Reactions promoted by hypervalent iodine reagents and boron Lewis acids

Understanding the role of boranes in hypervalent iodine chemistry will open up new reactivities which can be utilised in organic synthesis. Due to similar reactivities, λ 3 -iodanes have presented themselves as viable alternatives for many transformations dominated by transition metals whilst mitigating some of the associated drawbacks of metal systems. As showcased by recent reports, boranes can adopt a dual role in hypervalent iodine chemistry that surpasses mere activation of the hypervalent iodine reagent. Increased e ﬀ orts to harness this potential with diverse boranes will uncover exciting reactivity with high applicability across various disciplines including adoption in the pharmaceutical sciences. This review will be relevant to the wider synthetic community including organic, inorganic, materials, and medicinal chemists due to the versatility of hypervalent iodine chemistry especially in combination with borane activation or participation. We aim to highlight the development of hypervalent iodine compounds including their structure, bonding, synthesis and utility in metal-free organic synthesis in combination with Lewis acidic boranes.


Introduction
Since the discovery of dichloro( phenyl)-λ 3 -iodane (1) by Willgerodt, 1 chemical curiosity regarding hypervalent iodine compounds has resulted in numerous publications concerning their preparation, structure and application.][6] Further prominent representatives include (diacetoxyiodo) benzene (PIDA, 3), [bis(trifluoroacetoxy)iodo]benzene (PIFA, 4), where his research focused on the use of stereoelectronic effects in the design of functional small molecules.After a postdoctoral stay in the research group of Dr R. L. Melen at Cardiff University, he is currently working at Evotec (UK) Ltd.
Togni reagent II (5), and 2-iodoxybenzoic acid (IBX, 7) (Fig. 1) are also commercially available and remarkably useful for metal-free synthesis due to their high nucleofugality, controllable reactivity, high stability and easy handling.Hypervalent iodine compounds are valuable reagents, having broad applicability in organic synthesis, 6 and present themselves as non-toxic and environmentally benign alternatives to heavy metals. 7Moreover, hypervalent iodine compounds are commonly used in oxidation reactions, [8][9][10] they have also found widespread utilisation in functionalisations, and are ideally suited for applications in total synthesis as well as the pharmaceutical industry. 11,12When combined with boranes, typically Lewis acid, activation of the hypervalent iodine compound occurs as shown in Scheme 1.
However, in some cases, the borane can also play a dual role that goes beyond mere activation, for example by transferring one of its substituents to the hypervalent iodine compound.

Reactivities of hypervalent iodine compounds
The different types of hypervalent iodine compounds reported to date can be classified according to the oxidation state of the iodine atom. 13Two oxidation states, +3 and +5, are commonly found in these compounds which are generally represented as λ 3 -and λ 5 -iodanes.
Here the superscript states the number of bonds to an atom in comparison with its real or hypothetical parent hydride.iodine compounds is the formation of linear, polarisable, formal 3-centre 4-electron bonds (3c-4e − bonds) 14 between the iodine atom and its two trans ligands.These bonds are composed of two electrons in the unhybridised 5p-orbital of the iodine atom and an electron of each ligand.This bonding type renders the iodine atom partially positively charged ( polarised hypervalent bond) and highly electrophilic making it susceptible towards nucleophilic attack.
The typical reactivity of λ 5 -and λ 7 -iodanes involves oxidative processes, whereas λ 3 -iodanes display two types of reactivity which are determined by the number of heteroatom and carbon-ligands. 15The first group of compounds within λ 3iodanes are of the type RIL 2 and can act as potent oxidising agents.The presence of two heteroatom ligands is an essential requirement for this reactivity.The oxidation reaction consists of a two step process of initial ligand exchange followed by reductive elimination.These two processes constitute the fundamental reactivity behaviour of hypervalent iodine compounds.The second group, of the type R 2 IL, comprises two carbon-based ligands and one heteroatom ligand on the iodine atom.These compounds act as group transfer reagents of one carbon ligand (R) to a range of nucleophiles via reductive elimination of RI and are poor oxidising reagents. 15he exact mechanism of the ligand exchange reaction of λ 3iodanes is still unclear however, a dissociative or an associative pathway (Scheme 2) can be operative, depending on the nature of the λ 3 -iodanes. 15,16The former would proceed via the dissociation of a ligand L from λ 3 -iodane 9 generating iodonium ion 10 as an intermediate followed by nucleophilic attack to give compound 11.For the latter, the order of events would be reversed.The coordination of a nucleophile (Nu − ) to the electrophilic iodine centre in 9 gives the square planar [12-I-4] species trans-12 with a trans-arrangement of the ligands (L) which is in equilibrium with its cis-form (cis-12).Subsequent loss of a ligand L yields the iodine(III) compound 11.
