Hypervalent Iodine. Diaryl-λ 3 -iodanes vs. diaryliodonium salts (Ar 2 IL) [10-I-3] Dess-Martin periodinane (DMP) General reactivity

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1 ypervalent odine Baran Group eting 1. ntroduction ypervalent refers to a main group element that breaks the octet rule and formally has more than 8 electrons in its valence shell iodobenzene dichloride The hypervalent molecular orbitals δ - δ δ - Martin duengo nomenclature number of valence e - odine() [--] Ac Ac (bisacetoxyiodo)benzene (PDA, BAB) " " iodosylbenzene central atom number of ligands antibonding nonbonding bonding 2-iodoxybenzoic acid (B) Ac Ac Ac Dess-Martin periodinane (DMP) bond consists of an unhybridized p orbital 2 e - come from iodine and 1 e - comes from each, creating a 4 e -, 3 center bond egative charge accumulates on each, positive charge accumulates on central yl-λ 3 -iodanes ( 2 ) bond is a typical bond with sp 2 hybridization bonds are the hypervalent bonds n odine(v) odine(v) a sodium periodate [10--3] The most electronegative ligands reside in the apical (axial) positions Diaryl-λ 3 -iodanes vs. diaryliodonium salts ( 2 ) 2. Basic mechanisms igand exchange Driven by reduction to return to univalent iodide and by an increase in entropy eaving group ability 10 6 times greater than Tf, making it a "hypernucleofuge" (reason why alkyl-λ 3 -iodanes are so rare) Kitamura, J. Am. Chem. oc. 1999, TM (Tf) TBAF DCM, rt Configurational isomerization Can occur via intramolecular ligand exchange or Berry pseudorotation (Ψ) Y [10--3] Å vs. [8--2] "-ray structural data for the overwhelming majority of iodonium salts show a significant secondary bonding between the iodine atom and the anion." (Zhdankin, Chem. ev. 2008, 5299.) General reactivity odine() reactivity depends on the ligands attached vs. xidative processes Can theoretically proceed through either an associative or dissociative mechanism Tetracoordinated species have been isolated, suggesting an associative mechanism eductive elimination group transfer yl-λ 5 -iodanes ( 4 ) Ψ Y Ψ Ψ Y Y [12--5] Two orthogonal hypervalent bonds with each using an unhybridized p orbital bond is a typical bond with sp hybridization Kajigaeshi, Tetrahedron ett. 1988, Bn 3 DCM Most electropositive substituent resides in the apical position odine(v) and iodine(v) xidative processes TMF Bn 3 Y TBATf

2 ypervalent odine Baran Group eting 3. ot covered (extensively) Basic oxidations of alcohols to the corresponding carbonyl compounds Can oxidize allylic alcohols to enals with B and do Wittigs in one pot (Yadav, ynth. Commun. 2001, 149) xidative cleavage of diols using (Ac) 2, DMP, a 4, ect. alogenations using TolF 2, 2, ect. eactions where (Ac) 2 or similar reoxidizes a transition metal in a catalytic cycle Transition metal catalyzed cross coupling processes where an aryl, alkenyl, or alkynyl iodoinum salt serves as the organohalide F 3 C Togni's reagent B CF 3 transfer reagent and potentially explosive Waser, J. Chem. Commun. 2011, 102. aller, J. rg. Process. es. Dev. 2013, 318. Benzylic oxidation xidation to α,β-unsaturated carbonyl compounds xidation of silyl enol ethers in conjunction with MP Cyclization of -aryl amides, ureas, and carbamates icolaou, J. Am. Chem. oc. 2002, icolaou, J. Am. Chem. oc. 2000, icolaou, J. Am. Chem. oc. 2002, icolaou, Angew. Chem. nt. Ed. 2002, 996. Mixtures of DMP and Ac-B (hydrolyzed DMP) oxidizes -aryl amides, ureas, and Ac Ac carbamates to the o-imidoquinones Ac DMP icolaou, J. Am. Chem. oc. 2002, icolaou, J. Am. Chem. oc. 2002, B proposed to be activated prior to ET: hetero [42] Proceeds via ET [42] ' [] o-midoquinone reactivity 4. α-functionalizations Direct α-oxytosylation of ketones. Koser, J. rg. Chem. 1982, α-ydroxylation of ketones. Moriarty, Tetrahedron ett. 1981, ' () n or (Ac) 2 K, xygenation installed on more hindered face. Moriarty, J. rg. Chem. 1987, 153. (Ac) 2 (C) 3 Cr (C) 3 Cr ', K (C) 3 Cr Used in the total synthesis of cephalotaxine. anaoka, Tetrahedron ett. 1986, ()Ts C, Δ 94% () n K, (79%) Ts ilyl enol ethers and silyl ketene acetals can also be used as the nucleophile 3 (C) 3 Cr via: ' 40 70% (C) 3 Cr (±)-cephalotaxine

