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Photoredox-catalyzed C(sp2)–N coupling reactions
Tetrahedron Letters 59 (2018) 1605–1613
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Digest paper
Photoredox-catalyzed C(sp2)–N coupling reactions Xiao-De An, Shouyun Yu ⇑ State Key Laboratory of Analytical Chemistry for Life Science, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
a r t i c l e
i n f o
Article history: Received 25 January 2018 Revised 9 March 2018 Accepted 19 March 2018 Available online 20 March 2018
a b s t r a c t Photoredox-catalyzed radical reactions have attracted intense interest from synthetic chemists over the past several years. The photoredox-catalyzed C(sp2)–N coupling reactions, including Ullmann type C–N coupling (C–X/N–H type coupling), redox neutral C–N coupling (C–H/N–X type coupling) and oxidative C–N coupling (C–H/N–H type coupling), have been summarized in this digest. Ó 2018 Elsevier Ltd. All rights reserved.
Keywords: Photoredox catalysis Photochemistry C(sp2)–N coupling reactions Radical reactions Aryl amines
Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ullmann type C(sp2)–N coupling reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Redox neutral C(sp2)–N coupling reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidative (dehydrogenative) C(sp2)–N coupling reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N-Radical-triggered oxidative coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aryl cation radical-triggered oxidative coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N-Radical and aryl radical-triggered radical cross-coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transition-metal-mediated intramolecular oxidative coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Nitrogen-containing compounds exist in many biologically active molecules and natural products,1 and also act as functional groups in material science.2 Therefore, the development of efficient methods for the synthesis of nitrogen-containing compounds has been extensively investigated by synthetic chemists.3 Classic methods for construct carbon–nitrogen (C(sp2)–N) bonds involve: 1) Ullmann type C(sp2)–N coupling;4 2) Buchwald-Hartwig cross coupling.5 Recent years, the development of visible-light-promoted reactions offer a new approach toward C(sp2)–N bond con⇑ Corresponding author. E-mail address: [email protected] (S. Yu). https://doi.org/10.1016/j.tetlet.2018.03.050 0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
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struction via radical-triggered process. There is no doubt that novel photoredox catalyzed C(sp2)–N coupling reactions characterized with mild conditions and good functional group tolerance attract extensive interest from synthetic community. In this digest, we highlight recent progresses in the photoredox-catalyzed C (sp2)–N coupling reactions: 1) Ullmann type C(sp2)–N coupling reactions (C–X/N–H type coupling); 2) redox neutral C(sp2)–N coupling reactions (C–H/N–X type coupling); 3) oxidative C(sp2)–N coupling reactions (C–H/N–H type coupling) (Scheme 1). Ullmann type C(sp2)–N coupling reactions One of major drawbacks of classic Ullmann reactions is that the reactions have to be carried out at elevated temperature. In 2012,
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Scheme 1. Photoredox-catalyzed C(sp2)–N coupling reactions. Scheme 3. Visible-light induced coupling reaction of carbazole derivatives and aryl iodides.
Scheme 2. Photoinduced Ullmann C(sp2)–N bond formation via a copper–carbazolide complex.
Scheme 4. Ni-catalyzed C(sp2)–N coupling promoted by visible light.
Fu and Peters groups had reported an Ullmann type C(sp2)–N coupling reaction promoted by ultraviolet irradiation (Scheme 2a).6 Their coupling reactions were promoted by a stoichiometric or a catalytic amount of copper, which enabled the coupling of carbazolide and aryl iodides under unusually mild conditions (room temperature or even – 40 °C). An array of mechanistic studies revealed that the photo-induced C(sp2)–N bond formation proceed via a single-electron transfer (SET) process mediated by copper– carbazolide complex. When a carbon-centered radical is generated, copper-mediated C(sp2)–N bond formation can ensue.
Later on, they expanded the scope with respect to both the nucleophiles and the electrophiles of the photo-induced coppercatalyzed process (Scheme 2b).7 Nitrogen-based nucleophiles (such as indoles, benzimidazoles, and imidazoles) and diverse electrophiles (e.g., hindered/deactivated/heterocyclic aryl iodides, an aryl bromide, an activated aryl chloride, alkenyl halides, and an alkynyl bromide) could serve as suitable partners and give C–N coupling products in moderate to good yields. Kobayashi and co-workers also explored the Ullmann type C–N coupling reactions and reported a visible-light induced coupling
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Scheme 5. Photoinduced C(sp2)–N coupling involved cation radical accelerated nucleophilic aromatic substitution.
reaction of carbazole derivatives and aryl iodides (Scheme 3).8 The excited iridium polypyridyl complex 11 could be quenched by copper–carbazolide complex 9 to afford excited copper carbazolide 12 and the ground state Ir(ppy)3. After a SET from the excited 12 to iodobenzene, corresponding aryl radical 14, which could react with copper (II) amide 13 to produce the desired product 7. In 2016, Buchwald and MacMillan developed a ligand-free Ni(II) and photoredox-cocatalyzed C(sp2)–N coupling promoted by visible light (Scheme 4).9 The oxidative addition product 22 can undergo ligand exchange and subsequent deprotonation to arrive at Ni(II)-aryl amido complex 23. Then, a SET process from 23 to photoexcited Ir(III)⁄ 19 afford Ni(III) complex 24 and Ir(II) photocatalyst 20. Reductive elimination of the resultant Ni(III) complex yields Ni(I) bromide species 25 and the desired aniline product 17a. A variety of aryl bromides bearing electron-withdrawing group performed well under the reaction conditions. Electron-rich arenes were less reactive in this reaction. By lowering the photocatalyst loading (0.002 mol%), reaction efficiency could be increased and the desired product 17h was produced in 93% yield. Recently, Nicewicz and co-workers reported a cation radicalaccelerated nucleophilic aromatic substitution (SNAr) using meth-
Scheme 7. Hydroxylamine derivatives as N-radical precursors.
oxy- and benzyloxy-groups as the leaving groups (Scheme 5).10 The aryl CAN bonds were constructed via a direct SNAr using an acridinium photoredox catalyst. They proposed that Mes-Acr+⁄ oxidized the anisole derivatives leading to radical cation 26. Addition of the amine at the carbon bearing methoxy group gave rise to 27, which underwent loss of MeOH and was reduced by Mes-Acr, leading to the final SNAr product. It was worth mentioning that product 29 with benzyl aryl ether working as the leaving group or product 30 with ammonium carbamate working as the nucleophile could be obtained in this amination reaction. Redox neutral C(sp2)–N coupling reactions
Scheme 6. Redox neutral C–N coupling reactions.
