Photoredox-Catalyzed Dehydrogenative Csp³–Csp² Cross-Coupling of Alkylarenes to Aldehydes in Flow

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1. 1

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   (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 2013, 113, 5322– 5363,  DOI: 10.1021/cr300503r

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   Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis

   Prier, Christopher K.; Rankic, Danica A.; MacMillan, David W. C.

   Chemical Reviews (Washington, DC, United States) (2013), 113 (7), 5322-5363CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

   A review. This review will highlight the early work on the use of transition metal complexes as photoredox catalysts to promote reactions of org. compds. (prior to 2008), as well as cover the surge of work that has appeared since 2008. We have for the most part grouped reactions according to whether the org. substrate undergoes redn., oxidn., or a redox neutral reaction and throughout have sought to highlight the variety of reactive intermediates that may be accessed via this general reaction manifold.

   (b) Shaw, M.; Twilton, J.; MacMillan, D. W. C. Photoredox catalysis in organic chemistry. J. Org. Chem. 2016, 81, 6898– 6926,  DOI: 10.1021/acs.joc.6b01449

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   Photoredox Catalysis in Organic Chemistry

   Shaw, Megan H.; Twilton, Jack; MacMillan, David W. C.

   Journal of Organic Chemistry (2016), 81 (16), 6898-6926CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)

   In recent years, photoredox catalysis has come to the forefront in org. chem. as a powerful strategy for the activation of small mols. In a general sense, these approaches rely on the ability of metal complexes and org. dyes to convert visible light into chem. energy by engaging in single-electron transfer with org. substrates, thereby generating reactive intermediates. In this Perspective, we highlight the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon-carbon and carbon-heteroatom bonds.

   (c) Twilton, J.; Le, C.; Zhang, P.; Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. The merger of transition metal and photocatalysis. Nat. Rev. Chem. 2017, 1, 0052,  DOI: 10.1038/s41570-017-0052

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   The merger of transition metal and photocatalysis

   Twilton, Jack; Le, Chi; Zhang, Patricia; Shaw, Megan H.; Evans, Ryan W.; MacMillan, David W. C.

   Nature Reviews Chemistry (2017), 1 (7), 0052CODEN: NRCAF7; ISSN:2397-3358. (Nature Research)

   A review. The merger of transition metal catalysis and photocatalysis, termed metallaphotocatalysis, has recently emerged as a versatile platform for the development of new, highly enabling synthetic methodologies. Photoredox catalysis provides access to reactive radical species under mild conditions from abundant, native functional groups, and, when combined with transition metal catalysis, this feature allows direct coupling of non-traditional nucleophile partners. In addn., photocatalysis can aid fundamental organometallic steps through modulation of the oxidn. state of transition metal complexes or through energy-transfer-mediated excitation of intermediate catalytic species. Metallaphotocatalysis provides access to distinct activation modes, which are complementary to those traditionally used in the field of transition metal catalysis, thereby enabling reaction development through entirely new mechanistic paradigms. This Review discusses key advances in the field of metallaphotocatalysis over the past decade and demonstrates how the unique mechanistic features permit challenging, or previously elusive, transformations to be accomplished.

   For selected photoredox catalyzed C(sp²)–C(sp³) bond formations see

   (d) Tellis, J. C.; Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Single-electron transmetalation via Photoredox/Nickel dual catalysis: unlocking a new paradigm for sp³-sp² cross- coupling. Acc. Chem. Res. 2016, 49, 1429– 1439,  DOI: 10.1021/acs.accounts.6b00214

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   Single-Electron Transmetalation via Photoredox/Nickel Dual Catalysis: Unlocking a New Paradigm for sp3-sp2 Cross-Coupling

   Tellis, John C.; Kelly, Christopher B.; Primer, David N.; Jouffroy, Matthieu; Patel, Niki R.; Molander, Gary A.

   Accounts of Chemical Research (2016), 49 (7), 1429-1439CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)

   A review. The important role of transition metal-catalyzed cross-coupling in expanding the frontiers of accessible chem. territory is unquestionable. Despite empowering chemists with Herculean capabilities in complex mol. construction, contemporary protocols are not without their Achilles' heel: Csp3-Csp2/sp3 coupling. The underlying challenge in sp3 cross-couplings is 2-fold: (i) methods employing conventional, bench-stable precursors are universally reliant on extreme reaction conditions because of the high activation barrier of transmetalation; (ii) circumvention of this barrier invariably relies on use of more reactive precursors, thereby sacrificing functional group tolerance, operational simplicity, and broad applicability. Despite the ubiquity of this problem, the nature of the transmetalation step has remained unchanged from the seminal reports of Negishi, Suzuki, Kumada, and Stille, thus suggesting that the challenges in Csp3-Csp2/sp3 coupling result from inherent mechanistic constraints in the traditional cross-coupling paradigm. Rather than submitting to the limitations of this conventional approach, we envisioned that a process rooted in single-electron reactivity could furnish the same key metalated intermediate posited in two-electron transmetalation, while demonstrating entirely complementary reactivity patterns. Inspired by literature reports on the susceptibility of organoboron reagents toward photochem., single-electron oxidative fragmentation, realization of a conceptually novel open shell transmetalation framework was achieved in the facile coupling of benzylic trifluoroborates with aryl halides via cooperative visible-light activated photoredox and Ni cross-coupling catalysis. Following this seminal study, we disclosed a suite of protocols for the cross-coupling of secondary alkyl, α-alkoxy, α-amino, and α-trifluoromethylbenzyltrifluoroborates. Furthermore, the selective cross-coupling of Csp3 organoboron moieties in the presence of Csp2 organoboron motifs was also demonstrated, highlighting the nuances of this approach to transmetalation. Computational modeling of the reaction mechanism uncovered useful details about the intermediates and transition-state structures involved in the nickel catalytic cycle. Most notably, a unique dynamic kinetic resoln. process, characterized by radical homolysis/recombination equil. of a NiIII intermediate, was discovered. This process was ultimately found to be responsible for stereoselectivity in an enantioselective variant of these cross-couplings. Prompted by the intrinsic limitations of organotrifluoroborates, we sought other radical feedstocks and quickly identified alkylbis(catecholato)silicates as viable radical precursors for Ni/photoredox dual catalysis. These hypervalent silicate species have several notable benefits, including more favorable redox potentials that allow extension to primary alkyl systems incorporating unprotected amines as well as compatibility with less expensive Ru-based photocatalysts. Addnl., these reagents exhibit an amenability to alkenyl halide cross-coupling while simultaneously expanding the aryl halide scope. In the process of exploring these reagents, we serendipitously discovered a method to effect thioetherification of aryl halides via a H atom transfer mechanism. This latter discovery emphasizes that this robust cross-coupling paradigm is "blind" to the origins of the radical, opening opportunities for a wealth of new discoveries. Taken together, our studies in the area of photoredox/nickel dual catalysis have validated single-electron transmetalation as a powerful platform for enabling conventionally challenging Csp3-Csp2 cross-couplings. More broadly, these findings represent the power of rational design in catalysis and the strategic use of mechanistic knowledge and manipulation for the development of new synthetic methods.

   (e) Joe, C. L.; Doyle, A. G. Direct Acylation of C(sp³)-H Bonds Enabled by Nickel and Photoredox Catalysis. Angew. Chem., Int. Ed. 2016, 55, 4040– 4043,  DOI: 10.1002/anie.201511438

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   Direct Acylation of C(sp3)-H Bonds Enabled by Nickel and Photoredox Catalysis

   Joe, Candice L.; Doyle, Abigail G.

