The Chemistry of Hypervalent Iodine

MacMillan Group Meeting July 30, 2003 Sandra Lee

Key References:

T. Wirth, M. Ochiai, A. Varvgolis, V. V. Zhdankin, G. F. Koser, H. Tohma, Y. Kita, Topics in Current Chemistry: Hypervalent Iodine Chemistry -/- Modern Developments in Organic Synthesis, pp. 1-248, 224. Springer-Verlag, Berlin, 2002.

A. Varvoglis, Hypervalent Iodine in Organic Synthesis, pp. 1-223, Academic Press, London, 1997.

P. Stang, V. V. Zhdankin, Chem. Rev. 96, 1123-1178 (1996)

Background and Introduction n Iodine is most commonly in monovalent compounds with an oxidation state of -1, however, because it is the largest, most polarizable, and most electropositive of the group 17 elements, it also forms stable polycoordinate, multivalent compounds. n First polyvalent organic iodine complex, (dichloroiodo)benzene or PhICl2, was prepared was by German chemist C. Willgerodt in 1886. Although it's oxidizing properties were known since 1893, a renaissance in the field of polyvalent iodine has occured only in the past 20 years. n Factors leading to resurgence of interest:

(1) Chemical properties and reactivity is similiar to the heavy metal reagents such as Hg(III), Tl(III), Pb(IV) but without the toxicity & environmental issues. (2) Mild reaction conditions and easy handling of hypervalent iodine compounds (3) Commericial availaiblity of key precursors such as PhI(OAc)2. n Topics to be covered in this talk:

Nomenclature, Structures, and Properties

3 Reactivity Pattern and Mechanisms of Organo-l -Iodanes: RIL2 and R2IL Survey of Reactive Transformations Using Hypervalent Iodine Reagents

Selected Applications in Total Synthesis n Topics that are NOT covered in this talk: Transition Metal Mediated Reactions and Polymer Supported Reagents Nomenclature for Hypervalent Iodine n The term hypervalent was established in 1969 for molecules with elements of groups 15-18 bearing more electrons than an octet in their valence shell.

3 5 n IUPAC rules designate l as non-standard bonding; thus, H3I is l -iodane and H5I is l -iodane. 3 Most common decet structure is aryl-l -iodane ArIL2 (L = heteroatom) and for dodecet 5 structure is aryl-l -iodane ArIL4. n Polyvalent Iodine species differ in Martin-Arduengo designation [N-X-L] where N = # of valence electrons on central atom, X = central atom, L = # of ligands on central atom.

Iodinanes: trivalent iodine hypervalent Periodinanes: pentavalent iodine 3c-4e bond pure 5p orbital linear L-I-L bond - o d Cl 3.06 A Cl L Ar 87.2 o d+ L L L Ph I Ph I I I 109 o 2 92.6 o L L L 5sp hybrid d- 2 orthogonal Ph CAr-I s-bond Ph L 3c-4e bonds

8-I-2 10-I-3 10-I-4 12-I-5 n a b n o tetrahedral pseudotrigonal o pseudotrigonal square t n n i d

bipyramid i bipyramid pyramid n g n Diphenyliodonium chloride vs. Chloro(diphenyl)-l3-Iodane? Onium salts (such as ammonium, phosphonium,oxonium, etc.) refers to a tetrahedral geometry with an octet in the valence shell of a positively charged atom and are not hypervalent compounds. Also, X-ray structural data of iodine(III) compounds with a coordination of 2 (as in iodonium salts) have never been observed.

Classes of Hypervalent Iodine n Traditional classification is based on the # of carbon ligands on central iodine.

For Iodinanes 1C-bond: Iodosyl/ Iodoso compounds (RIO) and their derivatives (RIX2, where X = non-carbon ligands and R = aryl or CF ) + - 3 2 C-bonds: Iodonium salts (R2I X ) 3 C-bonds: (Iodanes with 3 C-I bonds are thermally unstable and not synthetically useful)

For Periodinanes 1C-bond: Iodyl/ Iodoxy compounds (RIO ) and their derivatives (RIX or RIX O) + - 2 4 2 2 C-bonds: Iodyl salts (R2IO X ) n Compounds with more than one formal carbon bond to iodine: Alkenyliodonium (PhI+C=CHR X-) and Alkynyliodonium (PhI+C≡CR X-) Salts

Iodonium Ylides (PhI=CXY, where X, Y = electron acceptors) where: XO Z = CO; X = H, Me, Ac, t-Bu, n Cyclic Iodinanes: I SO2R, PO(OPh)2 Z = SO ; X = H O 2 3 Z = CMe2 or C(CF3)2; X = H, NO2 l -Iodinanes: Benziodoxazoles based on o-iodosobenzoic acid. Z Z = P(O)Me or P(O)OH; X = H Z = I(OAc); X = Ac Z = C=NH2+; X = OTs l5-Iodinanes: Benziodoxazoles based on o-iodoxybenzoic acid. (ie. IBX and Dess-Martin Reagent)