Redox neutral C(sp2)–N coupling reactions usually involved nitrogen-centered radical (N-radical) addition process and an oxidative quenching photoredox catalytic cycle. As depicted in Scheme 6, N-radical precursors, such as hydroxylamine, amine halide, oxime and N-aminopyridinium derivatives, were reduced by excited photocatalyst to afford N-radical 31. The N-radical could add to an arene to generate a C N bond and a carbon-centered radical 32. The resultant carbon-centered radical could be oxidized to a carbocation followed by deprotonation to regenerate the final product (Scheme 6). Hydroxylamine derivatives are easily accessed and can serve as tunable nitrogen sources, which were employed in C–H amidation of arenes and heteroarenes over the past several years (Scheme 7). In 2014, Sanford and co-workers reported a visible light photocatalyzed method for the C–H amination of arenes and heteroarenes (Scheme 7a).11 A key enabling advance in this work was the design of N-acyloxyphthalimide 34 as the precursor to N-radical intermediate for this transformation. Independently, our group developed a C–H amidation of electron-rich heteroarenes, such as indoles,
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Scheme 8. Amine halide derivatives as N-radical precursors.
pyrroles, and furans using N, O-dibenzenesulfony-N-methyl hydroxylamine 35 as the nitrogen source (Scheme 7b).12 These reactions are highly regioselective, and all the products were isolated as a single regioisomer. Another relevant work published very recently employed 3,6-dimethoxy-9H-thioxanthen-9-one 37 as a catalyst in the CAH amination of arenes and heteroarenes (Scheme 7c).13 The thioxanthone catalyst also underwent an oxidative quenching cycle for homolytic aromatic substitution. Leonori and co-workers disclosed a transition-metal-free CAH amination of arenes and heteroarenes (Scheme 7d).14 The organic dye eosin Y was used as the photoredox catalyst. O-aryl hydroxylamines 38 could serve as general, bench-stable N-radical precursors that could deliver N-radicals upon photoredox activation under mild conditions. Later on, N, N-dialkyl arylamines assembled through aminyl radical addition approach in the presence of a Brønsted acid was reported (Scheme 7e).15 Dialkyl-substituted N-radicals showed lower stability because of the intrinsic nucleophilic nature of aminyls, which causes repulsive interactions between their lone pair and the aromatic ring.16 The strong acid would maintain the N-atom in protonated form during the entire reaction sequence. Recently, Luo,17 Lee,18 and Xiao19 reported that N-bromosaccharin 40 (Scheme 8a), N-chlorophthalimide 41 (Scheme 8b), and Nchloromorpholine 42 (Scheme 8c) could also work as the N-radical
Scheme 9. Oxime derivatives as N-radical precursors.
precursors for visible-light promoted C–H amination of arenes and heteroarenes. Iminyl-radical participating C(sp2)–N coupling reaction usually exists in the construction of N-heteroarenes via intramolecular homolytic aromatic substitution (HAS) following by oxidation (SET) and deprotonation process. In 2015, our group reported a mild, effective and direct construction of pyridines, quinolines, and phenanthridines from O-acyl oximes20 or aldehydes.21 In this reaction, an electron-deficient acyl worked as the leave group (Scheme 9a). Later on, Xie group developed a metal-free photoredox-catalyzed methods toward phenanthridines form O-(2,4-dinitrophenyl)oximes.22 In this study, the organic dye eosin Y and iPr2NEt were used as photocatalyst and terminal reductant, respectively (Scheme 9b). In 2015, Studer and co-workers introduced pyridinium salts 46 as efficient N-radical precursors, which were easily accessible from commercially available pyrylium salts (Scheme 10).23 Reduction of salts 46 by a single electron transfer promoted by visible light allowed for clean generation of amidyl radicals, which underwent HAS affording C–H amination products of arenes and heteroarenes. In 2015, König group reported the C–H amidation of heterocycles with benzoyl azides under very mild photocatalysis conditions (Scheme 11).24 The only byproduct in this atom economic process is dinitrogen. The energy transfer triggered the loss of dinitrogen yielding the benzoyl nitrene. The benzoyl nitrene might be protonated under the strongly acidic conditions, giving electrophilic nitrenium ions 50, which would react with the electron rich heteroarene. After loss of a proton, the amidation product was obtained.
Scheme 10. N-aminopyridinium derivatives as N-radical precursors.
Scheme 11. Benzoyl azide derivatives as N-radical precursors.
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Oxidative (dehydrogenative) C(sp2)–N coupling reactions Oxidative (dehydrogenative) couplings are fascinating means for C–N bond construction, which avoids the requirement for preactivation of both coupling partner and leads to atom and step economy in chemical synthesis. However, the direct C(sp2) N coupling reactions under photoredox catalysis are challenging. The reported methods for photoredox-catalyzed C(sp2)–N oxidative couplings include: 1) N-radical-triggered oxidative coupling; 2) aryl cation radical-triggered oxidative coupling; 3) N-radical and aryl radical-triggered radical cross-coupling; 4) transition-metalmediated intramolecular oxidative coupling (Scheme 12).
N-Radical-triggered oxidative coupling N-Radical triggered oxidative coupling undergoes generation of N-radical, radical addition to an arene, carbon-centered radical oxidation and deprotonation process. N-radical 53 is generated by reductive quenching of photocatalyst from N–H amide. Both of reduced state photocatalyst and the aryl radical species 54 undergo oxidation to close the catalytic cycle (Scheme 13). In 2012, an intramolecular C(sp2)–H oxidative amination of styryl aniline was reported by Zheng group (Scheme 14).25 The N-radical cation generated from styryl aniline could undergo electrophilic addition to the tethered alkene, thus triggering a cascade reaction involving either aromatization or C–C bond migration followed by aromatization to form indoles. More importantly, these studies revealed that arylamines could participate in C(sp2)–N bond formation directly under visible-light photoredox conditions.
