SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2015, 26, 1573–1577 1573 letter Syn lett M. Brown et al. Letter Synthesis of New Chiral Diaryliodonium Salts Michael Browna Marion Delormea Florence Malmedya Joel Malmgrenb Berit Olofssonb Thomas Wirth*a a School of Chemistry, Cardiff University, Park Place, Main Building, Cardiff CF10 3AT, UK [email protected] b Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden Dedicated to Prof. Dr. Peter Vollhardt Received: 06.03.2015 reactions with carbon nucleophiles including β-keto esters.9 Accepted after revision: 09.04.2015 Conditions have been established to predict which arene is Published online: 20.05.2015 DOI: 10.1055/s-0034-1380687; Art ID: st-20156-b0156-l transferred when unsymmetrical salts are employed and this has allowed the design of unsymmetrical salts as selec- tive arene-transfer reagents. Transfer of the most electron- Abstract A structurally diverse range of chiral diaryliodonium salts poor arene or those with ortho substituents can usually be have been synthesised which have potential application in metal-free predicted under metal-free conditions, thus allowing elabo- stereoselective arylation reactions. ration in the design of a non-transferable aryl ligand which often can be recycled as the iodoarene.10 Key words arylation, diaryliodonium salts, hypervalent iodine, stereo- selective synthesis Chiral diaryliodonium salts, where one substituent con- tains a stereogenic unit, have received very limited atten- tion since the first derivative of that type, diphenyliodoni- Hypervalent iodine compounds have gained popularity um tartrate, was reported in 1907.11 Ochiai described the in recent years as extremely versatile and environmentally synthesis of 1,1′-binaphth-2-yl(phenyl)iodonium salts 1 benign reagents. Iodine(III) reagents with two heteroatom (Figure 1) by a tin–iodine(III) exchange with tetraphenyltin, ligands are highly electrophilic and promote a range of se- and tested their efficacy in the arylation of a range of β-keto lective oxidative transformations of organic molecules in- esters, achieving selective phenyl transfer in moderate cluding the addition of heteroatom nucleophiles to unsatu- yields and enantioselectivites (up to 53% ee).12 Zhdankin rated systems, oxidations of alcohols, and skeletal rear- prepared amino acid derived benziodazoles 2 with an inter- rangements of carbon systems.1 nal anion by a similar tin–iodine(III) exchange.13 More re- Diaryliodonium salts are iodine(III) compounds bearing cently, Olofsson described the metal-free synthesis of (phe- Downloaded by: IP-Proxy Cardiff University, University. Copyrighted material. two aryl ligands. They are potent electrophilic arylation re- nyl)iodonium salts of type 3 via electrophilic aromatic sub- agents as reactions with these reagents are driven by the stitution with [hydroxy(tosyloxy)iodo]benzene (HTIB, reductive elimination of an iodoarene.2 They have been em- Koser’s reagent), these salts bearing one, two, or three ste- ployed extensively as aryl donors to copper and palladium reogenic centres derived from an enzymatic kinetic resolu- centres in metal-catalysed cross-coupling reactions,3 nota- tion of racemic 2-octanol.14 bly for the α-arylation of carbonyls via copper(I)-bisoxazo- A theoretical study on the mechanism of α-arylation of line catalysis,4 and for the α-arylation aldehydes in combi- carbonyl compounds with diaryliodonium salts revealed nation with chiral enamine catalysis.5 In combination with that asymmetric induction in this reaction could not be catalytic amounts of chiral Lewis acids, they have also re- provided by chiral anions or chiral phase-transfer cata- cently been successfully employed for the asymmetric α- lysts,15 therefore the design of iodonium salts bearing a chi- arylation of oxindoles.6 ral non-transferable aryl ligand is likely to be the most Of growing interest is the ability of diaryliodonium salts promising approach for enantiocontrol in metal-free reac- to take part in metal-free reactions. They have been suc- tions. cessfully employed for biaryl synthesis,7 arylations of het- In recent years a number of chiral iodoarenes have eroatom nucleophiles such as phenols and more challeng- emerged as highly efficient stereoselective reagents for cat- ing substrates such as sulfonic and carboxylic acids;8 and in © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1573–1577 1574 Syn lett M. Brown et al. Letter Inspired by the success of derivatives 4 in stereoselec- BF – Ph O 4 tive syntheses, we devised a short synthetic route to iodo- Ph I OMe + I N nium salt 6a, where the reaction of the C3-symmetric arene Bn R 9 with [hydroxy(tosyloxy)iodo]benzene would avoid prob- O lems with unwanted regioisomers from the electrophilic aromatic substitution. 