Iron-mediated modular decarboxylative cross-nucleophile coupling

•Unified solution to decarboxylative cross-nucleophile coupling reactions•Photoactive Fe(III) carboxylates + Fe(III)-mediated oxidation•Fe(III) salts are non-toxic, earth abundant, and low cost•Direct formation of C–C, C–O, C–S, C–N bonds without prefunctionalization Carboxylic acids valuable chemical building blocks because they widely available with significant structural diversity. Decarboxylative reactions increasingly utilized in modern drug discovery, but many the most general methods require preinstallation redox-active organic moieties as internal oxidants. Here, we report a photochemical method for direct functionalization carboxylic wide range simple carbon-, oxygen-, nitrogen-centered nucleophiles. Key success this process is diverse reactivity iron salts, which serve both light-absorbing center reaction sustainable terminal oxidant. pharmaceutical discovery their stability, commercial availability, enable versatile these feedstock chemicals, moieties. These oxidants can be costly, installation impedes rapid library synthesis, use results environmentally problematic byproducts. We herein cross-coupling native nucleophilic partners mediated by inexpensive, terrestrially non-toxic salts. This involves an initial decarboxylation followed radical-polar crossover, enables construction carbon–carbon, carbon–oxygen, carbon–nitrogen remarkable generality. Modern medicinal chemistry relies heavily on robust that assembly large libraries structurally candidates. Increasingly, accessibility block sets has become recognized important consideration; couple functionalities greater availability more efficiently span space accelerate discovery.1Kutchukian P.S. Dropinski J.F. Dykstra K.D. Li B. DiRocco D.A. Streckfuss E.C. Campeau L.-C. Cernak T. Vachal Davies I.W. et al.Chemistry informer libraries: chemoinformatics enabled approach evaluate advance synthetic methods.Chem. 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Benzylic tolerated, providing avenues further through orthogonal metal-mediated (41–43 48). ?-oxo furnish mixed acetal 41 demonstrates viability non-benzylic coupling. affect etherification NSAIDs (43–45 47–48). directly applicable thioetherification; sulfide 46 obtained 53% when cyclohexanethiol partner, noticeable sulfoxide sulfone examined Fe-promoted sulfonamides Electron-rich (49) electron-deficient (50) transformation quantitative Tertiary sulfonamide (51–53). To showcase potential relevance studied involving molecules. Zonisamide, topiramate, sultiame, all medications treat epilepsy, 54–56 coupled series COX-2-inhibitor sulfa drugs conjugates 57–59. highlight tolerance groups, sugars, benzisoxazoles, isoxazoles, pyrazoles, ketones, diaryl ethers, halogens. ease setup notable; throughout investigations, were set up under inert atmosphere easy handling hygroscopic After setup, conducted air S16). observed only modest loss added benchtop, sparge prior irradiation precaution S17). adjustments made maximize each class, single (FeCl3 Na3PO4) synthetically useful across major families investigated (53% 3, 64% 33, 99% 49), demonstrating exceptional S15). consistently superior previously 5A). notable modestly gave unsatisfactory FeCl3. exclusively alkenes S19 S20), adequate present protocol. Interestingly, implies different reactive intermediates likely involved. mechanisms notoriously difficult deconvolute,47Neidig M.L. Carpenter Curran DeMuth Fleischauer V.E. Iannuzzi T.E. Neate P.G.N. Sears J.D. 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S5–S8.Google promotes intermediate. Simple unfortunately, compatible possibly due strong binding affinity amines acidic S27). constraint introduction basic fragments molecules.51Roughley S.D. Jordan chemist’s toolbox: pursuit candidates.J. 54: 3451-3479https://doi.org/10.1021/jm200187yCrossref (1694) opportunity overcome limitation. Formal achieved adding after presence 6). Employing telescoped strategy, realized nitrogen-containing candidates, pyrrolidines (60), piperidines (61), piperazines (62), morpholines (63), alkylamines (64 65), (66), arylamines (67).46Messaoudi versatility encouraged us expand incompatible one-step When sodium p-toluenesulfinate employed nucleophile, formal sulfinylation affords 68 73% two-step suggests Fe-mediated leveraging example versatility, subjected Cu(I)-catalyzed 51% (69).52Ito Kubota Copper(I)-catalyzed boryl halides.Org. 890-893https://doi.org/10.1021/ol203413wCrossref (174) In conclusion, serves conventional ways. operational partners. place practicality environmental impact conduct should preparation lead straightforward specialized equipment blue LED source. demonstration utility hope stimulate ideas design