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C-H amination in the synthesis of N-heterocycles

Authors Yu J, Fu H

Received 12 January 2015

Accepted for publication 17 February 2015

Published 31 March 2015 Volume 2015:5 Pages 1—17

DOI https://doi.org/10.2147/ROC.S56037

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 6

Editor who approved publication: Dr Sean Kerwin



Jipan Yu, Hua Fu

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, People's Republic of China

Abstract: N-heterocycles are important motifs in natural products and pharmaceuticals. Recently, the transition metal–catalyzed C-H amination has become a subject in the synthesis of N-heterocycles because of use of the readily available starting materials, high efficiency, economy, and practicability of the methods. This review summarizes recent advances in the copper, iron, palladium, rhodium, ruthenium, and nickel-catalyzed synthesis of N-heterocycles via C-H amination strategy.

Keywords: N-heterocycles, C-H activation, amination, transition metal–catalyzed, synthetic methods


Introduction

N-heterocyclic compounds are of unique structural units and widely exist in the bioactive molecular and natural products.1 Because N-heterocyclic compounds tend to exhibit improved solubility and promote salt formation, which are helpful to improve oral absorption and bioavailability,2 they are privileged structures in drug development. Recently, transition metal–catalyzed C-H activation has attracted much attention because of its great application in organic synthesis.311 Over the past decade, the transition metal–catalyzed C-H amination has achieved remarkable progress, and the highly atom economical strategy has been applied to the synthesis of N-heterocyclic compounds.1215 This review is intended to provide an overview of copper, iron-, palladium-, rhodium-, ruthenium-, and nickel-catalyzed C-H amination in the synthesis of N-heterocyclic compounds.

Copper-catalyzed synthesis of N-heterocycles

At first, we discuss the C-H amination of arenes leading to N-heterocyclic compounds. In 2008, Brasche and Buchwald16 reported the copper-catalyzed C-H amination to lead to benzimidazoles (2) by using amidines (1) as the substrates (Figure 1). The intramolecular cyclization used 15 mol% Cu(OAc)2 as the catalyst, molecular oxygen as the oxidant in dimethyl sulfoxide in the presence of 5 equiv AcOH at 100°C, and the reactions provided the benzimidazole derivatives in good yields with good tolerance of functional groups including both electron-donating and electron-withdrawing substituents. Exact mechanism for the reaction is unclear, and the authors proposed three possible pathways (Figure 2). Treatment of 1 with Cu(OAc)2 provides I, intramolecular arylation of I leads to II, and deprotonation of II gives 2 (pathway a); intramolecular addition of I affords a metallacycle III, and 2 is subsequently obtained through rearomatization and reductive elimination of the metal (pathway b). Desorption of HOAc in II gives a copper nitrene IV, and a concerted insertion of the nitrogen into an aryl C-H bond provides 2 (pathway c).

Figure 1 Copper-catalyzed synthesis of benzimidazoles.

Figure 2 Proposed mechanism for the copper-catalyzed synthesis of benzimidazoles.

Sheng et al17 used substituted 3-iodochromones (3) and amidines (4) as the substrates, and the reactions underwent sequential intermolecular Ullmann-type N-arylation of amidines and intramolecular aerobic oxidation in air to afford chromento[2,3-d]imidazol-9(1H)-ones (5) in moderate to good yields (Figure 3).

Figure 3 Copper-catalyzed synthesis of chromento[2,3-d]imidazol-9(1H)-ones.

In 2011, Cho et al18 reported the copper-catalyzed preparation of carbazoles (7) from N-substituted amidobiphenyls (6) by using hypervalent iodine(III) as the oxidant (Figure 4A). The reactions were performed quickly under mild conditions, and a free radical mechanism was proposed. In 2014, Takamatsu et al19 used MnO2 as the oxidant, the reactions were carried out at 200°C in the presence of AcOH under microwave irradiation, and the similar C-H amination was achieved with picolinamide as the directing group (Figure 4B).

Figure 4 (A, B) Copper-catalyzed synthesis of carbazoles.

Zhou et al20 developed the intramolecular copper-catalyzed approach to N-aryl acridones (11) via C-H amination (Figure 5). The protocol used aryl-(2-arylaminoaryl)methanones (10) as the starting materials and air as the oxidant, and the reactions were performed well under neutral conditions. The reaction undergoes intramolecular aerobic oxidative cyclization of 10 leading to intermediate I, and subsequent reductive elimination of I provides the target products (11).

Figure 5 Copper-catalyzed synthesis of acridones.

In 2013, Li et al21 synthesized indazoles (13) via copper-catalyzed aerobic oxidative C-H amination of N-tosylhydrazones (12) (Figure 6). The method showed a good functional group tolerance. Similarly, pyrazoles (15) were also prepared through the intramolecular C-H amination strategy.

Figure 6 Copper-catalyzed synthesis of indazoles.

Berrino et al22 established synthesis of 4-aryl-2-quinolones (17) from 3,3-diarylacrylamides (16) through intramolecular copper-catalyzed C-H amination (Figure 7A). The protocol used 10 mol% CuI as the catalyst, 20 mol% PPh3 as the ligand, 2 equiv of KOtBu as the base, and the reactions were performed in o-xylene under air atmosphere. Gui et al23 developed a similar procedure for the synthesis of phenanthridin-6(5H)-one derivatives (19) by using 2-phenylbenzamides (18) as the substrates (Figure 7B).

Figure 7 (A, B) Copper-catalyzed synthesis of 4-ary-2-quinolones and phenanthridin-6(5H)-ones.

The synthesis of isoquinolin-1(2H)-ones via copper-mediated amination has been developed by Chary et al24 (Figure 8). Reaction of 2-iodobenzamides (20) with alkynes in PEG 400 afforded N-substituted isoquinolin-1(2H)-ones (21) in moderate to good yields. The reaction undergoes sequential Sonogashira-type coupling and intramolecular cycloaddition process.

Figure 8 Copper-catalyzed synthesis of isoquinolin-1(2H)-ones.

In 2012, Wang et al25 developed the copper-catalyzed aerobic oxidative intramolecular C-H amination, and the corresponding imidazobenzimidazole derivatives (23) were obtained in excellent yields (Figure 9A). The protocol used substituted 2-(1H-imidazol-1-yl)-N-alkylbenzenamines (22) as the starting materials, 20 mol% Cu(OAc)2 as the catalyst, 1,10-phenanthroline (1,10-phen) as the ligand, and molecular oxygen as the oxidant. A possible mechanism is proposed in Figure 9B. The treatment of Cu(OAc)2 with 1,10-phenanthroline forms complex LnCu(OAc)2, reaction of 22 with LnCu(OAc)2 provides I, and aerobic oxidative of I affords the target products (23) regenerating the Cu(II) catalyst.