3 ypervalent odine Baran Group eting α-xidations of ketones can also occur under catalytic conditions. chiai, J. Am. Chem. oc. 2005, product mcpba mcpba, (10 mol %) ' Ac ' ( BF 3 Et 2, 2 C) 2 Ac, 2 Ac ' 43 63% (Ac) Coupling of carbon nucleophiles. Zhdankin, J. rg. Chem. 1989, (90%) ' Used in the synthesis of the indole core of tabersonine. awal, J. Am. Chem. oc. 1998, C 2 C Ti 3, 1 4 Ac TB δ δ - E (94%) 2 C 2 major product (89%) 2 C TM () n BF 4 (BF 4 ) -78 C (63%) TM 1. K 2 2 8, 2 4, K F TM 2 2. AgF 1 2 tabersonine C 2 enylation of silyl enol ethers. Koser, J. rg. Chem. 1991, TM 2 F But: TM (50%) 2 F A mechanistic study reveals that the more electron deficient aryl group migrates in unsymmetrical salts. chiai, AKVC 2003, 43. K (81%) (51%) C 2 (BF 4 ) E α-ylation in a more modern setting. Aggarwal, Angew. Chem. nt. Ed. 2005, Boc 2 1. i (2 equiv.) 2. 2 (41%, 94% ee d.r. >20:1) 3 (21%) 2 Boc 2 (~70%) i ( )-epibatidine 2

4 ypervalent odine Baran Group eting 5. Azidonation, aziridination, and amination (Di)azidonation of silyl enol ethers. Magnus, J. Am. Chem. oc. 1992, 767. TM 3 () 3 3 n (2 equiv.) β-azidonation pathway: Azidonation of,-dimethylanilines. Magnus, ynthesis 1998, 547. TP () n TM 3 3 TP -15 C TEMP (cat.) -45 C TP -3 3 TP TP via: TP via radical addition 3 Enantioselective aziridination. Evans, J. Am. Chem. oc. 1993, Evans, J. Am. Chem. oc. 1994, An alternative ligand for enantioselective aziridination. Jacobsen, J. Am. Chem. oc. 1993, =Ts CuTf (5 mol %) 3 (6 mol %) =Ts CuTf (10 mol %) 4 (11 mol %) Ts 50 79% 58 98% ee DuBois' nitrene chemistry proceeds through an iminoiodinane. DuBois, Tetrahedron 2009, Ts 60 76% 94 97% ee TB () n TM 3 ubstrate controlled amination of allyl silanes. Panek, J. Am. Chem. oc. 1997, But: ' DMP =Ts CuTf (10 mol %) TBDP =Ts DMP CuTf (10 mol %) Ts Ts ' 60 65% > 30:1 de TBDP 64% 2:1 ds TB ationale: ' Ts DMP Cu Ts ' DMP 2 (Ac) 2-2 Ac [h] cat. yl C insertions can take place without the presence of transition metals. Tellitu, J. rg. Chem. 2005, ( 2 CCF 3 ) 2 CF 3 C 2 (70%) [h] Mo(C) 6, Δ (76%)

