Hypervalent Iodine 6/15/13

Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

Diaryl-λ3-iodanes vs. 1. Introduction 5 diaryliodonium salts (Ar2IL) Aryl-λ -iodanes (ArIL4) Hypervalent refers to a main group element that breaks the octet rule and formally 2.3–2.7 Å has more than 8 electrons in its valence shell L Two orthogonal Ar hypervalent L–I–L bonds L Ar L L Ar I vs. with each using an Iodine(III) Iodine(V) I I Ar L L unhybridized p orbital O O Ar Cl I Cl AcO I OAc [10-I-3] [8-I-2] [12-I-5] Ar–I bond is a typical bond with sp hybridization O O "X-ray structural data for the overwhelming I I OAc majority of iodonium salts show a significant OH AcO Most electropositive substituent O OAc secondary bonding between the iodine atom and resides in the apical position iodobenzene (bisacetoxyiodo)benzene 2-iodoxybenzoic Dess-Martin the anion." (Zhdankin, Chem. Rev. 2008, 5299.) dichloride (PIDA, BAIB) acid (IBX) periodinane (DMP) General reactivity Iodine(VII) " " Iodine(III) reactivity depends on the ligands attached Iodine(V) and iodine(VII) O O O I I Ph L I L R I L O O vs. Oxidative processes I I I O I O R R O Ph Ph O Na Oxidative processes R group transfer n sodium iodosylbenzene periodate 2. Basic mechanisms Ligand exchange The hypervalent molecular orbitals Kajigaeshi, Tetrahedron Lett. 1988, 5783. Can theoretically proceed through either an antibonding L–I–L bond consists of an unhybridized p orbital associative or dissociative mechanism BnMe3NCl Cl Cl ICl3 I BnNMe DCM Cl Cl 3 nonbonding 2 e- come from iodine and 1 e- comes from Tetracoordinated species have been isolated, suggesting an associative mechanism each L, creating a 4 e-, 3 center bond bonding Reductive elimination Negative charge accumulates on each L, L I L Driven by reduction to return to univalent Kitamura, J. Am. Chem. Soc. 1999, 11674. δ- δ+ δ- positive charge accumulates on central I iodide and by an increase in entropy TMS TBAF + PhI 3 Leaving group ability 106 times greater DCM, rt Martin–Arduengo nomenclature Aryl-λ -iodanes (ArIL2) IPh(OTf) than OTf, making it a "hypernucleofuge" + TMSF + TBAOTf [N-X-L] L 3 Ar–I bond is a typical (reason why alkyl-λ -iodanes are so rare) 2 Ar I bond with sp hybridization Configurational isomerization number of central number of - L Can occur via intramolecular ligand exchange or Berry pseudorotation (Ψ) valence e atom ligands I–L bonds are the hypervalent [10-I-3] bonds X Y Ψ X X Y Ψ Ψ I I I I I Ar X Ar The most electronegative ligands reside in the YAr Ar Y apical (axial) positions Y Ar X Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

3. Not covered (extensively) 4. α-Functionalizations Basic oxidations of alcohols to the corresponding carbonyl compounds Direct α-oxytosylation of ketones. ⋅Can oxidize allylic alcohols to enals with IBX and do Wittigs in one pot Koser, J. Org. Chem. 1982, 2487. (Yadav, Synth. Commun. 2001, 149) O via: O PhI(OH)OTs O Me Me Me Me Oxidative cleavage of diols using PhI(OAc)2, DMP, NaIO4, ect. Me Me MeCN, Δ OTs Ph I OH Halogenations using TolIF2, PhICl2, ect. 94% Silyl enol ethers and silyl ketene acetals can also be used as the nucleophile Reactions where PhI(OAc)2 or similar reoxidizes a transition metal in a catalytic cycle α-Hydroxylation of ketones. Transition metal–catalyzed cross coupling processes where an aryl, alkenyl, or Moriarty, Tetrahedron Lett. 1981, 1283. alkynyl iodoinum salt serves as the organohalide (PhIO) or n MeO OMe O + O PhI(OAc)2 H O F C I O OH 3 OH 3 R' Ar Ar Me CF transfer reagent and potentially explosive Ar KOH, 3 R' R' Me Waser, J. Chem. Commun. 2011, 102. MeOH Haller, J. Org. Process. Res. Dev. 2013, 318. 40–70% Oxygenation installed on more hindered face. Togni's reagent Moriarty, J. Org. Chem. 1987, 153. O MeO OMe O Benzylic oxidation PhI(OAc)2 OH Oxidation to , -unsaturated carbonyl compounds O α β Proceeds via SET MeOH, KOH Oxidation of silyl enol ethers in conjunction with MPO I (OC) Cr (OC) Cr Cyclization of N-aryl amides, ureas, and carbamates 3 3 O OH IBX O Nicolaou, J. Am. Chem. Soc. 2002, 2245. IBX proposed to be Nicolaou, J. Am. Chem. Soc. 2000, 7596. activated prior to SET: O O OMe MeO O OMe MeO Nicolaou, J. Am. Chem. Soc. 2002, 2233. O I O I Ph I Ph Nicolaou, Angew. Chem. Int. Ed. 2002, 996. O

