Synthesis of (2 H)-Indazoles through Rh (III)-Catalyzed Annulation

Mar 16, 2018 - *E-mail: [email protected]., *E-mail: [email protected]. ... This protocol leads to the efficient formation of 3-acyl (2H)-indazoles with...
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Cite This: J. Org. Chem. 2018, 83, 4070−4077

Synthesis of (2H)‑Indazoles through Rh(III)-Catalyzed Annulation Reaction of Azobenzenes with Sulfoxonium Ylides Hyunjung Oh,† Sangil Han,† Ashok Kumar Pandey, Sang Hoon Han, Neeraj Kumar Mishra, Saegun Kim, Rina Chun, Hyung Sik Kim, Jihye Park,* and In Su Kim* School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea S Supporting Information *

ABSTRACT: The rhodium(III)-catalyzed C−H functionalization followed by intramolecular annulation reactions between azobenzenes and sulfoxonium ylides is described. This protocol leads to the efficient formation of 3-acyl (2H)indazoles with a range of substrate scope. A high level of chemoselectivity and functional group tolerance of this transformation were also observed.

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INTRODUCTION Azobenzene derivatives have been used for surface-modified materials, polymers, protein probes, and chemosensors.1 Therefore, the development of various synthetic transformations of azobenzenes has been recognized as one of the important tasks in organic chemistry.2 With advances in catalytic C−H functionalization, great effort has been devoted to the construction of various azobenzene derivatives.3 Particularly, the formation of N-heterocycles has been intensively disclosed through sp2 C−H functionalization of azobenzenes followed by intramolecular C−N bond formation. In this context, indazoles, cinnolines, cinnolinones, benzotriazoles, indoles, and oxindoles have been synthesized under Pd, Re, Rh, and Co catalysis.4 For example, Ellman described the beautiful works on the formation of (2H)-indazoles derived from azobenzenes and aldehydes under Rh(III) catalysis.4a In addition, our group also demonstrated the Rh(III)-catalyzed direct synthesis of (2H)indazoles4b and oxindoles4c using azobenzenes. As a fascinating motif widely found in numerous bioactive compounds, 3-acyl indazoles have recently showed their great potential in pharmaceuticals with a broad spectrum of medicinal applications. Remarkably, a broad range of pharmacological profiles such as anti-inflammatory, viral polymerase inhibition, antiemetic, and anticancer activities has been reported (Figure 1).5 Sulfur ylides have been known as versatile precursors to ̈ and Li deliver metal−carbene complexes.6 Recently, Aissa independently reported the Rh(III)-catalyzed C−H alkylations of aromatic compounds with sulfoxonium ylides.7 In addition, Li and co-workers described the unique function of sulfoxonium ylides as a traceless bifunctional directing group for the formation of 1-naphthols.8 Very recently, Li et al. also disclosed the facile synthesis of isocoumarins/isoquinolones9 and 1,2-benzothiazines/2-arylimidazo[1,2-a]pyridines10 via the Rh(III)-catalyzed sp2 C−H functionalization and subsequent annulations. In previous reports for the formation of hetero© 2018 American Chemical Society

Figure 1. Selected bioactive 3-acyl indazoles.

cycles,9,10 carbonyl groups of sulfoxonium ylides were involved in annulation reactions with nucleophilic directing groups. It should be noted that the annulation reaction between electrophilic directing groups and methylene moiety on sulfoxonium ylides has been unexplored. In continuation of our recent studies on the Rh(III)-catalyzed synthesis of various heterocycles via C−H functionalization,11 we herein present the rhodium(III)-catalyzed C−H alkylation followed by intramolecular cyclization between azobenzenes and sulfoxonium ylides affording 3-acyl (2H)-indazoles. Additionally, the formation of (1H)-indazoles through the base-mediated annulations reaction of alkylated intermediates was demonstrated to prove the cyclization mode of this process (Scheme 1).

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RESULTS AND DISCUSSION Initially, we found that a cationic Rh(III) catalyst in the presence of Cu(OAc)2 (100 mol %) can promote the coupling Received: February 22, 2018 Published: March 16, 2018 4070

DOI: 10.1021/acs.joc.8b00501 J. Org. Chem. 2018, 83, 4070−4077

Article

The Journal of Organic Chemistry

condition in this coupling reaction to give 3-acyl (2H)-indazole 3a in 85% yield (Table 1, entries 10−15). Finally, the formation of 3a was highly dependent on the reaction temperature (Table 1, entry 16). With the optimal reaction conditions in hand, the substrate scope and limitation of this transformation were investigated, as shown in Scheme 2. In the case of electron-rich para-

Scheme 1. Sulfoxonium Ylides in C−H Functionalization

Scheme 2. Scope of Symmetrical Azobenzenesa

between azobenzene (1a) and sulfoxonium ylide 2a at 110 °C to afford our desired indazole 3a in 52% yield (Table 1, entries Table 1. Selected Optimization for Reaction Conditionsa

a

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16c

additive (mol %) Cu(OAc)2 (100) Cu(OAc)2 (50) Cu(OAc)2 (30) KOAc (50) AgOAc (50) Cu(OAc)2 (50) Cu(OAc)2 (50) Cu(OAc)2 (50) Cu(OAc)2 (50), AcOH (100) Cu(OAc)2 (50), Li2CO3 (100) Cu(OAc)2 (50), K2S2O8 (100) Cu(OAc)2 (50), CuCO3·Cu(OH)2 (100) Cu(OAc)2 (50), CuCO3·Cu(OH)2 (50) CuCO3·Cu(OH)2 (100) Cu(OAc)2 (50), CuCO3·Cu(OH)2 (100)

solvent

yield (3a/3aa, %)b

DCE DCE DCE DCE DCE DCE MeCN THF toluene DCE DCE DCE DCE

4/20 52/trace 50/7 42/12 7/12 17/15 17/trace 38/trace 28/10 58/7 64/trace 63/trace 85/trace

DCE

69/trace

DCE DCE

50/12 14/trace

Reaction conditions: 1a−1n (0.2 mmol), 2a (0.4 mmol), [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (50 mol %), CuCO3·Cu(OH)2 (100 mol %), and DCE (1 mL) at 110 °C for 24 h under air in reaction tubes. bIsolated yield by flash column chromatography.

substituted azobenzenes 1b and 1c, high yields of indazole adducts 3b and 3c were obtained. However, electron-deficient azobenzene 1d was coupled with 2a to provide indazole 3d in a moderate yield. In addition, electron-rich meta- and orthosubstituted azobenzenes 1e, 1f, and 1i−1k were successfully reacted with 2a, providing the corresponding products in good to high yields. However, electron-deficient meta-substituted azobenzenes 1g and 1h were found to be relatively less reactive for the formation of indazole products 3g and 3h. Moreover, disubstituted azobenzenes 1l and 1m were also compatible to afford 3l (65%) and 3m (77%), respectively. However, sterically congested disubstituted azobenzene 1n did not undergo the coupling reaction to deliver the corresponding 3acyl (2H)-indazole 3n. Additionally, in the case of unsymmetrical azobenzenes 1o− 1q, the reactions can predominantly occur at the C−H bonds on the electron-rich aromatic ring to provide the corresponding indazoles (3ob, 3pa, and 3qa) as major products (Scheme 3). Meanwhile, we investigated the steric effect on azobenzenes, and single products 3r and 3s were obtained in 93% and 58% yields, respectively. It should be mentioned that the steric environment of azobenzene is also highly important to control the regioselectivity of this transformation. Furthermore, the electronic and steric effects of this process was also observed by using unsymmetrical azobenzene 1t affording a mixture of 3acyl (2H)-indazoles 3ta and 3tb in 60% combined yield with a 1:1.7 ratio. To further explore the scope of this transformation, a wide range of sulfoxonium ylides 2b−2v were screened to couple with azobenzene 1b, as shown in Scheme 4. With electron-rich or electron-deficient groups on the aromatic ring of

a

Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [RhCp*Cl2]2 (2.5 mol %), additive (quantity noted), and solvent (1 mL) at 110 °C for 24 h under air in reaction tubes. bIsolated yield by flash column chromatography. cThe reaction was carried out at 60 °C.