Ph Ph n m-Oxo-bridged Iodanes (PhI(X)OI(X)Ph ,where X = OTf, ClO4, BF4, PF6, SbF6) O I I X X Established Hypervalent Iodide Reagents n Most Frequently Used Reagents

ICl2 IF2 I(OAc)2 I(OCOCF3)2

di(chloroiodo)benzene di(fluoroiodo)benzene di(acetoxyiodo)benzene [bis(trifluroacetoxy)iodo]benzene PhICl2 PhIF2 PhI(OAc)2 PhI(OCOCF3)2 DIB BTI Aldrich, Fluka, Aldrich, Fluka Lancaster, Merck

O AcO OAc I OH I OAc OH O O I=O I OTs O O iodosylbenzene* [(hydroxy)(tosyloxy)iodo]benzene 2-iodoxy-benzoic acid Dess-Martin Periodinane PhI(O) PhI(OH)(OTs) IBX DMP IOB HTI ICN, TCI America Koser's Reagent Aldrich n IBX Related Reagents n Newer Iodine(III) Reagents

O O -O OH O OH I I OH I O I O N NR + O O O 3 O S N S I(OAc)2 I(OAc)2 Tf I(OAc)2 RO O O O NHR CO2H OH CnF2n+1CH2 I OOtBu O O O O OTs I t-Bu I OH I O O N R

O R CF3 O

Physical Aspects of l3-Iodanes n Most hypervalent iodine reagents are solid (amorphous or crystalline) and are stable to atmospheric oxygen and moisture. Certain iodonuim salts are less stable and should be generated in situ. A mild + - explosion will occur if heated in the absence of solvent for PhI(OMe)2, PhIO, PhIO2, (PhI )2O 2BF4 , and o-iodylbenzoic acid. n In the solid state: Iodosylbenzene and (tosyliminoiodo)benzene are polymeric structures terminated by water: HO(PhIO)nH. Monomeric species are generated in reactive solvents. Secondary I-O bonds are also observed and result in macrocyclic structures. OH Ph I 2.3 < pH OH Ts Ts o 2 A Ph Ph Ph Ph 37 O O O N N 2. I I * 2. I I pH > 5.3 I 04 o I o * I I A 114 Ph I N N N O Ph O Ph O Ph Ph B F OH2 Ts Ts Ts n 3-E n t2 O O BF3 Ph I n In solution: OEt 3 Diaryl-l -iodanes (Ar2IL, where L = BF4, Cl, Br, OAc) in polar solvents show extensive dissociation into + solvated iodonium ions (Ar2IS where S = H2O, MeOH, and DMSO)

Alkenyl-l3-iodanes exist in equilibrium as an iodonium ion and as a halogen-bridged dimeric and aggregate structures. n-C8H17 Ph n-C8H17 n-C8H17 Br I Kdissoc Kassoc + Br Br Ph Br Ph I I I Ph S Br n-C8H17 General Reactivity of Hypervalent Iodine n Hypervalent iodine chemistry is based on the strongly electrophilic nature of the iodine making it suseptible to nucleophilic attack, in combination with the leaving group ability of phenyliodonio group -IPhX (~106 times greater than triflate!!!). The favorable reduction of the hypervalent iodide to normal valency by reductive elimination of iodobenzene is the key to its reactivity. n Organo-l3-iodanes have reactivity based on the number of carbon and heteroatom ligands. They generally fit in two classes:

(1) RIL2: Majority of reactions fit under this category. Performs oxidation of various functional groups. The two heteroatoms occupying the apical sites of the pseudotrigonal bipyramid are essential- one is used in ligand exchange and the other in reductive elimination.

Ligand Exchange

L- L L L L Nu- Ar I Ar I Nu Ar I L Ar I L L Nu Nu 12-I-4 L- L L Nu Nu Ar I Ar I Nu Ar I L Ar I Nu Nu Nu Nu

Reductive Elimination of the Hypernucleofuge

C I BF4 C PhI BF4 Ph hypernucleofuge

3 Reductive a- and b-Elimination of RIL2 Organo-l -Iodanes Reductive a-Elimination: Provides a method for the generation of carbenes.

