ir PhNeveP (1993PPh) Nocera (2012) N 2 2 CO tBu N X PhICl2 PhICl2 Neve (1993) Nocera (2012) N tBu PhICl2 PhICl2 Not shown: tBu Oxidation of Mn, Cr, Fe, Ru porphyrins Periana (2007) Not shown: tBu by PhI(OAc)2 and PhICl2 PhI(OAc)2 or PhI(OTFA)2 Oxidation of Mn, Cr, Fe, Ru porphyrins Periana (2007) by PhI(OAc)2 and PhICl2 PhI(OAc)2 or PhI(OTFA)2 Scheme 70. Examples of high oxidation state transition metal complexes accessed by oxidation with Scheme 70. Examples of high oxidation state transition metal complexes accessed by oxidation with PhI(OAc)Scheme 70.2 and Examples PhICl2. of high oxidation state transition metal complexes accessed by oxidation with PhI(OAc)2 and PhICl2. PhI(OAc)2 and PhICl2. 7.2. Catalytic Applications 7.2. Catalytic Applications 7.2. CatalyticAlthough Applications one-electron manifolds are not prototypical of hypervalent iodine reagents, Although one-electron manifolds are not prototypical of hypervalent iodine reagents, diaryliodoniumAlthough one-electronsalts have been manifolds reported toare serve not asprot one-electronotypical ofox idantshypervalent in both iodineiron and reagents, iridium diaryliodonium salts have been reported to serve as one-electron oxidants in both iron and iridium catalyzeddiaryliodonium transformations. salts have Photoredoxbeen reported catalysis to serve using as Ir(III)(phpy)one-electron3 ,ox withidants Ph2 I(BFin both4) as ironboth and the externaliridium catalyzed transformations. Photoredox catalysis using Ir(III)(phpy) , with Ph I(BF ) as both the oxidantcatalyzed and transformations. phenyl source, Photoredox was successfully catalysis applied using to Ir(III)(phpy) the methoxyphenylation3, with3 Ph2I(BF of4) asstyrene2 both4 thederivatives external external(Schemeoxidant oxidant and 71) [162].phenyl and It issource, phenyl proposed was source, thatsuccessfully Ph was2I(BF successfully4 )applied transfers to a appliedthe phenyl methoxyphenylation radical to the methoxyphenylationto styrene ofwith styrene in situ derivatives oxidation of styrene + + derivativesof(Scheme Ir(III)(phpy) 71) (Scheme [162].3 to It 71 Ir(IV)(phpy)is )[proposed162]. It 3that is. proposedFurther Ph2I(BF oxidation4) thattransfers Ph 2toI(BF a phenyla 4benzylic) transfers radical cation ato phenyl styrene followed radicalwith by in trapping situ to styrene oxidation with with + + inmethanolof situ Ir(III)(phpy) oxidation gives3+ ofthe to Ir(III)(phpy) difunctionalizedIr(IV)(phpy)33+. toFurther Ir(IV)(phpy)product. oxidation 3 .to Further a benzylic oxidation cation tofollowed a benzylic by trapping cation followed with bymethanol trapping gives with methanolthe difunctionalized gives the difunctionalizedproduct. product. OMe 1 mol% Ir(phpy)3, Ph Ph2I(BF4) OMe 1 mol% Ir(phpy)3, Ph MeOH,Ph I(BF 30 )W R bulb2 4 R MeOH,42-83% 30 W R bulb R 42-83%

Ph2I(BF4)

III + Ir (phpy)3 III + IrIV(phpy) + Ir (phpy)3 3 IV + Ph Ir (phpy)3 υ h Ph hυ III Ir (phpy)3 III Ir (phpy)3 Ph MeOH Ph MeOH Scheme 71. Ir(III)(phpy)3 catalyzed photoredox oxyarylation of styrene derivatives.