1 and 2). This reaction was also comparable with 50 mol % of Cu(OAc)2 additive (Table 1, entries 3 and 4). Screening of acetate such as KOAc and AgOAc did not provide the coupling products in a satisfactory yield (Table 1, entries 5 and 6). Subsequently, we evaluated the effect of the solvent under otherwise identical reaction conditions, and the DCE solvent proved to be superior to other solvents such as MeCN, THF, and toluene (Table 1, entries 7−9). Surprisingly, the combination of Cu(OAc)2 (50 mol %) and CuCO3·Cu(OH)2 (100 mol %) as coadditives was found to be an optimal reaction 4071

DOI: 10.1021/acs.joc.8b00501 J. Org. Chem. 2018, 83, 4070−4077

Article

The Journal of Organic Chemistry Scheme 4. Scope of Sulfoxonium Ylidesa

Scheme 3. Scope of Unsymmetrical Azobenzenes

a

Reaction conditions: 1b (0.2 mmol), 2b−2v (0.4 mmol), [RhCp*Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (50 mol %), CuCO3·Cu(OH)2 (100 mol %), and DCE (1 mL) at 110 °C for 24 h under air in reaction tubes. bIsolated yield by flash column chromatography.

Table 2. Mechanistic Study for Annulation Process sulfoxonium ylide, the C−H functionalization followed by intramolecular annulation reactions underwent smoothly to afford the corresponding 3-acyl (2H)-indazoles 4b−4p in good to high yields. This transformation also showed a good tolerance toward sulfoxonium ylides 2q and 2r containing naphthyl and heterocyclic moieties, respectively. It should be noted that this reaction was not limited to aryl sulfoxonium ylides, and alkyl-substituted sulfoxonium ylides 2s−2v also participated in the annulation process to provide our desired products 4s−4v, albeit in a slightly decreased reactivity. To recognize the formation of 3-acyl (2H)-indazoles in this transformation, some control experiments were performed, as shown in Table 2. Treatment of 3aa with Cu additives such as Cu(OAc)2 or CuCO3·Cu(OH)2 in air conditions provided indazole 3a in 56% and 57% yields, respectively (Table 2, entries 1 and 2). In addition, exchanging of Cu additive to KOAc was also found to give the annulated indazole product 3a in 65% yield (Table 2, entry 3). Surprisingly, a trace amount of 3a was observed with KOAc under an argon atmosphere (Table 2, entry 4). Additionally, treatment of 3aa with Cu(OAc)2 under an argon atmosphere provided 3a in 28% yield (Table 2, entry 5). These results can be rationalized by the base-mediated intramolecular cyclization of ortho-alkylated azobenzene 3aa delivering the corresponding 1,3-dihydroindazole intermediate, which might be subsequently oxidized by either molecular oxygen or Cu(II) additives to furnish (2H)-indazole 3a.12 To gain mechanistic insight of this reaction, the reversibility of the reaction and kinetic isotope effect (KIE) experiments was explored, as shown in Scheme 5. The deuterium-labeling experiments of azobenzene 1b using CD3OD was performed

entry

reaction conditions

yield (%)

1 2 3 4 5

Cu(OAc)2 (50 mol %), DCE, 110 °C, 24 h, air CuCO3·Cu(OH)2 (100 mol %), DCE, 110 °C, 24 h, air KOAc (100 mol %), DCE, 110 °C, 24 h, air KOAc (100 mol %), DCE, 110 °C, 24 h, argon Cu(OAc)2 (50 mol %), DCE, 110 °C, 24 h, argon

56 57 65 nr 28

Scheme 5. Mechanistic Investigation

(Scheme 5, eq 1). Remarkably, incorporation (81% D) at each of the ortho-positions on 1b was observed, which is indicative of the reversible rhodation−proto(deuterio)derhodation process. Next, a study of KIE’s was carried out for the reaction of 1b and 4072

DOI: 10.1021/acs.joc.8b00501 J. Org. Chem. 2018, 83, 4070−4077

Article

The Journal of Organic Chemistry

0.1 mmol, 50 mol %), CuCO3·Cu(OH)2 (44.2 mg, 0.2 mmol, 100 mol %), and sulfoxonium ylide 2a (78.5 mg, 0.4 mmol, 200 mol %) were added AgSbF6 (6.9 mg, 0.02 mmol, 10 mol %) and DCE (1 mL) under air at room temperature. The reaction mixture was allowed to stir at 110 °C for 24 h and cooled to room temperature. The reaction mixture was diluted with EtOAc (3 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/ EtOAc = 30:1) to afford 50.8 mg of 3a in 85% yield. Phenyl(2-phenyl-2H-indazol-3-yl)methanone (3a): 50.8 mg (85%); yellow solid; mp = 162.8−164.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.91−7.87 (m, 3H), 7.63−7.59 (m, 1H), 7.56−7.54 (m, 2H), 7.49−7.37 (m, 7H), 7.21−7.17 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.0, 148.6, 140.5, 137.8, 133.6, 132.3, 129.9, 129.1, 128.9, 128.6, 127.0, 125.5, 125.0, 124.1, 120.6, 118.6; IR (KBr) υ 1644 cm−1; HRMS (quadrupole, EI) calcd for C20H14N2O [M]+ 298.1106, found 298.1105. (E)-1-Phenyl-2-(2-(phenyldiazenyl)phenyl)ethan-1-one (3aa): 12.1 mg (20%); orange solid; mp = 111.2−113.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.07−8.05 (m, 2H), 7.79−7.73 (m, 3H), 7.57− 7.54 (m, 1H), 7.45−7.37 (m, 8H), 4.82 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 197.9, 152.8, 149.8, 136.9, 135.5, 133.0, 131.5, 131.3, 131.0, 129.0, 128.6, 128.4, 127.9, 123.0, 116.1, 41.3; IR (KBr) υ 1686 cm−1; HRMS (quadrupole, EI) calcd for C20H16N2O [M]+ 300.1263, found 300.1261. (5-Methyl-2-(p-tolyl)-2H-indazol-3-yl)(phenyl)methanone (3b): 60.7 mg (93%); yellow solid; mp = 143.7−145.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.6 Hz, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.23−7.19 (m, 3H), 7.11 (s, 1H), 2.37 (s, 3H), 2.36 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 186.1, 147.5, 138.8, 138.2, 137.9, 134.8, 133.4, 131.4, 129.9, 129.8, 129.6, 128.6, 125.2, 124.4, 118.6, 118.1, 22.1, 21.2; IR (KBr) υ 1644 cm−1; HRMS (quadrupole, EI) calcd for C22H18N2O [M]+ 326.1419, found 326.1418. (5-Ethyl-2-(4-ethylphenyl)-2H-indazol-3-yl)(phenyl)methanone (3c): 57.5 mg (81%); yellow solid; mp = 124.8−126.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.87−7.84 (m, 2H), 7.80 (d, J = 9.2 Hz, 1H), 7.61−7.56 (m, 1H), 7.46−7.40 (m, 4H), 7.27−7.21 (m, 3H), 7.14 (s, 1H), 2.69−2.63 (m, 4H), 1.24−1.18 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.2, 147.7, 145.1, 141.2, 138.3, 138.0, 133.3, 131.6, 129.9, 128.9, 128.5, 128.4, 125.3, 124.5, 118.3, 117.5. 29.3, 28.5, 15.4, 15.3; IR (KBr) υ 1646 cm−1; HRMS (quadrupole, EI) calcd for C24H22N2O [M]+ 354.1732, found 354.1734. Ethyl 3-Benzoyl-2-(4-(ethoxycarbonyl)phenyl)-2H-indazole-5carboxylate (3d): 39.2 mg (44%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.11 (d, J = 8.8 Hz, 2H), 8.04−8.01 (m, 1H), 7.89 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.66−7.62 (m, 3H), 7.48 (t, J = 7.6 Hz, 2H), 4.42−4.32 (m, 4H), 1.41−1.34 (m, 6H); 13 C{1H} NMR (100 MHz, CDCl3) δ 185.6, 166.2, 165.4, 149.9, 143.4, 137.1, 134.4, 134.3, 131.1, 130.6, 130.0, 128.9, 127.4, 127.3, 125.2, 124.7, 123.4, 118.4, 61.4, 61.2, 14.3, 14.2; IR (KBr) υ 1711, 1651, 1270, 1098 cm−1; HRMS (quadrupole, EI) calcd for C26H22N2O5 [M]+ 442.1529, found 442.1532. (6-Methoxy-2-(3-methoxyphenyl)-2H-indazol-3-yl)(phenyl)methanone (3e): 46.2 mg (64%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.86−7.84 (m, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 7.29−7.24 (m, 2H), 7.12−7.09 (m, 2H), 7.04−7.02 (m, 1H), 6.91−6.86 (m, 2H), 3.90 (s, 3H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.1, 160.0, 159.3, 149.6, 141.4, 137.7, 133.6, 132.4, 129.8, 129.7, 128.6, 121.3, 120.1, 119.9, 117.7, 114.8, 110.9, 95.0, 55.5, 55.4; IR (KBr) υ 1649, 1224, 1024 cm−1; HRMS (quadrupole, EI) calcd for C22H18N2O3 [M]+ 358.1317, found 358.1317. (6-Methyl-2-(m-tolyl)-2H-indazol-3-yl)(phenyl)methanone (3f): 59.6 mg (91%); yellow solid; mp = 136.8−138.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.90−7.87 (m, 2H), 7.65−7.60 (m, 2H), 7.50−7.46 (m, 2H), 7.41 (s, 1H), 7.30−7.27 (m, 3H), 7.22−7.20 (m, 1H), 7.04 (dd, J = 8.4, 1.2 Hz, 1H), 2.50 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.0, 149.1, 140.5, 139.2, 137.9, 137.0, 133.4, 132.1, 129.8, 129.6, 128.8, 128.6, 127.9, 126.0, 122.6, 122.5, 120.1,