   Angewandte Chemie, International Edition (2016), 55 (12), 4040-4043CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

   Using nickel and photoredox catalysis, the direct functionalization of C(sp3)-H bonds of N-aryl amines by acyl electrophiles is described. The method affords a diverse range of α-amino ketones at room temp. and is amenable to late-stage coupling of complex and biol. relevant groups. C(sp3)-H activation occurs by photoredox-mediated oxidn. to generate α-amino radicals which are intercepted by nickel in catalytic C(sp3)-C coupling. The merger of these two modes of catalysis leverages nickel's unique properties in alkyl cross-coupling while avoiding limitations commonly assocd. with transition-metal-mediated C(sp3)-H activation, including requirements for chelating directing groups and high reaction temps.

   (f) Deng, H. P.; Fan, X. Z.; Chen, Z. H.; Xu, Q. H.; Wu, J. Photoinduced Nickel-Catalyzed Chemo- and Regioselective Hydroalkylation of Internal Alkynes with Ether and Amide α-Hetero C(sp³)-H Bonds. J. Am. Chem. Soc. 2017, 139, 13579– 13584,  DOI: 10.1021/jacs.7b08158

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   Photoinduced Nickel-Catalyzed Chemo- and Regioselective Hydroalkylation of Internal Alkynes with Ether and Amide α-Hetero C(sp3)-H Bonds

   Deng, Hong-Ping; Fan, Xuan-Zi; Chen, Zhi-Hui; Xu, Qing-Hua; Wu, Jie

   Journal of the American Chemical Society (2017), 139 (38), 13579-13584CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   A direct hydroalkylation of disubstituted alkynes with unfunctionalized ethers and amides was achieved in an atom-efficient and additive-free manner through the synergistic combination of photoredox and nickel catalysis. The protocol was effective with a wide range of internal alkynes, providing products in a highly selective fashion. Notably, the obsd. regioselectivity is complementary to conventional radical addn. processes. Mechanistic investigations suggest that the photoexcited iridium catalyst facilitated the nickel activation via single-electron transfer.

   (g) Shaw, M. H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. D.; MacMillan, D. W. C. Native functionality in triple catalytic cross-coupling: sp³ C-H bonds as latent nucleophiles. Science 2016, 352, 1304– 1308,  DOI: 10.1126/science.aaf6635

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   Native functionality in triple catalytic cross-coupling: sp3 C-H bonds as latent nucleophiles

   Shaw, Megan H.; Shurtleff, Valerie W.; Terrett, Jack A.; Cuthbertson, James D.; MacMillan, David W. C.

   Science (Washington, DC, United States) (2016), 352 (6291), 1304-1308CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)

   The use of sp3 C-H bonds-which are ubiquitous in org. mols.-as latent nucleophile equiv. for transition metal-catalyzed cross-coupling reactions has the potential to substantially streamline synthetic efforts in org. chem. while bypassing substrate activation steps. Through the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have developed a highly selective and general C-H arylation protocol that activates a wide array of C-H bonds as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations to selectively functionalize α-amino and α-oxy sp3 C-H bonds in both cyclic and acyclic systems.

   (h) Heitz, D. R.; Tellis, J. C.; Molander, G. A. Photochemical Nickel Catalyzed C-H Arylation: Synthetic Scope and Mechanistic Investigations. J. Am. Chem. Soc. 2016, 138, 12715– 12718,  DOI: 10.1021/jacs.6b04789

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   1h

   Photochemical Nickel-Catalyzed C-H Arylation: Synthetic Scope and Mechanistic Investigations

   Heitz, Drew R.; Tellis, John C.; Molander, Gary A.

   Journal of the American Chemical Society (2016), 138 (39), 12715-12718CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   An iridium photocatalyst and visible light facilitate a room temp., nickel-catalyzed coupling of (hetero)aryl bromides with activated α-heterosubstituted or benzylic C(sp3)-H bonds. Mechanistic investigations on this unprecedented transformation have uncovered the possibility of an unexpected mechanism hypothesized to involve a Ni-Br homolysis event from an excited-state nickel complex. The resultant bromine radical is thought to abstr. weak C(sp3)-H bonds to generate reactive alkyl radicals that can be engaged in Ni-catalyzed arylation. Evidence suggests that the iridium photocatalyst facilitates nickel excitation and bromine radical generation via triplet-triplet energy transfer.

   (i) Sakai, H. A.; Liu, W.; Le, C.; MacMillan, D. W. C. Cross-Electrophile Coupling of Unactivated Alkyl Chlorides. J. Am. Chem. Soc. 2020, 142, 11691– 11697,  DOI: 10.1021/jacs.0c04812

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   Cross-Electrophile Coupling of Unactivated Alkyl Chlorides

   Sakai, Holt A.; Liu, Wei; Le, Chi "Chip"; MacMillan, David W. C.

   Journal of the American Chemical Society (2020), 142 (27), 11691-11697CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   Overcoming intrinsic limitations of C(sp3)-Cl bond activation, the development of a novel organosilane reagent Si(TMS)3(N)R1R2 (R1 = adamantyl, tert-Bu, i-Pr, n-Bu; R2 = H) that can participate in chlorine atom abstraction under mild photocatalytic conditions were reported. In particular, the application of this mechanism to a dual nickel/photoredox catalytic protocol that enables the first cross-electrophile coupling of unactivated alkyl chlorides R3Cl (R3 = cyclohexyl, oxan-4-yl, 4-cyanobutyl, etc.) and aryl chlorides R4Cl (R4 = pyridin-4-yl, quinolin-3-yl, 2-(methylsulfanyl)pyrimidin-5-yl, etc.) was described. Employing these low-toxicity, abundant, and com. available organochloride building blocks, this methodol. allows access to a broad array of highly functionalized C(sp2)-C(sp3) coupled adducts, e.g., I including numerous drug analogs.

   (j) Dewanji, A.; Krach, P. E.; Rueping, M. The Dual Role of Benzophenone in Visible-Light/Nickel Photoredox-Catalyzed C–H Arylations: Hydrogen-Atom Transfer and Energy Transfer. Angew. Chem., Int. Ed. 2019, 58, 3566– 3570,  DOI: 10.1002/anie.201901327

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   The Dual Role of Benzophenone in Visible-Light/Nickel Photoredox-Catalyzed C-H Arylations: Hydrogen-Atom Transfer and Energy Transfer

   Dewanji, Abhishek; Krach, Patricia E.; Rueping, Magnus

   Angewandte Chemie, International Edition (2019), 58 (11), 3566-3570CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

   A dual catalytic protocol for the direct arylation of non-activated C(sp3)-H bonds was developed. Upon photochem. excitation, the excited triplet state of a diaryl ketone photosensitizer abstrs. a hydrogen atom from an aliph. C-H bond. This inherent reactivity was exploited for the generation of benzylic radicals which subsequently enter a nickel catalytic cycle, accomplishing the benzylic arylation.
2. 2

   (a) Heitz, D. R.; Tellis, J. C.; Molander, G. A. Photochemical nickel-catalyzed C-H arylation: synthetic scope and mechanistic investigations. J. Am. Chem. Soc. 2016, 138, 12715– 12718,  DOI: 10.1021/jacs.6b04789

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   2a

   Photochemical Nickel-Catalyzed C-H Arylation: Synthetic Scope and Mechanistic Investigations

   Heitz, Drew R.; Tellis, John C.; Molander, Gary A.