Scheme 12. Types of oxidative (dehydrogenative) C(sp2)–N coupling reactions.
Scheme 13. N-radical-triggered oxidative (dehydrogenative) C(sp2)–N coupling reactions.
Scheme 14. Secondary aniline derivatives as N-radical precursors.
In 2016, our group reported the direct oxidative amidation of heteroarenes with sulfonamides (Scheme 15).26 N-radicals were directly generated from oxidative cleavage of N–H bonds under visible-light photoredox catalysis. NaClO served as the oxidant. A variety of heteroarenes, including indoles 56a, pyrroles 56b and benzofurans 56c, could undergo this amidation in high yields. These reactions were highly regioselective, and all the products were isolated as a single regioisomer. The fluorescence quenching experiments and Stern-Volmer analysis indicated that the photoexcited catalyst was quenched by NaClO. Itami and co-workers developed dehydrogenative C–H imidation of arenes using IBB (Scheme 16) as the oxidant, which got two electrons from RuII⁄ and the generated aryl radical 59.27 RuIII was furnished from excited RuII⁄ after the oxidation of RuII by IBB. Imidyl radical was generated after the oxidation of sulfonamide 57 by RuIII. Itoh group reported another cross-dehydrogenative C(sp2) N coupling (Scheme 17).28 The reaction was mediated by photocatalyst 2-tert-butylanthraquinone (2-t-Bu-AQN) and oxygen as the sole oxidant. Various substituted 2-phenylindoles, pyrroles, 2phenylbenzo[b]-thiophene could be employed for this reaction. Unfortunately, N-methylindole was not suitable under these reaction conditions (60).
Scheme 15. Sulfamide derivatives as N-radical precursors.
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an acridinium photoredox catalyst under an aerobic atmosphere (Scheme 19).30 A wide variety of primary amines, including amino acids and more complex amines, were competent coupling partners. Electron-rich arenes could not undergo amination through an arene cation radical and instead reacted via an amine cation radical pathway. For electron-rich arenes, both the amine and the arene quenched the acridinium excited state, which meant that both arene cation radical and amine cation radical might exist in this transformation. Very recently, Hong group developed a novel synthetic route to construct phenanthridinone and quinolinone scaffolds through amidyl radicals generated by visible-light photocatalysis, which led to oxidative intramolecular C–H amidation to furnish a C (sp2)–N bond (Scheme 20).31 For construction of quinolinones, the E/Z isomerization of cinnamamide was the key step. The excited state Ir(III)⁄ species played a dual role in the reaction: catalyzing triplet state energy (ET) transfer for E/Z olefin isomerization Scheme 16. Sulfamide derivatives as N-radical precursors.
Very recently, König and co-workers achieved CAH amination of benzene derivatives using DDQ as the photocatalyst and BocNH2 as the nitrogen source under aerobic conditions and visible light irradiation (Scheme 18).29 The amine scope of the reaction comprises BocNH2, carbamates, pyrazoles, sulfonimides and urea. They proposed two possible mechanistic pathways: 1) excited DDQ in its triplet state was a very strong oxidant and arenes were oxidized to their corresponding radical cations 62. The radical cation was attacked by the amine. 2) SET from amines to DDQ initiated by visible light gave amine radical 63 and radical cation 61. DDQ was regenerated by TBN. Nicewicz and co-workers reported the construction of aryl C–N bonds to primary amines via a direct C–H functionalization using
Scheme 19. Primary amine derivatives as N-radical precursors.
Scheme 17. Phthalimide derivatives as N-radical precursors.
Scheme 18. BocNH2 or pyrazole derivatives as N-radical precursors.
Scheme 20. Amide derivatives as N-radical precursors.
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and serving as a photooxidant to facilitate the amidyl radical via an oxidative proton-coupled electron transfer (PCET) protocol. The resultant amidyl radical intermediate 65 underwent intramolecular C–N bond formation to give aryl radical 67. This aryl radical would in turn undergo O2 addition to form a peroxy radical species 68, which would be reduced by Ir(II) to regenerate the catalytically active Ir(III) complex.
Aryl cation radical-triggered oxidative coupling Aryl cation radical-triggered oxidative coupling was usually suitable for electron-rich arenes, which possessed lower oxidation potentials and could stabilize the carbocation intermediate. A SET from electron-rich arene to photocatalyst (PC) furnished arene cation radical 70, which was attacked by nucleophilic amine. The nucleophilic attack product 71 underwent deprotonation and oxidization giving arene cation intermediate 73 followed by deprotonation (Scheme 21). Catalytic cycle of this coupling also involved reductive quenching of photocatalyst. In 2015, Nicewicz and co-workers reported site-selective amination of a variety of aromatics with heteroaromatic azoles promoted by an acridinium photooxidant and anitroxyl radical (Scheme 22).32 Para- and ortho-amination products were obtained when the arene was monosubstituted benzene ring (74a). On the basis of this work, they sought to develop a predictive model for site selectivity and extend this aryl functionalization chemistry to a selected set of heteroaromatic systems. Using electron density calculations, they were able to predict the site selectivity of direct C–H amination in a number of heterocycles and identify general trends observed across heterocycle classes.33 In 2016, König and co-workers reported a direct amination of pyrroles for the preparation of N-(2-pyrrole)-sulfonamides from sulfonamides and pyrroles (Scheme 23).34 They used acridiniumbased dye as the photocatalyst and oxygen as the terminal oxidant for the oxidative C–N bond formation. Pyrroles were tolerant in this reaction because of the available oxidation potential of the photocatalyst and the required stability of the generated carbocation intermediate. Recently, Laha group have developed Ru(bpy)3Cl2-catalyzed Narylation reaction via the direct C–H functionalization of methoxy-substituted benzenes. In this reaction, selectfluor worked as the oxidative quencher and H-atom-abstractor (Scheme 24).35 Lei group reported C2-amination of thiophenes using DDQ as a photocatalyst, tert-butyl nitrite (TBN) as an electron mediator and oxygen as a terminal oxidant under visible-light irradiation
(Scheme 25).36 Various thiophenes could be selectively transformed into corresponding amination products in high yields and H2O was the only byproduct. Recently, Lei group had reported an oxidant-free and selective C (sp2)–H amination of arenes catalyzed by synergistic acridinium 75 and cobalt oxime complex 76 (Scheme 26).37 The generated aromatic ring radical cation was attacked by nucleophile pyrazole, which was difficult to be oxidized by the excited state acridinium, leading to 77. Then the radical adduct 77 underwent a single electron transfer with CoII catalyst and deprotonation generating the
Scheme 22. Heteroaromatic azole derivatives as nucleophiles.