deuterio-1b with 2a under standard reaction conditions, which resulted in the observed kinetic isotope effect (kH/kD) value of 2.6 (Scheme 5, eq 2), thus indicating that the C−H bond cleavage might be involved in the rate-limiting step.13 Based on our mechanistic investigation and the precedent literatures on the C−H alkylation with sulfoxonium ylides,7,9,10 a plausible reaction mechanism for the formation of 3-acyl (2H)-indazoles is depicted in Scheme 6. Coordination of an azo Scheme 6. Plausible Reaction Mechanism

group of 1a to a cationic Rh(III) catalyst followed by C−H bond cleavage delivers a rhodacycle species I.14 Subsequent coordination of sulfoxonium ylide 2a affords a Rh(III)-alkyl intermediate II, which undergoes α-elimination of DMSO to afford a reactive α-oxo Rh-carbene species III.15 Migratory insertion takes place to give the six-membered rhodacycle IV, which then undergoes protonation furnishing the alkylated product 3aa. Next, the base-mediated intramolecular cyclization can generate a 1,3-dihydroindazole intermediate V,16 which is subsequently oxidized by either molecular oxygen or Cu(II) additives to furnish 3-acyl (2H)-indazole 3a.

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CONCLUSION In conclusion, we disclosed the rhodium(III)-catalyzed C−H alkylation followed by intramolecular annulation reactions between azobenzenes and sulfoxonium ylides, affording highly substituted indazoles. This protocol allows the generation of an array of C3-acylated (2H)-indazoles, which are known to be a crucial scaffold of bioactive molecules. Detailed mechanistic investigation and efforts to expand the utility of these coupling reactions are in progress.

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EXPERIMENTAL SECTION

General Procedure for the Annulation Reaction of Azobenzenes with Sulfoxonium Ylides. To an oven-dried sealed tube charged with azobenzene (1a) (36.4 mg, 0.2 mmol, 100 mol %), [RhCp*Cl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), Cu(OAc)2 (18.2 mg, 4073

DOI: 10.1021/acs.joc.8b00501 J. Org. Chem. 2018, 83, 4070−4077

Article

The Journal of Organic Chemistry 116.7, 22.1, 21.3; IR (KBr) υ 1648 cm−1; HRMS (quadrupole, EI) calcd for C22H18N2O [M]+ 326.1419, found 326.1418. (6-Bromo-2-(3-bromophenyl)-2H-indazol-3-yl)(phenyl)methanone (3g): 28.3 mg (31%); orange sticky oil; 1H NMR (700 MHz, CDCl3) δ 8.05 (dd, J = 2.1, 1.4 Hz, 1H), 7.84 (dd, J = 8.4, 1.4 Hz, 2H), 7.74 (t, J = 1.4 Hz, 1H), 7.65−7.63 (m, 1H), 7.54 (dq, J = 7.7, 0.7 Hz, 1H), 7.50−7.48 (m, 2H), 7.41 (dq, J = 8.4, 0.7 Hz, 1H), 7.29−7.24 (m, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 185.4, 149.2, 141.1, 137.4, 134.0, 132.8, 132.3, 130.3, 129.8, 129.1, 128.9, 128.6, 124.2, 122.6, 122.5, 122.0, 121.4, 120.9; IR (KBr) υ 1730, 1196 cm−1; HRMS (quadrupole, EI) calcd for C20H12Br2N2O [M]+ 453.9316, found 453.9314. (6-Nitro-2-(3-nitrophenyl)-2H-indazol-3-yl)(phenyl)methanone (3h): 19.4 mg (29%); orange solid; mp = 132.2−134.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.2 Hz, 2H), 7.68−7.62 (m, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.40−7.26 (m, 4H), 7.12 (td, J = 8.0, 1.6 Hz, 1H), 6.81 (dd, J = 10.8, 7.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.7, 162.6 (d, JC−F = 247.2 Hz), 154.9 (d, JC−F = 215.2 Hz), 150.5 (d, JC−F = 3.5 Hz), 141.0 (d, JC−F = 11.5 Hz), 137.3 (d, JC−F = 1.2 Hz), 134.3, 132.9 (d, JC−F = 5.9 Hz), 130.5 (d, JC−F = 8.9 Hz), 130.0, 128.7, 127.6 (d, JC−F = 7.0 Hz), 121.0 (d, JC−F = 3.4 Hz), 116.4 (d, JC−F = 21.4 Hz), 114.6 (d, JC−F = 4.9 Hz), 113.3, 113.0, 107.9 (d, JC−F = 18.1 Hz); IR (KBr) υ 1726, 1240 cm−1; HRMS (quadrupole, EI) calcd for C20H12N4O5 [M]+ 388.0808, found 388.0807. (7-Methoxy-2-(2-methoxyphenyl)-2H-indazol-3-yl)(phenyl)methanone (3i): 48.2 mg (67%); orange solid; mp = 102.6−105.2 °C; 1 H NMR (400 MHz, CDCl3) δ 7.88−7.86 (m, 2H), 7.77 (dd, J = 8.0, 1.6 Hz, 1H), 7.61−7.57 (m, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.38−7.33 (m, 1H), 7.11 (td, J = 7.6, 0.8 Hz, 1H), 7.04 (dd, J = 8.4, 7.6 Hz, 1H), 6.86−6.82 (m, 2H), 6.60 (d, J = 7.6 Hz, 1H), 4.04 (s, 3H), 3.47 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.8, 151.9, 150.8, 141.8, 137.6, 133.8, 133.0, 130.1, 130.0, 129.9, 128.3, 127.8, 125.3, 124.6, 121.1, 112.4, 111.5, 103.1, 55.6, 55.1; IR (KBr) υ 1649, 1260, 1021 cm−1; HRMS (quadrupole, EI) calcd for C22H18N2O3 [M]+ 358.1317, found 358.1318. (7-Methyl-2-(o-tolyl)-2H-indazol-3-yl)(phenyl)methanone (3j): 44.7 mg (68%); yellow solid; mp = 115.8−118.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.87−7.85 (m, 2H), 7.64−7.60 (m, 1H), 7.50−7.46 (m, 2H), 7.39−7.26 (m, 4H), 7.17−7.07 (m, 3H), 2.73 (s, 3H), 2.13 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.3, 148.7, 140.2, 138.0, 134.8, 133.5, 133.3, 130.8, 129.8, 129.5, 129.0, 128.5, 127.2, 126.4, 125.8, 125.3, 122.8, 118.1, 17.6, 17.1; IR (KBr) υ 1645 cm−1; HRMS (quadrupole, EI) calcd for C22H18N2O [M]+ 326.1419, found 326.1418. (7-Ethyl-2-(2-ethylphenyl)-2H-indazol-3-yl)(phenyl)methanone (3k): 46.8 mg (66%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.88−7.86 (m, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.50−7.38 (m, 4H), 7.34−7.26 (m, 2H), 7.19−7.10 (m, 3H), 3.17 (q, J = 7.6 Hz, 2H), 2.45 (q, J = 7.6 Hz, 2H), 1.43 (t, J = 7.6 Hz, 3H), 1.13 (t, J = 7.6 Hz, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 185.3, 147.9, 140.5, 139.7, 138.2, 135.1, 133.5, 133.2, 129.8, 129.7, 129.1, 128.5, 127.4, 126.2, 125.3, 123.8, 123.1, 118.1, 24.4, 24.1, 14.3, 14.2; IR (KBr) υ 1648 cm−1; HRMS (quadrupole, EI) calcd for C24H22N2O [M]+ 354.1732, found 354.1735. (2-(2,4-Dimethylphenyl)-5,7-dimethyl-2H-indazol-3-yl)(phenyl)methanone (3l): 46.2 mg (65%); yellow solid; mp = 149.1−149.9 °C; 1 H NMR (400 MHz, CDCl3) δ 7.87−7.84 (m, 2H), 7.63−7.59 (m, 1H), 7.47 (t, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.11 (br s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 7.00 (br s, 1H), 6.86 (br s, 1H), 2.68 (s, 3H), 2.36 (s, 3H), 2.32 (s, 3H), 2.07 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.4, 147.6, 139.3, 138.1, 137.9, 135.0, 134.4, 133.1, 132.8, 131.4, 129.9, 128.6, 128.5, 128.4, 127.0, 126.9, 123.2, 116.3, 22.1, 21.2, 17.5, 17.0; IR (KBr) υ 1644 cm−1; HRMS (quadrupole, EI) calcd for C24H22N2O [M]+ 354.1732, found 354.1734. (2-(2,3-Dimethylphenyl)-6,7-dimethyl-2H-indazol-3-yl)(phenyl)methanone (3m): 54.6 mg (77%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.86−7.83 (m, 2H), 7.63−7.58 (m, 1H), 7.48−7.44 (m, 2H), 7.24−7.16 (m, 3H), 7.01 (br s, 2H), 2.65 (s, 3H), 2.41 (s, 3H), 2.33 (s, 3H), 1.96 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.3, 149.3, 140.4, 138.2, 138.0, 133.6, 133.5, 133.1, 132.9, 130.8,