   Journal of the American Chemical Society (2016), 138 (39), 12715-12718CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   An iridium photocatalyst and visible light facilitate a room temp., nickel-catalyzed coupling of (hetero)aryl bromides with activated α-heterosubstituted or benzylic C(sp3)-H bonds. Mechanistic investigations on this unprecedented transformation have uncovered the possibility of an unexpected mechanism hypothesized to involve a Ni-Br homolysis event from an excited-state nickel complex. The resultant bromine radical is thought to abstr. weak C(sp3)-H bonds to generate reactive alkyl radicals that can be engaged in Ni-catalyzed arylation. Evidence suggests that the iridium photocatalyst facilitates nickel excitation and bromine radical generation via triplet-triplet energy transfer.

   (b) Shields, B. J.; Doyle, A. G. Direct C(sp³)-H cross coupling enabled by catalytic generation of chlorine radicals. J. Am. Chem. Soc. 2016, 138, 12719– 12722,  DOI: 10.1021/jacs.6b08397

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   Direct C(sp3)-H Cross Coupling Enabled by Catalytic Generation of Chlorine Radicals

   Shields, Benjamin J.; Doyle, Abigail G.

   Journal of the American Chemical Society (2016), 138 (39), 12719-12722CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   Here we report the development of a C(sp3)-H cross-coupling platform enabled by the catalytic generation of chlorine radicals by nickel and photoredox catalysis. Aryl chlorides serve as both cross-coupling partners and the chlorine radical source for the α-oxy C(sp3)-H arylation of cyclic and acyclic ethers. Mechanistic studies suggest that photolysis of a Ni(III) aryl chloride intermediate, generated by photoredox-mediated single-electron oxidn., leads to elimination of a chlorine radical in what amts. to the sequential capture of two photons. Arylations of a benzylic C(sp3)-H bond of toluene and a completely unactivated C(sp3)-H bond of cyclohexane demonstrate the broad implications of this manifold for accomplishing numerous C(sp3)-H bond functionalizations under exceptionally mild conditions.

   (c) Ishida, N.; Masuda, Y.; Ishikawa, N.; Murakami, M. Cooperation of a nickel-bipyridine complex with light for benzylic C-H arylation of toluene derivatives. Asian J. Org. Chem. 2017, 6, 669– 672,  DOI: 10.1002/ajoc.201700115

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   Cooperation of a Nickel-Bipyridine Complex with Light for Benzylic C-H Arylation of Toluene Derivatives

   Ishida, Naoki; Masuda, Yusuke; Ishikawa, Norikazu; Murakami, Masahiro

   Asian Journal of Organic Chemistry (2017), 6 (6), 669-672CODEN: AJOCC7; ISSN:2193-5807. (Wiley-VCH Verlag GmbH & Co. KGaA)

   The synthesis of diarylmethanes, e.g., 4-CH3C6H4CH2C6H5 has been reported via arylation of benzylic C-H bonds of toluene derivs. such as toluene, m-xylene, mesitylene, etc. with aryl bromides such as p-bromoanisole, bromobenzene, (E)-bromostyrene, etc. using a nickel-bipyridine catalytic system under irradn. with UV light. The catalyst system is simple and all the components are readily available, and thus, the present system offers a convenient maneuver to shape aryl-benzyl linkages.

   (d) Dewanji, A.; Krach, P. E.; Rueping, M. The dual role of benzophenone in visible-light/nickel photoredox-catalysed C-H arylations: hydrogen-atom transfer and energy transfer. Angew. Chem., Int. Ed. 2019, 58, 3566– 3570,  DOI: 10.1002/anie.201901327

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   The Dual Role of Benzophenone in Visible-Light/Nickel Photoredox-Catalyzed C-H Arylations: Hydrogen-Atom Transfer and Energy Transfer

   Dewanji, Abhishek; Krach, Patricia E.; Rueping, Magnus

   Angewandte Chemie, International Edition (2019), 58 (11), 3566-3570CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

   A dual catalytic protocol for the direct arylation of non-activated C(sp3)-H bonds was developed. Upon photochem. excitation, the excited triplet state of a diaryl ketone photosensitizer abstrs. a hydrogen atom from an aliph. C-H bond. This inherent reactivity was exploited for the generation of benzylic radicals which subsequently enter a nickel catalytic cycle, accomplishing the benzylic arylation.

   (e) Cheng, X.; Lu, H.; Lu, Z. Enantioselective benzylic C-H arylation via photoredox and nickel dual catalysis. Nat. Commun. 2019, 10, 3549  DOI: 10.1038/s41467-019-11392-6

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   Enantioselective benzylic C-H arylation via photoredox and nickel dual catalysis

   Cheng Xiaokai; Lu Huangzhe; Lu Zhan

   Nature communications (2019), 10 (1), 3549 ISSN:.

   The asymmetric cross-coupling reaction is developed as a straightforward strategy toward 1,1-diaryl alkanes, which are a key skeleton in a series of natural products and bioactive molecules in recent years. Here we report an enantioselective benzylic C(sp(3))-H bond arylation via photoredox/nickel dual catalysis. Sterically hindered chiral biimidazoline ligands are designed for this asymmetric cross-coupling reaction. Readily available alkyl benzenes and aryl bromides with various functional groups tolerance can be easily and directly transferred to useful chiral 1,1-diaryl alkanes including pharmaceutical intermediates and bioactive molecules. This reaction proceeds smoothly under mild conditions without the use of external redox reagents.

   (f) Ackerman, L. K. G.; Martinez Alvarado, J. I.; Doyle, A. G. Direct C-C bond formation from alkanes using Ni-photoredox catalysis. J. Am. Chem. Soc. 2018, 140, 14059– 14063,  DOI: 10.1021/jacs.8b09191

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   Direct C-C Bond Formation from Alkanes Using Ni-Photoredox Catalysis

   Ackerman, Laura K. G.; Martinez Alvarado, Jesus I.; Doyle, Abigail G.

   Journal of the American Chemical Society (2018), 140 (43), 14059-14063CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   A method for direct cross coupling between unactivated C(sp3)-H bonds and chloroformates has been accomplished via nickel and photoredox catalysis. A diverse range of feedstock chems., such as (a)cyclic alkanes and toluenes, along with late-stage intermediates, undergo intermol. C-C bond formation to afford esters under mild conditions using only 3 equiv of the C-H partner. Site selectivity is predictable according to bond strength and polarity trends that are consistent with the intermediacy of a chlorine radical as the hydrogen atom-abstracting species.

   (g) Lee, G. S.; Hong, S. H. Formal Giese addition of C(sp³)-H nucleophiles enabled by visible light mediated Ni catalysis of triplet enone diradicals. Chem. Sci. 2018, 9, 5810– 5815,  DOI: 10.1039/C8SC01827H

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   Formal Giese addition of C(sp3)-H nucleophiles enabled by visible light mediated Ni catalysis of triplet enone diradicals

   Lee, Geun Seok; Hong, Soon Hyeok

   Chemical Science (2018), 9 (26), 5810-5815CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)

   An unprecedented utilization of triplet excited enones in Ni-catalysis enabled a formal Giese addn. of C(sp3)-H nucleophiles for the synthesis of beta substituted ketones such as I [R1 = Me, Ph, 2-furyl, etc.; R2 = Me, Ph, 4-ClC6H4, etc.; R3R4 = O(CH2)3] was developed. The enone diradical acted as two distinct reaction centers, participating in both metalation and hydrogen atom transfer, ultimately furnished a range of formal Giese addn. products I in a highly general context. The reaction provided complementary access to traditional 1,4-addn. reactions of enones, with a future perspective to develop triplet diradical-based transition metal catalysis.

