Halogen-Atom Transfer Activation of Halides by Aminoalkyl Radicals

Activation of ubiquitous organic halides into radical intermediates has been a challenging topic. In a recent paper published in Science, Leonori, Juliá, and co-workers disclosed a new and robust strategy for halogen-atom-transfer activation of alkyl and aryl halides with the use of α-aminoalkyl radicals, easily generated from simple tertiary amines via single-electron transfer (SET) oxidation. Activation of ubiquitous organic halides into radical intermediates has been a challenging topic. In a recent paper published in Science, Leonori, Juliá, and co-workers disclosed a new and robust strategy for halogen-atom-transfer activation of alkyl and aryl halides with the use of α-aminoalkyl radicals, easily generated from simple tertiary amines via single-electron transfer (SET) oxidation. Organic halides are an important and versatile class of building blocks with wide applications in organic synthesis. Among the available methods for their activation, halogen-atom transfer (XAT) has still been one of the most powerful platforms because it generates diverse highly reactive open-shell carbon radicals. Conventionally, tin or silicon reagents (e.g., Bu3SnH or (TMS)3SiH) together with initiators or the Et3B/O2 system are often exploited for converting halides into the corresponding carbon radicals via XAT-based homolytic cleavage of carbon-halogen bonds.1Neumann W.P. Tri-n-butyltin hydride as reagent in organic synthesis.Synthesis. 1987; 1987: 665-683Crossref Scopus (662) Google Scholar,2Chatgilialoglu C. Ferreri C. Landais Y. Timokhin V.I. Thirty years of (TMS)3SiH: a milestone in radical-based synthetic chemistry.Chem. Rev. 2018; 118: 6516-6572Crossref PubMed Scopus (138) Google Scholar Mechanistically, the XAT process is driven by the formation of strong halogen-tin or halogen-silicon bonds, as well as a high degree of charge transfer caused by the nucleophilic property of tin and silicon radicals in the related transition state.3Tamblyn W.H. Vogler E.A. Kochi J.K. Polar effect in alkyl radical reactions. Carbon kinetic isotope effects in halogen atom transfer to tin(III) and chromium(II).J. Org. Chem. 1980; 45: 3912-3915Crossref Scopus (15) Google Scholar Despite being powerful, the development of generally applicable and more sustainable strategies that bypass the use of these hazardous or toxic reagents is still highly desirable. With the development of visible-light photoredox catalysis over the past decade, a plethora of widely applicable methods have been invented for the generation of various carbon radicals from diverse sets of readily available precursors. Despite a well-developed and growing body of research in the chemistry of carbon radicals,4Prier C.K. Rankic D.A. MacMillan D.W. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis.Chem. Rev. 2013; 113: 5322-5363Crossref PubMed Scopus (5968) Google Scholar the application of carbon radicals to XAT activation has never been explored. Sporadic examples of the activation of unactivated organic halides by photoredox catalysis are typically enabled through the SET-reduction process, but applications are limited to dehalogenation or intramolecular cyclizations.5Nguyen J.D. D'Amato E.M. Narayanam J.M. Stephenson C.R. Engaging unactivated alkyl, alkenyl and aryl iodides in visible-light-mediated free radical reactions.Nat. Chem. 2012; 4: 854-859Crossref PubMed Scopus (566) Google Scholar,6Shen Y. Cornella J. Juliá-Hernández F. Martin R. Visible-light-promoted atom transfer radical cyclization of unactivated alkyl iodides.ACS Catal. 2017; 7: 409-412Crossref Scopus (67) Google Scholar Because of the inherent highly negative reduction potentials of major unactivated alkyl and aryl halides (typically Ered < −2.0 V versus saturated calomel electrode [SCE]), meeting the redox match toward single-electron transfer (SET) activation often requires highly reducing photocatalytic systems, resulting in significant limitations on the substrate scope and reaction profiles. Recent inspiring works by MacMillan and colleagues demonstrated that photocatalytically generated silyl radicals allow efficient activation of aryl and alkyl bromides to the corresponding carbon radicals by XAT to facilitate their otherwise sluggish oxidative addition with copper and nickel catalysts.7Le C. Chen T.Q. Liang T. Zhang P. MacMillan D.W.C. A radical approach to the copper oxidative addition problem: trifluoromethylation of bromoarenes.Science. 2018; 360: 1010-1014Crossref PubMed Scopus (231) Google Scholar,8Zhang P. Le C.C. MacMillan D.W. Silyl radical activation of alkyl halides in metallaphotoredox catalysis: a unique pathway for cross-electrophile coupling.J. Am. Chem. Soc. 2016; 138: 8084-8087Crossref PubMed Scopus (335) Google Scholar Recently in Science, Leonori, Juliá, and co-workers demonstrated that photogenerated α-aminoalkyl radicals can serve as a robust and alternative class of XAT reagents because of the following properties: (1) their strong nucleophilicity analogous to that of tin and silicon radicals, (2) their availability from simple and abundant amines by photoinduced SET oxidation, and (3) their easy steric and electronic fine-tuning (Scheme 1A).9Constantin T. Zanini M. Regni A. Sheikh N.S. Juliá F. Leonori D. Aminoalkyl radicals as halogen-atom transfer agents for activation of alkyl and aryl halides.Science. 