Although the dicoordinated intermediate 10 has been observed in gas phase experiments, 17 solution phase based experimental data indicate the presence of trivalent species due to coordination by anions or solvent molecules.On the other hand, isolation and X-ray crystallographic analysis of stable tetracoordinated hypervalent iodine species with a square planar geometry such as the tetrachloroiodate anion strongly corroborates the associative pathway to be most likely. 18ypervalent iodine compounds commonly undergo reductive elimination to liberate an iodine(I) species.The exceptionally good leaving group aptitude of a λ 3 -iodane arises from the facile and energetically favourable generation of the monovalent iodine compound in a reductive process. 19By studying the solvolysis rates of cyclohexenyl derivatives, Ochiai and coworkers 20 identified the phenyliodo group as having a remarkably good leaving group capability.It is referred to as a hypernucleofuge (super leaving group) because it was determined to be about 10 6 times better as a leaving group than the corresponding triflate.Despite the homonymy, reductive elimination in transition metal catalysis differs from that of hypervalent iodine and the same reactivity in the context of hypervalent iodine chemistry should be referred to as ligand coupling, the concerted process retains the stereochemical configuration of the ligands.The actual pathway of the reductive elimination reaction in λ 3 -iodanes depends strongly on the nature of the ligands on the iodine(III) species, the reaction partner, and the reaction conditions.
Other distinct reaction pathways exhibited by λ 3 -iodanes are nucleophilic substitution, elimination, or fragmentation.The nucleophilic substitutions are most common and can proceed through either S N 2 or S N 1-type processes depending on the capability of the ligand to stabilise the positively charged intermediate.In either case, the same product(s) are formed.Basemediated elimination reactions occur in systems where an acidic proton is present in the αor β-position of one of the ligands.While β-elimination generates double bonds, 21 α-elimination results in the generation of carbenes. 22Less common are processes where the reductive elimination includes a fragmentation. 23nder suitable reaction conditions, iodine(III) compounds may also facilitate transformations which involve the gene-

Rebecca Melen
Dr Rebecca Melen studied for her PhD degree at the University of Cambridge (UK).Following Postdoctoral studies in Toronto (Canada) with Prof. D. W. Stephan and Heidelberg (Germany) with Prof. L. H. Gade, she took up a position at Cardiff University (UK) in 2014 where she is now a Reader in Inorganic Chemistry.In 2018, she was awarded an EPSRC early career fellowship and she was the 2019 recipient of the RSC Harrison Meldola Memorial Prize.Her research interests include diverse aspects of main group reactivity and catalysis, including the applications of main group chemistry in organic synthesis.ration of radical species either by homolytic cleavage of the I-L bond (Scheme 3, I) or by Single Electron Transfer (SET) to the λ 3 -iodane (Scheme 3, II). 24

Activation of hypervalent iodine compounds
Most reactions employing λ 3 -iodanes require activation of the hypervalent iodine compound 25 which is often achieved by addition of a Lewis or Brønsted acid or base.Lewis bases can be additives, the solvent or a substrate.Acid activation is arguably the most frequently employed method among the above mentioned activation modes.A range of Lewis (e.g.TMSOTf, BF 3 •OEt 2 , or metal cations such as Zn, Al, or Mg) or Brønsted (e.g.TfOH, TsOH, AcOH, TFA, or HF) acids that are competent in activating the λ 3 -iodane have been investigated. 26Although Lewis/Brønsted acid mediated cis-activation or trans-activation of λ 3 -iodane are common, recently a double-activation mode for hypervalent iodine reagents has also been reported by Liu (Scheme 1). 27ricoordinated boron Lewis acids are a popular choice for the activation of hypervalent iodine compounds, such as BF 3 , BAr 3 and borosilicates.Pervasive use of trivalent boron compounds (typically BF 3 ) to activate hypervalent iodine compounds can be explained due to their high Lewis acidity.The empty p-orbital of the central boron atom can easily be accesed by a lone pair of electrons from a Lewis site in the hypervalent iodine compound enabling activation through increased electrophilicity.This is especially true for iodosylbenzene (15)  which is an amorphous, pale yellow solid. 28Its polymeric zigzag structure with O-I⋯O linkages renders it insoluble in most organic solvents. 27In 1982, Ochiai and coworkers 29 suggested that BF 3 •OEt 2 activates iodosylbenzene (15) via coordination of the boron Lewis acid to the oxygen atom breaking up the polymeric structure.Analogously, BF 3 •OEt 2 coordination to the acetate oxygen of diacetoxy(m-nitrophenyl)iodane was assumed to activate the λ 3 -iodane at room temperature to effectively oxidise alcohols to carbonyl compounds (Scheme 4). 