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.