   (h) Ishida, N.; Masuda, Y.; Imamura, Y.; Yamazaki, K.; Murakami, M. Carboxylation of benzylic and aliphatic C-H bonds with CO₂ induced by light/ketone/nickel. J. Am. Chem. Soc. 2019, 141, 19611– 19615,  DOI: 10.1021/jacs.9b12529

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   Carboxylation of Benzylic and Aliphatic C-H Bonds with CO2 Induced by Light/Ketone/Nickel

   Ishida, Naoki; Masuda, Yusuke; Imamura, Yuuya; Yamazaki, Katsushi; Murakami, Masahiro

   Journal of the American Chemical Society (2019), 141 (50), 19611-19615CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   A photoinduced carboxylation reaction of benzylic and aliph. C-H bonds with CO2 is developed. Toluene derivs. capture gaseous CO2 at the benzylic position to produce phenylacetic acid derivs. when irradiated with UV light in the presence of an arom. ketone, a nickel complex, and potassium tert-butoxide. Cyclohexane reacts with CO2 to furnish cyclohexanecarboxylic acid under analogous reaction conditions. The present photoinduced carboxylation reaction provides a direct access from readily available hydrocarbons to the corresponding carboxylic acids with one carbon extension.

   (i) Rohe, S.; Morris, A. O.; McCallum, T.; Barriault, L. Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom Generation. Angew. Chem., Int. Ed. 2018, 57, 15664– 15669,  DOI: 10.1002/anie.201810187

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   Hydrogen Atom Transfer Reactions via Photoredox Catalyzed Chlorine Atom Generation

   Rohe, Samantha; Morris, Avery O.; McCallum, Terry; Barriault, Louis

   Angewandte Chemie, International Edition (2018), 57 (48), 15664-15669CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

   The selective functionalization of chem. inert C-H bonds remains to be fully realized in achieving org. transformations that are redox-neutral, waste-limiting, and atom-economical. The catalytic generation of chlorine atoms from chloride ions is one of the most challenging redox processes, where the requirement of harsh and oxidizing reaction conditions renders it seldom utilized in synthetic applications. We report the mild, controlled, and catalytic generation of chlorine atoms as a new opportunity for access to a wide variety of hydrogen atom transfer (HAT) reactions owing to the high stability of HCl.The discovery of the photoredox mediated generation of chlorine atoms with Ir-based polypyridyl complex, [Ir(dF(CF3)ppy)2(dtbbpy)]Cl, under blue LED irradn. is reported.
3. 3

   Huang, C.-Y.; Kang, H.; Li, J.; Li, C.-J. En route to intermolecular cross-dehydrogenative coupling reactions. J. Org. Chem. 2019, 84, 12705– 12721,  DOI: 10.1021/acs.joc.9b01704

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   En Route to Intermolecular Cross-Dehydrogenative Coupling Reactions

   Huang, Chia-Yu; Kang, Hyotaik; Li, Jianbin; Li, Chao-Jun

   Journal of Organic Chemistry (2019), 84 (20), 12705-12721CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)

   A review. Cross-coupling reaction between two C-H bonds has become a fundamental strategy in synthetic org. chem. A review. With its increasing importance in green chem., atom economy, and step economy, its development has sky-rocketed within the last 20 years, with the term "cross-dehydrogenative coupling (CDC)" popularized and progressed by the group of Li and others to describe direct Y-Z bond formations from Y-H and Z-H bonds under oxidative conditions. Among all types of CDC reactions, the C-C bond formations are of prime importance in building up the mol. complexity but their categorization currently remains disarray due to a wide diversity, resulting in frequent display in sep. topics. In this Perspective, a contemporary categorization via C-H activation strategies is presented herein, which could be vital for future CDC designs. With this mechanism-based categorization and discussion, we wish that this minireview will help more synthetic chemists gain insight into the design of CDC reactions and inspires more ideas on this topic.
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   Kawasaki, T.; Ishida, N.; Murakami, M. Dehydrogenative Coupling of Benzylic and Aldehydic C–H Bonds. J. Am. Chem. Soc. 2020, 142, 3366– 3370,  DOI: 10.1021/jacs.9b13920

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   Dehydrogenative Coupling of Benzylic and Aldehydic C-H Bonds

   Kawasaki, Tairin; Ishida, Naoki; Murakami, Masahiro

   Journal of the American Chemical Society (2020), 142 (7), 3366-3370CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

   A photoinduced dehydrogenative coupling reaction between benzylic and aldehydic C-H bonds was reported. When a soln. of an alkylbenzene and an aldehyde in Et acetate was irradiated with visible light in the presence of iridium and nickel catalysts, a coupled α-aryl ketone was formed with evolution of dihydrogen. An analogous C-C bond forming reaction occurs between a C-H bond next to the nitrogen of an N-methylamide and an aldehydic C-H bond to produce an α-amino ketone. These reactions provide a straightforward pathway from readily available materials leading to valued structural motifs of pharmacol. relevance.
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   A review with 242 refs. on the title subject including narcotics, stimulants, hallucinogens, dissociatve anesthetics, and depressants. Major synthetic methods for the class of drug (including analogs), occurrence of synthetic impurities, and the pharmacol./toxicol. assocd. with the analogs and the impurities are discussed.
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   (a) Beeler, A. B.; Corning, S. R. Photochemistry in Flow. Photochemistry 2016, 43, 173– 190

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   (b) Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I. Flow photochemistry: Old light through new windows. Beilstein J. Org. Chem. 2012, 8, 2025– 2052,  DOI: 10.3762/bjoc.8.229

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   6b

   Flow photochemistry: Old light through new windows

   Knowles, Jonathan P.; Elliott, Luke D.; Booker-Milburn, Kevin I.

   Beilstein Journal of Organic Chemistry (2012), 8 (), 2025-2052, No. 229CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)

   A review. Synthetic photochem. carried out in classic batch reactors has, for over half a century, proved to be a powerful but under-utilized technique in general org. synthesis. Recent developments in flow photochem. have the potential to allow this technique to be applied in a more mainstream setting. This review highlights the use of flow reactors in org. photochem., allowing a comparison of the various reactor types to be made.

   (c) Gilmore, K.; Seeberger, P. H. Continuous flow photochemistry. Chem. Rec. 2014, 14, 410– 418,  DOI: 10.1002/tcr.201402035

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   6c

   Continuous Flow Photochemistry

   Gilmore, Kerry; Seeberger, Peter H.

   Chemical Record (2014), 14 (3), 410-418CODEN: CRHEAK; ISSN:1527-8999. (Wiley-VCH Verlag GmbH & Co. KGaA)

   A review. Due to the narrow width of tubing/reactors used, photochem. performed in micro- and mesoflow systems is significantly more efficient than when performed in batch due to the Beer-Lambert Law. Owing to the const. removal of product and facility of flow chem. scalability, the degree of degrdn. obsd. is generally decreased and the productivity of photochem. processes is increased. In this Personal Account, the authors describe a wide range of photochem. transformations they have examd. using both visible and UV light, covering cyclizations, intermol. couplings, radical polymns., as well as singlet oxygen oxygenations.
7. 7

   Telmasani, R.; Sun, A. C.; Beeler, A. B.; Stephenson, C. R. J. Flow Chemistry in Organic Synthesis, 1st ed.; Jamison, T. F.; Koch, G., Eds.; Thieme: Germany, 2019; pp 103– 145.

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   There is no corresponding record for this reference.
8. 8

   (a) Shvydkiv, O.; Gallagher, S.; Nolan, K.; Oelgemöller, M. From conventional to microphotochemistry: photodecarboxylation reactions involving phthalimides. Org. Lett. 2010, 12, 5170– 5173,  DOI: 10.1021/ol102184u

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   8a

   From Conventional to Microphotochemistry: Photodecarboxylation Reactions Involving Phthalimides

   Shvydkiv, Oksana; Gallagher, Sonia; Nolan, Kieran; Oelgemoller, Michael

   Organic Letters (2010), 12 (22), 5170-5173CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)

   A series of acetone-sensitized photodecarboxylation reactions involving phthalimides have been investigated using conventional and microphotochem. Intra- and intermol. transformations were compared. In all cases examd., the reactions performed in microreactors were superior in terms of conversions or isolated yields. These findings unambiguously prove the advantage of microphotochem. over conventional photochem. techniques.