(OC) Cr (OC) Cr O [4+2] 3 (OC)3Cr 3 O R Mixtures of DMP and Ac-IBX (hydrolyzed O [O] DMP) oxidizes N-aryl amides, ureas, and N Used in the total synthesis of cephalotaxine. I OAc carbamates to the o-imidoquinones hetero Hanaoka, Tetrahedron Lett. 1986, 2023. AcO OAc [4+2] R' O O DMP O O O O Nicolaou, J. Am. Chem. Soc. 2002, 2212. o-Imidoquinone reactivity N N N Nicolaou, J. Am. Chem. Soc. 2002, 2221. (PhIO)n O O O H H KOH, H HO MeOH HO (79%) O MeO OMe OMe (±)-cephalotaxine Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

α-Oxidations of ketones can also occur under catalytic conditions. O Ochiai, J. Am. Chem. Soc. 2005, 12244. O O I product mCPBA Ph PhI I + mCPBA, O δ+ - O O δ CO2Me PhI (10 mol %) AcOH E R' major product R' R PhI(O2CR)2 R BF3•Et2O, O OAc AcOH, H2O R' 43–63% R OH Used in the synthesis of the indole core of tabersonine. Rawal, J. Am. Chem. Soc. 1998, 13523. IPh(OAc) R' R MeO C MeO2C MeO2C 2 TiCl , N N N 3 Coupling of carbon nucleophiles. 1 NH4OAc Zhdankin, J. Org. Chem. 1989, 2605. O (94%) (89%) O N N Me TBSO Me 2 O Me Ar H (90%)

TMS OTMS (PhIO)n O O N I(BF )Ph 1. K2S2O8, HBF 4 I IPhF Ar 4 Ar -78 °C (63%) Ar H2SO4, KI 2. AgF OTMS NO2 NO2 N Me H 1 CO2Me O tabersonine Ar α-Arylation in a more modern setting. (50%) O Aggarwal, Angew. Chem. Int. Ed. 2005, 5516. 1. Me Me Phenylation of silyl enol ethers. Koser, J. Org. Chem. 1991, 5764. O Ph N Ph Cl Li O OTMS O But: OTMS O H Cl Ph IF Ph2IF (2 equiv.) 2 Ph Ph N N (81%) (51%) Ph 2. 2 N (41%, 94% ee NBoc2 d.r. >20:1) NBoc2 (–)-epibatidine A mechanistic study reveals that the more electron deficient aryl group migrates in unsymmetrical salts. Li Ochiai, ARKIVOC 2003, 43. Cl O ICl2 Cl N OK IPh(BF ) ICl3 I 4 O + I HCl Cl (~70%) CO2Me (21%) Cl N N Cl O 2 E Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