1 2 Ochiai 1999 Zhdankin 2003 MesHN O 5 MsO CO2Me O O –OTs i–iii + + I MesHN Ph HO OH O O O O O O 5 NHMes 5 OH 9 3 MesHN O Olofsson 2010 Figure 1 Previously reported chiral diaryliodonium salts. O –OTs I+ PhI(OH)OTs Ph alytic oxidation reactions.16 Conformationally flexible io- MesHN dine reagents of type 4 (Figure 2) bearing stereogenic cen- TFE, r.t., 4 h O O 90% tres within coordinating side chains have been shown to O O provide excellent stereocontrol in stoichiometric alkene 17 NHMes functionalisation reactions. In contrast, conformationally 6a rigid iodoarenes such as 1,1-spiroindanone 5 have proven Scheme 1 Synthesis of diaryliodonium salt 6a. Reagents and conditions: 18 to be highly effective in spirocyclisation reactions. The re- i) K2CO3, MeCN, reflux, 5 d, 22%; ii) NaOH, THF–MeOH–H2O, r.t., 16 h, 19 cent interest in metal-free arylations prompted us to re- 97%; iii) SOCl2, toluene, 1 h reflux, then MesNH2, CH2Cl2, 0 °C to r.t., 16 port our synthetic routes to chiral diaryliodonium salts 6–8, h and separation of diastereomers, 12%. which bear non-transferable aryl ligands that are confor- mationally flexible (type 6), or possess a rigid chiral back- The required stereogenic centres were installed by tris- bone (types 7 and 8). Wherever possible, the use of transi- alkylation of 1,3,5-trihydroxybenzene with activated meth- tion metals was avoided. yl lactate. As previously observed in similar alkylation reac- tions, steric congestion resulted in a slow final alkylation and partial loss of stereochemical integrity. Chromato- O I O graphic separation of the resultant diastereomeric mixture O O I proved challenging, as did attempts at separation by crys- R R I tallisation after hydrolysis of the methyl esters. Fortunately, Downloaded by: IP-Proxy Cardiff University, University. Copyrighted material. after treatment with thionyl chloride and 2,4,6-trimeth- 4a R = NHMes ylaniline, amide 9 could be isolated as a single diastereomer 4b R = OMe 5 after extensive chromatography. Subsequent electrophilic aromatic substitution with [hydroxy(tosyloxy)iodo]ben- MesHN O zene14 gave diaryliodonium tosylate 6a as a single diaste- – X– BF4 reomer in 90% yield. Trifluoroethanol has been used as it is O X– Ph Ph known to be a versatile solvent in hypervalent iodine chem- I+ I+ I+ 20 Ph istry and in the synthesis of diaryliodonium(III) salts. OR I The need for chromatographic separation of diastereo- R O mers produced during the alkylation step and the low over- O all yield in the synthesis of 6a led us to consider a more di- rect route to iodonium salts of this type. Iodoarene 4a can NHMes 6 7 8 be accessed with minimal racemisation via Mitsunobu re- Figure 2 Chiral iodoarenes 4 and 5 employed in stereoselective reac- action of 2-iodo-1,3-dihydroxybenzene with methyl lac- tions and chiral diaryliodonium salts synthesised herein (6–8). tate.21 Fortunately, direct oxidation of 4a with MCPBA and © Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1573–1577 1575 Syn lett M. Brown et al. Letter BF3·OEt2 followed by boron–iodine(III) exchange with phen- of the intermediate radical by hydrogen abstraction from ylboronic acid22 gave (phenyl)iodonium tetrafluoroborate solvent or from extraneous sources would result in reduced 6b efficiently in a single step (Scheme 2). product 13, although all efforts were made to exclude sources of moisture and degassed solvents were routinely MesHN O MesHN O used. After installation of iodine in the 2-position, eclipsing – interactions between the iodine and 2′-substituents pro- BF4 O O vide a greatly increased barrier to racemisation. Indeed, no I+ I i,ii Ph racemisation was observed after hydrolysis of the me- thoxymethyl ester (ee >99%, as determined by chiral HPLC). 78% 25 O O Arylation with diphenyliodonium triflate or alkylation O O with iodomethane provided model systems 12a and 12b to study the oxidation and salt forming steps. NHMes NHMes Although a number of one-pot protocols have been de- 4a 6b veloped for the direct synthesis of diaryliodonium salts Scheme 2 Direct oxidation and boron–iodine(III) exchange providing from iodoarenes,2a electron-rich aryl ethers 12 proved to be diaryliodonium salt 6b. Reagents and conditions: i) MCBPA (1.8 equiv), challenging substrates. A range of oxidants were tested un- BF ·OEt (2.5 equiv), CH Cl , 0 °C, 2 h; ii) PhB(OH) , r.t., 4 h, 78%. 3 2 2 2 2 der conditions typically employed for iodoarene oxidation. When MCPBA, peracetic acid, Oxone®, or potassium persul- Chiral diaryliodonium salts of type 7 incorporating a fate were used under ambient conditions, complex product binaphthyl backbone were first introduced by Ochiai (Fig- mixtures resulted. At lower temperature (–78 °C to 0 °C), or ure 1). In contrast to conformationally flexible salts of type when HTIB was used as an oxidant, polyaromatic products 6, binaphthyl systems 7 bearing a rigid, axially chiral back- resulting from electrophilic substitution of the most elec- bone are anticipated to provide an asymmetric environ- tron-rich naphthalene ring could be tentatively assigned in ment around the iodine which is less susceptible to inter- the crude reaction mixture.