Figure 9 (A, B) Copper-catalyzed synthesis of imidazobenzimidazoles.

In the same year, Xu and Fu26 reported a sequential copper-catalyzed Ullmann-type N-arylation and aerobic oxidative intramolecular C-H amination by using substituted 2-halo-N-alkylbenzamides, 2-chloro-N-propylpyridine-3-carboxamide (24), imidazole, and benzimidazole derivatives (25) as the starting materials (Figure 10). The reactions applied inexpensive CuI/L-proline as the catalyst system and molecular oxygen as the oxidant. The imidazo/benzoimidazoquinazolinones (26) were obtained in good to excellent yields. The procedure involved sequential copper-catalyzed Ullmann-type N-arylation and aerobic oxidative intramolecular C-H amination. Later, Chen et al27 described a similar approach to azoquinazolinones.

Figure 10 Copper-catalyzed synthesis of imidazoquinazolinones.

In fact, the C-H amination of alkenes to N-heterocyclic compounds has been investigated. In 2011, Wang et al28 described copper-catalyzed synthesis of imidazo[1,2-a]pyridine-3-carbaldehydes (28) and 1,2-disubstituted imidazole-4-carbaldehydes (30) from readily available N-allyl-2-aminopyridines (27) and substituted N-allylamidines (29) (Figure 11). The reactions were carried out well by using 20 mol% Cu(II) hexafluoroacetylacetonate (hfacac) catalyst in DMF or DMA at 105°C under oxygen. As shown in Figure 12, the catalytic cycle is initiated by coordination of 27 with Cu(II) to form Cu(II)-N adduct (I); oxidation of the Cu(II)-N adduct generates a Cu(III) intermediate (II). Subsequently, intramolecular cyclization of II provides III, desorption of Cu(II)OH in III gives V, and oxidative aromatization of V affords the desired product (28).

Figure 11 (A, B) Copper-catalyzed synthesis of imidazo[1,2-a]pyridine-3-carbaldehydes and 1,2-disubstituted imidazole-4-carbaldehydes.

Figure 12 Proposed mechanism for the copper-catalyzed synthesis of imidazo[1,2-a]pyridine-3-carbaldehydes.

In 2007, Zeng and Chemler29 developed the asymmetric synthesis of six-membered N,S-heterocycles (32) via copper-catalyzed intramolecular carboamination of alkenes (33) by using chiral bisoxazoline as the ligand and MnO2 as the oxidant (Figure 13). In 2009, the same group reported the intramolecular copper-catalyzed carboamination of N-aryl-2-allylanilines (33), in which Cu(OTf)2 was used as the catalyst, 2,2′-bipyridyl as the ligand, and MnO2 as the oxidant (Figure 14).30 A possible mechanism for the procedure was proposed as follows: coordination of Cu(II) with nitrogen in N-aryl-2-allylaniline (33) gives I, intramolecular addition of N-CuL to the alkenyl C=C bond in I provides II, desorption of CuL in II leads to III, and cyclization of III affords the target product (34). When a chiral oxazoline ligand was used in the reactions, 10a,11-dihydro-10H-indolo[1,2-a]indoles (36) with high enantioselectivity were prepared (Figure 15).31

Figure 13 Copper-catalyzed synthesis of six-membered N,S-heterocycles.

Figure 14 Copper-catalyzed synthesis of 10a,11-dihydro-10H-indolo[1,2-a]indoles.

Figure 15 Copper-catalyzed enantioselective synthesis of hexahydro-1H-benz[f]indoles.

In 2011, Lu et al32 established the efficient copper-catalyzed aerobic oxidative intramolecular alkene C-H amination leading to N-heterocycles (38) (Figure 16). The protocol used substituted 3-methyleneisoindolin-1-ones (37) as the starting materials, Cu(O2CCF3)2 as the catalyst, and air as the oxidant, and the corresponding N-heterocycles were obtained in good to excellent yields.

Figure 16 Copper-catalyzed synthesis of fused N-heterocycles.

The copper-catalyzed C-H bond amination of alkynes is also applied in the synthesis of N-heterocyclic compounds. In 2013, Li and Neuville developed the copper-catalyzed synthesis of 1,2,4-trisubstituted imidazoles (40) from amidines (39) and terminal alkynes (Figure 17).33 The protocol used 20 mol% CuCl2 · H2O as the catalyst, 2 equiv of sodium carbonate and 2 equiv of pyridine as the additives, and molecular oxygen as the oxidant. A possible mechanism for the reaction is shown in Figure 18. Treatment of Cu(II) with 39 and terminal alkyne provides I, oxidation of I gives II, and reductive elimination of II leads to III. Cycloaddition of III affords IV, desorption of copper in IV in the presence of HX yields 40 freeing Cu(I)X, and oxidation of Cu(I)X regenerates Cu(II) catalyst.

Figure 17 Copper-catalyzed synthesis of imidazoles.

Figure 18 Proposed mechanism for the copper-catalyzed synthesis of imidazoles.

The copper-catalyzed C(sp3)-H bond amination is effective for the synthesis of heterocyclic compounds. In 2013, Huang et al34 described the Cu(I)-catalyzed intramolecular aerobic oxidative C-H amination of 2-aminoacetophenones (41) in the presence of 2,2′-bipyridine as the ligand, and various N-alkyl– or aryl-substituted isatins (42) were prepared in good to excellent yields (Figure 19). In the reactions, oxidation of 41 forms the corresponding acetaldehyde (I), intramolecular nucleophilic attack of imine to aldehyde in I leads to II, and further oxidation of II provides the desired product (42).

Figure 19 Copper-catalyzed synthesis of isatins.

Chen et al35 described the amination of aliphatic C-H bonds in N-alkylamidines (43), in which Cu(OAc)2 was used as the catalyst, PhI(OAc)2 as the oxidant (Figure 20). The intramolecular C-H amination was performed in the presence of K3PO4 at room temperature. As shown in Figure 21, treatment of 43 with copper catalyst in the presence of PhI(OAc)2 provides I, and desorption of copper in I forms free radical II. Transfer of a hydrogen free radical in II gives III, oxidation of III affords IV, and cyclization of IV affords the target product (44).

Figure 20 Copper-catalyzed synthesis of dihydroimidazoles.

Figure 21 Proposed mechanism for the copper-catalyzed synthesis of dihydroimidazoles.

Wang et al36 reported the efficient method for construction of four-membered β-lactams (46) based on copper-catalyzed C(sp3)-H amination with 8-aminoquinolinyl as the directing group (Figure 22A). A plausible mechanism is proposed in Figure 22B. Oxidation of Cu(II) by Ag2CO3 affords Cu(III), treatment of Cu(III) with 45 leads to I, and insertion of Cu(III) to C(sp3)-H gives II. Reaction of II with HOAc affords III, and reductive elimination of III provides the target product (46). At the same time, Wu et al37 independently reported a similar research in the presence of 20 mol% CuCl as the catalyst and duroquinone as the oxidant under air, and the corresponding products (48) were obtained in 69%–92% yields (Figure 23).