Scheme 23. Sulfonamide derivatives as nucleophiles.
Scheme 24. Azole derivatives as nucleophiles.
Scheme 21. Aryl cation radical triggered C(sp2)–N oxidative coupling.
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Scheme 25. Azole derivatives as nucleophiles.
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Scheme 26. Azole derivatives as nucleophiles (Oxidant-free).
amination product. At the same time, CoI could capture the present proton in the reaction system, yielding CoIII–H 78. After the protonation of CoIII–H, H2 was released and CoIII was regenerated, which oxidized the photocatalyst to close the catalytic cycle and regenerated CoII species.
Scheme 28. Dehydrogenative-coupling amination between phenols and acyclic diarylamines.
In general, it was difficult to provide an appropriate situation in the radical cross-coupling manner between the C-radical and Nradical simultaneously. The principle of persistent radical effect (PRE)38 should be followed to selectively afford the anticipated cross-coupling product rather than the homocoupling one. Therefore, N-radical and aryl radical-triggered radical cross-coupling remained an extremely challenging task. In 2016, Xia and co-workers described a visible-light mediated cross-dehydrogenative coupling amination reaction via a N-radical/C-radical cross-coupling pathway using K2S2O8 for dual oxida-
tion (Scheme 27).39 This reaction benefited from mild conditions, high regioselectivity and the absence of metal and/or photocatalysts. Under irradiation with visible light, the phenol and amine were both oxidized by S2O28 79 to form the radical intermediates 84 and 85 respectively. Then the C-radical/N-radical cross-coupling reaction occurred to furnish intermediate 86 which was isomerized to afford the final product 87. In the aforementioned work (Scheme 27), acyclic diarylamine was incapable of coupling with phenol to furnish the intermolecular aryl C N bond only with the help of oxidant and light irradiation. Oxidation potential values of the acyclic diarylamines, which were higher than those of phenothiazine, might account for the barrier of the transformation. Therefore, they developed an oxidative system combining a catalytic amount of organic photocatalyst (2,4,6-triphenylpyrylium salt 90) with stoichiometric amount of persulfate was developed to enable the successful
Scheme 27. Dehydrogenative coupling amination reaction via radical crosscoupling pathway.
Scheme 29. Transition-metal-mediated coupling.
N-Radical and aryl radical-triggered radical cross-coupling
intramolecular
C(sp2)–N
oxidative
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cross-dehydrogenative-coupling amination between phenols and acyclic diarylamines (Scheme 28).40 The excited state PC⁄ 88 abstracted an electron from aniline to produce PC anion radical 89. The ground state of PC was regenerated from 89 by donating an electron to 79 to finish the photoredox cycle. Transition-metal-mediated intramolecular oxidative coupling In the past several years, transition-metal-mediated intramolecular C–H bond amination promoted by an oxidant has attracted intense interest from synthetic chemists.41 However, the processes described above had limitations associated with the requirements of high reaction temperatures and stoichiometric use of strong ground-state oxidants. In 2015, Cho group reported an intramolecular C–H bond amination of N-substituted-2-amidobiarylsthe utilizing merged Pd catalysis and visible light photoredox, which was used for regeneration of the Pd catalyst instead of strong oxidants (Scheme 29).42 In the initial step, coordination of the amido group to PdII facilitated cyclopalladation, leading to the six-membered palladacycle 91. The palladacycle was oxidized to a PdIII complex 92 by SET to the photoexcited Ir catalyst. Reductive elimination of the palladacycle 92 led to the formation of carbazole. The PdI species was subsequently oxidized to generate the original PdII complex through SET to the photoexcited Ir catalyst or molecular oxygen. Various carbazoles could be generated without strong oxidants for regeneration of the Pd catalyst. Conclusions In this digest, we have summarized the recent advances of photoredox-catalyzed C(sp2)–N coupling reactions. Three types photoredox catalyzed C(sp2)–N coupling reactions, including Ullmann type C–N coupling reactions (C–X/N–H type coupling), redox neutral C–N coupling reactions (C–H/N–X type coupling) and oxidative C–N coupling reactions (C–H/N–H type coupling), have been presented in details. The photocatalysis features low reaction temperature, good functional group tolerance and high efficiency of photocatalyst. Major limitations of this strategy currently include narrow substrate scope, sometime poor site selectivity. Acknowledgments Financial support from the National Natural Science Foundation of China (21672098, 21472084, and 21732003) is acknowledged. References 1. (a) Kim J, Movassaghi M. Chem Soc Rev. 2009;38:3035–3050; (b) Evano G, Blanchard N, Toumi M. Chem Rev. 2008;108:3054–3131; (c) Evano G, Theunissen C, Pradal A. Nat Prod Rep. 2013;30:1467–1489; (d) Cho SH, Kim JY, Kwak J, Chang S. Chem Soc Rev. 2011;40:5068–5083; (e) Bagley MC, Dale JW, Merritt EA, Xiong A. Chem Rev. 2005;105:685–714; (f) Hili R, Yudin AK. Nat Chem Biol. 2006;2:284–287; (g) Okano K, Tokuyama H, Fukuyama T. Chem Commun. 2014;50:13650–13663. 2. Shirota Y, Kageyama H. Chem Rev. 2007;107:953–1010.