Scheme 71. Ir(III)(phpy)3 catalyzed photoredox oxyarylation of styrene derivatives. Scheme 71. Ir(III)(phpy)3 catalyzed photoredox oxyarylation of styrene derivatives. Loh has shown that Ph2I(OTf) can act as a one-oxidant in an Fe(II)/Fe(III) catalyzed intramolecular

radicalLoh cyclization has shown cascade that Ph (Scheme2I(OTf) can 72) act [163]. as a It one-oxidant is proposed in that an Fe(II)/Fe(III)Ph2I(OTf) produces catalyzed a phenylintramolecular radical uponradicalLoh oxidation hascyclization shown of that cascadeFe(II) Ph 2to I(OTf)(Scheme Fe(III) can 72)with act [163]. assubseq a one-oxidantIt isuent proposed hydrogen in that an Fe(II)/Fe(III)Phabstraction2I(OTf) produces from catalyzed dichloromethane. a phenyl intramolecular radical radicalupon cyclizationoxidation of cascade Fe(II) (Schemeto Fe(III) 72 with)[163 subseq]. It isuent proposed hydrogen that abstraction Ph2I(OTf) producesfrom dichloromethane. a phenyl radical upon oxidation of Fe(II) to Fe(III) with subsequent hydrogen abstraction from dichloromethane.

Molecules 2017, 22, 780 47 of 54 Molecules 2017, 22, 780 47 of 54

Although these one-electron pathways remain remain ra rare,re, these these reports show promise for the further development of hypervalent iodine reagents in these manifolds.

Me O 10 mol% FeCl2, CHCl2 Ph2I(OTf) O N CH2Cl2 N Me Me 80% Me

Scheme 72. FeCl2 catalyzed carbochloromethylation of activated alkenes. Scheme 72. FeCl2 catalyzed carbochloromethylation of activated alkenes.

7.3. Conclusions Conclusions The versatility of hypervalent iodine reagents is evident in the wide range of metal centers that theythey are are capable of oxidizing. Their Their application application in in the the isolation isolation and and characterization characterization of of late late transition transition metal complexes provides critical insights into the further development and application of these species. Furthermore, Furthermore, their their ability ability to to facilitate facilitate on one-electrone-electron pathways has enabled their extension into metal catalyzed photoredox and radical cascade reactions.

8. Conclusions Conclusions High valent metal catalysis is still an emerging field ﬁeld that continues to be rich with opportunities forfor novel novel and and creative creative reaction development. Hyperv Hypervalentalent iodine reagents have emerged as versatile oxidants in this this area, area, providing providing versatile versatile reactivity reactivity,, heteroatom heteroatom ligands, ligands, and and mild mild reaction reaction conditions. conditions. These reagents are also environmentally benign, no non-toxic,n-toxic, and relatively inexpensive compared to other inorganic oxidants. Despite Despite their their broad broad utility, utility, there there remain remain limitations limitations in in their their application; application; theythey produce stoichiometric organic organic byproducts, byproducts, there there is is a limited scope of heteroatoms ligands available, and their use in facilitating challenging reductive eliminations (i.e., –CF3, –F) is limited. available, and their use in facilitating challenging reductive eliminations (i.e., –CF3, –F) is limited. Future developments in more diverse hypervalent io iodinedine scaffolds, particularly in those that could act as “innocent” oxidants, or those that could bebe readilyreadily recycled/regenerated,recycled/regenerated, has has the the potential to greatly expand the utility of this already powerful reaction manifold.

Acknowledgments: TheThe authors authors would would like to thank Temple UniversityUniversity forfor theirtheir support.support. Additionally, Additionally, acknowledgement isis mademade to to the the donors donors of theof Americanthe American Chemical Chemical Society Society Petroleum Petroleum Research Research Fund for Fund support for supportof this research. of this research. Conﬂicts of Interest: The authors declare no conﬂict of interest. Conflicts of Interest: The authors declare no conflict of interest.

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