5 ypervalent odine Baran Group eting 6. xidative dearomatization of phenols There are several possible mechanisms. Quideau, Tetrahedron 2010, xidative dearomatization often initiates cascade sequences (eg. diazonamide A). arran, Angew. Chem. nt. Ed. 2003, P ' 2 (Ac) 2 -Ac - A radical pathway has also been proposed. igand coupling C 2 - ' (Ac) 2 iac, CF 3 C 2, -20 C C 2 (25%) Ac ' uc Associative ' Dissociative -Ac - uc -Ac - (uc) - -Ac ' ' - uc uc (uc) or ' ' uc - C 2 (uc) C 2 Can also be used in conjuction with 1,3-dipolar cycloadditions. orensen, rg. ett. 2009, TB (Ac) 2, CF 3 C 2 rt to 50 C (80%) cortistatin A? TB And Diels-Alder reactions. Danishefsky, J. Am. Chem. oc. 2006, Bn Bn (Ac) 2 µw ' B Ts ' (±)-11--debenzoyltashironin 20 99% ' Ts B can directly oxidize electron rich phenols to o-quinones. Pettus, rg. ett. 2002, 285. DMF Authors propose: ' B, 2, Pd/C Ac 2, K 2 C 3 (76%) (65%) Ac Ac TB Bn Ts '

6 ypervalent odine Baran Group eting The use of oxidative dearomatization can be more subtle. Pettus, rg. ett. 2005, yl charge transfer complexes ucleophilic substitution can also occur on para-substituted aryl ethers via a charge transfer complex. Kita, J. Am. Chem. oc. 1994, ( 2 CCF 3 ) 2 (CF 3 ) 2 C or CF 3 C 2 CF 3 C 2 2 CCF 3 ET ntramolecular biaryl coupling of electron rich aryl ethers. Kita, J. rg. Chem. 1998, Bn (±)-brazilin ( 2 CCF 3 ) 2 BF 3 Et 2-40 C (91%) Can also be used to add nucleophiles to heterocycles. Kita, J. rg. Chem. 2007, 109. Ts 2 Pd/C ( 2 CCF 3 ) 2 TMC BF 3 Et 2 (83%) B; a (58%) Bn Ts C Bn ( 2 CCF 3 ) 2 Bn uc ET uc uc = TM 3, TMAc, 1,3-dicarbonyls ntermolecular version uses C 6 F 5 ( 2 CCF 3 ) 2, gives no homocoupling. Kita, rg. ett. 2011, ( 2 CCF 3 ) 2 TMC BF 3 Et 2 (79%) Bn C ipr 2 Et, i (81%) Possible involvement of CT complex in dimerization of indoles at the 2 position? Kita, rg. ett. 2006, ( 2 CCF 3 ) 2, TM Application of charge transfer chemistry in total synthesis. Kita, ynthesis 1999, 885. ( 2 CCF 3 ) 2, BF 3 Et 2, DCM; Bn 8. adical processes emote steroidal C functionalization. eslow, J. Am. Chem. oc. 1991, DCM -78 C to -40 C Bn Ac 2 Bn (66%) ( 2 CCF 3 ) 2, TMTf (CF 3 ) 2 C, 2 (51%) 2 C 4, hν A variant of the ofmann-öffler-freytag reaction. uárez, Tetrahedron ett. 1985, EWG (Ac) 2, 2 C 6 12, Δ (77%) EWG 74% 29% makaluvamine F

7 ypervalent odine Baran Group eting uárez conditions can also generate alkoxy radicals. Pattenden, Tetrahdron ett. 1993, (Ac) 2, 2, hν 2. a (79%) (Ac) 2 2, hυ (58%) β-fragmentation paths can also lead to 2-dioxolanes. uárez, J. rg. Chem. 1998, En route to ()-epoxydictymene. Paquette, Tetrahedron ett. 1997, 195. Ac (Ac) 2, 2 C 6 12, Δ (95%) imilar reaction can perform C amidation. Zhdankin, Tetrahedron ett. 1997, 21. TMTf; C() 2, pyr (63 75%) 2 2, Δ (C 2 ) 2 Ac ( 2 C) 2 can be decarboxylated to give radicals. Togo, J. Chem. oc. Perkin Trans , adical generation: ( 2 C) 2 hν or Δ ( 2 CCF 3 ) 2 - hυ or Δ -C 2 = alkyl, C() (13-88%) C 2 2 (58%) P cat. = p-c 4 6 (58%) TBP undergoes a complicated decomposition pathway in the presence of (Ac) 2. Milas, J. Am. Chem. oc. 1968, TBP, -80 C - (Ac) 2 (tbu) 2 2 tbu tbutbu - 2 Ac tbu Et Et 2 - tbu tbu tbu Et tbu tbu Et A stable (alkylperoxy)iodane that oxidizes allyl and benzyl ethers. chiai, J. Am. Chem. oc. 1996, TBP BF 3 Et 2 (90%) tbu Allylic oxidation of alkenes to enones. Yeung, rg. ett. 2010, Ac Authors propose: ' (Ac) 2 TBP (Ac) 2, TBP, K 2 C 3 nprc 2 nbu 0 C (81%) (Ac) 2, TBP, K 2 C 3 tbu Ac ' tbutbu -5 C to 5 C Cs 2 C 3 n K 2 C 3 2 nprc 2 nbu 2-20 C (84%) tbu - 1 / C to -65 C tbutbu 2 (10 76%) (21 84%)