5. Azidonation, aziridination, and amination Enantioselective aziridination. Evans, J. Am. Chem. Soc. 1993, 5328. (Di)azidonation of silyl enol ethers. OTIPS Evans, J. Am. Chem. Soc. 1994, 2742. Magnus, J. Am. Chem. Soc. 1992, 767. PhI=NTs Me Me CuOTf O OTIPS O O O -15 °C (5 mol %) N3 Ar OR TMSN3 N I N 3 N N N (PhIO) 3 3 Ar OR n (6 mol %) Ts (2 equiv.) Ph TEMPO TIPSO N3 Ph Ph 60–76% (cat.) N3 via radical 3 addition 94–97% ee -45 °C An alternative ligand for enantioselective aziridination. OTIPS OTIPS Jacobsen, J. Am. Chem. Soc. 1993, 5326. Ph OTIPS I -N3 β-Azidonation pathway: PhI=NTs N3 CuOTf NTs H H H N3 (10 mol %) Ar Ar Cl N N Cl R 4 R Azidonation of N,N-dimethylanilines. (11 mol %) Magnus, Synthesis 1998, 547. Cl Cl 50–79% 4 Me Me via: Me 58–98% ee (PhIO) N n N N N Me 3 DuBois' nitrene chemistry proceeds through an iminoiodinane. R TMSN3 R R DuBois, Tetrahedron 2009, 3042.

O O O O O O O O NMe 2 MeN S PhI(OAc)2 S I [Rh] cat. S [Rh] S OTBS (PhIO)n Ph O NH2 O N Ph O N O NH + -2 AcOH OTBS Ph TMSN3 Ph Ph Ph Ph MeO MeO Aryl C–H insertions can take place without the presence of transition metals. Substrate controlled amination of allyl silanes. Tellitu, J. Org. Chem. 2005, 2256. Panek, J. Am. Chem. Soc. 1997, 6040. O O Rationale: MeO MeO R' R' N PhI(O CCF ) N PhI=NTs DMPS 2 3 2 R OH TsN OH H R MeO CF CH OH MeO CuOTf R' Cu HN 3 2 N DMPS R O (70%) (10 mol %) MeO O MeO O 60–65% H H NTs > 30:1 de O O But: MeO N MeO N OMe OMe Mo(CO)6, Δ PhI=NTs Me OTBDPS TsN OTBDPS R' TsN H (76%) MeO H CuOTf R OH MeO N N O O DMPS (10 mol %) Me 64% H MeO 2:1 ds DMPS Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

6. Oxidative dearomatization of phenols Can also be used in conjuction with 1,3-dipolar cycloadditions. Sorensen, Org. Lett. 2009, 5394. There are several possible mechanisms. OTBS Quideau, Tetrahedron 2010, 2235. O Me O PhI(OAc)2, N OH O Dissociative R Nuc CF3CH2OH N Me -PhI -AcO- rt to 50 °C O OTBS H (80%) Ph HO OAc R' H I OH O O O Nuc Nuc R R R O N PhI(OAc)2 Associative R O or OH ? - cortistatin A Me -AcO -PhI O OTBS -AcO- R' R' R' R' Nuc H Ligand +Nuc -PhI -PhI coupling -AcO- And Diels-Alder reactions. Danishefsky, J. Am. Chem. Soc. 2006, 16440. IPh(Nuc) O O O OH O IPh(Nuc) OH OBn A radical pathway R IPh(Nuc) OBn O has also been R PhI(OAc)2 µW proposed. (65%) Me Me Me Me R' R' I R' OTs OTs HO H Me O Oxidative dearomatization often initiates cascade sequences (eg. diazonamide A). O Harran, Angew. Chem. Int. Ed. 2003, 4961. OH O OBn Me Me Me Me O O HO Me Me O ArSO2NH N ArSO2NH N Me Me OTs N CO Me N CO Me (±)-11-O-debenzoyltashironin H 2 H 2 O PhI(OAc)2 O IBX can directly oxidize electron–rich phenols to o-quinones. LiOAc, Pettus, Org. Lett. 2002, 285. OH CF3CH2OH, O N -20 °C N IBX, H2, H H HO R O R HO OMe AcO OMe Br Br IBX Pd/C Me Me DMF Me Me R' O R' Ac2O, AcO K CO N 2 3 N CO Me 20–99% (76%) HN CO2Me HN 2 Authors propose: ArSO NH O ArSO2NH O 2 O O NP O O O R (25%) O O R H O R O I I O O R' O R' Br Br NH R' O NH O Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