30resumably, the transformation consists of two steps, both of which are catalysed by BF 3 .The initial ligand exchange reaction on λ 3 -iodanes with the alcohol afforded 13 with sub-sequent β-elimination generating aryliodide 14 along with the respective carbonyl compound.A detailed study of the commercially available PIDA (3)/BF 3 •OEt 2 combination utilised a combined experimental and computational approach for the full investigation of the activation phenomenon. 31 A recent study by Hopkins and Murphy revealed that borosilicates can also be used to activate λ 3 -iodanes and successfully employed for the gem-difluorination reaction.For these reactions, borosilicate was found to be a better activator compared with BF 3 •OEt 2 (Scheme 6). 32 3 -mediated synthesis of iodonium salts under suitable conditions. 33For example, PIDA (3) can be synthesised by treating iodobenzene with peracetic acid in the presence of acetic acid. 34ome λ 3 -iodanes, most often iodosylbenzene (15) and PIDA (3), can themselves serve as precursors for the synthesis of more complex alkenyl(aryl)iodonium ( 16), 35 alkynyl(aryl)iodonium ( 17) 36 or diaryliodonium salts (18) (Scheme 7). 35Alkenyl (aryl)iodonium compounds represent versatile intermediates providing access to functionalised alkenes upon reaction with a variety of nucleophiles via an addition-elimination process (a formal S N 2-type reaction).Additionally, they can undergo α or β-elimination reactions to yield alkylidene carbenes or alkynes, respectively.Reaction of a nucleophilic alkene with 15 or 3 in the presence of BF 3 •OEt 2 followed by anion exchange with NaBF 4 yields the corresponding alkenyl(aryl)iodonium tetrafluoroborates 16 in a stereospecific fashion.Synthesis of vinyliodonium salts can be obtained from the reaction between the corresponding β,β-disubstituted vinylsilanes, vinylboronic acid esters and iodine(III) species.It's noteworthy that this electrophilic substitution reaction leads to retention of configuration of the olefin.Using this reaction condition, (E)-alk-1-enylboronates stereoselectively afforded (E)-alk-1-enyliodonium salts.
Okuyama reported that alkenylboronic esters bearing an acyloxy, alkoxy, or methoxycarbonyl group reacted with PIDA (3) in the presence of BF 3 •OEt 2 to give the alkenyliodonium tetrafluoroborates with complete inversion of configuration. 37hus (E)-and (Z)-boronates gave (Z)-and (E)-iodonium salts, respectively (Scheme 8). 37A strong solvent effect was evident as selectivity was reversed upon addition of ether to the dichloromethane solution.Neighbouring oxy group participation in the reaction was found to be responsible for the stereoselectivity of these reactions.The anti-addition of an internal oxy group to the electrophilic carbon centre (β-position of the boronic ester) and iodine(III) compound led to the formation of a six membered cyclic intermediate.Concerted anti-elimin-ation of the oxy group and boronic ester afforded the iodonium salts with inversion of configuration of the olefin.
Compounds 19 and 23 constitute rather unusual examples of vinyl( phenyl)iodonium species.Ochiai and coworkers described the cyclisation of alkynoic acids to iodine(III)-enol species 19 mediated by BF 3 -activated 15 (Scheme 9, top). 38tang reported the synthesis of dihydrofuranyl ( phenyl)iodonium salt 23 which was obtained from the reaction of allenylphosphonate 20 and PhIF 2 in the presence of BF 3 •OEt 2 in CH 2 Cl 2 at −60 °C (Scheme 9, bottom). 39Presumably, the initially formed allyl cation 21, obtained from the regioselective addition of the BF 3 -activated λ 3 -iodane to 20, undergoes intramolecular cyclisation (22) followed by loss of the methyl group to afford 23.
Furthermore, Ochiai demonstrated a mild reaction protocol for the synthesis of alkynyl( phenyl)iodonium salts. 40eaction between alkynyltrimethylsilanes and iodosylbenzene (15) in the presence of a Lewis acid led to the formation of iodonium salts 25 and 26 with the trimethylsilyl group replaced by a phenyliodonium group in the product.Initially ethynyltrimethylsilane reacted with 15 and BF 3 •OEt 2 in CH 2 Cl 2 to afford (E)-ethoxy(vinyl)iodonium tetrafluoroborate (24).Protodesilylation of 24 using stoichiometric tetrabutylammonium fluoride in THF at −78 °C produced 25 in 63% yield (Scheme 10, top).The reaction was found to be highly Scheme 7 Common strategy for the synthesis of alkenyl-( 16) and alkynylaryl iodonium (17) as well as diaryliodonium tetrafluoroborates (18).Organic & Biomolecular Chemistry Review stereoselective and retention of configuration was observed.However, when commercially available bis(trimethylsilyl) ethyne was employed for the reaction with 15 in the presence of BF 3 •OEt 2 , phenyl(trimethylsilylethynyl)iodonium tetrafluoroborate (26) was obtained (Scheme 10, bottom). 41Treatment of 26 with hydrogen fluoride afforded the ethynyl( phenyl)iodonium tetrafluoroborate 27 in 83% yield.