129.8, 129.0, 128.5, 125.7, 125.5, 124.9, 121.5, 117.3, 20.2, 19.1, 14.3, 13.2; IR (KBr) υ 1644 cm−1; HRMS (quadrupole, EI) calcd for C24H22N2O [M]+ 354.1732, found 354.1734. Phenyl(2-(p-tolyl)-2H-indazol-3-yl)methanone (3oa) and (5Methyl-2-phenyl-2H-indazol-3-yl)(phenyl)methanone (3ob): 55.8 mg (89%, 1:1.5); yellow solid; mp = 121.3−125.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.90−7.84 (m, 5H), 7.78 (d, J = 8.8 Hz, 1H), 7.63−7.33 (m, 15H), 7.24−7.22 (m, 3H), 7.19−7.17 (m, 1H), 7.15 (br s, 1H), 2.36 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.1, 186.0, 148.5, 147.7, 140.6, 139.0, 138.1, 137.9, 137.8, 135.0, 133.5, 133.4, 132.2, 131.5, 130.0, 129.9, 129.8, 129.7, 129.0, 128.7, 128.6, 128.5, 126.9, 125.5, 125.3, 124.9, 124.6, 124.0, 120.5, 118.7, 118.5, 118.2, 22.1, 21.2; IR (KBr) υ 1645 cm−1; HRMS (quadrupole, EI) calcd for C21H16N2O [M]+ 312.1263, found 312.1260. Phenyl(2-(4-(trifluoromethyl)phenyl)-2H-indazol-3-yl)methanone (3pa): 23.2 mg (32%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.93−7.88 (m, 3H), 7.74−7.65 (m, 5H), 7.51 (t, J = 8.0 Hz, 2H), 7.43−7.39 (m, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 7.6, 6.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.7, 148.9, 143.2, 137.6, 134.0, 132.4, 130.9 (q, JC−F = 29.5 Hz), 130.0, 128.8, 127.5, 126.3 (q, JC−F = 3.6 Hz), 125.9, 125.6, 123.6 (q, JC−F = 271.1 Hz), 120.6, 118.7, 101.8; IR (KBr) υ 1649, 1236 cm−1; HRMS (quadrupole, EI) calcd for C21H13F3N2O [M]+ 366.0980, found 366.0979. Phenyl(2-phenyl-5-(trifluoromethyl)-2H-indazol-3-yl)methanone (3pb): 13.4 mg (18%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 9.2 Hz, 1H), 7.83−7.80 (m, 3H), 7.64−7.60 (m, 1H), 7.58−7.53 (m, 3H), 7.48−7.42 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.7, 148.8, 140.0, 137.1, 134.1, 134.0, 129.8, 129.4, 129.3, 128.8, 126.9 (q, JC−F = 32.0 Hz), 125.4, 124.2 (q, JC−F = 270.5 Hz), 123.1 (q, JC−F = 2.9 Hz), 122.5, 119.7, 119.4 (q, JC−F = 5.0 Hz); IR (KBr) υ 1652, 1225 cm−1; HRMS (quadrupole, EI) calcd for C21H13F3N2O [M]+ 366.0980, found 366.0977. Ethyl 4-(3-Benzoyl-5-methoxy-2H-indazol-2-yl)benzoate (3qa): 28.9 mg (36%); yellow sticky oil; 1H NMR (700 MHz, CDCl3) δ 8.07 (d, J = 9.1 Hz, 2H), 7.84 (dd, J = 8.4, 1.4 Hz, 2H), 7.75 (d, J = 9.1 Hz, 1H), 7.58−7.57 (m, 3H), 7.45 (t, J = 7.7 Hz, 2H), 7.07 (dd, J = 9.8, 2.8 Hz, 1H), 6.58 (d, J = 2.8 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 3.67 (s, 3H), 1.39 (t, J = 7.7 Hz, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 185.9, 165.6, 157.9, 145.9, 143.9, 137.8, 133.5, 131.6, 130.4, 130.3, 129.7, 128.6, 125.5, 125.1, 122.7, 122.0, 96.8, 61.3, 55.3, 14.3; IR (KBr) υ 1714, 1643, 1269, 1099 cm−1; HRMS (quadrupole, EI) calcd for C24H20N2O4 [M]+ 400.1423, found 400.1425. Ethyl 3-Benzoyl-2-(4-methoxyphenyl)-2H-indazole-5-carboxylate (3qb): 16.1 mg (20%); yellow sticky oil; 1H NMR (700 MHz, CDCl3) δ 8.23 (s, 1H), 8.01 (dd, J = 9.1, 1.4 Hz, 1H), 7.88 (d, J = 9.1 Hz, 1H), 7.83 (dd, J = 8.4, 1.4 Hz, 2H), 7.62−7.60 (m, 1H), 7.47−7.45 (m, 4H), 6.92 (d, J = 8.4 Hz, 2H), 4.34 (q, J = 7.0 Hz, 2H), 3.82 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 186.0, 166.4, 160.1, 137.3, 133.9, 133.2, 129.9, 128.7 (two carbons overlap), 126.8, 126.7, 126.6 (two carbons overlap), 124.6, 118.2, 114.3 (two carbons overlap), 61.1, 35.6, 14.3; IR (KBr) υ 1708, 1650, 1290, 1099 cm−1; HRMS (quadrupole, EI) calcd for C24H20N2O4 [M]+ 400.1423, found 400.1425. (2-(3,5-Dimethylphenyl)-2H-indazol-3-yl)(phenyl)methanone (3r): 60.9 mg (93%); orange solid; mp = 133.0−140.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.86−7.84 (m, 2H), 7.60−7.57 (m, 1H), 7.54− 7.51 (m, 2H), 7.46−7.37 (m, 5H), 6.70 (s, 1H), 6.96 (s, 1H), 2.70 (s, 3H), 2.33 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.2, 148.0, 140.8, 138.0, 135.3, 133.3, 131.8, 129.9, 129.1, 129.0, 128.6, 128.5, 128.4, 125.7, 124.5, 116.1, 22.1, 16.9; IR (KBr) υ 1644 cm−1; HRMS (quadrupole, EI) calcd for C22H18N2O [M]+ 326.1419, found 326.1418. (2-(3-Chloro-5-methylphenyl)-2H-indazol-3-yl)(phenyl)methanone (3s): 40.5 mg (58%); yellow solid; mp = 124.8−127.0 °C; 1 H NMR (400 MHz, CDCl3) δ 7.85−7.82 (m, 2H), 7.63−7.59 (m, 1H), 7.54−7.51 (m, 2H), 7.49−7.39 (m, 5H), 7.21−7.19 (m, 1H), 7.12−7.11 (m, 1H), 2.71 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.8, 147.4, 140.4, 137.5, 133.7, 132.2, 131.0, 130.9, 129.8, 129.1, 129.0, 128.7, 127.3, 125.6, 124.2, 116.7, 16.8; IR (KBr) υ 1646, 1143 4074