   (b) Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Applications of continuous-flow photochemistry in organic synthesis, material science, and water treatment. Chem. Rev. 2016, 116, 10276– 10341,  DOI: 10.1021/acs.chemrev.5b00707

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   8b

   Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment

   Cambie, Dario; Bottecchia, Cecilia; Straathof, Natan J. W.; Hessel, Volker; Noel, Timothy

   Chemical Reviews (Washington, DC, United States) (2016), 116 (17), 10276-10341CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

   A review. Continuous-flow photochem. in microreactors receives a lot of attention from researchers in academia and industry as this technol. provides reduced reaction times, higher selectivities, straightforward scalability, and the possibility to safely use hazardous intermediates and gaseous reactants. In this review, an up-to-date overview is given of photochem. transformations in continuous-flow reactors, including applications in org. synthesis, material science, and water treatment. In addn., the advantages of continuous-flow photochem. are pointed out and a thorough comparison with batch processing is presented.
9. 9

   (a) Tucker, J. W.; Zhang, Y.; Jamison, T. F.; Stephenson, R. R. J. Visible-light photoredox catalysis in flow. Angew. Chem., Int. Ed. 2012, 124, 4220– 4223,  DOI: 10.1002/ange.201200961

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   There is no corresponding record for this reference.

   (b) Nguyen, J. D.; Reiß, B.; Dai, C.; Stephenson, C. R. J. Batch to flow deoxygenation using visible light photoredox catalysis. Chem. Commun. 2013, 49, 4352– 4354,  DOI: 10.1039/C2CC37206A

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   9b

   Batch to flow deoxygenation using visible light photoredox catalysis

   Nguyen, John D.; Reiss, Barbara; Dai, Chunhui; Stephenson, Corey R. J.

   Chemical Communications (Cambridge, United Kingdom) (2013), 49 (39), 4352-4354CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)

   Herein we report a one-pot deoxygenation protocol for primary and secondary alcs. developed via the combination of the Garegg-Samuelsson reaction, visible light-photoredox catalysis, and flow chem. This procedure is characterized by mild reaction conditions, easy-to-handle reactants and reagents, excellent functional group tolerance, and good yields.

   (c) Elliott, L. D.; Knowles, J. P.; Koovits, P. J.; Maskill, K. G.; Ralph, M. J.; Lejeune, G.; Edwards, L. J.; Robinson, R. I.; Clemens, I. R.; Cox, B.; Pascoe, D. D.; Koch, G.; Eberle, M.; Berry, M. B.; Booker-Milburn, K. Batch versus flow photochemistry: a revealing comparison of yield and productivity. Chem. - Eur. J. 2014, 20, 15226– 15232,  DOI: 10.1002/chem.201404347

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   9c

   Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity

   Elliott, Luke D.; Knowles, Jonathan P.; Koovits, Paul J.; Maskill, Katie G.; Ralph, Michael J.; Lejeune, Guillaume; Edwards, Lee J.; Robinson, Richard I.; Clemens, Ian R.; Cox, Brian; Pascoe, David D.; Koch, Guido; Eberle, Martin; Berry, Malcolm B.; Booker-Milburn, Kevin I.

   Chemistry - A European Journal (2014), 20 (46), 15226-15232CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

   The use of flow photochem. and its apparent superiority over batch has been reported by a no. of groups in recent years. To rigorously det. whether flow does indeed have an advantage over batch, a broad range of synthetic photochem. transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an av. productivity 20 % lower than that of batch, whereas three-layer reactors were 20 % more productive. Finally, the utility of flow chem. was demonstrated in the scale(coating process)-up of the ring-opening reaction of a potentially explosive [1.1.1] propellane with butane-2,3-dione.

   (d) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The hitchhiker’s guide to flow chemistry. Chem. Rev. 2017, 117, 11796– 11893,  DOI: 10.1021/acs.chemrev.7b00183

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   9d

   The Hitchhiker's Guide to Flow Chemistry

   Plutschack, Matthew B.; Pieber, Bartholomaeus; Gilmore, Kerry; Seeberger, Peter H.

   Chemical Reviews (Washington, DC, United States) (2017), 117 (18), 11796-11893CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)

   Flow chem. involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask. Flow equipment provides chemists with unique control over reaction parameters, enhancing reactivity or in some cases enabling new reactions. This relatively young technol. has received a remarkable amt. of attention in the past decade with many reports on what can be done in flow. Until recently, however, the question, "Should we do this in flow" has merely been an afterthought. This review introduces readers to the basic principles and fundamentals of flow chem. and critically discusses recent flow chem. accounts.

   (e) Lima, F.; Grunenberg, L.; Rahman, H. B. A.; Labes, R.; Ley, S. V. Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow. Chem. Commun. 2018, 54, 5606– 5609,  DOI: 10.1039/C8CC02169D

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   9e

   Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow

   Lima, Fabio; Grunenberg, Lars; Rahman, Husaini B. A.; Labes, Ricardo; Sedelmeier, Joerg; Ley, Steven V.

   Chemical Communications (Cambridge, United Kingdom) (2018), 54 (44), 5606-5609CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)

   We report an acridium-based org. photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivs. by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward scale up approach using continuous flow photoreactors is also reported affording gram an hour throughput.

   (f) Chen, Y.; May, O.; Blakemore, D. C.; Ley, S. V. A photoredox coupling reaction of benzylboronic esters and carbonyl compounds in batch and flow. Org. Lett. 2019, 21, 6140– 6144,  DOI: 10.1021/acs.orglett.9b02307

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   9f

   A Photoredox Coupling Reaction of Benzylboronic Esters and Carbonyl Compounds in Batch and Flow

   Chen, Yiding; May, Oliver; Blakemore, David C.; Ley, Steven V.

   Organic Letters (2019), 21 (15), 6140-6144CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)

   Mild cross-coupling reaction between benzylboronic esters with carbonyl compds. and some imines was achieved under visible-light-induced iridium-catalyzed photoredox conditions. Functional group tolerance was demonstrated by 51 examples, including 13 heterocyclic compds. Gram-scale reaction was realized through the use of computer-controlled continuous flow photoreactors.
10. 10

    (a) Isse, A. A.; Lin, C. Y.; Coote, M. L.; Gennaro, A. Estimation of Standard Reduction Potentials of Halogen Atoms and Alkyl Halides. J. Phys. Chem. B 2011, 115, 678– 684,  DOI: 10.1021/jp109613t

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    10a

    Estimation of Standard Reduction Potentials of Halogen Atoms and Alkyl Halides

    Isse, Abdirisak A.; Lin, Ching Yeh; Coote, Michelle L.; Gennaro, Armando

    Journal of Physical Chemistry B (2011), 115 (4), 678-684CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)

    Std. redn. potentials, SRPs, of the halogen atoms were calcd. in H2O from an appropriate thermochem. cycle. Using the best up-to-date thermodn. data available in the literature, the authors have calcd. EθX·/X- values of 3.66, 2.59, 2.04, and 1.37 V vs. SHE for F·, Cl·, Br·, and I·, resp. Addnl., the authors have computed the SRPs of Cl·, Br·, and I· in MeCN and DMF by correcting the values obtained in H2O for the free energies of transfer of X· and X- from H2O to the nonaq. solvent S and the intersolvent potential between H2O and S. From the values of EθX·/X- in MeCN and DMF, the SRPs of alkyl halides of relevance to atom transfer radical polymn. and other important processes such as pollution abatement were calcd. in these two solvents. This was done with the aid of a thermochem. cycle involving the gas-phase homolytic dissocn. of the C-X bond, solvation of RX, R·, and X·, and redn. of X· to X- in soln.