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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Digest paper
Photoredox-catalyzed C(sp2)–N coupling reactions Xiao-De An, Shouyun Yu ⇑ State Key Laboratory of Analytical Chemistry for Life Science, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China
a r t i c l e
i n f o
Article history: Received 25 January 2018 Revised 9 March 2018 Accepted 19 March 2018 Available online 20 March 2018
a b s t r a c t Photoredox-catalyzed radical reactions have attracted intense interest from synthetic chemists over the past several years. The photoredox-catalyzed C(sp2)–N coupling reactions, including Ullmann type C–N coupling (C–X/N–H type coupling), redox neutral C–N coupling (C–H/N–X type coupling) and oxidative C–N coupling (C–H/N–H type coupling), have been summarized in this digest. Ó 2018 Elsevier Ltd. All rights reserved.
Keywords: Photoredox catalysis Photochemistry C(sp2)–N coupling reactions Radical reactions Aryl amines
Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ullmann type C(sp2)–N coupling reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Redox neutral C(sp2)–N coupling reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidative (dehydrogenative) C(sp2)–N coupling reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N-Radical-triggered oxidative coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Aryl cation radical-triggered oxidative coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N-Radical and aryl radical-triggered radical cross-coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Transition-metal-mediated intramolecular oxidative coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Introduction Nitrogen-containing compounds exist in many biologically active molecules and natural products,1 and also act as functional groups in material science.2 Therefore, the development of efficient methods for the synthesis of nitrogen-containing compounds has been extensively investigated by synthetic chemists.3 Classic methods for construct carbon–nitrogen (C(sp2)–N) bonds involve: 1) Ullmann type C(sp2)–N coupling;4 2) Buchwald-Hartwig cross coupling.5 Recent years, the development of visible-light-promoted reactions offer a new approach toward C(sp2)–N bond con⇑ Corresponding author. E-mail address: [email protected] (S. Yu). https://doi.org/10.1016/j.tetlet.2018.03.050 0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
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struction via radical-triggered process. There is no doubt that novel photoredox catalyzed C(sp2)–N coupling reactions characterized with mild conditions and good functional group tolerance attract extensive interest from synthetic community. In this digest, we highlight recent progresses in the photoredox-catalyzed C (sp2)–N coupling reactions: 1) Ullmann type C(sp2)–N coupling reactions (C–X/N–H type coupling); 2) redox neutral C(sp2)–N coupling reactions (C–H/N–X type coupling); 3) oxidative C(sp2)–N coupling reactions (C–H/N–H type coupling) (Scheme 1). Ullmann type C(sp2)–N coupling reactions One of major drawbacks of classic Ullmann reactions is that the reactions have to be carried out at elevated temperature. In 2012,
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Scheme 1. Photoredox-catalyzed C(sp2)–N coupling reactions. Scheme 3. Visible-light induced coupling reaction of carbazole derivatives and aryl iodides.
Scheme 2. Photoinduced Ullmann C(sp2)–N bond formation via a copper–carbazolide complex.
Scheme 4. Ni-catalyzed C(sp2)–N coupling promoted by visible light.
Fu and Peters groups had reported an Ullmann type C(sp2)–N coupling reaction promoted by ultraviolet irradiation (Scheme 2a).6 Their coupling reactions were promoted by a stoichiometric or a catalytic amount of copper, which enabled the coupling of carbazolide and aryl iodides under unusually mild conditions (room temperature or even – 40 °C). An array of mechanistic studies revealed that the photo-induced C(sp2)–N bond formation proceed via a single-electron transfer (SET) process mediated by copper– carbazolide complex. When a carbon-centered radical is generated, copper-mediated C(sp2)–N bond formation can ensue.
Later on, they expanded the scope with respect to both the nucleophiles and the electrophiles of the photo-induced coppercatalyzed process (Scheme 2b).7 Nitrogen-based nucleophiles (such as indoles, benzimidazoles, and imidazoles) and diverse electrophiles (e.g., hindered/deactivated/heterocyclic aryl iodides, an aryl bromide, an activated aryl chloride, alkenyl halides, and an alkynyl bromide) could serve as suitable partners and give C–N coupling products in moderate to good yields. Kobayashi and co-workers also explored the Ullmann type C–N coupling reactions and reported a visible-light induced coupling
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Scheme 5. Photoinduced C(sp2)–N coupling involved cation radical accelerated nucleophilic aromatic substitution.
reaction of carbazole derivatives and aryl iodides (Scheme 3).8 The excited iridium polypyridyl complex 11 could be quenched by copper–carbazolide complex 9 to afford excited copper carbazolide 12 and the ground state Ir(ppy)3. After a SET from the excited 12 to iodobenzene, corresponding aryl radical 14, which could react with copper (II) amide 13 to produce the desired product 7. In 2016, Buchwald and MacMillan developed a ligand-free Ni(II) and photoredox-cocatalyzed C(sp2)–N coupling promoted by visible light (Scheme 4).9 The oxidative addition product 22 can undergo ligand exchange and subsequent deprotonation to arrive at Ni(II)-aryl amido complex 23. Then, a SET process from 23 to photoexcited Ir(III)⁄ 19 afford Ni(III) complex 24 and Ir(II) photocatalyst 20. Reductive elimination of the resultant Ni(III) complex yields Ni(I) bromide species 25 and the desired aniline product 17a. A variety of aryl bromides bearing electron-withdrawing group performed well under the reaction conditions. Electron-rich arenes were less reactive in this reaction. By lowering the photocatalyst loading (0.002 mol%), reaction efficiency could be increased and the desired product 17h was produced in 93% yield. Recently, Nicewicz and co-workers reported a cation radicalaccelerated nucleophilic aromatic substitution (SNAr) using meth-
Scheme 7. Hydroxylamine derivatives as N-radical precursors.
oxy- and benzyloxy-groups as the leaving groups (Scheme 5).10 The aryl CAN bonds were constructed via a direct SNAr using an acridinium photoredox catalyst. They proposed that Mes-Acr+⁄ oxidized the anisole derivatives leading to radical cation 26. Addition of the amine at the carbon bearing methoxy group gave rise to 27, which underwent loss of MeOH and was reduced by Mes-Acr, leading to the final SNAr product. It was worth mentioning that product 29 with benzyl aryl ether working as the leaving group or product 30 with ammonium carbamate working as the nucleophile could be obtained in this amination reaction. Redox neutral C(sp2)–N coupling reactions
Scheme 6. Redox neutral C–N coupling reactions.