Figure 22 (A, B) Copper-catalyzed synthesis of four-membered β-lactams.

Figure 23 (A, B) Similar copper-catalyzed synthesis of four-membered β-lactams.

Iron-catalyzed synthesis of N-heterocycles

Iron is more abundant and inexpensive than other transition metals in nature, and it is used in C-H amination for the synthesis of N-heterocycles. Iron-catalyzed C-H amination of arenes to N-heterocycles has been investigated by some groups. In 2013, Zhang and Bao38 developed the iron-catalyzed aerobic oxidative synthesis of substituted 1H-indazoles (50) and 1H-pyrazoles (52) from arylhydrazones (Figure 24). The protocol used molecular oxygen as the oxidant, the inexpensive FeBr3 as the catalyst, and water was a sole by-product. A possible mechanism is shown in Figure 25. The reaction is proposed to proceed via a Fe-catalyzed one-electron transfer process of (49) to get a radical cationic ion I, which undergoes intramolecular C-N bond formation to lead to II. Subsequently, deprotonation of II provides III, and III loses one electron and hydrogen to yield the desired product (50).

Figure 24 Iron-catalyzed synthesis of substituted 1H-indazoles and 1H-pyrazoles.

Figure 25 Proposed mechanism for iron-catalyzed synthesis of substituted 1H-indazoles.

In 2009, Fan et al39 developed synthesis of 2-pyrrolines (55) from readily available substrates (53 and 54) under mild conditions (Figure 26). Under FeCl3 catalysis, the reaction of aziridines with arylalkynes provided the corresponding functionalized 2-pyrrolines in moderate to good yields. The proposed reaction mechanism is shown in Figure 27. Aziridine is activated by FeCl3 to form a zwitterionic intermediate (I), and then reaction of I with phenylacetylene provides an aryl-substituted alkenyl cation (II). Intramolecular nucleophilic addition gives the desired product (55) regenerating the iron catalyst.

Figure 26 Iron-catalyzed synthesis of 2-pyrrolines.

Figure 27 Proposed mechanism for iron-catalyzed synthesis of 2-pyrrolines

In 2014, Sun et al40 described the synthesis of 4,5-dihydropyrroles (58) through iron-catalyzed [4C +1N] cyclization of 4-acetylenic ketones (56) and primary amines (57) (Figure 28). The protocol used FeCl3 as the catalyst and 1,5-pentanediol as solvent, and various substituted 4,5-dihydropyrroles were obtained in moderate to good yields. The reaction was performed through enamine formation and subsequent cyclization.

Figure 28 Iron-catalyzed synthesis of 4,5-dihydropyrroles.

In 2014, Liu et al41 developed inter- and intramolecular amination using primary arylamines as a nitrogen source for nitrene/imide insertion and transfer reactions (Figure 29). The reaction was performed using [Fe(F20TPP)Cl] (H2F20TPP = meso-tetrakis(pentafluorophenyl)porphyrin) as the catalyst and PhI(OAc)2 as the oxidant. The protocol can be applied to both intra- and intermolecular amination of sp2 and sp3 C-H bonds, affording the amination products 60 and 62 in moderate to good yields. A possible mechanism was proposed (Figure 30). Under catalysis of [Fe(F20TPP)Cl]/PhI(OAc)2, arylamine (59 or 61) was converted into reactive intermediate (I), and then the nitrene/imide insertion to C-H bond provides 59 or 61.

Figure 29 Iron-catalyzed inter- and intramolecular C-H amination.

Figure 30 Proposed mechanism for iron-catalyzed inter- and intramolecular C-H amination.

In 2014, Karthikeyan and Sekar42 described the iron-catalyzed intramolecular C-H amination of 2-benzhydrylpyridine derivatives (63), and the corresponding pyrido[1,2-a]indoles (64) were prepared under catalysis of FeCl3 and FeCl2 in the presence of molecular oxygen. In the reactions, the pyridine nitrogen atom was a directing group as well as a nucleophile (Figure 31).

Figure 31 Iron-catalyzed synthesis of pyrido[1,2-a]indoles.

The same group reported synthesis of benzimidazoles (67) from o-aminoarylazides (65) and arylaldehydes (Figure 32).43 The procedure was divided into two steps: reaction of o-aminoarylazides and arylaldehydes firstly produced imines in the presence of MgSO4, and then iron-catalyzed desorption of nitrogen and cyclization provided the target products in the presence of powered 4 Å molecular sieves.

Figure 32 Iron-catalyzed synthesis of benzimidazoles.

In 2011, Bonnamour and Bolm44 described the iron-catalyzed synthesis of indoles (69) via intramolecular C-H amination (Figure 33). The protocol used iron(III) triflate as the catalyst, and THF as the solvent, and various 2-subsitituted indoles were obtained with a broad range of functional groups, including ethers, CF3, C-F, and C-Cl bonds.

Figure 33 Iron-catalyzed synthesis of indoles.

Jana et al45 developed the FeCl2-catalyzed synthesis of 2,3-disubstituted indoles (71) from 2H-azirines (70) (Figure 34). The reactions underwent the sequential ring opening of 2H-azirines (70) to lead to the formation of iron vinyl nitrene intermediate (II) and intramolecular cyclization to form III (Figure 35). The method could tolerate a variety of functional groups such as Br, F, NO2, OMe, CF3, OTBS, alkenes, and OPiv.

Figure 34 Iron-catalyzed synthesis of 2,3-disubstituted indoles.

Figure 35 Proposed catalytic cycle for iron-catalyzed synthesis of 2,3-disubstituted indoles.

Hennessey and Betley46 developed the iron-dipyrrinato catalyst that promoted the direct aliphatic C-H amination, and various pyrrolidine derivatives (73) were obtained in reasonable yields (Figure 36). The reactions were performed under mild conditions, and a free radical intermediate process was proposed. The azetidines and piperidines were also prepared following similar procedures. The authors suggested a possible mechanism (Figure 37). Treatment of 72 with iron catalyst provides I, and isomerization of I leads to II. Cyclization of II gives III, and freeing of iron catalysts gets the target product (73).

Figure 36 Iron-catalyzed synthesis of pyrrolidines.

Figure 37 Proposed mechanism for iron-catalyzed synthesis of pyrrolidines.