    (b) Wehlin, S. A. M.; Troian-Gautier, L.; Li, G.; Meyer, G. J. Chloride Oxidation by Ruthenium Excited-States in Solution. J. Am. Chem. Soc. 2017, 139, 12903– 12906,  DOI: 10.1021/jacs.7b06762

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    10b

    Chloride Oxidation by Ruthenium Excited-States in Solution

    Wehlin, Sara A. M.; Troian-Gautier, Ludovic; Li, Guocan; Meyer, Gerald J.

    Journal of the American Chemical Society (2017), 139 (37), 12903-12906CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Photodriven HCl splitting to produce solar fuels is an important goal that requires strong photo-oxidants capable of chloride oxidn. In a mol. approach toward this goal, three ruthenium compds. with 2,2'-bipyrazine backbones were found to oxidize chloride ions in acetone soln. Nanosecond transient absorption measurements provide compelling evidence for excited-state electron transfer from chloride to the Ru metal center with rate consts. in excess of 1010 M-1 s-1. The Cl atom product was trapped with an olefin. This reactivity was promoted through pre-organization of ground-state precursors in ion pairs. Chloride oxidn. with a tetra-cationic ruthenium complex was most favorable, as the dicationic complexes were susceptible to photochem. ligand loss. Marcus anal. afforded an est. of the chlorine formal redn. potential E°(Cl•/-) = 1.87 V vs NHE that is at least 300 meV more favorable than the accepted values in water.
11. 11

    (a) Dingwall, P.; Greb, A.; Crespin, L. N. S.; Labes, R.; Musio, B.; Poh, J. S.; Pasau, P.; Blakemore, D. C.; Ley, S. V. C-H functionalisation of aldehydes using light generated, non-stabilised diazo compounds in flow. Chem. Commun. 2018, 54, 11685– 11688,  DOI: 10.1039/C8CC06202A

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    11a

    C-H functionalisation of aldehydes using light generated, non-stabilised diazo compounds in flow

    Dingwall, Paul; Greb, Andreas; Crespin, Lorene N. S.; Labes, Ricardo; Musio, Biagia; Poh, Jian-Siang; Pasau, Patrick; Blakemore, David C.; Ley, Steven V.

    Chemical Communications (Cambridge, United Kingdom) (2018), 54 (83), 11685-11688CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)

    The use of oxadiazolines, non-stabilized diazo precursors which are bench stable, in direct, non-catalytic, aldehyde C-H functionalization reactions under UV photolysis in flow and free from additives was explored. Com. available aldehydes were coupled to afford unsym. aryl-alkyl and alkyl-alkyl ketones while mild conditions and lack of transition metal catalysts allow for exceptional functional group tolerance. Examples were given on small scale and in a larger scale continuous prodn.

    (b) Lima, F.; Grunenberg, L.; Rahman, H. B. A.; Labes, R.; Sedelmeier, J.; Ley, S. V. Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow. Chem. Commun. 2018, 54, 5606– 5609,  DOI: 10.1039/C8CC02169D

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    11b

    Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow

    Lima, Fabio; Grunenberg, Lars; Rahman, Husaini B. A.; Labes, Ricardo; Sedelmeier, Joerg; Ley, Steven V.

    Chemical Communications (Cambridge, United Kingdom) (2018), 54 (44), 5606-5609CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)

    We report an acridium-based org. photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivs. by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward scale up approach using continuous flow photoreactors is also reported affording gram an hour throughput.

    (c) Greb, A.; Poh, J. S.; Greed, S.; Battilocchio, C.; Pasau, P.; Blakemore, D. C.; Ley, S. V. A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl-Alkyl Cross-Coupling Reactions. Angew. Chem., Int. Ed. 2017, 56, 16602– 16605,  DOI: 10.1002/anie.201710445

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    11c

    A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl-Alkyl Cross-Coupling Reactions

    Greb, Andreas; Poh, Jian-Siang; Greed, Stephanie; Battilocchio, Claudio; Pasau, Patrick; Blakemore, David C.; Ley, Steven V.

    Angewandte Chemie, International Edition (2017), 56 (52), 16602-16605CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Coupling of readily available boronic acids and diazo compds. has emerged recently as a powerful metal-free carbon-carbon bond forming method. However, the difficulty in forming the unstable diazo compd. partner in a mild fashion has hitherto limited their general use and the scope of the transformation. Here, authors report the application of oxadiazolines as precursors for the generation of an unstable family of diazo compds. using flow UV photolysis and their first use in divergent protodeboronative and oxidative C(sp2)-C(sp3) cross-coupling processes, with excellent functional-group tolerance.

    (d) Lima, F.; Kabeshov, M. A.; Tran, D. N.; Battilocchio, C.; Sedelmeier, J.; Sedelmeier, G.; Schenkel, B.; Ley, S. V. Visible light activation of boronic esters enables efficient photoredox C(sp²)-C(sp³) cross-couplings in flow. Angew. Chem., Int. Ed. 2016, 55, 14085– 14089,  DOI: 10.1002/ange.201605548

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    11d

    Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)-C(sp3) Cross-Couplings in Flow

    Lima, Fabio; Kabeshov, Mikhail A.; Tran, Duc N.; Battilocchio, Claudio; Sedelmeier, Joerg; Sedelmeier, Gottfried; Schenkel, Berthold; Ley, Steven V.

    Angewandte Chemie, International Edition (2016), 55 (45), 14085-14089CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

    A method for photoredox activation of boronic esters is reported. An efficient and high-throughput continuous flow process was developed to perform a dual iridium- and nickel-catalyzed C(sp2)-C(sp3) coupling by circumventing soly. issues assocd. with potassium trifluoroborate salts. Formation of an adduct with a pyridine-derived Lewis base was found to be essential for the photoredox activation of the boronic esters. A simplified visible light-mediated C(sp2)-C(sp3) coupling method using boronic esters and cyano heteroarenes under flow conditions was developed.
12. 12

    Bourne, S. L.; Ley, S. V. A Continuous Flow Solution to Achieving Efficient Aerobic Anti-Markovnikov Wacker Oxidation. Adv. Synth. Catal. 2013, 355, 1905– 1910,  DOI: 10.1002/adsc.201300278

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    12

    A Continuous Flow Solution to Achieving Efficient Aerobic Anti-Markovnikov Wacker Oxidation

    Bourne, S. L.; Ley, S. V.