Redox neutral C(sp2)–N coupling reactions usually involved nitrogen-centered radical (N-radical) addition process and an oxidative quenching photoredox catalytic cycle. As depicted in Scheme 6, N-radical precursors, such as hydroxylamine, amine halide, oxime and N-aminopyridinium derivatives, were reduced by excited photocatalyst to afford N-radical 31. The N-radical could add to an arene to generate a C N bond and a carbon-centered radical 32. The resultant carbon-centered radical could be oxidized to a carbocation followed by deprotonation to regenerate the final product (Scheme 6). Hydroxylamine derivatives are easily accessed and can serve as tunable nitrogen sources, which were employed in C–H amidation of arenes and heteroarenes over the past several years (Scheme 7). In 2014, Sanford and co-workers reported a visible light photocatalyzed method for the C–H amination of arenes and heteroarenes (Scheme 7a).11 A key enabling advance in this work was the design of N-acyloxyphthalimide 34 as the precursor to N-radical intermediate for this transformation. Independently, our group developed a C–H amidation of electron-rich heteroarenes, such as indoles,
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Scheme 8. Amine halide derivatives as N-radical precursors.
pyrroles, and furans using N, O-dibenzenesulfony-N-methyl hydroxylamine 35 as the nitrogen source (Scheme 7b).12 These reactions are highly regioselective, and all the products were isolated as a single regioisomer. Another relevant work published very recently employed 3,6-dimethoxy-9H-thioxanthen-9-one 37 as a catalyst in the CAH amination of arenes and heteroarenes (Scheme 7c).13 The thioxanthone catalyst also underwent an oxidative quenching cycle for homolytic aromatic substitution. Leonori and co-workers disclosed a transition-metal-free CAH amination of arenes and heteroarenes (Scheme 7d).14 The organic dye eosin Y was used as the photoredox catalyst. O-aryl hydroxylamines 38 could serve as general, bench-stable N-radical precursors that could deliver N-radicals upon photoredox activation under mild conditions. Later on, N, N-dialkyl arylamines assembled through aminyl radical addition approach in the presence of a Brønsted acid was reported (Scheme 7e).15 Dialkyl-substituted N-radicals showed lower stability because of the intrinsic nucleophilic nature of aminyls, which causes repulsive interactions between their lone pair and the aromatic ring.16 The strong acid would maintain the N-atom in protonated form during the entire reaction sequence. Recently, Luo,17 Lee,18 and Xiao19 reported that N-bromosaccharin 40 (Scheme 8a), N-chlorophthalimide 41 (Scheme 8b), and Nchloromorpholine 42 (Scheme 8c) could also work as the N-radical
Scheme 9. Oxime derivatives as N-radical precursors.
precursors for visible-light promoted C–H amination of arenes and heteroarenes. Iminyl-radical participating C(sp2)–N coupling reaction usually exists in the construction of N-heteroarenes via intramolecular homolytic aromatic substitution (HAS) following by oxidation (SET) and deprotonation process. In 2015, our group reported a mild, effective and direct construction of pyridines, quinolines, and phenanthridines from O-acyl oximes20 or aldehydes.21 In this reaction, an electron-deficient acyl worked as the leave group (Scheme 9a). Later on, Xie group developed a metal-free photoredox-catalyzed methods toward phenanthridines form O-(2,4-dinitrophenyl)oximes.22 In this study, the organic dye eosin Y and iPr2NEt were used as photocatalyst and terminal reductant, respectively (Scheme 9b). In 2015, Studer and co-workers introduced pyridinium salts 46 as efficient N-radical precursors, which were easily accessible from commercially available pyrylium salts (Scheme 10).23 Reduction of salts 46 by a single electron transfer promoted by visible light allowed for clean generation of amidyl radicals, which underwent HAS affording C–H amination products of arenes and heteroarenes. In 2015, König group reported the C–H amidation of heterocycles with benzoyl azides under very mild photocatalysis conditions (Scheme 11).24 The only byproduct in this atom economic process is dinitrogen. The energy transfer triggered the loss of dinitrogen yielding the benzoyl nitrene. The benzoyl nitrene might be protonated under the strongly acidic conditions, giving electrophilic nitrenium ions 50, which would react with the electron rich heteroarene. After loss of a proton, the amidation product was obtained.
Scheme 10. N-aminopyridinium derivatives as N-radical precursors.
Scheme 11. Benzoyl azide derivatives as N-radical precursors.
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Oxidative (dehydrogenative) C(sp2)–N coupling reactions Oxidative (dehydrogenative) couplings are fascinating means for C–N bond construction, which avoids the requirement for preactivation of both coupling partner and leads to atom and step economy in chemical synthesis. However, the direct C(sp2) N coupling reactions under photoredox catalysis are challenging. The reported methods for photoredox-catalyzed C(sp2)–N oxidative couplings include: 1) N-radical-triggered oxidative coupling; 2) aryl cation radical-triggered oxidative coupling; 3) N-radical and aryl radical-triggered radical cross-coupling; 4) transition-metalmediated intramolecular oxidative coupling (Scheme 12).
N-Radical-triggered oxidative coupling N-Radical triggered oxidative coupling undergoes generation of N-radical, radical addition to an arene, carbon-centered radical oxidation and deprotonation process. N-radical 53 is generated by reductive quenching of photocatalyst from N–H amide. Both of reduced state photocatalyst and the aryl radical species 54 undergo oxidation to close the catalytic cycle (Scheme 13). In 2012, an intramolecular C(sp2)–H oxidative amination of styryl aniline was reported by Zheng group (Scheme 14).25 The N-radical cation generated from styryl aniline could undergo electrophilic addition to the tethered alkene, thus triggering a cascade reaction involving either aromatization or C–C bond migration followed by aromatization to form indoles. More importantly, these studies revealed that arylamines could participate in C(sp2)–N bond formation directly under visible-light photoredox conditions.