R R R C I L C PhI L H Ph R

n-C8H17 n-C H NEt3 8 17 Example: n-C8H17 D Ph 0 °C D I D 92%D BF4 89%D Reductive b-Elimination

R R R C M C M PhI L (where M = C, N, O, S) H I Ph R L On carbon atoms (M=C) produces C-C multiple bonds: O O

SiMe3 Bu4NF R CH Cl , rt I 2 2 N Ph OTf R N3 N N

Oxygen and nitrogen atoms (M=O and N) provides oxidation of benzylic/ allylic alcohols and amines to the corresponding carbonyl and imine compounds. (ie. Dess-Martin l5-iodane oxidations) H HO H O

(PhIO)n NH N I OH N N I OH NH Ph Ph PhI PhI 3 More Reductive Eliminations of RIL2 Organo-l -Iodanes Reductive Elimination with Fragmentation OH

n-C10H21 (PhIO)n n-C H CHO one-step synchronous fragmentation 10 21 with exclusive formation of the trans olefin DCC SnBu3 BF -EtO PhI 3 2 Ph NCy O I OCNHCy BF3 Cy CyN N n-C10H21 C BF CyN C NCy 2 O F I SnBu3 Ph Reductive Elimination with Substitution: Elimination of l3-iodanes with 2 carbon ligands with attack by a nucleophile on the carbon atom attached to the iodine(III) gives substitution products. Ph Ph Nu R I L Nu R I L R Nu

O OH OAc O O PhI(OAc)2 OAc AcOH Example: I Ph I OAc Ar Me AcOH Ar Ar Ph Ar OAc PhI AcOH Reductive Elimination with Rearrangement: Elimination with concomitant 1,2-alkyl or aryl shift gives rearranged products. O Ph Ph PhI(OCOCF3)2 O H2O RCONH2 I I RN C O RNH2 R N OCOCF3 H PhI CO2 O OMe O OMe O (PhIO)n Ph Ar Ph Ar MeO Ar BF3-EtO2 PhI MeOH MeO I Ph Ph

3 Reductive Elimination by Ligand Coupling of RIL2 Organo-l -Iodanes Ligand Coupling

1 2 X Ar X + Ar I D Ar1 I 2 Ar Ar2 x + Ar1 I

Br I d+ Br Br minor Me I Me d- I + path

Me Cl

Cl Cl Br I d+ Br Br major Cl I Cl d- I + path

Cl Me

Me Me

Ph O O I BF4 t-BuOK CO2Me Example: + CO2Me R Ph 3 Other Mechanisms of RIL2 Organo-l -Iodanes Homolytic Cleavage: Photochemical decomposition of a hypervalent I-O bond generates a reactive radical.

(Diacyloxyiodo)arenes

OCOR R Ph I SO2Ph SO Ph hn, rt OCOR 2

SO2Ph R RCO2 R SO2Ph

PhIOCOR CO2

Alkylperoxy-l3-iodanes O O O O S Se OH R3P O R O R R' R R' R R' O OR S S

R R' RSR' RSeR R3P ROH, THF O R O

t-BuOO I O t-BuOO I O O R Ar OR R O O Ar OR O OH

R O O NAc Ar NHR

R OO-t-Bu NAc NAc Ar NR

O OO-t-Bu

3 Other Mechanisms of RIL2 Organo-l -Iodanes (Continued) Single-Electron Transfer Single-electron transfer from phenol ethers to l3-iodanes generates an arene cation radical resulting in a direct nucleophilic substitution. O Me OMe OMe O O Me OCOCF3 Ph I (CF ) CHOH 3 2 O OCOCF3 OMe OMe OMe OMe

L Me

Ph I O O L OMe OMe

L = OCOCF3 The method for reactivity umpolung of diaryl-, alkenyl(aryl)-, and alkynyl(aryl)-l3-iodanes involves the generation of organochromium(III) and nucleophilic addition to aldehydes is shown below. Ph

Ph H Ph CrCl2 OH MeO I Ph O DMF Ph OH BF4 MeO 75 : 25 p-MeOC6H4I Cr(III) Cr(II) Ph PhCr(III) I Cr(II) Ph 75 : 25 Cr(II) MeO p-MeOC6H4 p-MeOC6H4Cr(III) 9-I-2 PhI 3 Reactivity of R2IL Organo-l -Iodanes

(2) R2IL: Acts mainly to transfer a carbon ligand (R) to nucleophiles with reductive elimination of ArI. The nature of the carbon ligands are important in determining reactivity.

Alkyl(aryl)-l3-Iodanes: Generally labile and decompose readily by heterolysis of C-I bond and reductive elimination of ArI. HO (PhIO)n PhH Me3Si I

BF3-Et2O Ph PhI 3 BF3-catalyzed ligand exchange of allylsilane, germane, or stannane with iodosylbenzene generates allyl-l -iodane. This is a highly reactive species that is equivalent to an allyl cation. Also may serve as a perfluoroalkylating agent.