The use of oxidative dearomatization can be more subtle. Possible involvement of CT complex in dimerization of indoles at the 2 position? Pettus, Org. Lett. 2005, 5841. Kita, Org. Lett. 2006, 2007. Me Me H Me H HO HO O PhI(O2CCF3)2, OH OH OH TMSBr N N IBX; PhI(O2CCF3)2 + HO O DCM N N BnO O Na S O BnO O BnO O N 2 2 4 -78 °C to -40 °C H H (58%) H Me Me 74% 29% HO O OH Application of charge transfer chemistry in total synthesis. OH iPr NEt, 2 Kita, Synthesis 1999, 885. LiI H HO O HO Br PhI(O CCF ) , HN 2 H O (81%) 2 3 2 Br (±)-brazilin BF3•Et2O, DCM; Pd/C BnO S MeNH 2 BnO S Bn (66%) HN N OBn OBn H O S 7. Aryl charge transfer complexes N3 N PhI(O2CCF3)2, Nucleophilic substitution can also occur on para-substituted aryl ethers via a charge TMSOTf transfer complex. (CF ) CHOH, Kita, J. Am. Chem. Soc. 1994, 3684. MeO N 3 2 MeO N Br OH Ac H2O H makaluvamine F OMe OMe OMe OMe (51%) O CF3CO2 Nuc PhI(O2CCF3)2 SET Nuc Ph I O2CCF3 8. Radical processes (CF3)2CHOH SET Remote steroidal C–H functionalization. or CF3CH2OH MeO R R R R Breslow, J. Am. Chem. Soc. 1991, 8977. Me Me Nuc = TMSN3, TMSOAc, Me Me 1,3-dicarbonyls Me Me Intramolecular biaryl coupling of electron–rich aryl ethers. Me Me PhICl2 Kita, J. Org. Chem. 1998, 7698. H Me Br Me CBr , MeO MeO O 4 O hν PhI(O2CCF3)2 Intermolecular version I I BF •Et O O O 3 2 uses C6F5I(O2CCF3)2, MeO -40 °C MeO gives no homocoupling. (91%) Kita, Org. Lett. 2011, 6208. A variant of the Hofmann-Löffler-Freytag reaction. MeO MeO Suárez, Tetrahedron Lett. 1985, 2493. Can also be used to add nucleophiles to heterocycles. Me Me Kita, J. Org. Chem. 2007, 109. Me PhI(OAc)2, Me I PhI(O2CCF3)2 Me PhI(O2CCF3)2 Me 2 TMSCN TMSCN Me H Me Me C H , Δ N N CN 6 12 N EWG Me (77%) N EWG Me Ts BF3•Et2O Ts BF3•Et2O CN (83%) S (79%) S Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

Suárez conditions can also generate alkoxy radicals. TBHP undergoes a complicated decomposition pathway in the presence of PhI(OAc)2. Pattenden, Tetrahdron Lett. 1993, 127. Me Milas, J. Am. Chem. Soc. 1968, 4450. O TBHP, HO O H -80 °C -PhI PhI(OAc)2 PhI(OAc)2 PhI(OOtBu)2 2 tBuOO tBuOOOOtBu 1 - 2 AcOH - /2 O2 I2, hυ (58%) (58%) -75 °C to H H O H Et2O EtO Me tBuO + tBuOO tBuOOOtBu -65 °C β-Fragmentation paths can also lead to 2-dioxolanes. - tBuOH -5 °C tBuOO Suárez, J. Org. Chem. 1998, 4697. O to 5 °C EtO O tBuOOtBu PhO S H Me H H Me OtBu + tBuOH 2 1. PhI(OAc)2, + O EtO Me 2 H I2, hν PhO2S Me H O O O O 2. NaOMe A stable (alkylperoxy)iodane that oxidizes allyl and benzyl ethers. OH H (79%) H Ochiai, J. Am. Chem. Soc. 1996, 7716. MeO O OR O PhO S H Me PhO S I Me PhO S I Me 2 2 2 Cs CO H H H HO I O tBuOO I O 2 3 OR TBHP O O O (10–76%) O O O O O O H O H H BF3•Et2O (90%) Ar OR O OMe MeO O En route to (+)-epoxydictymene. K2CO3 Ar OR Paquette, Tetrahedron Lett. 1997, 195. (21–84%) Me Me H Me H Me Allylic oxidation of alkenes to enones. Me PhI(OAc)2, H I2 Me Yeung, Org. Lett. 2010, 2128. H H NP Me Me O O HO C6H12, Δ O Me Me H (95%) H Me PhI(OAc)2, Me OAc OAc TBHP, K2CO3 Me H Me H PhI(O2CR)2 can be decarboxylated to give radicals. nPrCO2nBu Togo, J. Chem. Soc. Perkin Trans. 1 1993, 2417. Radical generation: H H 0 °C H H Me Me (81%) PhI(O2CR)2 h or AcO AcO O O PhI(O CCF ) ν Δ 2 3 2 -PhI + PhI(OAc)2, R OH hυ or Δ -CO2 TBHP, K CO R RCO 2 3 R = alkyl, RC(O) N (13-88%) R N 2 O2N nPrCO2nBu O2N O Similar reaction can perform C–H amidation. -20 °C Zhdankin, Tetrahedron Lett. 1997, 21. (84%) O HO I O O Authors propose: TMSOTf; R N I O RO O PhI(OAc) O H R N 2 R' RC(O)NH , PhCl, Δ + tBuOO 2 O H tBuOO I O pyr (PhCO2)2 RO R' TBHP n (63–75%) cat. R = p-ClC4H6 (58%) Ph Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