Employing similar reaction conditions, Ochiai demonstrated the tandem oxidative intramolecular cyclisation of 3-phenylpropanol. 42Formation of 6-chromanyl( phenyl)-λ 3iodanes 28 (Scheme 11, top) originates from the reaction of 15 with either chromane or 3-phenylpropan-1-ol in the presence of BF 3 •OEt 2 .The reported work described the tandem oxidative cyclisation and λ 3 -iodanation of phenylpropanol in which a hypervalent phenyl-λ 3 -iodanyl group was regioselectively introduced at the C6-position of chromane.A more general approach to access these structures was reported by Olofsson et al. (Scheme 11, bottom). 43After in situ oxidation of an aryl iodide using meta-chloroperoxybenzoic acid (m-CPBA) in the presence of BF 3 •OEt 2 , an arylboronic acid was added to the reaction mixture, resulting in the formation of the iodonium borate salt 29.
This protocol enables the rapid synthesis of a variety of symmetrical and unsymmetrical diaryliodonium compounds with electron-withdrawing or donating substituents in moderate to good yields.
Whilst BF 3 •OEt 2 is the most widely used Lewis acidic borane for the activation of hypervalent iodine compounds, we have demonstrated their activation with the highly Lewis acidic tris( pentafluorophenyl)borane [B(C 6 F 5 ) 3 ]. 47The reaction between triacetoxyiodane, B(C 6 F 5 ) 3 and 2,6-lutidine in CH 2 Cl 2 at −40 °C afforded the ion pair 35.X-Ray crystallographic analysis revealed the formation of a lutidine-stabilised diacetoxyiodonium cation, originating from the abstraction of one acetate unit by B(C 6 F 5 ) 3 generating acetoxytriarylborate as the counterion.The reported structure of 35 showed a bidentate binding mode of one acetate with the second acetate being covalently bound via one oxygen atom (Scheme 14).Reaction of B(C 6 F 5 ) 3 and 2,6-lutidine with the related tris(trifluoroacetoxy)iodane yielded diaryliodonium 36 and perfluorophenyliodane 37 (Fig. 2) by double and single ligand exchange, respectively.

Review
Organic & Biomolecular Chemistry boronate ester afforded better yields than BPin.Due to the lower Lewis-acidity of the boronates, it is unlikely that a direct activation of the iodine(III) reagent occurs.

Synthetic applications of the BF 3 •OEt 2 / iodane system
Stereoselective 1,2-difunctionalisation of alkenes provides the simplest way to introduce useful vicinal bifunctional groups onto a hydrocarbon chain. 49Hypervalent iodine reagents can replace the ubiquitous use of transition metals, commonly utilised as catalysts for such transformations.Lewis acidic boranes, mostly BF 3 •OEt 2 , in combination with chiral trivalent iodine compounds have been employed successfully as powerful facilitating tools for enantioselective 1,2-difunctionalisation of alkenes. 50he synthesis of a variety of chiral trivalent iodine compounds bearing an α-tetralol was reported recently by Wirth. 51he alcohol was subsequently employed for the synthesis of iodine(III) species 39a-e (Scheme 16, top) in excellent yields (up to 88%).Pyridine containing substituents 39a (N-methyl salicylamide), amide containing substituents 39b, and 5-methoxy-1-tetralone-based substrates 39c-e were introduced at the oxygen centre of α-tetralol to generate the corresponding iodine(III) species.A mild, efficient, and practical reaction pro-tocol has been demonstrated to prepare such chiral trivalent iodine compounds which can be employed as catalysts in combination with boranes for the stereoselective diacetoxylation of styrene (Scheme 16, bottom).Although good to excellent yields of the diacetoxylated compounds were obtained (yields up to 87%), the enantioselectivities (enantiomeric ratio: up to 61 : 39) were modest.The enantioselective oxyarylation of internal alkenes has also been studied using BF 3 •OEt 2 in combination with a lactate-based chiral iodine(III).