In 2012, Nguyen et al47 described an interesting iron(II) bromide–catalyzed C-H bond amination 1,2-migration reaction, in which ortho-substituted aryl azides (74) transformed into 2,3-disubstituted indoles (75) in toluene at 140°C (Figure 38). The 1,2-shift component was selective, and the migration aptitude was Me < 1° < 2° < Ph. A possible mechanism is proposed in Figure 39. Reaction of 74 with iron catalyst forms an iron nitrene (II), and intramolecular hydride shift in II provides an oxocarbenium ion intermediate (III). Intramolecular cyclization of III leads to IV, and desorption of iron catalyst from IV affords V. Further treatment of V with iron catalyst gives VIII, and deprotonation of VIII provides the desired product (75).

Figure 38 Iron-catalyzed synthesis of 2,3-disubstituted indoles.

Figure 39 Possible mechanism for iron-catalyzed synthesis of 2,3-disubstituted indoles.

Iron catalysts are also used in the C(sp3)-H amination. For example, Liu et al48 reported the intramolecular C(sp3)-H amination of sulfamate esters (76) (Figure 40). The protocol used nonheme iron complex as the active catalyst and PhI(OAc)2 as the oxidant, and the reactions were performed well under mild conditions. Furthermore, the benzylic, allylic, and cycloalkylic C(sp3)-H amination with PhI=NR was also effective.

Figure 40 Iron-catalyzed C(sp3)-H amination of sulfamate esters.

Palladium-catalyzed synthesis of N-heterocycles

Palladium catalysts exhibit high catalytic activity, and they are widely applied in C-H activation. In 2008, Tsang et al49 developed the palladium-catalyzed intramolecular C-H amination leading to unsymmetrical carbazoles (79) (Figure 41). The protocol used Pd(OAc)2 as the catalyst and oxygen and Cu(OAc)2 as the oxidants, and the reactions were performed well in the presence of powered 4-Å molecular sieves with excellent functional group compatibility. A possible mechanism is shown in Figure 42. Coordination of 78 with Pd(OAc)2 provides a Pd-N intermediate (I) with the extrusion of HOAc. Intramolecular electrophilic palladation and subsequent deprotonation generates a six-membered cyclic palladium amide intermediate (III) that undergoes reductive elimination to give the target product (79).

Figure 41 Palladium-catalyzed synthesis of carbazoles.

Figure 42 Proposed mechanism for palladium-catalyzed synthesis of carbazoles.

In the same year, Jordan-Hore et al50 also reported a similar procedure (Figure 43A). They used Ph(OAc)2 as the oxidant. It is worthwhile to note that the reactions were performed well at room temperature, and the method was applied in the synthesis of N-glycosyl carbazoles (83) (Figure 43B). In 2011, Youn et al prepared carbazoles (85) from N-Ts-2-arylanilines (84) via palladium-catalyzed intramolecular oxidative C-H amination by using oxone as the oxidant at ambient temperature (Figure 43C).51

Figure 43 (AC) Palladium-catalyzed synthesis of carbazoles.

In 2012, Yang and Zhang52 reported an efficient palladium-catalyzed intramolecular aerobic aza-Wacher cyclization for the synthesis of isoindolinones (87) and isoquinolin-1(2H)-ones (88) from the same substrates (86) under different catalytic conditions (Figure 44). Isoindolinones (87) were prepared using Pd(OAc)2 as the catalyst and Phen as the ligand, and isoquinolin-1(2H)-ones were obtained by using (MeCN)2PdCl2 as the catalyst and Et3N as the base.

Figure 44 Palladium-catalyzed synthesis of isoindolinones and isoquinolin-1(2H)-ones.

In 2010, Shi et al53 described C-H functionalization and C-N bond formation in the Pd-catalyzed synthesis of β- and γ-carbolinones (91 or 94) from readily available indole-carboxamides (89 or 92) and alkynes (90 or 93) (Figure 45). The reactions were performed well under catalysis of palladium(II) acetate in the presence of tetra-n-butylammonium-bromide and oxygen. A plausible mechanism is shown in the Figure 46. Palladation of 89 with Pd(OAc)2 affords the Pd(II) intermediate (I), and addition of I to alkyne (90) provides vinylic Pd(II) adduct. Subsequent aminopalladation and reductive elimination generates the β-carbolinones (91) leaving Pd(0). Oxidation of Pd(0) regenerates Pd(II) catalyst under air or O2 atmosphere.

Figure 45 Palladium-catalyzed synthesis of β- and γ-carbolinones.

Figure 46 Plausible mechanism for the palladium-catalyzed synthesis of β-carbolinones.

In 2012, Zhang et al54 reported the direct palladium-catalyzed synthesis of isoquinolone derivatives (97) via C-H and C-N bond oxidative coupling reactions (Figure 47). The protocol used palladium acetate as the catalyst, copper acetate and O2 as the oxidants, and various substituted isoquinolones (97) were obtained in good yields. A proposed mechanism is shown in Figure 48. Treatment of 95 with Pd(II) in the presence of base provides I, and reaction of I with 96 leads to II. Addition of II yields III, and reductive elimination of III gives the target product (97) freeing Pd(0). Oxidation of Pd(0) by Cu(OAc)2 and O2 regenerates Pd(II) catalyst.

Figure 47 Palladium-catalyzed synthesis of isoquinolones.

Figure 48 Proposed mechanism for palladium-catalyzed synthesis of isoquinolones.

In 2009, Halland et al55 developed a convenient and practical one-pot method for the synthesis of 2H-indazoles (100) from readily available 2-halophenylacetylenes (98) and hydrazines (99) through a regioselective palladium-catalyzed intermolecular C-N coupling and intramolecular addition cascade process (Figure 49). The reaction showed high tolerance to various functionalities, including ester, amide, cyano, carboxylic acid, ether, and ketone groups.

Figure 49 Palladium-catalyzed synthesis of carbazoles.

In 2008, Zhang et al56 developed the synthesis of pyrroles (102 and 104) from simple amino alcohols (101 and 103) (Figure 50). The protocol applied palladium(II) acetate as the catalyst, copper(II) triflate as the oxidant and alcohol as the solvent. The reaction was performed well under mild conditions.

Figure 50 Palladium-catalyzed synthesis of pyrroles.

In 2010, Majumdar et al57 developed the synthesis of pyrrolo-fused heterocycles and carbocycles (106) catalyzed by palladium(II) acetate in the presence of IBX as the oxidant (Figure 51). The intramolecular oxidative amination of alkenes (105) provides the target product in excellent yields.

Figure 51 Palladium-catalyzed synthesis of carbazoles.

In 2009, Kip et al58 reported a highly diastereoselective synthesis of fused heterocycles (108 and 109) using palladium(II) acetate as the catalyst (Figure 52). The protocol used isoquinoline or quinoline as the ligand and O2 as the oxidant. The oxidative cascade cyclization reaction constructed three bonds and two chiral centers in one step and provided the target products in moderate yields.

Figure 52 Palladium-catalyzed synthesis of carbazoles.