Oxidation of unactivated C–H bonds. Shown to not proceed through the originally proposed α-carbon attack (13C labeling). Yeung, Org. Lett. 2011, 4308. Proposed intermediate: Ochiai, J. Am. Chem. Soc. 1986, 8281. ONa O O PhI(OAc)2, O O Ph I BF4 TBHP(aq.) R O n-C6H13 + R X Ph MeCN R X tBuOO I OOtBu O (32–56%) O O O Ph Ph Ph Ph Ph I n-C H 6 13 n-C6H13 n-C H BF4 3 6 13 9. Alkynyl(aryl)-λ -iodanes O O O

Although not commerically available, there a many ways to synthesize. Can be utilized in a conjugate addition–carbene insertion cascade. Ochiai, J. Am. Chem. Soc. 1986, 8281.

For R = alkyl or Ph. ONa O n-C5H11 Fujita, Tetrahedron Lett. 1985, 4501. n-C H I BF Ph + 8 17 4 PhIO NaBF4 R I BF Ph Ph R TMS 4 (84%) Et O•BF H O Ph O O 2 3 2 n-C5H11 DCM, rt O H For R = TMS or alkyl. Ph Stang, J. Org. Chem. 1991, 3912. R SnBu3 or O Tf2O OTf OTf R TMS R I OTf PhIO Provides a route to amino cyclopropanes. DCM, Ph I O I Ph DCM, 0 °C to rt Ph Lee, Synlett 2001, 1656. 0 °C NHTs For electron poor alkynes. nBuLi; Me + Stang, J. Am. Chem. Soc. 1994, 93. HCl Me N N Me IPh(OTs) Ts O NHTs TfO I CN DCM EWG I OTf (76%) Ts EWG SnBu3 + Ph -42 °C Ph With a cascade ending with a formal Stevens shift. Feldman, Org. Lett. 2000, 2603. Alkynylation of of nucleophiles with alkynyl(aryl) iodonium salts. Beringer, J. Org. Chem. 1965, 1930. IPh(OTf) O ONa O Ph TolSO2Na O O O Ph I Cl O + Ph + O Ph Ph (73%) TolO S TolO S O 2 2 O O TolO S 2 41% 27% Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

Used in key step of pareitropone synthesis. 10. Alkenyl(aryl)-λ3-iodanes Feldman, J. Org. Chem. 2002, 8528. OTIPS OTIPS O Alkenyl iodonium salts can be synthesized analogously to the alkynyl iodonium salts and undergo similar chemistry via base-induced alkylidinecarbenes. KF/ Ochiai, J. Am. Chem. Soc. 1988, 6565. LiNTMS2 Al2O3 IPh(OTf) O (PhIO) , O O 64% n H MeO Me Me tBuOK MeO MeO BF3•Et2O; NTs N Me -78 °C MeO NHTs SnBu NaBF4 IPh(BF ) MeO MeO 3 (80%) 4 (61%) H pareitropone