In 2010, Fujita described the enantioselective oxyarylation of (E)-6-aryl-1-silyloxylhex-3-ene to afford 40 (Scheme 17, top). 52Different Lewis and Brønsted acids were screened for the cyclisation reaction and BF 3 •OEt 2 was found to be the most efficient.To test the effect of the steric bulk, different silyl groups were employed for the cyclisation reaction with slightly better enantioselectivity being observed with the bulky tertbutyldiphenyl silane (TBDPS) compared to the tert-butyldi-  methylsilyl ether (TBS) group.Several substrates were examined and good yields (up to 88%) of the desired products with high enantioselectivities (up to 93%) were observed.Mechanistic studies (Scheme 18) revealed that the Lewis acidic boranes are required to activate the hypervalent iodine compound which facilitates the electrophilic addition to the olefins.The nucleophilic addition of the internal oxy group afforded 42, and product 40 formed after further nucleophilic addition of the aryl group.The authors determined that the lactate-based hypervalent iodine reagent 41 reacts particularly well with one of the enantiotopic faces of the olefin (which is the rate-determining step) and induces the formation of the cyclised product.
Preparation of biologically useful isochromanone scaffolds have been carried out using λ 3 -iodane.In 2010, Fujita demonstrated the regio-and diastereo-selective oxidative lactonisation of 2-vinylbenzoic acid to 4-oxyisochroman-1-one 43a using λ 3iodane as a catalyst (Scheme 19, top). 53BF 3 •OEt 2 was used as the Lewis acidic component to activate the iodine reagent.Vast studies revealed that different oxy groups such as methoxymethyl and hydroxymethyl in the alkenyl moiety does not affect the formation of δ lactone.The reported methodology can be utilised to prepare synthetically useful biologically active compounds 44 (Scheme 19, bottom).
Prévost and Woodward reactions for dioxyacetylation of alkenes using chiral hypervalent iodine compounds have also been carried out by Fujita (Scheme 20).An optically active hypervalent iodine reagent (45) in combination with a Lewis acidic boron BF 3 •OEt 2 and acetic acid were employed for the reaction with different cinnamyl derivative (46) at −80 °C to afford enantioselective dioxyacetylated products (47). 54iastereoselectivities (syn/anti selectivity) in the dioxyacetylated products showed a dependence on the reaction temperature.When the reaction was carried out at −80 °C to −40 °C, a regioisomeric mixture of monoacetoxy and diacetoxy compounds were obtained.Further treatment with pyridine enabled full conversion to the diacetoxy compounds 47a (Scheme 20, top).High enantioselectivity (up to 96%) of the syn product (1S,2S) and excellent diastereoselectivity between the syn and anti-conformer (98 : 2) was observed.Intriguingly, the reaction at −80 °C to room temperature afforded the anticonfigured diacetoxy compound 47b (1R,2S) as the major product with excellent enantioselectivity (up to 96%) and diastereoselectivity (syn : anti 2 : 98) (Scheme 20, bottom).
Wirth and coworkers investigated the enantioselective synthesis of α-acetoxylated ketones using catalytic amounts of chiral λ 3 -iodanes. 55The λ 3 -iodanes were generated in situ from the reaction of chiral λ 3 -iodanes 48 and an oxidising agent in the presence of acetic acid.Lewis acidic BF 3 •OEt 2 was employed to activate the hypervalent λ 3 -iodanes and then subsequent reaction with the enol ether 49 afforded an intermediate in which the activated λ 3 -iodane was attached to the α-carbon of the carbonyl functional group.Nucleophilic attack by an acetate anion (S N 2 reaction) led to the formation of the desired product 50 (Scheme 21).Excellent yields (up to 97%) of the α-acetoxylated ketones and good enantioselectivities (up to 88%) were obtained.However, cyclic substrates (for
Further investigations by Wirth 56 on the stereoselective intramolecular diamination reaction of alkenes using a chiral hypervalent iodine reagent 51 revealed that equimolar mixtures of trimethylsilyl triflate (TMSOTf ) and BF 3 •OEt 2 afforded BF 2 OTf•OEt 2 which acted as a Lewis acid to activate the λ 3iodanes 51 (Scheme 22).Excellent enantioselectivities (up to 92%) were observed in the products 52.
