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A Photochemical Organocatalytic Strategy for the Α‐Alkylation Of Angewandte Research Articles Chemie How to cite: Angew.Chem. Int. Ed. 2020, 59,9485–9490 Radical Chemistry International Edition: doi.org/10.1002/anie.201915814 German Edition: doi.org/10.1002/ange.201915814 APhotochemical Organocatalytic Strategyfor the a-Alkylation of Ketones by using Radicals Davide Spinnato+,Bertrand Schweitzer-Chaput+,Giulio Goti, Maksim Osˇeka, and Paolo Melchiorre* In memory of Dieter Enders (1946–2019) Abstract: Reported herein is avisible-light-mediated radical approach to the a-alkylation of ketones.This method exploits the ability of anucleophilic organocatalyst to generate radicals upon SN2-based activation of alkylhalides and blue light irradiation. The resulting open-shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers,which would be unable to directly attackthe alkylhalides through atraditional two-electron path. The mild reaction conditions allowed functionalization of the a position of ketones with functional groups that are not compatible with classical anionic strategies.Inaddition, the redox-neutral nature of this process makes it compatible with acinchona-based primary amine catalyst, whichwas used to develop arare example of enantioselective organocatalytic radical a-alkylation of ke- tones. Introduction Figure 1. (a) Traditional strategies for the a-alkylation of ketones by The a-alkylation of ketones is afundamental C Cbond- using enolate equivalents via anionic pathways. (b) Radical approach À forming process.[1] Classically,itisaccomplished by means of to the alkylation of silyl enol ethers 1.(c) The presented photochemical highly nucleophilic alkali metal enolates,generated by strategy uses anucleophilic catalyst A and visible light to generate radicals from redox-inertalkyl electrophiles, which are then trapped by deprotonation of the corresponding ketones,which can react weakly nucleophilic silyl enol ethers. [2] with alkyl halides through an SN2pathway (Figure 1a). This two-electron, anionic strategy has found extensive use in synthesis.However,italso brings about some chemoselectiv- can be tolerated. Milder alternatives,which avoid the use of ity issues because the strongly basic and nucleophilic nature of strongly basic metal enolates,are therefore highly sought- the metal enolates limits the range of functional groups that after. Silyl enol ethers are stable enolate equivalents that are easy to synthesize and to handle.[3] These compounds have been extensively used in nucleophilic addition chemistry [+] [+] [*] D. Spinnato, Dr.B.Schweitzer-Chaput, Dr.G.Goti, Dr.M.Osˇeka, (aldol, Michael, and Mannich-type processes).[4] However, Prof. Dr.P.Melchiorre the poor nucleophilicity[5] of silyl enol ethers makes them ICIQ—Institute of Chemical Research of Catalonia the Barcelona Institute of Science and Technology unsuitable for alkylation reactions with alkyl halides via an Avenida Països Catalans 16, 43007 Tarragona (Spain) SN2pathway (Figure 1a,right arrow). Theliterature contains E-mail:[email protected] only afew reports of silyl enol ether alkylation, generally [6] Homepage: http://www.iciq.org/research/research group/prof-pao- limited to SN1-type substitution processes. lo-melchiorre/ In principle,the high reactivity of open-shell intermedi- Prof. Dr.P.Melchiorre ates,which can easily engage in C Cbond-forming process- À ICREA es,[7] could be used for effective reactions with the weakly Passeig LluísCompanys 23, 08010 Barcelona (Spain) nucleophilic silyl enol ethers 1 (Figure 1b). Moving from + [ ]These authors contributed equally to this work. atwo-electron logic to aradical reactivity pattern could Supportinginformation and the ORCID identification number(s) for therefore provide the desired degree of chemoselectivity and the author(s) of this article can be found under: functional-group tolerance to the a-alkylation of ketones. https://doi.org/10.1002/anie.201915814. However,effective strategies to generate alkyl halide-derived 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. radicals would be required. To date,the few reported KGaA. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, protocols are limited to the use of specific radical precursors distribution and reproduction in any medium, provided the original that can be easily activated by initiators or through single- work is properly cited, and is not used for commercial purposes. electron-transfer (SET) processes,including perfluoralkyl Angew.Chem. Int.Ed. 2020, 59,9485 –9490 2020 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 9485 Angewandte Research Articles Chemie iodides,[8] a-bromo ketones and esters,[9] and N-(acyloxy)- 10 mol%ofthe dithiocarbonyl anion catalyst A,adorned phthalimide derivatives.