β-Elimination can produce cyclohexyne. Cyclocondensation with thioamides to thiazoles. O Wipf, J. Org. Chem. 1996, 8004. Fujita, J. Am. Chem. Soc. 2004, 7548. R' S Ph Ph MsO I R' base N + Ph Ph R NH2 R IPh(BF ) Ph S 4 Bu4NOAc Ph Ph R = Ar, C(O)R, NH2 R' = Ph, nBu 32–62% 60 °C (90%) Ph via: R NH H H R' R N R' R' Ph [3,3] R N R' N S Pt(PPh3)3 Pt(PPh ) I S S 3 2 R S tBuOK Ph IPh

Counterintuitive regiochemical outcome in Diels–Alder reactions. Direct SN2 reaction of vinyliodonium salts and isotopic labeling studies provide Stang, J. Org. Chem. 1997, 5959. evidence for β-elimination. δ− Ochiai, J. Am. Chem. Soc. 1991, 7059. IPh(OTf) (TfO)PhI R R nBu NX rt (TfO)PhI 4 R X + + + R + MeCN, rt δ (68–84%) EWG IPh(BF4) EWG R R EWG ~85% ~15% major minor Mechanistically: X Benziodoxoles in direct alkynylations of pyrroles and indoles. R R Waser, J. Angew. Chem. Int. Ed. 2009, 9346. Ph H R X H I I OH TIPS I O Cl I Ph 1. NaIO4, AcOH, H2O O O Cl 2. TMSOTf, pyr. R Computationally, the σ* of the vinyliodonium MeCN salt was found to be lower in energy than the π*. TIPS N R (Okuyama, Can. J. Chem. 1999, 577) TIPS TMS H Ph -HCl AuCl R H I Can also use: AcOH, DMF, ArSH, R2S, R2Se, (1–5 mol %) -PhI Can also use (benzo)thiophenes (need TFA). R Cl RC(S)NH2 Waser, Angew. Chem. Int. Ed. 2010, 7304. N (48–93%) (X = F proceeds via alkylidinecarbene) H Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

11. Iodonium ylides Mixed phosphonium–iodonium ylides. Zhadankin, J. Org. Chem. 2003, 1018.

Iodonium ylides as an alternative to α-diazo dicarbonyl compounds in intramolecular O O O cyclopropanations. PhI(OH)OTs KBr Ph P Ph P Ph P Moriarty, J. Am. Chem. Soc. 1989, 6443. 3 Me 3 Me 3 Me DCM MeOH, 0 °C Cu(I) or H (50%) IPh(OTs) (81%) Br O O PhI(OAc)2 Cu(II) O Can also use PhSLi and PhSO2Na O KOH, O (90% PhI MeOH overall) O Iodonium ylides undergo a net 1,3-dipolar cycloadditions upon photolysis. OMe OMe MeO Hadjiarapoglou, Tetrahedron Lett. 2000, 9299. Authors propose: H H O O O O IPh Ph O Ph O Me MeCN, Me I I O O Me hν Me Ph OMe Ph OMe (96%)

Transition metal–catalyzed iodonyl ylide chemistry proceeds through metal carbenoids. Intermolecular transylidation can generate reactive alkyl iodonium ylides. Müller, Helv. Chim. Acta. 1995, 947. Hadjiarapoglou, Synlett 2004, 2563.