Hypervalent iodine compounds in combination with Lewis acidic boranes have also been used to introduce the nitrile functionality into an organic molecule.Electrophilic cyanation using iodanes provides an alternate to metal catalysed reactions which are useful for the generation of several biologically active compounds. 57Further investigations revealed that the cyano group can also be introduced enantioselectively into an organic molecule utilising chiral hypervalent iodanes.In 2017, Minakata described the use of 1-cyano-3,3-dimethyl-3-(1H)-1,2benziodoxole (CDBX) 53 as the source of a CN group which can be activated by the strongly Lewis acidic borane B(C 6 F 5 ) 3 and successively employed for catalytic electrophilic cyanation of silyl enol ethers to afford β-ketonitriles 54 (Scheme 23). 58ommonly used Lewis acidic boranes such as BF 3 •OEt 2 and BEt 3 both failed to activate 53 and no product formation was observed, but the more Lewis acidic B(C 6 F 5 ) 3 would activate the CDBX reagent.Mechanistic studies revealed that coordination between the cyano functionality of 53 and B(C 6 F 5 ) 3 (which was confirmed from in situ IR and 13 C NMR spec-troscopy, see later) resulted in the generation of a highly electrophilic species which facilitates the cyanation reaction.The interaction between the cyano functionality of 53 and B(C 6 F 5 ) 3 was examined spectroscopically.The CuN stretch in the IR spectrum was shifted from 2137 cm −1 (starting material-53) to 2216 cm −1 (53 + B(C 6 F 5 ) 3 ).Moreover, when an equimolar mixture of B(C 6 F 5 ) 3 and 53 in CD 2 Cl 2 was monitored using 13 C NMR, a significant downfield shift of the carbon atom of the CuN group was seen.Moreover, the tertiary carbon adjacent to the oxygen also exhibits a downfield shift.Based on these observations, it was concluded that the cyano group was coordinated to the Lewis acidic boranes to assist cyano group transfer to silyl enol ethers to generate β-ketonitriles.
Kita demonstrated the oxidative cyanation 59,60 of electronrich heterocycles including pyrroles, thiophenes, and indoles.Initial investigations showed that direct oxidative cyanations of electron-rich heterocyclic compounds were possible using a hypervalent iodine(III) reagent (PIFA, 4) and BF 3 •OEt 2 .TMSCN was used as the source of the CN group.Premixing of PIFA (4) and TMSCN in situ generated the hypervalent iodine(III)-CN species which was further activated by BF 3 •OEt 2 .Cyanation of 1H-pyrrole was investigated but only poor yields of the desired products were obtained.The authors observed that the presence of a strong electron withdrawing group at the nitrogenposition significantly improved the yields of the desired product.Therefore, a tosyl group was introduced and employed for the cyanation reaction.Using the optimised reaction conditions, N-tosylpyrrole was selectively converted to 2-cyano-N-tosylpyrrole in 83% yield but 2 equivalents of PIFA (4) were required.To demonstrate a broad substrate scope, N-tosylpyrroles, substituted thiophenes, and N-tosylindole were tested with satisfactory yields of the products 55 being obtained (Scheme 24).
The reactivity of λ 3 -iodanes was further investigated and successfully employed for the halogenation reaction. 61etal-free facile synthesis of organofluorine compounds are desirable as they are ubiquitous structural motifs in pharmaceutical compounds and agrochemicals. 62n 2018, Hu reported the fluorination of aromatic diazonium salts (Scheme 25). 63Catalytic Balz-Schiemann fluorination reactions were investigated using different trivalent iodine compounds and BF 3 •OEt 2 .All reactions were carried out in trifluorotoluene and many examples with yields of the products 56 up to 90% were reported using this methodology.Reactive functional groups (iodo, ketone, ester, carboxylic acid, nitrile, and sulfamide) remained intact and formation of undesirable products was not observed.To highlight the mechanistic Scheme 22 Enantioselective cyclisation reaction using chiral λ 3iodanes.
details, the authors suggested that the Lewis acidic component BF 3 •OEt 2 activated the aryliodonium(III) and generated the aryl cation intermediates. 63Addition of the borane increased the leaving group aptitude of dinitrogen which resulted in the formation of an Ar + BF 4 − salt and successive nucleophilic attack by a fluoride anion afforded the fluorinated product.
In 2017, Murphy used phenylallene derivatives 57 for the synthesis of α-difluoromethyl styrene compounds 58 which can be employed as fluorinated building blocks. 64Stoichiometric amounts of difluoro(p-tolyl)-λ 3 -iodane and BF 3 •OEt 2 were reacted with phenylallenes to afford the α-difluoromethyl styrenes 58.The reaction was found to be highly chemoselective with high functional group tolerance and proceeded via a fluorinative rearrangement mechanism.Several substrates such as substituted phenylallenes ( phenylallenes bearing phenyl and α-allenyl substituents) and diphenylallenes were investigated.
Moderate to good yields of the desired products (many examples, yields up to 79%) were obtained (Scheme 26, top).To investigate the reaction mechanism, deuterated phenylallene [D2] was used (Scheme 26, bottom) and the crude reaction mixture analysed by multinuclear NMR spectroscopy ( 1 H, 2 H, or 19 F NMR).As no deuterium scrambling was observed in the product (58a) it was concluded that the terminal double bond of the allene was not reacting (Scheme 26, bottom).