Alkenyl(aryl)-l3-Iodanes Progenitor of alkylidene carbene that are formed by base abstraction of an acidic a-hydrogen of an alkyenyl-l3-iodane. The free alkylidene carbene can form solvent-alkylidene carbene complexes (ie. in ethereal solvents an oxonium ylide is observed) Me Me Me Me Me Me Me Ph Me I Me Me Me NEt3 PhI BF4 Et N+HBF - 3 4 Me Performs nucleophilic vinylic substiutions by SN2 reaction with inversion of configuration. Nucleophiles that undergo vinylic SN2 reactions are sulfides, selenides, carboxylic acids, amides, thioamides, and phosphoroselenoates. n-C8H17 reductive Ph n-C8H17 H I syn b-elimination Cl

n-C8H17 Cl n-C8H17 Cl Bu4NCl n-C8H17 Ph H H I H I Ph Cl Cl

3 Reactivity of RIL2 Organo-l -Iodanes (Continued) Alkynyl(aryl)-l3-Iodanes

The highly electron-deficient nature of the b-acetylenic carbon atom make these reagents good Michael acceptors towards soft nucleophiles (O, N, and S) and undergo tandem Michael-carbene insertion (MCI) to give cyclopentene annulation products. (ie. substituted furans) R Nu R R I BF4 Nu I+Ph Nu Ph [5+0] MCI Reaction R1 1 R 1 R = H R

H Nu Nu [2+3] MCI Reaction R R Nu = R1 H H R1 Because the electron-deficient nature of the carbenic center of the alkylidene carbene, nucleophiles with high tendency to migrate undergo Michael-carbene rearrangements (MCR). When the migratory apptitude of a nucleophile is poor, the MCI pathway competes with the MCR reaction R Nu R I BF4 R Nu Nu Ph

Nu = NSC, TsS, (RO)2P(S)S, ArS, RSO3, RCO2, (RO)2P(O)O, Ph2N, Br, I

PhSO2Na n-C5H11 + Example: n-C8H17 I BF4 n-C8H17 SO2Ph H2O Ph PhSO2 74 : 26

Other useful reactions include Diels-Alder reactoins, 1,3-dipolar cycloadditions, and reactions with transition metal complexes. Transformations Enacted by Hypervalent Iodide Reagents n C-C Bond Bond Forming Reactions

Radical Decarboxylation of Organic Substrates Spirolactonization of para- and ortho-Substituted Phenols Intramolecular Oxidative Coupling of Phenol Ethers Reactions of Iodonium Salts and Ylides n C-Heteroatom Bond Forming Reactions (N, O, P, S, Se, Te, X)

Reactions of Aryl-l3-Iodanes Arylations and Alkenylations of Nucleophiles Reactions of Alkynyl(aryl)iodonium Salt Cyanation with Cyanobenziodoxoles Aziridations and Amidations by Sulfonyliminoiodane Reactions of Iodonium Enolates

n Heteroatom-Heteroatom Bond Forming Reactions

Reactions of Aryl-l3-Iodanes Reactions of Sulfonylimino(aryl)iodanes n Oxidations and Rearrangements

Sulfoxides from Sulfides Oxdations of Alcohols, Phenols, Heteroaromatic Compounds Functionalization of Carbonyl Compounds Functionalization in the a-position Forming a,b-Unsaturation Oxidation of C-H Bonds Rearrangements

C-C Bond Forming Rxns: Radical Decarboxylative Alkylation of [Bis(acyloxy)iodo]arenes

OCOR Hg - hn or D Ph I R OCOR -PhI, -CO2 n Alkylation of Nitrogen Heterocycles O PhI(CO2CF3) + R R OH N hn or heat N where R = 1-adamantyl, cyclohexyl, 2-PhCH2, PhOCH2, PhC(O), etc. and Me CN Br N N = , , , , etc. S N N N N n Radical Alkylation of Electron-Deficient Alkenes

Yield of products depends on the stability and nucleophilicity of the alkyl radicals (tertiary > secondary > primary). R1 hn, 1,4-cyclohexadiene Z R 1 + PhI(O2CR)2 Z R 44-99%

1 where Z = SO2Ph, SOPh, CO2Me, P(O)(OEt)2; R = H, Me R = 1-adamantyl, cyclohexyl, 2-PhCH2CH2, etc. C-C Bond Forming Rxns: Oxidative Cyclization of Phenols and Phenol Ethers

X O I Ph

OH -PhI O -X- PhIX2 R1 Nu -HX O O R1 Nu R1 Nu

-PhI -X- R1 Nu R1 Nu

X = OAc or OCOCF3 Imporant in constructing of various polycyclic systems from p- or o-substituted phenols with an external or internal nucleophile like alcohols, fluoride ions, amides, allylsilanes, and electron-rich aromatic rings.

O O HO X O X PhI(COCF3)2 Example: where R = H, TMS, TBDM; X = C or N CF3CH2OH N X N X rt, 20 min H H O 30-76% O Oxidation of phenol ether in the presence of an external or internal nucleophileaffords products of nucleophilic substitution via formation of a cation radical intermediate.