DOI: 10.1021/acs.joc.8b00501 J. Org. Chem. 2018, 83, 4070−4077

Article

The Journal of Organic Chemistry cm −1; HRMS (quadrupole, EI) calcd for C21 H15ClN2O [M] + 346.0873, found 346.0870. Phenyl(2-(m-tolyl)-2H-indazol-3-yl)methanone (3ta) and (6Methyl-2-phenyl-2H-indazol-3-yl)(phenyl)methanone (3tb): 37.5 mg (60%, 1:1.7); orange sticky oil; 1H NMR (700 MHz, CDCl3) δ 7.90−7.88 (m, 2H), 7.87−7.86 (m, 3H), 7.63 (s, 1H), 7.61−7.59 (m, 2H), 7.53−7.52 (m, 2H), 7.47−7.45 (m, 4H), 7.43−7.41 (m, 2H), 7.40−7.39 (m, 3H), 7.38 (s, 1H), 7.29−7.28 (m, 2H), 7.25 (d, J = 8.4 Hz, 1H), 7.21−7.17 (m, 2H), 7.02 (dd, J = 8.4, 0.7 Hz, 1H), 2.48 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (175 MHz, CDCl3) δ 186.0, 185.9, 149.2, 148.5, 140.6, 140.4, 139.3, 137.9, 137.1, 133.5 (two carbons overlap), 132.3, 132.1, 129.9, 129.8 (two carbons overlap), 129.7, 129.0, 128.8, 128.7, 128.6 (two carbons overlap), 128.0, 127.0, 126.1, 125.5, 125.0, 124.1, 122.7, 122.6, 120.6, 120.1, 118.5, 116.8, 22.1, 21.3; IR (KBr) υ 1647 cm−1; HRMS (quadrupole, EI) calcd for C21H16N2O [M]+ 312.1263, found 312.1263. (5-Methyl-2-(p-tolyl)-2H-indazol-3-yl)(p-tolyl)methanone (4b): 63.5 mg (93%); orange solid; mp = 139.0−141.8 °C; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 8.0 Hz, 3H), 7.13 (br s, 1H), 2.45 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 185.8, 147.5, 144.5, 138.7, 138.2, 135.3, 134.5, 131.6, 130.2, 129.7, 129.6, 129.3, 125.1, 124.2, 118.7, 118.1, 22.0, 21.8, 21.2; IR (KBr) υ 1644 cm−1; HRMS (quadrupole, EI) calcd for C23H20N2O [M]+ 340.1576, found 340.1574. (4-Methoxyphenyl)(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4c): 49.8 mg (70%); orange solid; mp = 140.0−142.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.4 Hz, 3H), 7.15 (br s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 2.37 (s, 6H); 13 C{1H} NMR (100 MHz, CDCl3) δ 184.9, 164.0, 147.4, 138.7, 138.2, 134.3, 132.5, 131.7, 130.7, 129.7, 129.6, 125.0, 124.1, 118.6, 118.0, 113.9, 55.6, 22.0, 21.2; IR (KBr) υ 1642, 1243, 1022 cm−1; HRMS (quadrupole, EI) calcd for C23H20N2O2 [M]+ 356.1525, found 356.1522. (4-(tert-Butyl)phenyl)(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4d): 65.3 mg (85%); orange solid; mp = 121.8−124.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.22−7.17 (m, 4H), 2.38 (s, 3H), 2.36 (s, 3H), 1.36 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.9, 157.3, 147.5, 138.6, 138.2, 135.2, 134.6, 131.7, 130.0, 129.8, 129.5, 125.5, 125.2, 124.3, 118.8, 118.0, 35.2, 31.1, 22.1, 21.1; IR (KBr) υ 1645 cm−1; HRMS (quadrupole, EI) calcd for C26H26N2O [M]+ 382.2045, found 382.2042. [1,1′-Biphenyl]-4-yl(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4e): 62.8 mg (78%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 9.6 Hz, 1H), 7.71−7.65 (m, 4H), 7.49 (t, J = 7.2 Hz, 2H), 7.44−7.42 (m, 3H), 7.26−7.21 (m, 4H), 2.38 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.7, 147.5, 146.1, 139.7, 138.8, 138.2, 136.6, 134.8, 131.5, 130.6, 129.8, 129.6, 129.0, 128.4, 127.3, 127.2, 125.2, 124.3, 118.6, 118.1, 22.1, 21.1; IR (KBr) υ 1643 cm−1; HRMS (quadrupole, EI) calcd for C28H22N2O [M]+ 402.1732, found 402.1732. (4-Fluorophenyl)(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4f): 65.4 mg (95%); yellow solid; mp = 185.7−188.1 °C; 1 H NMR (400 MHz, CDCl3) δ 7.92−7.87 (m, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.39−7.37 (m, 2H), 7.24−7.20 (m, 3H), 7.16−7.10 (m, 3H), 2.38 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.6, 165.9 (d, JC−F = 254.0 Hz), 147.5, 139.0, 138.1, 135.0, 134.3 (d, JC−F = 2.9 Hz), 132.6, 132.5, 131.1, 129.9, 129.7, 125.2, 124.4, 118.3 (d, JC−F = 19.3 Hz), 115.8 (d, JC−F = 21.8 Hz), 22.1, 21.2; IR (KBr) υ 1648, 1226 cm−1; HRMS (quadrupole, EI) calcd for C22H17FN2O [M]+ 344.1325, found 344.1328. (4-Chlorophenyl)(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4g): 64.2 mg (89%); orange solid; mp = 194.6−197.1 °C; 1H NMR (400 MHz, CDCl3) δ 7.82−7.77 (m, 3H), 7.44−7.41 (m, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.24−7.20 (m, 3H), 7.14 (br s, 1H), 2.39 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.8, 147.5, 139.9, 139.0, 138.1, 136.3, 135.2, 131.3, 131.0, 129.9, 129.7, 128.9, 125.2, 124.4, 118.4, 118.3, 22.1, 21.2; IR (KBr) υ 1647, 1170