O O iPr O O iPr SO Ph MeI SO2Ph SO2Ph SO Ph [Rh {(–)-(S)-ptpa} ] 2 2 Ph 2 4 Me Me O iPr PhO S I PhO S O iPr PhO2S IPh DCM 2 2 I PhO2S Me X (56%) Ph

Iodonium ylides perform the same chemistry X = N2 (89%, 69% ee) as the corresponding diazo species X = IPh (78%, 67% ee) (albiet in slightly lower yields). SO2Ph SO2Ph SO2Ph SO2Ph SO Ph Iodonium ylides can also undergo Wolff rearrangements. + I 2 Spyroudi, J. Org. Chem. 2003, 5627. PhO2S IPh MeI, DCM PhO2S IMe PhO2S Me H rt H 34% 46% O O O OH O PhI(OAc)2 PhNH2 O IPh DCM, Δ (84%) SO2Ph SO2Ph SO2Ph O O O SO Ph SO Ph SO Ph O I 2 I 2 I 2 OH H Me H Me H Me H H H NHPh O Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

A mechanistic controversy arising from an I to O Ph migration. Chiral 1,1'-spirobiindane iodine(III) reagent dearomatizes phenols enantioselectively. Nozaki, Tetrahedron 1970, 1243. Kita, Angew. Chem. Int. Ed. 2008, 3787. Me Me via: Me Me Me Me O OH OH O 5 O OAc O (0.55 equiv) I pyr O O O O O O O * I I (81–86% I I Δ 80–86% ee) OAc R R Reaction can also be ran catalytically with Me Me 5 Me mCPBA as the stoichiometric oxidant and Bakalbassis, J. Org. AcOH as an additive: gives 70% with 69% ee Moriarty, J. Org. Chem. 2005, 2893. Chem. 2006, 7060. An alternative, conformationally flexible iodoarene catalyzes the same reaction. Me Me Tol Me Me Ishihara, Angew. Chem. Int. Ed. 2010, 2175. O O OH OH 6 I Tol I O O (10 mol%), O mCPBA Me O O Me O O I O O O O * Me I O (59–92% HN O O NH I Tol Me 83–90% ee) R Mes 6 Mes L Me Me R Me Proposed active oxidant: MesHN NHMes Mes Mes Monocarbonyl iodonium ylides. O L O N L N Ochiai, J. Am. Chem. Soc. 1997, 11598. O H H O I I Ochiai, J. Org. Chem. 1999, 3181. Me Me or R' O O O L O O L O O Me Me -30 °C R R' R EtOLi O (51–92%) IPh -78 °C R A related lactate–derived reagent promotes and "enatiodifferentiating endo-selective AcO IPhBr EWG R' N O EWG oxylactonization." N Fujita, Angew. Chem. Int. Ed. 2010, 7068. -30 °C R R' OAc AcO I(OAc) (39–81%) 7 (1.5 equiv.), 2 R R AcOH Me O O Me O Secondary bonding + BF Et O, O O O O I responsible for stability? CO R' 3• 2 >-30 °C vs. Ph 2 -80 to -40 °C O OMe MeO O IPh Br Varvoglis, Acta Crystallogr., O O 7 R R O O Sect. C: Crystal Structure 57–88% 3–8% unstable stable Commun. 1990, 1300. 75–96% ee 6–51% ee via: AcO Ar OAc OAc AcO I R I 12. Chiral iodanes for enantioselective transformations Ar R CO2R' CO2R' Baran Group Meeting Julian Lo Hypervalent Iodine 6/15/13

13. Miscellaneous reactivity Room temperature benzylic oxidation using catalytic iodine. Zhdankin, Chem. Eur. J. 2009, 11091. Ru(III) PhIO Oxone 2 Ar R PhI (5 mol %) O O RuCl3 (0.16 mol %) Ar R Oxone Ar R Ru(V) PhIO Ar R MeCN, H2O 23–95% O Utilization of allenyl iodanes in propargylations. Ochiai, J. Am. Chem. Soc. 1991,1319. Ochiai, Chem. Commun. 1996, 1933. R' R' I(OAc)2 I TMS AcO I [3,3] R BF •Et O -20 °C R 3 2 R R' MgSO4 -20 °C ipso and meta If R = m-NO2 propargylation if R''OH or MeCN ortho positions are Ar Ar (100 equiv.) or both substituted R''O AcHN

One last application of hypervalent iodine in total synthesis. Moriarty, J. Med. Chem. 1998, 468. Ph Ph

PhI(OAc)2 PhI(OAc)2

KOH, CO H I2, AIBN MeOH O 2 (92%) CO2Me O (40%)

PhI(OH)OTs (90%) NH CONH I 2 2 O Br Br (22%) K2CO3

(analog) N