Scheme 12. Types of oxidative (dehydrogenative) C(sp2)–N coupling reactions.
Scheme 13. N-radical-triggered oxidative (dehydrogenative) C(sp2)–N coupling reactions.
Scheme 14. Secondary aniline derivatives as N-radical precursors.
In 2016, our group reported the direct oxidative amidation of heteroarenes with sulfonamides (Scheme 15).26 N-radicals were directly generated from oxidative cleavage of N–H bonds under visible-light photoredox catalysis. NaClO served as the oxidant. A variety of heteroarenes, including indoles 56a, pyrroles 56b and benzofurans 56c, could undergo this amidation in high yields. These reactions were highly regioselective, and all the products were isolated as a single regioisomer. The fluorescence quenching experiments and Stern-Volmer analysis indicated that the photoexcited catalyst was quenched by NaClO. Itami and co-workers developed dehydrogenative C–H imidation of arenes using IBB (Scheme 16) as the oxidant, which got two electrons from RuII⁄ and the generated aryl radical 59.27 RuIII was furnished from excited RuII⁄ after the oxidation of RuII by IBB. Imidyl radical was generated after the oxidation of sulfonamide 57 by RuIII. Itoh group reported another cross-dehydrogenative C(sp2) N coupling (Scheme 17).28 The reaction was mediated by photocatalyst 2-tert-butylanthraquinone (2-t-Bu-AQN) and oxygen as the sole oxidant. Various substituted 2-phenylindoles, pyrroles, 2phenylbenzo[b]-thiophene could be employed for this reaction. Unfortunately, N-methylindole was not suitable under these reaction conditions (60).
Scheme 15. Sulfamide derivatives as N-radical precursors.
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an acridinium photoredox catalyst under an aerobic atmosphere (Scheme 19).30 A wide variety of primary amines, including amino acids and more complex amines, were competent coupling partners. Electron-rich arenes could not undergo amination through an arene cation radical and instead reacted via an amine cation radical pathway. For electron-rich arenes, both the amine and the arene quenched the acridinium excited state, which meant that both arene cation radical and amine cation radical might exist in this transformation. Very recently, Hong group developed a novel synthetic route to construct phenanthridinone and quinolinone scaffolds through amidyl radicals generated by visible-light photocatalysis, which led to oxidative intramolecular C–H amidation to furnish a C (sp2)–N bond (Scheme 20).31 For construction of quinolinones, the E/Z isomerization of cinnamamide was the key step. The excited state Ir(III)⁄ species played a dual role in the reaction: catalyzing triplet state energy (ET) transfer for E/Z olefin isomerization Scheme 16. Sulfamide derivatives as N-radical precursors.
Very recently, König and co-workers achieved CAH amination of benzene derivatives using DDQ as the photocatalyst and BocNH2 as the nitrogen source under aerobic conditions and visible light irradiation (Scheme 18).29 The amine scope of the reaction comprises BocNH2, carbamates, pyrazoles, sulfonimides and urea. They proposed two possible mechanistic pathways: 1) excited DDQ in its triplet state was a very strong oxidant and arenes were oxidized to their corresponding radical cations 62. The radical cation was attacked by the amine. 2) SET from amines to DDQ initiated by visible light gave amine radical 63 and radical cation 61. DDQ was regenerated by TBN. Nicewicz and co-workers reported the construction of aryl C–N bonds to primary amines via a direct C–H functionalization using
Scheme 19. Primary amine derivatives as N-radical precursors.
Scheme 17. Phthalimide derivatives as N-radical precursors.
Scheme 18. BocNH2 or pyrazole derivatives as N-radical precursors.
Scheme 20. Amide derivatives as N-radical precursors.
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and serving as a photooxidant to facilitate the amidyl radical via an oxidative proton-coupled electron transfer (PCET) protocol. The resultant amidyl radical intermediate 65 underwent intramolecular C–N bond formation to give aryl radical 67. This aryl radical would in turn undergo O2 addition to form a peroxy radical species 68, which would be reduced by Ir(II) to regenerate the catalytically active Ir(III) complex.
Aryl cation radical-triggered oxidative coupling Aryl cation radical-triggered oxidative coupling was usually suitable for electron-rich arenes, which possessed lower oxidation potentials and could stabilize the carbocation intermediate. A SET from electron-rich arene to photocatalyst (PC) furnished arene cation radical 70, which was attacked by nucleophilic amine. The nucleophilic attack product 71 underwent deprotonation and oxidization giving arene cation intermediate 73 followed by deprotonation (Scheme 21). Catalytic cycle of this coupling also involved reductive quenching of photocatalyst. In 2015, Nicewicz and co-workers reported site-selective amination of a variety of aromatics with heteroaromatic azoles promoted by an acridinium photooxidant and anitroxyl radical (Scheme 22).32 Para- and ortho-amination products were obtained when the arene was monosubstituted benzene ring (74a). On the basis of this work, they sought to develop a predictive model for site selectivity and extend this aryl functionalization chemistry to a selected set of heteroaromatic systems. Using electron density calculations, they were able to predict the site selectivity of direct C–H amination in a number of heterocycles and identify general trends observed across heterocycle classes.33 In 2016, König and co-workers reported a direct amination of pyrroles for the preparation of N-(2-pyrrole)-sulfonamides from sulfonamides and pyrroles (Scheme 23).34 They used acridiniumbased dye as the photocatalyst and oxygen as the terminal oxidant for the oxidative C–N bond formation. Pyrroles were tolerant in this reaction because of the available oxidation potential of the photocatalyst and the required stability of the generated carbocation intermediate. Recently, Laha group have developed Ru(bpy)3Cl2-catalyzed Narylation reaction via the direct C–H functionalization of methoxy-substituted benzenes. In this reaction, selectfluor worked as the oxidative quencher and H-atom-abstractor (Scheme 24).35 Lei group reported C2-amination of thiophenes using DDQ as a photocatalyst, tert-butyl nitrite (TBN) as an electron mediator and oxygen as a terminal oxidant under visible-light irradiation
(Scheme 25).36 Various thiophenes could be selectively transformed into corresponding amination products in high yields and H2O was the only byproduct. Recently, Lei group had reported an oxidant-free and selective C (sp2)–H amination of arenes catalyzed by synergistic acridinium 75 and cobalt oxime complex 76 (Scheme 26).37 The generated aromatic ring radical cation was attacked by nucleophile pyrazole, which was difficult to be oxidized by the excited state acridinium, leading to 77. Then the radical adduct 77 underwent a single electron transfer with CoII catalyst and deprotonation generating the
Scheme 22. Heteroaromatic azole derivatives as nucleophiles.