cm−1; HRMS (quadrupole, EI) calcd for C 22H17ClN2 O [M] + 360.1029, found 360.1026. (4-Bromophenyl)(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4h): 68.4 mg (84%); yellow solid; mp = 175.4−178.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.8 Hz, 1H), 7.74− 7.71 (m, 2H), 7.61−7.58 (m, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.24−7.20 (m, 3H), 7.14 (br s, 1H), 2.39 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.9, 147.5, 139.0, 138.1, 136.7, 135.2, 131.9, 131.4, 131.0, 129.9, 129.7, 128.6, 125.2, 124.4, 118.4, 118.3, 22.1, 21.2; IR (KBr) υ 1645, 1170 cm−1; HRMS (quadrupole, EI) calcd for C22H17BrN2O [M]+ 404.0524, found 404.0525. (5-Methyl-2-(p-tolyl)-2H-indazol-3-yl)(4-(trifluoromethyl)phenyl)methanone (4i): 72.7 mg (92%); yellow solid; mp = 108.8−110.9 °C; 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.4 Hz, 2H), 7.26− 7.23 (m, 1H), 7.18 (d, J = 8.0 Hz, 3H), 2.40 (s, 3H), 2.36 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 184.8, 147.6, 140.9, 139.2, 139.0, 135.7, 134.3 (q, JC−F = 32.5 Hz), 130.9, 130.0, 129.9, 129.6, 125.5 (q, JC−F = 3.6 Hz), 125.4, 124.7, 123.5 (q, JC−F = 270.1 Hz), 118.4, 118.3, 22.1, 21.1; IR (KBr) υ 1649, 1232 cm−1; HRMS (quadrupole, EI) calcd for C23H17F3N2O [M]+ 394.1293, found 394.1293. (5-Methyl-2-(p-tolyl)-2H-indazol-3-yl)(o-tolyl)methanone (4j): 60.1 mg (88%); orange solid; mp = 143.8−146.7 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.42−7.38 (m, 3H), 7.27 (d, J = 8.8 Hz, 1H), 7.23−7.18 (m, 4H), 6.78 (br s, 1H), 2.41 (s, 3H), 2.39 (s, 3H), 2.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.0, 147.5, 138.9, 138.5, 138.4, 137.7, 135.3, 132.1, 131.4, 129.7, 129.6, 129.5 (two carbons overlap), 125.6, 125.4, 124.8, 118.7, 118.2, 22.1, 21.2, 20.0; IR (KBr) υ 1647 cm−1; HRMS (quadrupole, EI) calcd for C23H20N2O [M]+ 340.1576, found 340.1574. (2-Methoxyphenyl)(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4k): 44.9 mg (63%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 1H), 7.47 (dd, J = 7.6, 2.0 Hz, 1H), 7.42−7.39 (m, 1H), 7.38−7.34 (m, 2H), 7.20 (dd, J = 8.8, 1.2 Hz, 1H), 7.16 (br s, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.99 (td, J = 7.6, 0.8 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 3.56 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 185.0, 157.6, 147.4, 138.6, 138.1, 135.0, 133.1, 133.0, 130.2, 129.6, 129.1, 129.0, 125.6, 124.4, 120.7, 118.9, 118.0, 111.1, 55.5, 22.1, 21.1; IR (KBr) υ 1650, 1248, 1020 cm−1; HRMS (quadrupole, EI) calcd for C23H20N2O2 [M]+ 356.1525, found 356.1525. (2-Fluorophenyl)(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4l): 53.8 mg (78%); yellow solid; mp = 128.8−130.9 °C; 1 H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 9.2 Hz, 1H), 7.56 (td, J = 7.2, 1.6 Hz, 1H), 7.48−7.42 (m, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.24− 7.14 (m, 5H), 6.96 (t, J = 9.2 Hz, 1H), 2.39 (s, 3H), 2.35 (s, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 181.9, 160.1 (d, JC−F = 252.4 Hz), 147.5, 139.0, 137.9, 135.8, 133.8, 133.7, 132.2, 130.6 (d, JC−F = 2.0 Hz), 129.9, 129.3, 127.7 (d, JC−F = 13.1 Hz), 125.7, 124.7, 124.4 (d, JC−F = 3.6 Hz), 118.4 (d, JC−F = 21.9 Hz), 116.2 (d, JC−F = 21.4 Hz), 22.2, 21.1; IR (KBr) υ 1647, 1225 cm−1; HRMS (quadrupole, EI) calcd for C22H17FN2O [M]+ 344.1325, found 344.1330. (2-Chlorophenyl)(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4m): 47.2 mg (65%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1H), 7.41−7.28 (m, 6H), 7.23− 7.17 (m, 3H), 6.92 (br s, 1H), 2.37 (s, 3H), 2.35 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 183.7, 147.5, 139.1, 138.8, 138.1, 136.1, 131.9, 131.8, 131.5, 130.2, 129.9, 129.8, 129.3, 127.0, 125.7, 125.0, 118.5, 118.4, 22.2, 21.2; IR (KBr) υ 1648, 1224 cm−1; HRMS (quadrupole, EI) calcd for C22H17ClN2O [M]+ 360.1029, found 360.1028. (5-Methyl-2-(p-tolyl)-2H-indazol-3-yl)(m-tolyl)methanone (4n): 56.0 mg (82%); yellow solid; mp = 127.0−130.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1H), 7.67−7.66 (m, 2H), 7.42− 7.32 (m, 4H), 7.23−7.19 (m, 3H), 7.14 (br s, 1H), 2.38 (s, 3H), 2.37 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.3, 147.5, 138.7, 138.4, 138.3, 137.9, 134.7, 134.2, 131.6, 130.3, 129.8, 129.6, 128.4, 127.3, 125.2, 124.4, 118.7, 118.1, 22.0, 21.2, 21.1; IR (KBr) υ 1648 4075