    Advanced Synthesis & Catalysis (2013), 355 (10), 1905-1910CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)

    An aerobic anti-Markovnikov Wacker oxidn. for the flow-synthesis of arylacetaldehydes is reported. In the process, flow chem. techniques have provided a means to control and minimize the over-oxidn. of sensitive products. The reaction showed general applicability to various functionalized styrenes and provided a process capable of a multi-gram scale.
13. 13

    Alsabeh, P. G.; Stradiotto, M. Addressing Challenges in Palladium-Catalyzed Cross-Couplings of Aryl Mesylates: Monoarylation of Ketones and Primary Alkyl Amines. Angew. Chem., Int. Ed. 2013, 52, 7242– 7246,  DOI: 10.1002/anie.201303305

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    13

    Addressing Challenges in Palladium-Catalyzed Cross-Couplings of Aryl Mesylates: Monoarylation of Ketones and Primary Alkyl Amines

    Alsabeh, Pamela G.; Stradiotto, Mark

    Angewandte Chemie, International Edition (2013), 52 (28), 7242-7246CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)

    The first examples of ketone mono-α-arylation using aryl mesylates are disclosed and the amination of these inexpensive phenol derivs. with primary aliph. amines have been successfully demonstrated. The [{Pd(cinnamyl)Cl}2]/Mor-DalPhos catalyst system allowed a range of substituted aryl mesylates to be coupled with both cyclic and acyclic dialkyl ketones, including acetone, which is normally a challenging reagent in mono-α- arylation chem. Applying these optimized ketone α-arylation conditions to Buchwald-Hartwig amination enabled the mono-N-arylation of primary and secondary aliph. amines, including methylamine, by employing aryl mesylates featuring electron-donating or electron-withdrawing functionality, ortho-substitution, as well as base-sensitive groups. The amination protocol displayed chemoselectivity, thus favoring cross-coupling of the primary amine in each case.
14. 14

    Nie, X.-X.; Huang, Y.-H.; Wang, P. Thianthrenation-Enabled α-Arylation of Carbonyl Compounds with Arenes. Org. Lett. 2020, 22, 7716– 7720,  DOI: 10.1021/acs.orglett.0c02913

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    14

    Thianthrenation-Enabled α-Arylation of Carbonyl Compounds with Arenes

    Nie, Xiao-Xue; Huang, Yu-Hao; Wang, Peng

    Organic Letters (2020), 22 (19), 7716-7720CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)

    The Pd-catalyzed α-arylation of carbonyl compds. with simple arenes enabled by site-selective thianthrenation has been demonstrated. This one-pot process using thianthrenium salts as the traceless arylating reagents features mild conditions and a broad substrate scope. In addn., this protocol could also tolerate the heterocyclic carbonyl compds. and complex bioactive mols., which is appealing for medicinal chem.
15. 15

    Zhang, G.; Hu, X.; Chiang, C.-W.; Yi, H.; Pei, P.; Singh, A. K.; Lei, A. Anti-Markovnikov Oxidation of β-Alkyl Styrenes with H₂O as the Terminal Oxidant. J. Am. Chem. Soc. 2016, 138, 12037– 12040,  DOI: 10.1021/jacs.6b07411

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    15

    Anti-Markovnikov Oxidation of β-Alkyl Styrenes with H2O as the Terminal Oxidant

    Zhang, Guoting; Hu, Xia; Chiang, Chien-Wei; Yi, Hong; Pei, Pengkun; Singh, Atul K.; Lei, Aiwen

    Journal of the American Chemical Society (2016), 138 (37), 12037-12040CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)

    Oxygenation of alkenes is one of the most straightforward routes for the construction of carbonyl compds. Wacker oxidn. provides a broadly useful strategy to convert the mineral oil into higher value-added carbonyl chems. However, the conventional Wacker chem. remains problematic, such as the poor activity for internal alkenes, the lack of anti-Markovnikov regioselectivity, and the high cost and chem. waste resulting from noble metal catalysts and stoichiometric oxidant. Here, we describe an unprecedented dehydrogenative oxygenation of β-alkyl styrenes and their derivs. with water under external-oxidant-free conditions by utilizing the synergistic effect of photocatalysis and proton-redn. catalysis that can address these challenges. This dual catalytic system possesses the single anti-Markovnikov selectivity due to the property of the visible-light-induced alkene radical cation intermediate.
16. 16

    Kim, J.; Yi, C. S. Intermolecular Markovnikov-Selective Hydroacylation of Olefins Catalyzed by a Cationic Ruthenium–Hydride Complex. ACS Catal. 2016, 6, 3336– 3339,  DOI: 10.1021/acscatal.6b00856

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    16

    Intermolecular Markovnikov-Selective Hydroacylation of Olefins Catalyzed by a Cationic Ruthenium-Hydride Complex

    Kim, Junghwa; Yi, Chae S.

    ACS Catalysis (2016), 6 (5), 3336-3339CODEN: ACCACS; ISSN:2155-5435. (American Chemical Society)

    The cationic Ru-H complex was found to be an effective catalyst for the intermol. hydroacylation of aryl-substituted olefins with aldehydes to form branched ketone products. The preliminary kinetic and spectroscopic studies elucidated a ruthenium-acyl complex as the key intermediate species. The catalytic method directly afforded branched ketone products in a highly regioselective manner while tolerating a no. of heteroatom functional groups.
17. 17

    Methyl arene 1n was synthesized following a known literature procedure

    Alp, C.; Özsoy, S.; Alp, N.; Erdem, D.; Gültekin, M.; Küfrevioğlu, Ö.; Şentürk, M.; Supuran, C. Sulfapyridine-like benzenesulfonamide derivatives as inhibitors of carbonic anhydrase isoenzymes I, II and VI. J. Enzyme Inhib. Med. Chem. 2012, 27, 818– 824,  DOI: 10.3109/14756366.2011.617745

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    17

    Sulfapyridine-like benzenesulfonamide derivatives as inhibitors of carbonic anhydrase isoenzymes I, II and VI

    Alp, Cemalettin; Ozsoy, Seyda; Alp, Nurdan Alcan; Erdem, Deryanur; Gultekin, Mehmet Serdar; Kufrevioglu, Omer Irfan; Senturk, Murat; Supuran, Claudiu T.

    Journal of Enzyme Inhibition and Medicinal Chemistry (2012), 27 (6), 818-824CODEN: JEIMAZ; ISSN:1475-6366. (Informa Healthcare)

    The inhibition of two human cytosolic carbonic anhydrase (hCA, EC 4.2.1.1) isoenzymes I, II and human serum isoenzyme VI, with a series of tosylited arom. amine derivs. was investigated. The KI ranges of compds. 1-14 and acetazolamide against hCA I ranged between 1.130 and- 448.2 μM, against hCA II between 0.103 and- 14.3 μM, and against hCA VI ranged between 0.340 and- 42.39 μM. Tosylited arom. amine derivs. are thus interesting hCA I, II and VI inhibitors, and might be used as leads for generating enzyme inhibitors eventually targeting other isoforms which have not been assayed yet for their interactions with such agents.
18. 18

    Methyl arene 1o was synthesized following a known literature procedure

    Lavrard, H.; Popowycz, F. Harnessing Cascade Suzuki-Cyclization Reactions of Pyrazolo[3,4-b]pyridine for the Synthesis of Tetracyclic Fused Heteroaromatics. Eur. J. Org. Chem. 2017, 2017, 600– 608,  DOI: 10.1002/ejoc.201601242

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    18

    Harnessing Cascade Suzuki-Cyclization Reactions of Pyrazolo[3,4-b]pyridine for the Synthesis of Tetracyclic Fused Heteroaromatics

    Lavrard, Hubert; Popowycz, Florence

    European Journal of Organic Chemistry (2017), 2017 (3), 600-608CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Numerous procedures have been described for the functionalization of pyrazolo[3,4-b]pyridine, mainly involving nucleophilic substitutions at the C-4 position or esterifications/amidations at the C-5 position. In this paper, we describe a robust, easy to implement protocol for the Suzuki cross-coupling reaction of chloroarene, followed by in-situ lactonization to provide chromenopyrazolopyridines. The extension of the scope of the reaction to fused naphthyridinones is also reported. This strategy gave access to 10 original pyrazolopyridine-contg. tetracyclic compds I (X = O, NH; R = H, 10-F, 9-F, 10-ipr, 10-Cl, 10-Me, 10-MeO).
19. 19