In 2010, Jaegli et al reported59 an efficient difunctionalization of alkenes (110) through intramolecular C-N and aromatic C-H bond formation (Figure 53). The reactions were performed using palladium dichloride as the catalyst, PhI(OAc)2 as the oxidant, and MeCN as the solvent. The products (111) containing spirooxindole unit were prepared in moderate yields.

Figure 53 Palladium-catalyzed synthesis of carbazoles.

In 2014, Jeong and Youn60 reported the palladium-catalyzed oxidative C-H amination from (Z)-N-Ts-dehydroaminodehydroamino acid esters (112), and the protocol used Pd(OAc)2 as the catalyst and oxone as the oxidant, and the reactions were carried out in the presence of powered 4-Å molecular sieves at 80°C (Figure 54). Furthermore, N-Ts-hydrazones were also used as the substrates to prepare indazoles (113).

Figure 54 Palladium-catalyzed synthesis of indole-2-carboxylic acid esters.

In 2008, Wasa and Yu61 developed the synthesis of lactams (115 and 117) via palladium-catalyzed intramolecular C-H amination using AgOAc and CuCl2 as oxidants (Figure 55). In the reactions, both N-alkoxy-2-phenylacetamides (114) and N-methoxy-2-phenylacryl- amides (116) were effective substrates.

Figure 55 Palladium-catalyzed synthesis of lactams.

Palladium-catalyzed amination of alkenes was also investigated. In 2005, Streuff et al62 reported the palladium-catalyzed intramolecular oxidative diamination of alkenes (118) (Figure 56). Cyclic ureas (119) were prepared through this strategy by using Pd(OAc)2 as the catalyst and PhI(OAc)2 as the oxidant at room temperature. A possible mechanism is proposed in Figure 57. An intermediary vicinal amino palladium compound (I) is formed under Pd(II) catalysis, and oxidation of I provides the target product regenerating Pd(II) catalyst.

Figure 56 Palladium-catalyzed intramolecular deamination.

Figure 57 Proposed mechanism for palladium-catalyzed intramolecular deamination.

Rhodium-catalyzed synthesis of N-heterocycles

Rhodium-catalyzed C-H amination is effective for the synthesis of N-heterocycles. In 2008, Stuart et al63 described the synthesis of indoles (122) via rhodium-catalyzed oxidative coupling from readily available acetanilides (120) and alkynes (121) (Figure 58). The protocol used [RhCp*Cl2]2 as the catalyst, AgSbF5 as the additive, copper acetate as the oxidant, and 2-methyl-2-butanol as the solvent. Various indoles were synthesized in moderate to good yields.

Figure 58 Rhodium-catalyzed synthesis of indoles.

In 2010, Morimoto et al64 reported the synthesis of indolo[2,1-a]isoquinoline derivatives (125) through the rhodium-catalyzed oxidative coupling of 2-phenylindoles (123) and alkynes (124) (Figure 59). The protocol used [RhCp*Cl2]2 as the catalyst and copper acetate as the oxidant in the presence of sodium carbonate under air. The corresponding polycyclic products (125) were obtained in good yields. The cascade reaction included an intermolecular C-N bond formation and intramolecular cyclization by C-C coupling. A possible mechanism is shown in Figure 60. Coordination of Cp*Rh(III)X2 with 123 gives a five-membered intermediate (I), addition of I to 124 provides II or III, and reductive elimination of II or III affords the target product (125) releasing Cp*Rh(I). Oxidation of Cp*Rh(I) by copper acetate and air regenerates Cp*Rh(III) catalyst.

Figure 59 Rhodium-catalyzed synthesis of indolo[1,2-a] isoquinolines.

Figure 60 Proposed mechanism for rhodium-catalyzed synthesis of indolo[1,2-a]isoquinolines.

In 2009, the same group reported a similar procedure for the synthesis of isoquinoline derivatives (128) through rhodium-catalyzed oxidative coupling from aromatic imines (126) and alkynes (127) (Figure 61).65 The reaction proceeded via cleavage of N-H bond and subsequent C-N/C-C bond formation.

Figure 61 Rhodium-catalyzed synthesis of isoquinolines.

In 2010, Hyster and Rovis66 reported the construction of isoquinolone derivatives (131) via C-H/N-H activation from benzamides (129) and alkynes (130) under catalysis of [RhCp*Cl2]2 (Figure 62). The cascade reactions could tolerate various functional groups, and the target products were obtained in moderate to good yields

Figure 62 Rhodium-catalyzed intramolecular isoquinolones.

In 2010, Guimond et al67 reported the rhodium(III)-catalyzed synthesis of isoquinolones (134) from N-methoxylamides (132) and alkynes (133) (Figure 63). The reaction provided 3,4-disubstituted isoquinolones in moderate to good yields. A postulated mechanism is shown in Figure 64. Treatment of 132 with Rh(III) leads to I through C-H cleavage, addition of I to 133 provides II, and desorption of Rh(III) catalyst affords the target product (134).

Figure 63 Rhodium-catalyzed synthesis of isoquinolones.

Figure 64 Proposed mechanism for rhodium-catalyzed synthesis of isoquinolones.

In 2013, Hyster et al68 reported the rhodium(III)-catalyzed synthesis of isoquinolones (137) from amides (135) and cyclopropenes (136) (Figure 65). The protocol used [RhCp*Cl2]2 as the catalyst, cesium acetate as the base, and methanol as the solvent. The sequential ring opening and cycloaddition provided the desired product in moderate to excellent yields.

Figure 65 Rhodium-catalyzed synthesis of isoquinolones.

Ruthenium-catalyzed synthesis of N-heterocycles

Ruthenium-catalyzed C-H amination is also used in the synthesis of N-heterocycles. In 2013, Li and Ackermann69 developed a novel and efficient Ru-catalyzed oxidative annulation of ketimines (138) with alkynes (139) to provide 1-methylene-1,2-dihydroisoquinolines (140) (Figure 66). In the reaction, carboxylate-assisted ruthenium(II) catalyst proved to be key for the synthesis of products in high yields with excellent chemo-, site-, and regioselectivities under an air atmosphere.

Figure 66 Ruthenium-catalyzed annulation of ketimines and alkynes.

In 2012, Li et al70 developed a ruthenium-catalyzed oxidative C-H bond olefination for the synthesis of 3,4-dihydroisoquinolinone derivatives (143) from readily available N-methoxybenzamides (141) and styrenes (142) (Figure 67). The corresponding products were obtained in good yields with a broad substrate scope. A proposed mechanism is shown in Figure 68. Treatment of 141 with Ru catalyst provides I, addition of I to 142 leads to II, and reductive elimination of II affords the target product (143).

Figure 67 Ruthenium-catalyzed synthesis of 3,4-dihydroisoquinolinoes.