Ph OCOCF3 OMe I OMe OMe H OCOCF3 R R = alkyl, alkoxy, halogen, etc. PhI(COCF3)2 SET Nu Nu = N , OAc, SAr, SCN, etc. MeO R 3 or internal nucleophilic group CF3CHOH -PhI or CF3CH2OH charge-transfer R complex R R

Examples in Total Synthesis: Epoxysorbicillinol and Bisorbicillinol n Hypervalent Iodide(III) Induced Oxidative Dearomatization

F3COCO O O Ph I O O O HO O Me O Me Me HO N Me Me OH 2.2 equiv BIT O O O Me DEAD, PPh3 CH2Cl2/ MeNO2 O O Me Me CH2Cl2 (spiroannulation/ epoxidation) 40% OH O N N N

O O OH O Me Me O O Me O or OH Me O O O HO Me O HO O Epoxysorbicillinol Me Me O HO O Me Bisorbicillinol

(Pettus:Org. Lett. 2001,3, 905) Examples in Total Synthesis: Quinone-Imine Formation in Dynemicin A

n Danishefsky's Approach (J. Am. Chem Soc. 1996,118, 9509)

MOMO O 1) O

Me Me Me MOMO O CO MOM CO MOM TEOC CO2MOM DIB 2 LHMDS 2 N N MOMO N O O O THF, 0 °C 2) BTI, THF, 0C OMe 49% OMe OMe

1) air, daylight MOMO OH OH OH O THF TEOC: trimethylsilyl- high conc. ethoxycarbonyl 2) MgBr2

Me

CO2MOM OH O HN O OMe n Myers' Approach (J. Am. Chem Soc. 1997,119, 6072)

OH O OH Dynemicin A

Alloc N Me N MeO Bu3SnH Alloc CO2TIPS IOB Pd(II) N O MeOH CH2Cl-H2O OMe 89% 78% OH OH

OH Alloc: allyloxycarbonyl

C-C Bond Forming Rxns: Reactions of Iodonium Salts n Stabilized Alkyliodonium Salts

PhC CCnF2n+1 RCnF2n+1 (100%) (60-80%) PhC CH RMgCl CH3OH

H2C CH2 F2n+1Cn CnF2n+1 I OTf CnF2n+1CH2CH2OCH3 pyridine CH OH Ph 3 (50%) (46%) n = 2-8 OSiMe3 C Me CH 2 C F O pyridine n 2n+1 C Me CH2CnF2n+1 (88%) (97%)

O O Ph Ph

SiMe3 (63%) (90%)

Ph

C CH2IPh O BF4 OSiMe3 C Ar CH2 OSiMe3 O O Ph Ph Ar

O O (50%) Ar = Ph, 4-MeC6H4, 4-NO2C6H4, 4-MeOC6H4 (30-60%) C-C Bond Forming Rxns: Reactions of Iodonium Salts (Continued) n Stabilized Alkenyliodonium Salts O O O H Me t-BuOK Me Generation of Akylidienecarbenes Me THF, -78 C IPh H BF4 (61%) Ph I BF4 O O R THF, rt, 1-4 hr R Alkenylation of C-Nucleophiles + R = Ph, Me K (86%)

O t-Bu O t-Bu Transition Metal Mediated Cross-Coupling with Cu, Zn, Sn, Pd n Stabilized Aryliodonium Salts 1. NaH, DMF R = H, CH ,, CH CH=CH EtO2C CO2Et EtO2C CO2Et 3 2 2 Arylation of C-Nucleophiles Ar = Ph, 4-MeC6H4 + - X = BF4, OTf R 2. Ar2I X , rt to 70C, 2-4 hr R Ar (27-95%) Generation of Benzynes

Ar Ar S S C H SiMe3 (44-45%) Ar Bu4NF CH Cl Ph IPh 2 2 (86%) OTf 0 to rt O R -CO O O Me Ph O Ph Ph Ph Ph Ph O (100%) (100%) Ph Ph Ph Ph (100%) Ph Me

C-C Bond Forming Rxns: Reactions of Iodonium Salts (Continued) n Alkynyliodonium Salts

product of acetylenic R C C Nu nucleophilic substitution

carbene rearrangement

Nu -PhI Nu Nu R C C IPh C C IPh C C b a R H R

C-H carbene insertion (R or N must be >C3 chain)

R R five-membered or carbocycle or heterocycle Nu Nu R

MeC C-I(Ph)OTf Me Example of Indole Synthesis: Li Me + R = H, Me, 46-66% OMe, N N R N R COMe, Ts Ts CO -t-Bu Ts 2

Example of [4+2] Cycloaddition: I(Ph)OTf

R I(Ph)OTf RC C-l(Ph)OTf MeCN, 20 C Me Me R I(Ph)OTf Me

Me R C-C Bond Forming Rxns: Reactions with Iodonium Ylides and Cyanation n Reactions with Iodonium Ylides

CF3SO2 Cycloaddition product (40%) CF3SO2 CH2Cl2, hn PhICH2(SO2CF3)2 (61-72%) (CF3SO2)2HC R C-H insertion product