DOI: 10.1021/acs.joc.8b00501 J. Org. Chem. 2018, 83, 4070−4077

Article

The Journal of Organic Chemistry cm−1; HRMS (quadrupole, EI) calcd for C23H20N2O [M]+ 340.1576, found 340.1574. (3-Fluorophenyl)(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4o): 48.3 mg (70%); yellow solid; mp = 129.1−131.8 °C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.48−7.41 (m, 3H), 7.35− 7.24 (m, 4H), 7.20 (br s, 1H), 2.43 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.7 (d, JC−F = 2.2 Hz), 162.6 (d, JC−F = 247.2 Hz), 147.5, 140.0 (d, JC−F = 6.5 Hz), 139.0, 138.1, 135.3, 130.9, 130.2, 130.1, 129.9, 129.7, 125.7 (d, JC−F = 12.0 Hz), 125.2, 124.5, 120.3 (d, JC−F = 21.3 Hz), 118.3 (d, JC−F = 19.0 Hz), 116.3 (d, JC−F = 22.5 Hz), 22.1, 21.2; IR (KBr) υ 1649, 1255 cm−1; HRMS (quadrupole, EI) calcd for C22H17FN2O [M]+ 344.1325, found 344.1323. (3-Bromophenyl)(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)methanone (4p): 68.2 mg (84%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.94−7.93 (m, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.70−7.67 (m, 1H), 7.39−7.36 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.26−7.25 (m, 1H), 7.22−7.19 (m, 3H), 2.40 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.5, 147.6, 139.7, 139.0, 138.1, 136.0, 135.5, 132.6, 130.9, 130.1, 130.0, 129.7, 128.4, 125.3, 124.7, 122.8, 118.5, 118.3, 22.1, 21.2; IR (KBr) υ 1646, 1175 cm −1; HRMS (quadrupole, EI) calcd for C22 H17BrN2O [M] + 404.0524, found 404.0529. (5-Methyl-2-(p-tolyl)-2H-indazol-3-yl)(naphthalen-2-yl)methanone (4q): 62.6 mg (83%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 8.40 (br s, 1H), 7.98 (dd, J = 8.4, 1.6 Hz, 1H), 7.94− 7.87 (m, 3H), 7.81 (d, J = 8.8 Hz, 1H), 7.64 (td, J = 6.8, 1.2 Hz, 1H), 7.58−7.54 (m, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.23 (dd, J = 8.8, 1.2 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.15 (br s, 1H), 2.33 (s, 3H), 2.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.0, 147.5, 138.8, 138.3, 135.8, 135.2, 134.9, 132.4, 132.3, 131.6, 129.9, 129.7, 129.6, 128.8, 128.6, 127.9, 126.9, 125.2, 125.1, 124.4, 118.6, 118.2, 22.0, 21.1; IR (KBr) υ 1644 cm−1; HRMS (quadrupole, EI) calcd for C26H20N2O [M]+ 376.1576, found 376.1580. (5-Methyl-2-(p-tolyl)-2H-indazol-3-yl)(thiophen-2-yl)methanone (4r): 48.0 mg (72%); yellow solid; mp = 138.8−139.6 °C; 1H NMR (400 MHz, CDCl3) δ 7.78−7.75 (m, 2H), 7.66 (dd, J = 3.6, 1.2 Hz, 1H), 7.44−7.42 (m, 2H), 7.38 (br s, 1H), 7.24−7.21 (m, 3H), 7.13 (dd, J = 4.8, 3.6 Hz, 1H), 2.41 (s, 3H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.1, 147.5, 144.4, 138.8, 138.1, 135.3, 135.2, 134.6, 131.2, 129.9, 129.7, 128.2, 125.0, 123.9, 118.4, 118.0, 22.1, 21.2; IR (KBr) υ 1625 cm−1; HRMS (quadrupole, EI) calcd for C20H16N2OS [M]+ 332.0983, found 332.0984. 2-Methyl-1-(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)propan-1-one (4s): 11.8 mg (20%); yellow solid; mp = 218.4−219.9 °C; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.8 Hz, 1H), 7.67 (br s, 1H), 7.35− 7.29 (m, 4H), 7.26−7.24 (m, 1H), 3.35−3.25 (m, 1H), 2.52 (s, 3H), 2.45 (s, 3H), 1.21 (s, 3H), 1.19 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 195.6, 147.5, 139.2, 139.1, 135.6, 131.5, 129.6, 129.5, 125.6, 123.0, 118.8, 118.6, 39.1, 22.3, 21.3, 18.6; IR (KBr) υ 1656 cm−1; HRMS (quadrupole, EI) calcd for C19H20N2O [M]+ 292.1576, found 292.1573. 2,2-Dimethyl-1-(5-methyl-2-(p-tolyl)-2H-indazol-3-yl)propan-1one (4t): 21.4 mg (35%); orange solid; mp = 86.7−87.8 °C; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 2H), 7.30−7.26 (m, 3H), 7.18 (dd, J = 8.8, 1.2 Hz, 1H), 2.43 (s, 3H), 2.42 (s, 3H), 1.08 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 206.5, 147.5, 139.0, 138.9, 133.1, 133.0, 130.0, 129.9, 124.7, 121.9, 118.0, 117.6, 45.7, 26.9, 22.0, 21.2; IR (KBr) υ 1681 cm−1; HRMS (quadrupole, EI) calcd for C20H22N2O [M]+ 306.1732, found 306.1729. (1S,4S)-4,7,7-Trimethyl-1-(5-methyl-2-(p-tolyl)-2H-indazole-3carbonyl)-2-oxabicyclo[2.2.1]heptan-3-one (4u): 27.6 mg (34%); yellow sticky oil; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.8 Hz, 1H), 7.66 (br s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.22 (dd, J = 8.8, 1.6 Hz, 1H), 2.49 (s, 3H), 2.43 (s, 3H), 2.42− 2.35 (m, 1H), 1.94−1.79 (m, 2H), 1.67−1.61 (m, 1H), 1.13 (s, 3H), 1.05 (s, 3H), 0.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.6, 177.9, 147.6, 139.5, 139.2, 135.5, 132.0, 129.8, 129.7, 125.6, 123.4,

118.8, 118.2, 95.2, 57.0, 54.9, 31.8, 29.4, 22.3, 21.3, 17.3, 16.7, 9.6; IR (KBr) υ 1789, 1656, 1162 cm−1; HRMS (quadrupole, EI) calcd for C25H26N2O3 [M]+ 402.1943, found 402.1942. 1-(5-Methyl-2-(p-tolyl)-2H-indazol-3-yl)propan-1-one (4v): 24.5 mg (44%); yellow solid; mp = 106.2−109.1 °C; 1H NMR (700 MHz, CDCl3) δ 7.78 (br s, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.34−7.33 (m, 2H), 7.32−7.30 (m, 2H), 7.24 (dd, J = 9.8, 2.1 Hz, 1H), 2.86 (q, J = 7.0 Hz, 2H), 2.52 (s, 3H), 2.45 (s, 3H), 1.17 (t, J = 7.7 Hz, 3H); 13 C{1H} NMR (175 MHz, CDCl3) δ 191.3, 147.4, 139.4, 139.2, 135.8, 132.1, 129.6, 129.5, 125.9, 123.4, 119.2, 118.5, 35.7, 22.3, 21.3, 7.9; IR (KBr) υ 1668 cm−1; HRMS (quadrupole, EI) calcd for C18H18N2O [M]+ 278.1419, found 278.1416. Experimental Procedure for H/D Exchange Reaction. To an oven-dried sealed tube charged with (E)-1,2-di-p-tolyldiazene (1b) (63.1 mg, 0.3 mmol, 100 mol %), [RhCp*Cl2]2 (4.6 mg, 0.0075 mmol, 2.5 mol %), Cu(OAc)2 (27.2 mg, 0.15 mmol, 50 mol %), CuCO3· Cu(OH)2 (66.3 mg, 0.3 mmol, 100 mol %), and AgSbF6 (10.3 mg, 0.03 mmol, 10 mol %) were added CD3OD (216.4 mg, 6.0 mmol, 20.0 equiv) and DCE (1 mL) under air at room temperature. The reaction mixture was allowed to stir at 110 °C for 24 h and cooled to room temperature. The reaction mixture was diluted with EtOAc (3 mL) and concentrated in vacuo. The residue was purified by flash column chromatography (n-hexanes/EtOAc = 30:1) to afford deuterio-1b with 81% D incorporation at each of the ortho-positions. Kinetic Isotope Effect (KIE) Experiment. To a mixture of 1b (42.1 mg, 0.2 mmol, 100 mol %), deuterio-1b (42.9 mg, 0.2 mmol, 100 mol %, 97% D incorporation), [RhCp*Cl2]2 (3.1 mg, 0.005 mmol, 2.5 mol %), Cu(OAc)2 (18.2 mg, 0.1 mmol, 50 mol %), CuCO3· Cu(OH)2 (44.2 mg, 0.2 mmol, 100 mol %), and sulfoxonium ylide 2a (39.3 mg, 0.2 mmol, 100 mol %) were added AgSbF6 (6.9 mg, 0.02 mmol, 10 mol %) and DCE (1 mL) under air at room temperature. The reaction mixture was allowed to stir at 110 °C for 30 min and cooled to room temperature. After filtration on a Celite pad and evaporation of solvent in vacuo, the crude product was purified by column chromatography on silica gel (n-hexanes/EtOAc = 30:1) to yield 3b and deuterio-3b as a yellow solid. The kinetic isotope effect (kH/kD) value was determined to be 2.6 by 1H NMR analysis.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00501. 1 H and 13C NMR spectra for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

In Su Kim: 0000-0002-2665-9431 Author Contributions †

H.O. and S.H. equally contributed.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Research Foundation of Korea (NRF) funded by the Korea government (MSIFP) (2016R1A4A1011189, 2016R1C1B2010456, and 2017R1A2B2004786).