Figure 68 Proposed mechanism for ruthenium-catalyzed synthesis of 3,4-dihydroisoquinolinoes.

In 2013, Reddy et al71 developed the ruthenium-catalyzed synthesis of isoquinolones (146) from readily available aromatic and heteroaromatic nitriles (144) and alkynes (145) (Figure 69). The protocol used 5 mol% [RuCl2(p-cymene)]2 as the catalyst, copper acetate as the oxidant, KPF6 as the additive, and acetic acid as the solvent. The procedure was useful and attractive for the preparation of biologically relevant isoquinolone derivatives. The proposed mechanism is shown in Figure 70. Treatment of nitriles with acetic acid in the presence of copper acetate gives arylamide (III). Coordination of III with [{RuCl2(p-cymene)}2] provides a Ru-N intermediate (IV) with extrusion of HOAc. Cycloaddition of IV to alkyne (145) forms seven-membered intermediate (V), and reductive elimination of V affords the target product (146).

Figure 69 Ruthenium-catalyzed synthesis of isoquinolones.

Figure 70 Proposed mechanism for ruthenium-catalyzed synthesis of isoquinolones.

Ackermann et al72 developed the ruthenium-catalyzed synthesis of 2-pyridone derivatives (149) via the oxidative cyclization of acrylamides (147) with alkynes (148) (Figure 71). The reaction displays a notable chemo- and regioselectivity.

Figure 71 Ruthenium-catalyzed synthesis of 2-pyridones.

In 2012, the same group reported an example of ruthenium-catalyzed oxidative annulation to synthesis of indoles (152) from anilines (150) and alkynes (151) (Figure 72).73 The reaction was performed by using N-2-pymidyl as the directing group.

Figure 72 Ruthenium-catalyzed synthesis of indoles.

Nickel-catalyzed synthesis of N-heterocycles

Nickel-catalyzed N-heterocycles are found via C-H amination. In 2010, Liu et al74 reported the synthesis of isoquinolone derivatives (155) via nickel-catalyzed annulation using 2-halobenzamides (153) and alkynes (154) as the substrates (Figure 73). A possible mechanism is shown in Figure 74. Ni(II) is reduced to Ni(0) by zinc, and oxidative addition of Ni(0) by 153 gives five-membered Ni(II) intermediate (I). Subsequently, cycloaddition of I to 154 provides II or III, and reductive elimination of II or III gets the target product (155). Furthermore, the present method was successfully used in the total synthesis of oxyavicine (160) (Figure 75).

Figure 73 Nickel-catalyzed synthesis of isoquinolone derivatives.

Figure 74 Proposed mechanism for the nickel-catalyzed synthesis of isoquinolone derivatives.

Figure 75 Total synthesis of oxyavicine.

Conclusion

In this review, copper, iron, palladium, rhodium, ruthedium, and nickel-catalyzed C-H amination leading to N-heterocycles have been summarized. The methods show high efficiency, economy, and practicability. It should be noted that the examples for other transition metal–catalyzed construction of N-heterocycles through this strategy are existing, and any omissions on this wide topic are unintentional. We believe that the application of transition metal–catalyzed C-H amination leading to N-heterocycles is still an active area of research, and more new methods for N-heterocyclic synthesis will be discovered in the future.

Acknowledgments

The authors thank the National Natural Science Foundation of China (grant nos 21172128, 21372139, and 21221062) and the Ministry of Science and Technology of China (grant no 2012CB722605) for financial support.

Disclosure

The authors report no conflicts of interest in this work.


References

1.

DeSimone RW, Currie KS, Mitchell SA, Darrow JW, Pippin DA. Privileged Structures: applications in drug discovery. Comb Chem High Throughput Screen. 2004;7(5):473–493.

2.

Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medical chemistry. Nat Rev Drug Discov. 2007;6(11):881–890.

3.

Jia CG, Kitamura T, Fujiwara Y. Catalytic functionalization of arenes and alkanes via C-H bond activation. Acc Chem Res. 2001;34(8):633–639.

4.

Hassan J, Sevignon M, Gozzi C, Schulz E, Lemaire M. Aryl-aryl bond formation one century after the discovery of the Ullman reaction. Chem Rev. 2002;102(5):1359–1470.

5.

Davies HML, Beckwith REJ. Catalytic enantioseletive C-H activation by means of metal-carbenoid induced C-H insertion. Chem Rev. 2003;103(8):2861–2904.

6.

Alberico D, Scott ME, Lautens M. Aryl-aryl bond formation by transition-metal-catalyzed direct arylation. Chem Rev. 2007;107(1):174–238.

7.

Seregin IV, Gevorgyan V. Direct transition metal-catalyzed functionalization of heteroaromatic compounds. Chem Soc Rev. 2007;36(7):1173–1193.

8.

Park YJ, Park JW, Jun CH. Metal-organic cooperative catalysis in C-H and C-C bond activation and its concurrent recovery. Acc Chem Res. 2008;41(2):222–224.

9.

Lewis JC, Bergman RG, Ellman JA. Direct functionalization of nitrogen heterocycles via Rh-catalyzed C-H bond activation. Acc Chem Res. 2008;41(8):1031–1025.

10.

Daugulis O, Do HQ, Shabashov D. Palladium- and copper-catalyzed arylation of carbon-hydrogen bonds. Acc Chem Res. 2009;42(8):1074–1086.

11.

Lyons TW, Sanford MS. Palladium-catalyzed ligand-directed C-H functionalization reactions. Chem Rev. 2010;110(2):1147–1169.

12.

Collet F, Dodd RH, Dauban P. Catalytic C-H amination: recent progress and future directions. Chem Commun (Camb). 2009;(34):5061–5074.

13.

Thomas A, Ramirez TA, Zhao B, Shi Y. Recent advances in transition metal-catalyzed sp3 C-H amination adjacent to double bonds and carbonyl groups. Chem Soc Rev. 2012;41(2):931–942.

14.

Dauban P, Dodd RH. In Amino Group Chemistry. Ricci A Ed. Wiley-VCH: Weinheim, Germany, 2008:55–92.

15.

Collet F, Lescot C, Dauban P. Catalytic C-H amination: the stereoselectivity issue. Chem Soc Rev. 2011;40(4):1926–1936.

16.

Brasche G, Buchwald SL. C-H functionalization/C-N bond formation: copper-catalyzed synthesis of benzimidazoles from amidines. Angew Chem Int Ed. 2008;47(10):1932–1934.

17.

Sheng J, Chao B, Chen H, Hu Y. Synthesis of chromeno-[2,3-d]imidazol-9(1H)-ones via tandem reactions of 3-iodochromones with amidines involving copper-catalyzed C-H functionalization and C-O bond formation. Org Lett. 2013;15(17):4508–4511.

18.

