Chemoselective cascade arylation

Diaryliodonium salts are versatile arylating agents but generally feature poor atom economy. In this issue of Chem, Olofsson and co-workers describe a novel chemoselective SNAr reaction that sets up second in situ arylation incorporates the iodoarene component cascade with excellent The N- O-based functionalities, producing diarylamine ether structures essential to many biologically active molecules functional materials, is fundamental transformation synthetic chemistry. Reliable methods for their synthesis focal point chemistry most commonly involve disconnecting C–N or C–O bond exploit native nucleophilicity heteroatom combination an electrophilic agent. This encapsulated nucleophilic aromatic substitution (SNAr) (Scheme 1A), classic approach proceeds through addition nucleophile 2 electron-deficient arene 1, typically aryl fluoride, deliver arylated amine alcohol. Advances transition-metal catalysis have substantially increased scope arylation; example, cross-coupling techniques such as Buchwald-Hartwig Chan-Evans-Lam reactions established far broader range heteroaromatic motifs. Nevertheless, remains tool molecule building; recent industry survey ranks it third used class medicinal chemistry.1Brown D.G. Boström J. Analysis past present methodologies on chemistry: Where all new gone?.J. Med. Chem. 2016; 59: 4443-4458Google Scholar Hypervalent diaryliodonium represent important alternative fluorides Although first prepared characterized over century ago,2Hartmann C. Meyer V. Ueber eine neue Klasse jodhaltiger, stickstofffreier organischer.Basen. Ber. 1894; 27: 426-432Google superb versatility has become increasingly apparent years modes been discovered. straightforward prepare, handle, store bench-stable crystalline solids amenable direct nucleophiles via ligand coupling (LC) processes,3Beringer F.M. Brierley A. Drexler M. Gindler E.M. Lumpkin C.C. salts. II. phenylation organic inorganic bases.J. Am. Soc. 1953; 75: 2708-2712Google oxidative catalysts participate cross-couplings,4Kalyani D. Deprez N.R. Desai L.V. Sanford M.S. Oxidative C-H activation/C-C forming reactions: Synthetic mechanistic insights.J. 2005; 127: 7330-7331Google single-electron-transfer access radical chemistry5Baralle Fensterbank L. Goddard J.-P. Ollivier Aryl formation by copper(I) photocatalyzed reduction salts: NMR evidence Cu(II)/Cu(I) mechanism.Chemistry. 2013; 19: 10809-10813Google precursors benzyne arylations.6Sundalam S.K. Nilova Seidl T.L. Stuart D.R. A selective deprotonation strategy functionalized arynes using hypervalent iodine.Angew. Int. Ed. 55: 8431-8434Google successful transfer each case driven expulsion 1 equiv iodoarene, exceptional leaving group. turn represents principal drawback iodonium arylation: very economy where greater than half molecular weight reagent jettisoned waste. Given overall highly favorable conditions employed aryliodonium reagents, solution would significant impact sustainability translation into industrial application. Strategies date include capture side product event7Modha S.G. Greaney M.F. Atom-economical tandem N-H indoles.J. 2015; 137: 1416-1419Google use cyclic salts, retained target intramolecularity.8Wang Chen S. Jiang X. applications salts.Chem. Asian 2018; 13: 2195-2207Google Now, reporting group at Stockholm University describes iodine arylation—one showcases en route multitude heteroarene structures.9Linde E. Bulfield Kervefors G. Purkait N. B. Diarylation O-nucleophiles metal-free reaction.Chem. 2022; 8: 850-865Google Taking 7 (containing fluoroaryl group) exemplar, observed typical was fluoro when heated 40°C–60°C presence mild base. surprising observation given center LC facile requires no special activation ring; indeed, preferred mode similar fluoroarene lack ortho para activation. Here, however, takes place set unique transfer, spectating can then react further create doubly products 9, retaining iodo subsequent derivatization. milder temperature critical—attempted higher temperatures, which be more typical, gave mixtures diarylated products. discovery opens powerful space speaks two aspects sustainable arylation. First, incorporating structure skillfully solves atom-economy problems characterize only formal waste from components metal salt comprising counterion, triflate. Second, combining sequential arylations one enhances process efficiency space- time yields, reduces labor costs, minimizes intermediate processing. authors could showcase these features modular transformation, creates opportunities control selectivity three initial step. They rich around alkylamines N extensive structural functional-group diversity 1D). non-SNAr (shown green) tolerant various electron demand functionalities (e.g., 12 13), well sterically encumbering substituents (14). did perforce require withdrawal, broad groups NO2, CN, SO2R, CO2R) were effective 15 16). Anilines examined because resulting triarylamine valuable electronic optical properties especially ring differentiated 1D, iii). weak effectively incorporated modified involving MgSO4 additive. assembled 40 structurally diverse triarylamines single step exemplify power approach, although constraint required strong activating groups, NO2. oxygen series water nucleophile. Minor amendments (EtOAc dioxane solvent) delivered diarylethers iv) analogous process. Finally, demonstrated proof principle ammonia nucleophile, challenging anhydrous avoid occur common aqueous solutions compound 24). ortho-iodo substituent utility difficult carry conventional transition-metal-catalyzed preparations spectator exemplified additional chemoselectivity dimension post-process Suzuki, Sonogashira, Heck, Buchwald-Hartwig, C–H transformations 25 26), illustrating potential system rapidly generate complexity synthesis. carried out experiments found support proposed SNAr-LC pathway. For 28 isolated under slightly reduced heating before being converted 29, cross-over intramolecular key dichotomy probed computationally; energy difference 10 kcal/mol calculated rate-determining Meisenheimer complex versus iodine. summary, laboratory defined O exploiting reaction. assembles differentiated, multi-arene complete predictability operationally simple precious-metal costly ligands. exquisite reactivity highlights iodine(III) reagents signposts future directions atom-economical application reactionLinde et al.ChemFebruary 14, 2022In BriefN- O-arylated compounds prevalent pharmaceuticals materials. Methods simultaneous introduction different lacking, time-consuming expensive multi-step syntheses. Herein, we efficient difunctionalization incorporation (>100 examples). method enabled discovered specifically designed fluorinated unveils pathways Full-Text PDF Open Access