R

where R = H or Me

R2 R2

n CuCl n Intramolecular Cycloaddition Example: O 1 CH2Cl2, -45 °C 1 R PhI R O CO2Me CO2Me (65-90%) n Cyanation with Cyanobenziodoxoles

Prepared in one step by cyanomethylsilane and hydroxybenziodoxoles and a stable radical precursor NC I O R for an otherwise unstable I-CN bond. Efficient cyanating agents towards N,N-dialkylarylamines. R

1. ClCH2CH2Cl, reflux, 1 hr CH3 CH3 2. KOH, H2O Ar N Ar N where Ar = Ph, 4-BrC6H4, 4-MeC6H4, 1-naphthyl, etc. R = Me, CF3, O (80-96%) CH3 CH2CN

C-Heteroatom Bond Forming Rxns: Aryl-l3-Iodanes

L L Ar I + Nu Ar I + L L Nu n Azidonation Applications have been on TIPS enol ethers, glycals, dihydropyrans, aryl N,N-dialkylamines, cyclic amides, and cyclic sulfides.

OTIPS OTIPS TIPSO N3 PhIO/ TMSN3 (A : B) N3 "PhI(N3)2" -78 C (9:1) + -45 C (1:1) CH2Cl2 -20 C (1:20) N3 A B n Oxidative Addition of C,C-Multiple Bonds

C,C-Double Bonds: DIB with appropriate reagents results in co-introduction of equivalent/ non-equivalent heteroatom groups.

Dithiocyanation: TMSNCS Phenylselenyl-thiocyanation: TMSNCS and (PhSe)2 Phenylselenyl-acetoxylation: (PhSe)2 Azido-phenylselenation: NaN3 and (PhSe)2 + - Haloacetoxylation: Ph4P I + - O Haloazidonation: Et4N X and TMSN3 TsO R2 O I2, rt C,C-Triple Bonds R1 R2 + R = OPh, Ph 1 1 2 I ClCH2CH2Cl R I R , R = Ph, Ph OTs Ph, H O Ph, Me OH 2 I2, rt R2PO R n-Pr,n-Pr R1 R2 + Ph I R n-Bu, H ClCH CH Cl 1 O P 2 2 R I R O C-Heteroatom Bond Forming Rxns: Aryl-l3-Iodanes (Continued) n Functionalization of Aromatic Compounds

OMe OMe OMe

OCOCF3 Nu (CF3)CH2OH TMS-Nu + Ph I

OCOCF3 R R R - Nu = N3, OAc, SCN, SPh (from PhSH)

OH O

BTI or DIB MeOH R'n R'n R OMe R R = alkyl, alkoxy n a-Functionalization of Carbonyl Compounds

O L1 O Koser's Salt R' + Ph I R' + L1H + PhI R R L2 L2

2 L = OH, OR, OCOR, OSO2R, OPO(OR)2 n C-Fluorine Bond Formations p-(Difluoroiodo)toluene (DFIT) with appropriate reagents results in C-fluorine bond formation.

vicinal-difluorination of terminal alkynes: Et3N 5HF trans-iodofluorination of terminal alkynes: Et3N 5HF then CuI/ KI monofluorination of b-dicarbonyl: (DFIT generated in situ) difluorination of dithioketals of benzophenone (to diarylfluoromethanes): (in situ generated p-(difluoroiodo)anisole) fluorination of a-phenylsulfanyl esters and lactones: (DFIT-induced fluoro-Pummerer rxn) alcohols to 1 °- and 2 °-alkyl fluorides: converion to xanthate esters followed by DFIT

C-Heteroatom Bond Forming Rxns: Diaryliodonium and Alkenyl(aryl)iodonium Salts n Diaryliodonium Salts

solvent + - + - Ar2I X + M Nu Ar Nu + ArI + MX D

O O

Nu (solvent) = (RO)2P=O (DMF), R S (DMF), A r S S (MeCN) O O - - (RO)2P-S (cyclohexane), ArSe (DMF), ArTe (DMF)

Arylations of weak organic nucleophiles are best with iodonium salts with nucleofugic anions and in some cases can be faciliated with transistion metal catalysts (Cu, Pd)

n Alkenyl(aryl)iodonium Salts

Alkenylations of heteroatom nucleophiles occur by a variety of mechanisms; SN1, SN2, alkylidene carbene, and addition- elimination pathways.