Recently, Shafir investigated the iodine directed ortho and para C-H alkylation of (diacetoxyiodo)benzene (3) to afford poly-substituted arenes. 67A new synthetic strategy for paraselective C-H benzylation, and ortho-selective sulfonylation have been reported (Scheme 28).The reaction between PhI (OAc) 2 (3) and ArCH 2 SiMe 3 in the presence of BF 3 •OEt 2 afforded C-C cross-coupled products 61 selectively at the para position to the iodine in good to excellent yields (Scheme 28, top).When para substituted (4-benzylphenyl)-λ 3 -iodanediyl diacetate (62) was employed for the oxidation reaction with different silane compounds 63 and 64, using the optimised reaction conditions, ortho alkylation (ortho to iodine) compounds 65 and 66 were formed in 63% and 53% yields respectively (Scheme 28, bottom).Further treatment of 66 with cyclic allylsilane 63 led to the formation of 69 (76%), and reaction of 65 with trimethyl( prop-2-yn-1-yl)silane 67 afforded compound 68 in 42% yield.A [3,3] sigmatropic rearrangement mechanism was proposed to account for the formation of these products.
Additionally, hypervalent iodine compounds were tested for multicomponent coupling reactions.A mild reaction protocol was developed by Hu for the synthesis of N-substituted benzimidazolones 70 (Scheme 29). 68romatic hydroxylamines, aldehydes, and TMSCN were reacted together in the presence of stoichiometric amounts of PhI(OAc) 2 (3) and excess BF 3 •OEt 2 to afford benzimidazolone derivatives in good yields (Scheme 29).Mechanistic details revealed that the aromatic hydroxylamines and aldehydes Although high functional group tolerance for these reactions was observed, heterocyclic aldehydes, aliphatic aldehydes, and ketones failed to produce the desired product.

Beyond mere activation: dual role of the borane
In certain cases, the Lewis acidic boranes do not only activate the hypervalent iodine compounds, but also actively participate in the reaction.Hypervalent iodine compounds in combination with Lewis acidic boranes have successfully been employed for hydroboration and fluorination reactions.
Zhang demonstrated the use of BF 3 •OEt 2 as a fluorinating agent with iodosylbenzene for the fluorination of homoallylic amines. 70  In 2017, Zhang demonstrated the use of hypervalent iodine compounds towards the ring-contraction monofluorination reaction using BF 3 etherate as the fluorine source. 71In the reported work, N-(cyclohex-2-en-1-yl)benzamide 79 was reacted together with iodosobenzene and BF 3 •OEt 2 in CH 2 Cl 2 to afford monofluorinated fused five-membered oxazoline ring products (yields up to 35%).A dramatic change in the yield of the product was observed when 3,5-dichloroiodosobenzene 78 was employed as the oxidant instead of iodosobenzene.Different N-cyclohexenyl amides 79 were tested and good to excellent yields of the desired products were obtained.In contrast with 79a (no substitution at C4 of the cyclohexenyl ring) which afforded 81 in satisfactory yield (up to 72%) (Scheme 32, bottom), when 79b (two methyl groups at C4 of the cyclohexenyl ring) was employed for the fluorination reaction, a very different product (80) with yields up to 97% were obtained (Scheme 32, top).The formation of the different products can be explained based on the stability of the carbocation intermediate.In the reaction, λ 3 -Iodanes 78 and BF 3 •OEt 2 react together to form an iodine(III) intermediate which activates the double bond of 79 and form the iodonium intermediate.
Intramolecular nucleophilic attack by the oxygen atom of the amide followed by reductive elimination formed the intermediate 82 (Scheme 33).Depending on the nature of the R group, different products were formed.When R = H, alkyl and double hydride shifts generated the carbocation intermediated 83a and successive fluoride attack afforded the product 81.However, when R = CH 3 , 82 undergoes an alkyl migration to form a more stable tertiary carbocation 83b which reacts with the fluoride ion to afford 80.
The reactions between hydrazones and hydrazides with Lewis acidic triarylfluoroboranes have also been investigated.Recently, we demonstrated the synthesis of different boron dienolates 84 from the iodonium ylides in moderate to good yields (up to 74%). 72Acyclic iodonium ylides reacted with several triarylfluoroboranes to afford the 1,3-carboboration compounds in which aryl group transfer from boron to the iodonium ylide had occurred (Scheme 34).In these reactions, the mechanism of activation was found to be the initial coordination of a boron Lewis acid to the carbonyl group.Cyclic iodonium ylides failed to afford the 1,3-carboboration products.