Scheme 23. Sulfonamide derivatives as nucleophiles.
Scheme 24. Azole derivatives as nucleophiles.
Scheme 21. Aryl cation radical triggered C(sp2)–N oxidative coupling.
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Scheme 25. Azole derivatives as nucleophiles.
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Scheme 26. Azole derivatives as nucleophiles (Oxidant-free).
amination product. At the same time, CoI could capture the present proton in the reaction system, yielding CoIII–H 78. After the protonation of CoIII–H, H2 was released and CoIII was regenerated, which oxidized the photocatalyst to close the catalytic cycle and regenerated CoII species.
Scheme 28. Dehydrogenative-coupling amination between phenols and acyclic diarylamines.
In general, it was difficult to provide an appropriate situation in the radical cross-coupling manner between the C-radical and Nradical simultaneously. The principle of persistent radical effect (PRE)38 should be followed to selectively afford the anticipated cross-coupling product rather than the homocoupling one. Therefore, N-radical and aryl radical-triggered radical cross-coupling remained an extremely challenging task. In 2016, Xia and co-workers described a visible-light mediated cross-dehydrogenative coupling amination reaction via a N-radical/C-radical cross-coupling pathway using K2S2O8 for dual oxida-
tion (Scheme 27).39 This reaction benefited from mild conditions, high regioselectivity and the absence of metal and/or photocatalysts. Under irradiation with visible light, the phenol and amine were both oxidized by S2O28 79 to form the radical intermediates 84 and 85 respectively. Then the C-radical/N-radical cross-coupling reaction occurred to furnish intermediate 86 which was isomerized to afford the final product 87. In the aforementioned work (Scheme 27), acyclic diarylamine was incapable of coupling with phenol to furnish the intermolecular aryl C N bond only with the help of oxidant and light irradiation. Oxidation potential values of the acyclic diarylamines, which were higher than those of phenothiazine, might account for the barrier of the transformation. Therefore, they developed an oxidative system combining a catalytic amount of organic photocatalyst (2,4,6-triphenylpyrylium salt 90) with stoichiometric amount of persulfate was developed to enable the successful
Scheme 27. Dehydrogenative coupling amination reaction via radical crosscoupling pathway.
Scheme 29. Transition-metal-mediated coupling.
N-Radical and aryl radical-triggered radical cross-coupling
intramolecular
C(sp2)–N
oxidative
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cross-dehydrogenative-coupling amination between phenols and acyclic diarylamines (Scheme 28).40 The excited state PC⁄ 88 abstracted an electron from aniline to produce PC anion radical 89. The ground state of PC was regenerated from 89 by donating an electron to 79 to finish the photoredox cycle. Transition-metal-mediated intramolecular oxidative coupling In the past several years, transition-metal-mediated intramolecular C–H bond amination promoted by an oxidant has attracted intense interest from synthetic chemists.41 However, the processes described above had limitations associated with the requirements of high reaction temperatures and stoichiometric use of strong ground-state oxidants. In 2015, Cho group reported an intramolecular C–H bond amination of N-substituted-2-amidobiarylsthe utilizing merged Pd catalysis and visible light photoredox, which was used for regeneration of the Pd catalyst instead of strong oxidants (Scheme 29).42 In the initial step, coordination of the amido group to PdII facilitated cyclopalladation, leading to the six-membered palladacycle 91. The palladacycle was oxidized to a PdIII complex 92 by SET to the photoexcited Ir catalyst. Reductive elimination of the palladacycle 92 led to the formation of carbazole. The PdI species was subsequently oxidized to generate the original PdII complex through SET to the photoexcited Ir catalyst or molecular oxygen. Various carbazoles could be generated without strong oxidants for regeneration of the Pd catalyst. Conclusions In this digest, we have summarized the recent advances of photoredox-catalyzed C(sp2)–N coupling reactions. Three types photoredox catalyzed C(sp2)–N coupling reactions, including Ullmann type C–N coupling reactions (C–X/N–H type coupling), redox neutral C–N coupling reactions (C–H/N–X type coupling) and oxidative C–N coupling reactions (C–H/N–H type coupling), have been presented in details. The photocatalysis features low reaction temperature, good functional group tolerance and high efficiency of photocatalyst. Major limitations of this strategy currently include narrow substrate scope, sometime poor site selectivity. Acknowledgments Financial support from the National Natural Science Foundation of China (21672098, 21472084, and 21732003) is acknowledged. References 1. (a) Kim J, Movassaghi M. Chem Soc Rev. 2009;38:3035–3050; (b) Evano G, Blanchard N, Toumi M. Chem Rev. 2008;108:3054–3131; (c) Evano G, Theunissen C, Pradal A. Nat Prod Rep. 2013;30:1467–1489; (d) Cho SH, Kim JY, Kwak J, Chang S. Chem Soc Rev. 2011;40:5068–5083; (e) Bagley MC, Dale JW, Merritt EA, Xiong A. Chem Rev. 2005;105:685–714; (f) Hili R, Yudin AK. Nat Chem Biol. 2006;2:284–287; (g) Okano K, Tokuyama H, Fukuyama T. Chem Commun. 2014;50:13650–13663. 2. Shirota Y, Kageyama H. Chem Rev. 2007;107:953–1010.
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