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REFERENCES

(1) (a) Burland, D. M.; Miller, R. D.; Walsh, C. A. Second-order nonlinearity in poled-polymer systems. Chem. Rev. 1994, 94, 31−75. (b) Kanis, D. R.; Ratner, M. A.; Marks, T. J. Design and construction

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Article

The Journal of Organic Chemistry of molecular assemblies with large second-order optical nonlinearities. Quantum chemical aspects. Chem. Rev. 1994, 94, 195−242. (c) Muraoka, T.; Kinbara, K.; Aida, T. Mechanical twisting of a guest by a photoresponsive host. Nature 2006, 440, 512−515. (2) For selected examples, see: (a) Tsai, W. H.; Shiao, Y. J.; Lin, S. J.; Chiou, W. F.; Lin, L. C.; Yang, T. H.; Teng, C. M.; Wu, T. S.; Yang, L. M. Selective COX-2 inhibitors. Part 1: synthesis and biological evaluation of phenylazobenzenesulfonamides. Bioorg. Med. Chem. Lett. 2006, 16, 4440−4443. (b) Grirrane, A.; Corma, A.; Garcia, H. Goldcatalyzed synthesis of aromatic azo compounds from anilines and nitroaromatics. Science 2008, 322, 1661−1664. (c) Zhang, C.; Jiao, N. Copper-catalyzed aerobic oxidative dehydrogenative coupling of anilines leading to aromatic azo compounds using dioxygen as an oxidant. Angew. Chem., Int. Ed. 2010, 49, 6174−6177. (3) For a recent review, see: Nguyen, T. H. L.; Gigant, N.; Joseph, D. Advances in direct metal-catalyzed functionalization of azobenzenes. ACS Catal. 2018, 8, 1546−1579. (4) (a) Lian, Y.; Bergman, R. G.; Lavis, L. D.; Ellman, J. A. Rhodium(III)-catalyzed indazole synthesis by C−H bond functionalization and cyclative capture. J. Am. Chem. Soc. 2013, 135, 7122−7125. (b) Jeong, T.; Han, S. H.; Han, S.; Sharma, S.; Park, J.; Lee, J. S.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Access to 3-acyl-(2H)-indazoles via Rh(III)-catalyzed C−H addition and cyclization of azobenzenes with α-Keto aldehydes. Org. Lett. 2016, 18, 232−235. (c) Han, S. H.; Mishra, N. K.; Jo, H.; Oh, Y.; Jeon, M.; Kim, S.; Kim, W. J.; Lee, J. S.; Kim, H. S.; Kim, I. S. One-pot synthesis of oxindoles through C−H alkylation and intramolecular cyclization of azobenzenes with internal olefins. Adv. Synth. Catal. 2017, 359, 2396−2401. (5) (a) Halim, R.; Harding, M.; Hufton, R.; Morton, C. J.; Jahangiri, S.; Pool, B. R.; Jeynes, T. P.; Draffan, A. G.; Lilly, M. J.; Frey, B. Preparation of phenylmethylsulfonylaminoindazolecarboxa mide derivatives and analogs for use as viral polymerase inhibitors. WO 2012051659A1, 2012. (b) Aman, W.; Lee, J.; Kim, M.; Yang, S.; Jung, H.; Hah, J.-M. Discovery of highly selective CRAF inhibitors, 3carboxamido-2H-indazole-6-arylamide: in silico FBLD design, synthesis and evaluation. Bioorg. Med. Chem. Lett. 2016, 26, 1188−1192. (6) For selected recent examples, see: (a) Dias, R. M. P.; Burtoloso, A. C. B. Catalyst-free insertion of sulfoxonium ylides into aryl thiols. A direct preparation of β-keto thioethers. Org. Lett. 2016, 18, 3034− 3037. (b) Phelps, A. M.; Chan, V. S.; Napolitano, J. G.; Krabbe, S. W.; Scho-maker, J. M.; Shekhar, S. Ligand-controlled synthesis of azoles via Ir-catalyzed reactions of sulfoxonium ylides with 2-amino heterocycles. J. Org. Chem. 2016, 81, 4158−4169. (c) Vaitla, J.; Bayer, A.; Hopmann, K. H. Synthesis of indoles and pyrroles utilizing iridium carbenes generated from sulfoxonium ylides. Angew. Chem., Int. Ed. 2017, 56, 4277−4281. (d) Wu, X.; Xiong, H.; Sun, S.; Cheng, J. Rhodiumcatalyzed relay carbenoid functionalization of aromatic C−H bonds toward fused heteroarenes. Org. Lett. 2018, 20, 1396−1399. (7) (a) Barday, M.; Janot, C.; Halcovitch, N. R.; Muir, J.; Aïssa, C. Cross-coupling of α-carbonyl sulfoxonium ylides with C−H bonds. Angew. Chem., Int. Ed. 2017, 56, 13117−13121. (b) Xu, Y.; Zhou, X.; Zheng, G.; Li, X. Sulfoxonium ylides as a carbene precursor in Rh(III)catalyzed C−H acylmethylation of arenes. Org. Lett. 2017, 19, 5256− 5259. (8) Xu, Y.; Yang, X.; Zhou, X.; Kong, L.; Li, X. Rhodium(III)catalyzed synthesis of naphthols via C−H activation of sulfoxonium ylides. Org. Lett. 2017, 19, 4307−4310. (9) Xu, Y.; Zheng, G.; Yang, X.; Li, X. Rhodium(III)-catalyzed chemodivergent annulations between N-methoxybenzamides and sulfoxonium ylides via C−H activation. Chem. Commun. 2018, 54, 670−673. (10) Zheng, G.; Tian, M.; Xu, Y.; Chen, X.; Li, X. Rhodium(III)catalyzed annulative coupling between arenes and sulfoxonium ylides via C−H activation. Org. Chem. Front. 2018, 5, 998. (11) (a) Sharma, S.; Oh, Y.; Mishra, N. K.; De, U.; Jo, H.; Sachan, R.; Kim, H. S.; Jung, Y. H.; Kim, I. S. Rhodium-catalyzed [3 + 2] annulation of cyclic N-acyl ketimines with activated olefins: anticancer activity of spiroisoindolinones. J. Org. Chem. 2017, 82, 3359−3367. (b) Pandey, A. K.; Han, S. H.; Mishra, N. K.; Kang, D.; Lee, S. H.;

Chun, R.; Hong, S.; Park, J. S.; Kim, I. S. Synthesis of 2-benzazepines from benzylamines and MBH adducts under Rhodium(III) catalysis via C(sp2)−H functionalization. ACS Catal. 2018, 8, 742−746. (12) Zenchoff, G. S.; Walser, A.; Fryer, R. I. The synthesis of indazoles via 2,3-dihydroindazoles. J. Heterocycl. Chem. 1976, 13, 33− 39. (13) (a) Jones, W. D. Isotope effects in C−H bond activation reactions by transition metals. Acc. Chem. Res. 2003, 36, 140−146. (b) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N. A RuH2(CO)(PPh3)3-catalyzed regioselective arylation of aromatic ketones with arylboronates via carbon−hydrogen bond cleavage. J. Am. Chem. Soc. 2005, 127, 5936−5945. (14) For a selected review for the heteroatom-directed rhodacycle intermediates, see: Colby, D. A.; Bergman, R. G.; Ellman, J. A. Rhodium-catalyzed C−C bond formation via heteroatom-directed C− H bond activation. Chem. Rev. 2010, 110, 624−655. (15) For a review on α-oxo carbenoids in catalysis, see: Xiao, J.; Li, X. Gold α-oxo carbenoids in catalysis: catalytic oxygen-atom transfer to alkynes. Angew. Chem., Int. Ed. 2011, 50, 7226−7236. (16) Long, Z.; Wang, Z.; Zhou, D.; Wan, D.; You, J. Rh(III)catalyzed regio- and chemoselective [4 + 1]-annulation of azoxy compounds with diazoesters for the synthesis of 2H-indazoles: roles of the azoxy oxygen atom. Org. Lett. 2017, 19, 2777−2780.

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