8 ypervalent odine Baran Group eting xidation of unactivated C bonds. Yeung, rg. ett. 2011, (Ac) 2, TBP (aq.) C (32 56%) 9. Alkynyl(aryl)-λ 3 -iodanes Proposed intermediate: tbu tbu hown to not proceed through the originally proposed α-carbon attack ( 13 C labeling). chiai, J. Am. Chem. oc. 1986, n-c 6 13 a n-c 6 13 n-c 6 13 BF 4 n-c 6 13 BF 4 Although not commerically available, there a many ways to synthesize. For = alkyl or. Fujita, Tetrahedron ett. 1985, For = TM or alkyl. tang, J. rg. Chem. 1991, Tf 2 DCM, 0 C For electron poor alkynes. tang, J. Am. Chem. oc. 1994, 93. nbu 3 or Tf Tf TM DCM, 0 C to rt Tf Tf C DCM EWG Tf EWG nbu 3-42 C Alkynylation of of nucleophiles with alkynyl(aryl) iodonium salts. Beringer, J. rg. Chem. 1965, a TM Et 2 BF 3 DCM, rt abf 4 2 (73%) BF 4 Can be utilized in a conjugate addition carbene insertion cascade. chiai, J. Am. Chem. oc. 1986, a Ts (Ts) n-c 8 17 nbui; (76%) BF 4 Provides a route to amino cyclopropanes. ee, ynlett 2001, Ts (84%) With a cascade ending with a formal tevens shift. Feldman, rg. ett. 2000, (Tf) Tol 2 a Tol 2 n-c 5 11 Ts Tol 2 Tol 2 41% 27% n-c 5 11 Ts

9 ypervalent odine Baran Group eting Used in key step of pareitropone synthesis. Feldman, J. rg. Chem. 2002, TP (Tf) Ts itm 2 64% TP Ts KF/ Al 2 3 Cyclocondensation with thioamides to thiazoles. Wipf, J. rg. Chem. 1996, ' Ms ' base 2 =, C(), 2 ' =, nbu 32 62% via: ' [3,3] Counterintuitive regiochemical outcome in Diels Alder reactions. tang, J. rg. Chem. 1997, δ (Tf) EWG δ rt (68 84%) ' (Tf) EWG major Benziodoxoles in direct alkynylations of pyrroles and indoles. Waser, J. Angew. Chem. nt. Ed. 2009, a 4, Ac, 2 2. TMTf, pyr. C TP TM Can also use (benzo)thiophenes (need TFA). Waser, Angew. Chem. nt. Ed. 2010, TP ' (Tf) TP pareitropone EWG minor (48 93%) ' Au (1 5 mol %) 10. Alkenyl(aryl)-λ 3 -iodanes Alkenyl iodonium salts can be synthesized analogously to the alkynyl iodonium salts and undergo similar chemistry via base-induced alkylidinecarbenes. chiai, J. Am. Chem. oc. 1988, nbu 3 () n, BF 3 Et 2 ; abf 4 (80%) β-elimination can produce cyclohexyne. Fujita, J. Am. Chem. oc. 2004, (BF 4 ) Pt(P 3 ) 3 tbuk Bu 4 Ac (BF 4 ) 60 C (90%) Pt(P 3 ) 2 tbuk -78 C (61%) Direct 2 reaction of vinyliodonium salts and isotopic labeling studies provide evidence for β-elimination. chiai, J. Am. Chem. oc. 1991, chanistically: - - (BF 4 ) ( = F proceeds via alkylidinecarbene) nbu 4 C, rt ~85% ~15% Computationally, the σ* of the vinyliodonium salt was found to be lower in energy than the π*. (kuyama, Can. J. Chem. 1999, 577) Can also use: Ac, DMF,, 2, 2 e, C() 2