Conclusions
Expanding the toolbox of the synthetic chemist is crucial for the development of enabling strategies for metal-free synthesis while simultaneously simplifying the formation of ever more complex structures.Hypervalent iodine chemistry is presented as a reliable source to achieve these goals and inspires further development.However, the prerequisite activation of Dasgupta Dr Ayan Dasgupta received his PhD degree from IIT Madras (India) in 2016 where he worked under the supervision of Prof. S. Sankararaman.He subsequently worked with Prof. H. Hopf as an Indigo exchange student at TU Braunschweig (Germany) in 2013.He later joined TU Munich (Germany) as a postdoctoral research associate in 2017 and worked on hypervalent iodine catalysis under the supervision of Prof. T. Gulder.Ayan joined the Melen research group as a postdoctoral research associate in 2018.His research focus is on the use of main group elements as catalysts in organic synthesis.Christian Thiehoff Dr Christian Thiehoff studied chemistry at the Westfälische Wilhelms-Universität Münster (Germany) and received his M.Sc. in 2014.During this time, he spent several months in the group of Prof. R. A. Batey at the University of Toronto (Canada) in 2013.He completed his doctoral studies under the supervision of Prof. R. Gilmour at the Westfälische Wilhelms-Universität Münster (Germany)

λ 7 -
Iodanes are also known in which the iodine atom has a +7 oxidation state.The unique structural features of hypervalent Paul D. Newman Dr Paul D. Newman obtained his PhD in 1991 under the guidance of Prof. P. Williams at Cardiff University (UK).He then worked as a PDRA with Dr R. Cross and Dr R. Peacock at the University of Glasgow (UK) followed by a return to Cardiff to work with Prof. P. G. Edwards.From 2003-2009 he was a research fellow in the Cardiff Catalysis Institute to which he remains affiliated in his current senior Lecturer role.He has a longstanding interest in asymmetric coordination compounds and their application notably with phosphine and/or NHC-based ligands and has authored or co-authored 66 publications in the field.Thomas Wirth Dr Thomas Wirth is professor of organic chemistry at Cardiff University (UK).He received his PhD after studying chemistry at Bonn (Germany) and the Technical University of Berlin (Germany).After a postdoctoral stay at Kyoto University (Japan) as a JSPS fellow, he worked independently at the University of Basel (Switzerland) before taking up his current position at Cardiff University in 2000.He was invited as a visiting professor to a number of places: Toronto (1999), Tokyo (2000), Osaka (2004, 2008), Kyoto (2012).He was awarded the Werner-Prize from the New Swiss Chemical Society (2000), the Furusato Award from JSPS London (2013), the Wolfson Research Merit Award from the Royal Society (2016) and the Bader-Award from the Royal Society of Chemistry (2016).In 2016, he was elected as a fellow of The Learned Society of Wales.His main interests of research concern stereoselective electrophilic reactions, oxidative transformations with hypervalent iodine reagents and flow chemistry performed in microreactors.
Comparison of the 1 H NMR spectra of PIDA (3) and a mixture of PIDA/ BF 3 •OEt 2 (1 : 1) in CDCl 3 indicated a downfield shift of the aromatic signals in the latter (ca.0.1 ppm) which implies the formation of an electron-deficient species. 1 H NMR analysis of the titration of PIDA/BF 3 •OEt 2 mixture resulted in the gradual downfield shift of the aromatic and acetyl resonances, confirming the initial finding (Scheme 5).Upon cooling a solution of PIDA/BF 3 •OEt 2 in CDCl 3 , the single resonance for the acetate ligands splits into two separate signals.This suggests the change of either a fast equilibrium between the BF 3 coordinated and the non-coordinated acetate ligand, or an unsymmetrical species with two distinct acetates.X-ray crystallographic analysis 31 of the PIDA-BF 3 adduct further corroborates the solution phase NMR analysis as the BF 3 unit is coordinated to the carbonyl oxygen of one acetate group.Structural comparison of the adduct and PIDA shows a lengthening of d = 0.13 Å for the I-O bond of the BF 3 •OAc ligand (d I-O = 2.15 Å in PIDA, d I-O = 2.28 Å in the adduct) associated with a contraction of the other I-O bond of d ≈ 0.07 Å (d I-O = 2.076 Å in the adduct) indicative of the existence of the cationic acetoxy( phenyl)iodonium.However, no interaction was observed when PIDA (3) was replaced by PIFA (4) which was attributed to the lower basicity of the latter.

Scheme 18
Scheme 18 Proposed reaction mechanism for enantioselective oxy arylation reaction.
Scheme 28 Iodine directed ortho and para C-H alkylation of PhI (OAc) 2 .

cation intermediate 77 .
This cationic intermediate was readily trapped by the fluoride anion to produce the desired fluoropyrrolidines 74.
λ 3iodanes by boranes has been limited almost exclusively to BF 3 •OEt 2 with just a few examples with triarylboranes and borosilicate.The few reported examples of other borane-based Lewis acidic activators indicate sufficiently exciting reactivity to promise a great future potential for the further advancement of synthetic protocols.The increased availability of boron reagents and understanding of their Lewis acidities and reactivities will allow the field of hypervalent iodine to expand into novel areas of synthetic applications.