Cho SH, Yoon J, Chang S. Intramolecular oxidative C-N bond formation for the synthesis of carbazoles: comparison of reactivity between the copper-catalyzed and metal-free conditions. J Am Chem Soc. 2011;133(15):5996–6005.

19.

Takamatsu K, Hirano K, Satoh T, Miura M. Synthesis of carbazoles by copper-catalyzed intramolecular C-H/N-H coupling. Org Lett. 2014;16(11):2892–2895.

20.

Zhou W, Liu Y, Yang Y, Deng GJ. Copper-catalyzed intramolecular direct amination of sp2 C-H bonds for the synthesis of N-aryl acridones. Chem Commun (Camb). 2012;48(86):10678–10680.

21.

Li XW, He L, Chen HJ, Wu WQ, Jiang HF. Copper- catalyzed aerobic C(sp2)-H functionalization for C-N bond formation: synthesis of pyrazoles and indazoles. J Org Chem. 2013;78(8):3636–3646.

22.

Berrino R, Cacchi S, Fabrizi G, Goggiamani A. 4-Aryl-2-quinolones from 3,3-diarylacrylamides through intramolecular copper-catalyzed C-H functionalization/C-N bond formation. J Org Chem. 2012;77(5):2537–2542.

23.

Gui QW, Yang ZY, Chen X, et al. Synthesis of phenanthridin-6(5H)-ones via copper-catalyzed cyclization of 2-phenylbenzamides. Synlett. 2013;24(8):1016–1020.

24.

Chary RG, Dhananjaya G, Prasad KV, et al. A simple access to N-(un)substituted isoquinolin-1(2H)-ones: unusual formation of regioisomeric isoquinolin-1(4H)-ones. Chem Commun (Camb). 2014;50(51);6797–6800.

25.

Wang XQ, Jin YH, Zhao YF, Zhu L, Fu H. Copper-catalyzed aerobic oxidative intramolecular C-H amination leading to imidazobenzimidazole derivatives. Org Lett. 2012;14(2):452–455.

26.

Xu H, Fu H. Copper-catalyzed one-pot synthesis of imidazo/benzoimidazoquinazolinones by sequential Ullmann-type coupling and intramolecular C-H amidation. Chem. Eur. J. 2012;18(4):1180–1186.

27.

Chen DB, Chen QF, Liu MC, et al. Cascade synthesis of azoquinazolinones by Cu(I)- catalyzed C-N coupling/C-H activation/C-N formation reactions under O2. Tetrahedron. 2013;69(31):6461–6467.

28.

Wang HG, Wang Y, Liang DD, Liu LY, Zhang JC, Zhu Q. Copper-catalyzed intramolecular dehydrogenative amino- oxygenation: direct access to formyl-substituted aromatic N-heterocycles. Angew Chem Int Ed. 2011;50(25):5678–5681.

29.

Zeng W, Chemler SR. Copper(II)-catalyzed enantioselective intramolecular carboamination of alkenes. J Am Chem Soc. 2007;129(43):12948–12949.

30.

Sherman ES, Chemler SR. Copper(II)-catalyzed aminooxygenation and carboamination of N-aryl-2-llyl- anilines. Adv Synth Catal. 2009;351(3):467–471.

31.

Miao L, Haque I, Manzoni MR, Tham WS, Chemler SR. Diastereo- and enantioselective copper-catalyzed intramolecular carboamination of alkenes for the synthesis of hexahydro-1H-benz[f]indoles. Org Lett. 2010;12(21):4739–4741.

32.

Lu JY, Jin YB, Liu HX, Jiang YY, Fu H. Copper-catalyzed aerobic oxidative intramolecular alkene C-H amination leading to N-heterocycles. Org Lett. 2011;13(14):3694–3697.

33.

Li JH, Neuville L. Copper-catalyzed oxidative diamination of terminal alkynes by amidines: synthesis of 1,2,4-trisubstituted imidazoles. Org Lett. 2013;15(7):1752–1755.

34.

Huang PC, Gandeepan P, Cheng CH. Cu(I)-catalyzed intramolecular oxidative C-H amination of 2-aminoacetophenones: a convenient route toward isatins. Chem Commun. 2013;49(76):8540–8542.

35.

Chen H, Sanjaya S, Wang YF, Chiba S. Copper-catalyzed aliphatic C-H amination with an amidine moiety. Org Lett. 2013;15(1):212–215.

36.

Wang Z, Ni JZ, Kuninobu Y, Kanai M. Copper-catalyzed intramolecular C(sp3)-H and C(sp2)-H amidation by oxidative cyclization. Angew Chem Int Ed. 2014;53(13):3496–3499.

37.

Wu XS, Zhao Y, Zhang GW, Ge HB. Copper-catalyzed site-selective intramolecular amidation of unactivated C(sp3)-H bonds. Angew Chem Int Ed. 2014;53(14):3706–3710.

38.

Zhang TS, Bao WL. Synthesis of 1H-Indazoles and 1H-Pyrazoles via FeBr3/O2 mediated intramolecular C-H amination. J Org Chem. 2013;78(3):1317–1322.

39.

Fan J, Gao L, Wang Z. Facile construction of highly functionalized 2-pyrrolines via FeCl3-catalyzed reaction of aziridines with arylalkynes. Chem Commun. 2009;(33):5021–5023.

40.

Sun B, Ma Q, Wang Y, Zhao Y, Liao P, Bi X. Iron-catalyzed [4C +1N] cyclization of 4-acetylenic ketones with primary amines: synthesis of 5-(aryl)alkylidene-4,5-dihydropyrroles. Eur J Org Chem. 2014;2014(34):7552–7555.

41.

Liu Y, Chen GQ, Tse CW, et al. [Fe(F20TPP)Cl]-catalyzed amination with arylamines and {[Fe(F20TPP)(NAr)](PhI=NAr)}+. Intermediate assessed by high resolution ESI-MS and DFT calculations. Chem Asian J. 2015;10(1):100–105.

42.

Karthikeyan I, Sekar G. Iron-catalyzed C-H Bond functionalization for the exclusive synthesis of pyrido[1,2- a]indoles or triarylmethanols. Eur J Org Chem. 2014;2014(36):8055–8063.

43.

Shen MH, Driver TG. Iron(II) bromide-catalyzed synthesis of benzimidazoles from aryl azides. Org Lett. 2008;10(15):3367–3370.

44.

Bonnamour J, Bolm C. Iron(II) triflate as a catalyst for the synthesis of indoles by intramolecular C-H amination. Org Lett. 2011;13(8):2012–2014.

45.

Jana S, Clements MD, Sharp BK, Zheng N. Fe(II)-catalyzed amination of aromatic C-H bonds via ring opening of 2H-azirines: synthesis of 2,3-disubstituted indoles. Org Lett. 2010;12(17):3736–3739.

46.