    Methyl arene 1p was synthesized following a known literature procedure

    Kanamori, T.; Masaki, Y.; Mizuta, M.; Tsunoda, H.; Ohkubo, A.; Sekine, M.; Seio, K. DNA duplexes and triplex-forming oligodeoxynucleotides incorporating modified nucleosides which can form stable and selective triplexes. Org. Biomol. Chem. 2012, 10, 1007– 1013,  DOI: 10.1039/C1OB06411H

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    19

    DNA duplexes and triplex-forming oligodeoxynucleotides incorporating modified nucleosides forming stable and selective triplexes

    Kanamori, Takashi; Masaki, Yoshiaki; Mizuta, Masahiro; Tsunoda, Hirosuke; Ohkubo, Akihiro; Sekine, Mitsuo; Seio, Kohji

    Organic & Biomolecular Chemistry (2012), 10 (5), 1007-1013CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)

    We have previously reported DNA triplexes contg. the unnatural base triad G-PPI·C3, in which PPI is an indole-fused cytosine deriv. incorporated into DNA duplexes and C3 is an abasic site in triplex-forming oligonucleotides (TFOs) introduced by a propylene linker. In this study, we developed a new unnatural base triad A-ψ·CR1 where ψ and CR1 are base moieties 2'-deoxypseudouridine and 5-substituted deoxycytidine, resp. We examd. several electron-withdrawing substituents for R1 and found that 5-bromocytosine (CBr) could selectively recognize ψ. In addn., we developed a new PPI deriv., PPIMe, having a Me group on the indole ring in order to achieve selective triplex formation between DNA duplexes incorporating various Watson-Crick base pairs, such as T-A, C-G, A-ψ, and G-PPIMe, and TFOs contg. T, C, CBr, and C3. We studied the selective triplex formation between these duplexes and TFOs using UV-melting and gel mobility shift assays.
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    Methyl arene 1q was synthesized following a known literature procedure

    Kuwano, R.; Kashiwabara, M. Ruthenium-Catalyzed Asymmetric Hydrogenation of N-Boc-Indoles. Org. Lett. 2006, 12, 2653– 2655,  DOI: 10.1021/ol061039x

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    Zhai, R. L.; Xue, Y. S.; Liang, T.; Mi, J. J.; Xu, Z. Regioselective Arene and Heteroarene Functionalization: N-Alkenoxypyridinium Salts as Electrophilic Alkylating Agents for the Synthesis of α-Aryl/α-Heteroaryl Ketones. J. Org. Chem. 2018, 83, 10051– 10059,  DOI: 10.1021/acs.joc.8b01388

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    Regioselective Arene and Heteroarene Functionalization: N-Alkenoxypyridinium Salts as Electrophilic Alkylating Agents for the Synthesis of α-Aryl/α-Heteroaryl Ketones

    Zhai, Rong L.; Xue, Yun S.; Liang, Ting; Mi, Jia J.; Xu, Zhou

    Journal of Organic Chemistry (2018), 83 (17), 10051-10059CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)

    Gold-catalyzed regioselective Friedel-Crafts reactions of terminal alkynes with arenes and heteroarenes mediated an N-hydroxypyridinium salt (generated in situ from pyridine-N-oxide and triflimide) yielded 1-(hetero)aryl-2-alkanones. The Friedel-Crafts reactions occurred via alkenyloxypyridinium salts formed in situ from an N-hydroxypyridinium salt and the terminal alkynes. The mechanism of the reaction was studied using DFT calcns., isolation and reaction of a methylenedecyloxypyridinium salt, and detn. of the deuterium kinetic isotope effect in Friedel-Crafts reactions with benzene and hexadeuterobenzene.
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    Pulikottil, F. T.; Pilli, R.; Suku, R. V.; Rasappan, R. Nickel-Catalyzed Cross-Coupling of Alkyl Carboxylic Acid Derivatives with Pyridinium Salts via C–N Bond Cleavage. Org. Lett. 2020, 22, 2902– 2907,  DOI: 10.1021/acs.orglett.0c00554

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    Nickel-Catalyzed Cross-Coupling of Alkyl Carboxylic Acid Derivatives with Pyridinium Salts via C-N Bond Cleavage

    Pulikottil, Feba Thomas; Pilli, Ramadevi; Suku, Rohith Valavil; Rasappan, Ramesh

    Organic Letters (2020), 22 (8), 2902-2907CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)

    In the presence of (2,2'-bipyridine)NiBr2, alkylcarbonyl chlorides and anhydrides (generated in situ from carboxylic acids with acid-sensitive functional groups, Boc2O, and MgCl2) underwent chemoselective coupling reactions with N-alkylpyridinium tetrafluoroborates mediated by Mn in THF/N,N-dimethylacetamide to yield dialkyl ketones. Reaction in the presence of TEMPO did not yield a ketone product but instead the trapping product of the radical derived from the pyridinium salt with TEMPO, consistent with a radical mechanism.
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    Ackermann, L.; Mehta, V. P. Palladium-Catalyzed Mono-α-Arylation of Acetone with Aryl Imidazolylsulfonates. Chem. - Eur. J. 2012, 18, 10230– 10233,  DOI: 10.1002/chem.201201394

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    Palladium-Catalyzed Mono-α-Arylation of Acetone with Aryl Imidazolylsulfonates

    Ackermann, Lutz; Mehta, Vaibhav P.

    Chemistry - A European Journal (2012), 18 (33), 10230-10233, S10230/1-S10230/80CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)

    Pd(OAc)2 and XanPhos catalyzed the mono-α-arylation of acetone and other alkyl ketones with aryl 1H-imidazole-1-sulfonates. E.g., in presence of Pd(OAc)2, XantPhos, and Cs2CO3, mono-α-arylation of acetone with 4-methoxyphenyl 1H-imidazole-1-sulfonate gave 98% I.
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    Mamidala, R.; Samser, S.; Sharma, N.; Lourderaj, U.; Venkatasubbaiah, K. Isolation and Characterization of Regioisomers of Pyrazole-Based Palladacycles and Their Use in α-Alkylation of Ketones Using Alcohols. Organometallics 2017, 36, 3343– 3351,  DOI: 10.1021/acs.organomet.7b00478

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    Isolation and Characterization of Regioisomers of Pyrazole-Based Palladacycles and Their Use in α-Alkylation of Ketones Using Alcohols

    Mamidala, Ramesh; Samser, Shaikh; Sharma, Nishant; Lourderaj, Upakarasamy; Venkatasubbaiah, Krishnan

    Organometallics (2017), 36 (17), 3343-3351CODEN: ORGND7; ISSN:0276-7333. (American Chemical Society)

    Regioisomers of 3,5-diphenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole based palladacycles I (1) and II (2) were synthesized by the arom. C-H bond activation of the N- or 3-aryl ring. The application of these regio-isomers as catalysts to enable the formation of α-alkylated ketones or quinolines with alcs. using H borrowing process is evaluated. Palladacycle 2 is superior over palladacycle 1 to catalyze the reaction under similar reaction conditions. The reaction mechanisms for the palladacycles 1 and 2 catalyzed α-alkylation of acetophenone were studied using d. functional theor. (DFT) methods. The DFT studies indicate that palladacycle 2 has a lower energy barrier than palladacycle 1 for the alkylation reaction consistent with the better catalytic activity of palladacycle 2 seen in the expts. The palladacycle-phosphine system was found to tolerate a wide range of functional groups and serve as an efficient protocol for the synthesis of α-alkylated products under solvent-free conditions. The synthetic protocol was successfully applied to prep. donepezil, a drug for Alzheimer's disease from simple starting materials.