2020; 367: 1021-1026Crossref PubMed Scopus (177) Google Scholar The developed approach offers a mild and general strategy for allowing engagement of various unactivated alkyl and aryl halides in many diverse redox radical transformations. To validate this concept, Leonori and colleagues first investigated the kinetic feasibility of iodine-atom transfer between cyclohexyl iodide and a simple triethylamine-derived α-aminoalkyl radical by density functional theory calculation and laser flash photolysis. The findings suggest that the XAT event is slightly exothermic, but the facile and irreversible formation of iminium iodide from the initially formed α-iodide would significantly render the XAT process thermodynamically favored (Scheme 1A). After screening four sets of catalytic systems commonly used for the SET oxidation of amines, the authors identified that a combination of organic photocatalyst 4CzIPN and triethylamine under the illumination of blue light-emitting diodes in the presence of methyl thioglycolate-H2O as the hydrogen source allowed efficient dehalogenation reduction of 4-iodo-N-Boc-piperidine 3a to give product 4 (Scheme 1B). Conversely, switching from triethylamine to other electron donors commonly used in photoredox-catalyzed reduction, such as Ph2N(PMP) or Hantzsch ester, inhibited the desired reactivity, implying that the role of triethylamine should not only be an electron sacrificial donor. The proposed working hypothesis for dehalogenation reduction is outlined in Scheme 1B. First, triethylamine 1a undergoes visible-light photoredox-catalyzed SET oxidation and deprotonation to give the key α-aminoalkyl radical 1a-I and the reduced catalyst 4CzIPN·−. This step has been well documented in the literature. Next, radical species 1a-I abstracts an iodine atom from 3a to afford alkyl radical 3a-I, which undergoes hydrogen-atom transfer with methyl thioglycolate to yield product 4 with the release of the thiyl radical. Notably, at this juncture, facile conversion of the resulting 1a-II to iminium iodide 1a-III could significantly facilitate the XAT process. Then, a SET from 4CzIPN·− to the thiyl radical occurs to regenerate the ground-state photocatalyst 4CzIPN and thiol catalyst after protonation by H2O, closing both photoredox and organocatalytic cycles. Notably, this mechanism is also supported by the redox properties of 4CzIPN and Et3N given that neither the photoexcited (∗Eox = −1.04 V versus SCE) nor the reduced (Ered = −1.21 V versus SCE) form of the photocatalyst10Luo J. Zhang J. Donor–acceptor fluorophores for visible-light-promoted organic synthesis: photoredox/Ni dual catalytic C(sp3)–C(sp2) cross-coupling.ACS Catal. 2016; 6: 873-877Crossref Scopus (480) Google Scholar or radical 1a-I (Eox = −1.12 V versus SCE) can be sufficiently reduced to drive direct SET reduction of 2a (Ered = −2.35 V versus SCE), ruling out the possible SET activation pathway. The authors realized that this activation strategy shows broad synthetic applications, enabling a wide variety of redox radical reactions. For instance, upon brief optimization, they established that the reaction system consisting of 4CzIPN, Bu3N, and HSCH2CO2Me with D2O as the deuterium source in EtOAc allowed efficient dehalogenation-deuteration reactions of a wide range of primary, secondary, and tertiary alkyl iodides, furnishing diverse deuterated products 5 with excellent yields. Remarkably, the catalytic system could also be successfully extended to the activation of challenging alkyl bromides (although with moderate yield), which are not feasible under the traditional Et3B/O2 system. A salient feature of this α-aminoalkyl radical-mediated XAT is the possibility of fine-tuning the N-substitution pattern in amines to modulate their reactivity. By selecting an appropriate tertiary amine (e.g., triethyl amine 1a, tribenzylamine 1b, 1,2,2,6,6-pentamethylpiperidine 1c, or triisobutylamine 1d), the authors disclosed that the competitive direct addition of the α-aminoalkyl radical to certain electron-deficient alkenes can be completely circumvented. Accordingly, they further developed a broadly applicable Giese-type hydroalkylation of alkyl and aryl iodides with differently substituted electron-poor alkenes (Scheme 1D). The corresponding highly functionalized products 6 were obtained with moderate to high yields. Remarkably, using a simple allyl chloride as the radical acceptor could also achieve an efficient and practical allylation of diverse alkyl and aryl halides (Scheme 1E). By combining this XAT activation mode with cobaloxime catalysis, the authors developed a widely applicable Heck-type olefination reaction of diverse alkyl iodides and bromides with styrene derivatives and electron-rich alkenes (Scheme 1F). Notably, in most cases the alkene products were obtained exclusively as E isomers. To further highlight the generality of this XAT strategy, Leonori and colleagues attempted to apply it to direct C–H alkylation of (hetero)arenes. Given the requirement of another SET oxidation of the radical intermediate formed by radical addition to (hetero)arenes, they employed stoichiometric K2S2O8 as the external oxidant under simple thermal conditions without light irradiation or a catalyst (Scheme 1G). Again, this protocol accommodates a wide range of alkyl and aryl iodides, thus enabling efficient sp3-sp2 and sp2-sp2 couplings. In summary, Leonori and co-workers have demonstrated an elegant and robust strategy for the activation of carbon-halogen bonds by α-aminoalkyl radical-promoted XAT. This interesting method allows the implementation of a wide variety of redox radical transformations starting from various readily available chemicals, providing access to diverse value-added molecules. The fundamental outcomes and insight described in this work also open up new opportunities for carbon radical chemistry.