Hennessy ET, Betley TA. Complex N-heterocycle synthesis via iron-catalyzed, direct C-H bond amination. Science. 2013;340(6132):591–595.

47.

Nguyen Q, Nguyen T, Driver TG. Iron(II) bromide-catalyzed intramolecular C-H bond amination [1,2]-shift tandem reactions of aryl azides. J Am Chem Soc. 2013;135(2):620–623.

48.

Liu YG, Guan XG, Wong ELM, Liu P, Huang JS, Che CM. Nonheme iron-mediated amination of C(sp3)-H bonds. Quinquepyridine-supported iron-imide/nitrene intermediates by experimental studies and DFT calculations. J Am Chem Soc. 2013;135(19):7194–7204.

49.

Tsang WCP, Munday RH, Brasche G, Zheng N, Buchwald SL. Palladium-catalyzed method for the synthesis of carbazoles via tandem C-H functionalization and C-N bond formation. J Org Chem. 2008;73(19):7603–7610.

50.

Jordan-Hore JA, Johansson CCC, Gulias M, Beck EM, Guant MJ. Oxidative Pd(II)-catalyzed C-H bond amination to carbazole at ambient temperature. J Am Chem Soc. 2008;130(48):16184–16186.

51.

Youn SW, Bihn JH, Kim BS. Pd-catalyzed intramolecular oxidative C-H amination: synthesis of carbazoles. Org Lett. 2011;13(14):3738–3741.

52.

Yang G, Zhang W. Regioselective Pd-catalyzed aerobic Aza-Wacker cyclization for preparation of isoindolinones and isoquinolin-1(2H)-ones. Org Lett. 2012;14(1):268–271.

53.

Shi Z, Cui Y, Jiao N. Synthesis of β- and γ-carbolinones via Pd-catalyzed direct dehydrogenative annulation (DDA) of indole-carboxamides with alkynes using air as the oxidant. Org Lett. 2010; 12(13):2908–2911.

54.

Zhang N, Li B, Zhong H, Huang J. Synthesis of N-alkyl and N-aryl isoquinolones and derivatives via Pd-catalysed C-H activation and cyclization reaction. Org Biomol Chem. 2012;10(47):9429–9439.

55.

Halland N, Nazaré M, R’kyek O, Alonso J, Urmann M, Lindenschmidt A. A general and mild palladium-catalyzed domino reaction for the synthesis of 2H-indazoles. Angew Chem Int Ed. 2009;48(37):6879–6882.

56.

Zhang Z, Zhang J, Tan J, Wang Z. A facile access to pyrroles from amino acids via an Aza-Wacker cyclization. J Org Chem. 2008;73(13):5180–5182.

57.

Majumdar KC, Samanta S, Nandi RK, Chattopadhyay B. Palladium-catalyzed regioselective oxidative amination of alkenes: an efficient route to the synthesis of pyrrolocoumarin and pyrroloquinolone derivatives. Tetrahedron Lett. 2010;51(29):3807–3800.

58.

Kip KT, Zhu NY, Yang D. Palladium-catalyzed highly diastereoselective oxidative cascade cyclization reactions. Org Lett. 2009;11(9):1911–1914.

59.

Jaegli S, Dufour J, Wei HL, et al. Palladium-catalyzed carbo-heterofunctionalization of alkenes for the synthesis of oxindoles and spirooxindoles. Org Lett. 2010;12(20):4498–4501.

60.

Jeong EJ, Youn SW. Pd(II)-Catalyzed C-H amination for N-heterocyclic synthesis. Bull Korean Chem Soc. 2014;35(9):2611–2612.

61.

Wasa M, Yu JQ. Synthesis of β-, γ-, and δ-lactams via Pd(II)-catalyzed C-H activation reactions. J Am Chem Soc. 2008;130(43):14058–114059.

62.

Streuff J, Hövelmann CH, Nieger M, Muñiz K. Palladium(II)-catalyzed intramolecular diamination of unfunctionalized alkenes. J Am Chem Soc. 2005;127(42):14586–14587.

63.

Stuart DR, Bertran-Laperle M, Burgess KMN, Fagnou K. Indole synthesis via rhodium catalyzed oxidative coupling of acetanilides and internal alkynes. J Am Chem Soc. 2008;130(49):16474–16475.

64.

Morimoto K, Hirano K, Satoh T, Miura M. Rhodium-catalyzed oxidative coupling/cyclization of 2-phenylindoles with alkynes via C-H and N-H bond cleavages with air as the oxidant. Org Lett. 2010;12(9):2068–2071.

65.

Fukutani T, Umeda N, Hirano K, Satoh T, Miura M. Rhodium-catalyzed oxidative coupling of aromatic imines with internal alkynes via regioselective C-H bond cleavage. Chem Commun. 2009;(34):5141–5143.

66.

Hyster T, Rovis T. Rhodium-catalyzed oxidative cycloaddition of benzamides and alkynes via C-H/N-H activation. J Am Chem Soc. 2010;132(30):10565–10569.

67.

Guimond N, Gouliaras C, Fagnou K. Rhodium(III)-catalyzed isoquinolone synthesis: the N-O bond as a handle for C-N bond formation and catalyst turnover. J Am Chem Soc. 2010;132(20):6908–6909.

68.

Hyster TK, Rovis T. Rhodium(III)-catalyzed C-H activation mediated synthesis of isoquinolones from amides and cyclopropenes. Synlett. 2013;24(14):1842–1844.

69.

Li J, Ackermann L. Ruthenium- catalyzed oxidative alkyne annulation by C-H activation on ketimines. Tetrahedron. 2014;70(20):3342–3348.

70.

Li B, Ma J, Wang N, Feng H, Xu S, Wang B. Ruthenium-catalyzed oxidative C-H bond olefination of N-methoxybenzamides using an oxidizing directing group. Org Lett. 2012;14(3):736–739.

71.

Reddy MC, Manikandan R, Jeganmohan M. Ruthenium-catalyzed aerobic oxidative cyclization of aromatic and heteroaromatic nitriles with alkynes: a new route to isoquinolones. Chem Commun. 2013;49(54):6060–6062.

72.

Ackermann L, Lygin AV, Hofmann N. Ruthenium-catalyzed oxidative synthesis of 2-pyridones through C-H/N-H bond functionalizations. Org Lett. 2011;13(12):3278–3281.

73.

Ackermann L, Lygin AV. Cationic ruthenium(II) catalysts for oxidative C-H/N-H bond functionalizations of anilines with removable directing group: synthesis of in doles in water. Org Lett. 2012;14(3):764–767.

74.

Liu CC, Parthasarathy K, Cheng CH. Synthesis of highly substituted isoquinolone derivatives by nickel-catalyzed annulation of 2-halobenzamides with alkynes. Org Lett. 2010;12(15):3518–3521.

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