[10] In addition, redox-based strategies with an indole chromophoric unit, and aslight excess of (e.g. photoredox catalysis)[11] offer an additional challenge 1 (1.5 equiv). When using the trimethylsilyl derivative 1a, because the low oxidation potentials of silyl enol ethers[12] these conditions furnished the desired ketone product 3a in make them prone to degradation upon SET oxidation. good yield along with traces of the silyl derivative 4 (entry 1). Our laboratory recently reported aunique photochemical Theuse of different silyl protecting groups,including tert- catalytic radical generation strategy that is not reliant on the butyldimethylsilyl (TBS) and triisopropylsilyl (TIPS), pro- redox properties of the substrates.[13] This method exploits the vided better chemical yields and selectively favored the ability of ahighly nucleophilic[14] dithiocarbonyl anion formation of the O-silylated adduct 4 (entries 2and 3, organocatalyst A to generate radicals upon blue light respectively). Considering the cost of the silyl enol ethers irradiation and SN2-based activation of substrates (including and the efficiency of the reaction, we continued our inves- alkyl chlorides and mesylates) that would be inert to classical tigations with the TBS derivative 1b.Adding water to the radical-generating strategies (Figure 1c). Herein, we demon- reaction mixture allowed us to directly achieve ketone 3a as strate how this catalytic platform can provide ageneral the major product (entry 4). However,this hydrolysis step radical approach for the a-alkylation of ketones by using silyl was not uniformly effective for all of the silyl enol ethers enol ethers.This approach synthetically complements and evaluated, therefore,wetreated the crude mixture with enriches traditional two-electron strategies.This is because trifluoroacetic acid or tetrabutylammonium fluoride (TBAF), the mild reaction conditions and functional-group tolerance which quantitatively and consistently led to complete con- allowed us to functionalize the a position of ketones with version of 4 into the target product 3a (entry 5). Effective moieties that are incompatible with classical anionic pro- hydrolysis can be also achieved in the presence of acids; cesses. methanesulfonic acid or HCl in H2O(4equiv,entry 6) afforded 3a in high yields. Control experiments confirmed that the alkylation reac- Results and Discussion tion could not proceed in the absence of light or catalyst A (entries 7and 8). Thepresence of aradical scavenger We commenced our studies by evaluating the alkylation of (TEMPO,1equiv) completely suppressed the reaction (en- acetophenone-derived silyl enol ether 1,using the commer- try 9), whereas traces of the cyanomethyl–TEMPO adduct cially available chloroacetonitrile 2a as the radical precursor could be detected. Importantly,our attempts to perform the (Table 1). Theexperiments were conducted at 258Cin model reaction by using classical enolate chemistry,for acetonitrile,with ablue LED strip emitting at 465 nm, example,treating acetophenone with strong bases,met with failure (see Table S2 in the Supporting Information). Finally, we demonstrated that the strongly reducing fac-Ir(ppy)3 Table 1: Optimization studies and control experiments.[a] photoredox catalyst provided vastly inferior results (en- try 10), presumably because of adifficult generation of the reactive radical from 2a. Using the optimized conditions described in Table 1, entry 5, we tested the generality of the photochemical organocatalytic a-alkylation process (Figure 2). Firstly,we evaluated the scope of the carbon radicals that could be intercepted by the silyl enol ether 1b.Alarge variety of electrophilic primary radicals afforded the corresponding a- [b] Entry Deviation from SiR3 1 Yield 3/4 [%] alkylated ketones in good yields (3a, 3e, 3h). Secondary standard conditions radicals could also be generated and efficiently intercepted by 1none TMS a 71 /5 1b,albeit, in some cases,there was aneed to perform the 2none TBS b 7/93 reaction at 608C(adducts 3b–d, 3f–g). Benzylic radical 3none TIPS c <5/> 95 precursors,bearing both electron-rich and electron-poor aryl 4H2O(20 equiv) TBS b 90 /8 5work up:TFA or TBAF TBS b 91[c] /0 substituents,were also competent substrates (products 3i–n). Thestrategy can be used to implement aradical a-amino- 6work up:CH3SO3HorHCl(aq) TBS b > 95 /0 7nolight TBS b 0 methylation process,allowing the introduction of aprotected 8nocatalyst A TBS b 0 primary amine (3o)along with atrifluoromethyl moiety (3p). 9TEMPO (1 equiv) TBS b 0 Thereaction could be performed on agram scale without the 10 fac-Ir(ppy)3 (1 mol%);nocatalyst A TBS b 5/40 loss of efficiency(7.0 mmol scale, 3a obtained in 91%yield, [a] Reactionsperformed on a0.2 mmol
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