M+Nu- IPh BF4 Nu R R solvent

R = Ph or n-C4H9 MNu (solvent) = R1R2NCS2Na (THF), ROCS2K (THF), RSCS2K (THF), (RO)2P(O)SK (THF, CuI), (RO)SP(O)SeK (THF), (RO)sPS2K (THF, CuI), ArSeNa (EtOH), ArTeNa (EtOH) C-Heteroatom Bond Forming Rxns: Alkynyl(aryl)iodonium Salts n Alkynylation solvent R IPh OTs + M+Nu- R Nu + PhI

MNu = (RO)2PONa (DMF, EtOH), ArSeNa (DMF), ArTeNa (DMF) N N K N , (THF, t-BuOH, CH2Cl2)

1) n-BuLi, PhMe H 2) TMS I Ph OTs H Ts N TMS N R R (28-89%)

R = n-Bu, PhCH2, CH2=CH(CH2)2, CH2=CHCH(Ph)CH2,CH2=CHCH2CH(Ph), CH2=CHCH2CH(CH2)3CH3, (CH2=CHCH2)2CH n C-H Bond Insertions

1 2 R R Ts R1 1) n-BuLi H 2) Me I Ph OTs N R2 TsN H Me R1 H H N H Ts Me R2 1 2 R , R = Ph, Me; H, Ph; H, Me; TBSMS, (CH2)4

Intramolecular C-H bond insertions result in bicyclizations R1 H R1 R2 O R O R n 2 R 3 N O R N Ts OBn

C-Heteroatom Bond Forming Rxns: Alkynyl(aryl)iodonium Salts and Enolates n C-Heteroatom Bond Insertions n Cyclocondensations

R 1 S R - - + O R O H O p tolSO2 Na N + 2 R NH2 THF, 65° C 2 solvent, base R IPh Ts Ts S 1 OTs (35-68%) (0-27%) Se R N Ar NH R R1 I Ph A 2 OR O R2 MeOH, Et N Se 3 R1 N Ts Ts H2NCS2NH4 DMF, H O HS 2 S O O O O R = TBDMS, , , , R1 = aryl, alkyl, CH OR; A- = MsO- or TsO- Me O 2 n Iodonium Enolates

AcO IPh X LiOEt, THF O IPh R H R H

X = Br, BF4; R = Me, n-C8H17, t-Bu

O O O AcO IPh Br LiOEt, THF H Example: + n-C8H17 R H ° n-C8H17 H -30 C R H E/Z = 85:15 to 96:4 (57-91%)

R = R'C6H4 (R' = H, 2-Me, 4-Me, 4-F, 4-Cl, 4-Br, 4-NO2), Et, n-C9H19, i-Pr, iBu, (E)-MeCH=CH C-Heteroatom Bond Forming Rxns: Sulfonylimino(aryl)iodanes n Aziridation PhI=NTs as a nitrene transfer agents has been demonstrated with Mn(III)- and Fe(III) porphyrins and more generally with Cu(I)/ Cu(II) salts (Evan's aziridation reaction) on cyclic/ acylic alkenes, arylalkenes, and a,b-unsaturated esters.

Ts 1 Cu(I) or Cu(II) R N (5-10 mol%) R1 + PhI NTs R2 R3 MeCN, 25 °C R2 R3 (5 equiv) (1 equiv)

1 2 3 R , R , R = H, alkyl, aryl, CO2Me

Product yields increase with substition on the arenesulfonyl moiety (p-OMe > p-Me > p-NO2). Chiral ligands (bis(oxazolines) and bis(benzylidene)diaminocyclohexanes give asymmetric tosylaziridations (e.e. = 66%-94%) More reactive are [nosylimino)iodo]benzene (PhI=NNs) and [(2-trimethylsilylethanesulfonylimino)iodo]benzene (PhI=NSes). n Amidations

TMSO PhI NTs O CuCl4 R2 R1 PhI NTs R1 1 1 2 MeCN R Cu(OTf)2 R R R2 TMS R2 NHTs -20 - 0 °C NTs (53-75%) MeCN or PhH (37-78%) 1 2 R , R = Ph, H; Ph, Me; n-Butyl, H; (CH2)4; CH CH 1 2 2 2 R , R = H, H; CH2Cl, H; CH2OAc, H; H, Ph

Chiral allylic and benzylictosylamidations are performed with salen-Mn(III) complexes, Ru(II) and Mn(III)-porphyrins, and Ru(II)- and Ru(III)-amine complexes as catalysts. (e.e. = 41-67% for cyclic compounds and 12-53% for acyclic compounds)

Heteroatom-Heteroatom Bond Forming Rxns n Aryl-l3-Iodanes: Oxidation of S, P, Se, Te, Sn, & Bi Sulfide Oxidation Diaryldisulfide Oxidation

O O BTI, CH2Cl2 Ar S S Ar PhICl2 or DIB or BTI (51-83%) R1 S R2 S 1 2 O or IOB, p-TsOH (10 mol%) R R Ar S S Ar O (80-100%) BTI, ROH S R1 OH (51-90%) 1 2 R , R = alkyl or aryl Ar = alkyl; R = Me, Et, i-Pr, t-Bu n Sulfonylimino(aryl)iodanes: Constructing P-N, S-N, Se-N, As-N Bonds Phosphorous and Arsenic Ylide Formation PhI=NTs Reaction Products