10 ypervalent odine Baran Group eting 11. odonium ylides odonium ylides as an alternative to α-diazo dicarbonyl compounds in intramolecular cyclopropanations. Moriarty, J. Am. Chem. oc. 1989, (Ac) 2 K, Authors propose: Cu() or Cu() (90% overall) Transition metal catalyzed iodonyl ylide chemistry proceeds through metal carbenoids. Müller, elv. Chim. Acta. 1995, 947. Mixed phosphonium iodonium ylides. Zhadankin, J. rg. Chem. 2003, P ()Ts DCM (50%) 3 P (Ts) K, 0 C (81%) 3 P Can also use i and 2 a odonium ylides undergo a net 1,3-dipolar cycloadditions upon photolysis. adjiarapoglou, Tetrahedron ett. 2000, C, hν (96%) ntermolecular transylidation can generate reactive alkyl iodonium ylides. adjiarapoglou, ynlett 2004, ipr ipr odonium ylides perform the same chemistry as the corresponding diazo species (albiet in slightly lower yields). [h 2 {( )-()-ptpa} 4 ] odonium ylides can also undergo Wolff rearrangements. pyroudi, J. rg. Chem. 2003, (Ac) 2 2 DCM, Δ (84%) ipr ipr = 2 (89%, 69% ee) = (78%, 67% ee) DCM (56%), DCM rt % %

11 ypervalent odine Baran Group eting A mechanistic controversy arising from an to migration. ozaki, Tetrahedron 1970, via: Monocarbonyl iodonium ylides. chiai, J. Am. Chem. oc. 1997, chiai, J. rg. Chem. 1999, Ac Tol >-30 C Tol Eti -78 C pyr Moriarty, J. rg. Chem. 2005, unstable Δ vs. Tol stable ' -30 C (51 92%) Bakalbassis, J. rg. Chem. 2006, ' ' EWG EWG -30 C ' (39 81%) econdary bonding responsible for stability? Varvoglis, Acta Crystallogr., ect. C: Crystal tructure Commun. 1990, Chiral iodanes for enantioselective transformations Chiral 1,1'-spirobiindane iodine() reagent dearomatizes phenols enantioselectively. Kita, Angew. Chem. nt. Ed. 2008, (0.55 equiv) (81 86% 80 86% ee) eaction can also be ran catalytically with mcpba as the stoichiometric oxidant and Ac as an additive: gives 70% with 69% ee * 5 Ac Ac An alternative, conformationally flexible iodoarene catalyzes the same reaction. shihara, Angew. Chem. nt. Ed. 2010, (10 mol%), mcpba * (59 92% 83 90% ee) s 6 s Proposed active oxidant: s s or s s A related lactate derived reagent promotes and "enatiodifferentiating endo-selective oxylactonization." Fujita, Angew. Chem. nt. Ed. 2010, Ac Ac (Ac) 7 (1.5 equiv.), 2 Ac C 2 ' BF 3 Et 2, -80 to -40 C % 3 8% 75 96% ee 6 51% ee via: Ac Ac Ac Ac C 2 ' C 2 '

12 ypervalent odine Julian o 13. Miscellaneous reactivity oom temperature benzylic oxidation using catalytic iodine. Zhdankin, Chem. Eur. J. 2009, u() xone (5 mol %) u (0.16 mol %) 2 3 xone C, 2 u(v) 23 95% Utilization of allenyl iodanes in propargylations. chiai, J. Am. Chem. oc. 1991,1319. chiai, Chem. Commun. 1996, ' ' (Ac) 2 Ac TM BF 3 Et 2 Mg 4-20 C '' or [3,3] -20 C ' ipso and meta propargylation if ortho positions are both substituted f = m-2 '' or C (100 equiv.) Ac ne last application of hypervalent iodine in total synthesis. Moriarty, J. d. Chem. 1998, 468. (Ac) 2 (Ac) 2 K, (40%) C 2 C 2 2, AB (92%) ()Ts (90%) 2 (22%) C 2 K 2C3 (analog) Baran Group eting