O O PPh3 Ph3As R P NSO C H R S AsPh NSO C H R NTs 3 2 6 4 3 2 6 4 TsN O (56-78%) N C6H4R (65-85%) R = Me, H, 4-Cl, 3-NO Se S Ph I 2 Ar Bn Ar R

O Me O NTs I NTs S O O S N Me NTs S 1 2 R S R PR3 N S t-Bu R P NTs O O 1 2 3 Me Me R R (82-90%) (83-88%) Me Me N N R1, R2 = Me, Me; R = Ph, n-Bu Me Me Ph, Ph; Me,p-tolyl Summary of Oxidations with Hypervalent Iodine Compounds n Chalcogen Oxidation n Oxidations of Phenols Sulfides to sulfoxides with IOB and BTI. H Disulfides to sulfinic esters or thiosulfonic S-esters. Iodine (V) Reagents N O

Diselenides to seleosulfonates. IBX: Phenol to ortho -quinone only R' Ditellurides to mixed arenetellurinic anhydrides. DMP + water: Anilides to o -imidoquinones and R p -anilines to para -quinones DMP, H2O n Alcohols to Carbonyls

Iodine (III) Reagents O Iodine (V) Reagents BIT or DIB: Phenols to quinones by oxidations at N O DMP or IBX: alcohol to aldehydes & ketones o - or p -position. R' IBX + Wittig Ylides: benzylic, allylic, propargylic DIB + water: Phenols or anilines to p -quinones R O O H alcohol to a,b-unsaturated ester I O : (water soluable reagent) benzylic, n Oxidations of Heteroaromatic Compounds allylic, propargylic alc. oxidation Aromatization of 5 and 6 membered rings using BIT or DIB O CO2H Iodine (III) Reagents R R N N N N DIB + TEMPO: selective 1° alcohol to aldehyde DIB ° R' R'' R' R'' IOB + cat. KBr: 1 alcohol to RCO2H, (52-70%) 2 ° alcohol to ketone

DIB + TMSN : desilation and oxidation of glycals MeO C CO Me 3 MeO2C CO2Me 2 2 Me BTI Ar Me R' Ar N N O K HO CO2Me H (25%) Ph I R (PhO)n Br

O K O O R O R KBr Ph I H IOB DIB O R' R' R R PhI, H2O, O O O O R

Oxidations & Rearrangements Using Hypervalent Iodine Compounds n a-Functionalization of Carbonyl Cmpds n Rearrangements (Nucleophilic attack on phenyliodinated intermediate) Hofmann-type Rearrangements IBX/ BID/ IOB + base: Yields a-hydroxylated acetals BID: Cyclizations of aromatic amides with a nucleophile in the HTI: a-tosylation of ketone (silyl enol ethers) ortho -position. TsO OH I O O R 1 : a-tosylation wtih about 40% e.e. H N NH2 DIB 4 2 R O R R3 R R Y X Y X n Introduction of , -Unsaturation (52-84%) a b Y = CH, N; X = O, NR' HO O- O + N + N : Dehydrogenation of enone via in situ Rearrangement of Amidines O O formation of silyl enol ether BID: Forms urea derivatives via carbodiimide intermediate. O IBX: Dehydrogenation by single electron transfer process NR' NR' NHR' DIB AcOH R O OH O NH NHR 2 NR (28-83%) R = aliphatic or aromatic

Cyclization of Unsaturated Carboxylic Acids O O AcO I AcO DIB O R = H O Ph O O R CO H 2 R R n Oxidation of C-H Bonds O : Oxidation of benzyl, allyl, or propargyl R = Ph O t - B u O O ethers to esters by a radical process. I : Removal of benzyl ether protecting grps Ph O O O R O Rearrangements Using Hypervalent Iodine Compounds n Rearrangements (Continued)

Rearrangement of Chalcones BTI: 1,2-phenyl migration and formation of b-acetal

O OMe O BTI Ar OMe Ar Ar' MeOH D Ar' up to 56%

Iodonio-Claisen Rearrangement Alkenyl(phenyl)iodine(III) compounds or DIB derivatives + propargyl silanes: Access to propynyl cmpds.

I(OAc)2 SiMe3 + R

R'

R R AcO AcO I I R R NuH [3,3]

Nu R' R' (49-91%) (41-96%)

Alkynyl(phenyl)iodine(III) coupounds: Thioamides yield thiazoles Furan derivative ring enlargements to yield pyrones

Conclusions and Future Direction of the Hypervalent Iodine Chemistry

n Future Goals

Searching for newer reagents that will lead to new reaction transformations.

Recycleable polymer supported reagents

Broadening the scope of reactivity by studying transistion metal-mediated reactions

n Conclusions

The chemistry of hypervalent iodine reagents is cool because:

(1) Fundamental reactions with versatility have been developed

(2) Mild reactivity with good yields

(3) Readily available reagents that easy to work with

(4) Non-toxic, enviromentally-friendly reagents