English

• 1.   Introduction

  Indazole heterocycles have attracted significant interest among the medicinal chemistry community because of their promising pharmaceutical applications and biological activities.^[1] In particular, the 3-carboxylate indazole scaffolds are constituents of key privileged molecules, acting as anti-cancer drug, viral polymerase inhibition and anti-inflammatory agent, etc. (Figure 1).^[2] Thus, the development of robust synthetic approaches for affording substituted 3-carboxylate indazoles has been the focus of intensive research. The classical routes to 3-carboxylate indazoles involve direct lithiation at the C3-position of indazoles followed by the addition of electrophiles, but these strategies are limited by their low yields and harsh reaction conditions.^[3] Therefore, there is a continued strong demand for constructing 3-carboxylate indazoles in simple operation from cheap starting materials.

  Figure 1

  

  Figure 1.  Selected bioactive indazole compounds

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  Transition-metal-catalyzed C—H bond functionaliza- tion has emerged a powerful strategy to the rapid assembly of various heterocycles.^[4] In this regard, the recent progress has been focused on the synthesis of indazoles via C—H bond activation process under Rh(Ⅲ), Co(Ⅲ) and Re(Ⅰ) catalysts. For example, the pioneering work by Ellman took advantage of the directing character of azo group to enable a Rh(Ⅲ)-catalyzed C—H activation/cyc- lization of azobenzenes with aryl aldehydes for the synthesis of 2, 3-diaryl-2H-indazoles (Scheme 1).^[5] Moreover, Ellman and Wang^[6] also reported representative works on the synthesis of 2, 3-diaryl-2H-indazoles via the Co(Ⅲ)- or Re(Ⅰ)-catalyzed redox-neutral coupling of azobenzenes with aryl aldehydes, respectively. However, these methods are only limited to furnishing 3-aryl indazole under expensive catalysts. On the other hand, Ru(Ⅱ) complexes have been shown to efficiently catalyze arene C—H functionalization with outstanding catalytic efficiency.^[7] In continuation of our effort in developing efficient Ru(Ⅱ)-catalyzed C—H functionlization for the assembly of various heterocycles, ^[8] we herein report an efficient Ru(Ⅱ)-catalyzed C—H bond [4+1] cycloaddition of azobenzenes with ethyl glyoxalate for the production of the desired 3-car- boxylate indazoles (Scheme 1).

  Scheme 1

  

  Scheme 1.  Indazole synthesis via C—H functionalization

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  2.   Results and discussion

  Initially, we commenced our studies by screening reaction conditions for the envisioned C—H bond [4+1] cycloaddition of azobenzenes 1a with ethyl glyoxalate 2a (Table 1). To our delight, the desired 3-carboxylate indazole 3a was obtained in 24% yield by using [Ru(p-cy-mene)Cl₂]₂/AgSbF₆ as the co-catalyst (Entry 1). It is well- known that the OAc source is important for the current C—H functionalization reactions. We next investigated the effects of additives for this reaction optimization. Further investigation revealed that additives such as NaOAc, KOAc, LiOAc, CsOAc and AgOAc led to a significantly increase in the product yield (38%~51%, Entries 2~6), whereas the reaction of 1a with 2a in the presence of acid additives such as AcOH and PivOH furnished the product 3a in slightly decreased yields (41% and 26%, Entries 6, 7). Subsequently, a variety of solvents were screened, and these results showed that 1, 2-dichloroethane (DCE) was the optimal solvent (Entries 8~12 vs 13). In addition, 3a was formed in 76% yield when the reaction temperature increased to 100 ℃ (Table 1, Entry 14). To our delight, we soon found that extending the reaction time could afford the improved reaction yield of 82% (Entries 15). Finally, various Ru complexes were tested, but only [Ru(p-cyme-ne)Cl₂]₂ was active. The other complexes, including Ru- Cl₂(PPh₃)₄, Ru₃(CO)₁₂ and RuHCl(CO)(PPh₃)₃ were totally ineffective (Entries 16~18).

  Table 1

  

  Table 1.  Optimization of the reaction parameters^a

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  Entry	Catalyst	Additive	Solvent	Yieldb/%
  1	[Ru(p-cymene)Cl2]	None	Dioxane	24
  2	[Ru(p-cymene)Cl2]	NaOAc	Dioxane	51
  3	[Ru(p-cymene)Cl2]	KOAc	Dioxane	46
  4	[Ru(p-cymene)Cl2]	LiOAc	Dioxane	47
  5	[Ru(p-cymene)Cl2]	CsOAc	Dioxane	40
  6	[Ru(p-cymene)Cl2]	AgOAc	Dioxane	38
  7	[Ru(p-cymene)Cl2]	PivOH	Dioxane	41
  8	[Ru(p-cymene)Cl2]	AcOH	CH3CN	26
  9	[Ru(p-cymene)Cl2]	NaOAc	Toluene	Trace
  10	[Ru(p-cymene)Cl2]	NaOAc	THF	48
  11	[Ru(p-cymene)Cl2]	NaOAc	TFE	21
  12	[Ru(p-cymene)Cl2]	NaOAc	MeOH	Trace
  13	[Ru(p-cymene)Cl2]	NaOAc	DCE	64
  14	[Ru(p-cymene)Cl2]	NaOAc	DCE	76c
  15	[Ru(p-cymene)Cl2]	NaOAc	DCE	82d
  16	RuCl2(PPh3)4	NaOAc	DCE	0
  17	Ru3(CO)12	NaOAc	DCE	0
  18	RuHCl(CO)(PPh3)3	NaOAc	DCE	0
  a Unless otherwise noted, all the reactions were carried out using azobenzenes (1a, 0.20 mmol) and ethyl glyoxalate (2a, 0.40 mmol) with catalysts (5 mol%) in the presence of AgSbF6 (20 mol%) and additive (50 mol%) in solvent (2.0 mL) at 80 ℃ for 12 h under Ar in a sealed reaction tube, followed by flash chromatography on SiO2. b Isolated yield. c The reaction temperature is 100 ℃. d The reaction time is 24 h. TFE＝2, 2, 2-trifluoroethanol.

  With an optimized catalytic system in hand, we then turned our attention toward exploring scope and limitation of Ru(Ⅱ)-catalyzed C—H bond [4+1] cycloaddition of azobenzenes (1) with ethyl glyoxalate (2a). As shown in Table 2, the reactivity of substituted azobenzenes 1 was obviously dependent on the electronic properties of substitutents. Azobenzenes bearing electron-donating groups (Me, MeO) on the para-position afforded excellent yields of 3b (84% yield) and 3c (88% yield), respectively. In contrast, electron-withdrawing halogen group (Cl), ester group (COOEt) and cyano group (CN) slightly decreased the reaction conversion and produced 3d~3f in moderate to good yields (59%~77% yields), which indicated that C—H activation was involved in an electrophilic aromatic substitution process. Notably, this reaction protocol could also smoothly convert ortho- or meta-substituted azobenzenes to the desired 3g or 3h with excellent yields (80% and 83%) in spite of steric congestion. Moreover, 3, 5-demethyl-substituted azobenzene 1i could afford the desired product 3i with 78% yield, in which no significant effect of steric hindrance from methyl moiety was observed in this transformation. In addition, the unsymmetrical azobenzene 1j having both methy group and methoxy group on one aryl ring is also allowed for this transformation to assemble the corresponding indazole 3j in 76% yield. Beside, methyl 2-oxoacetate and 2-oxo-2-phenylace- taldehyde could also react with 1a to afford the corresponding products 3k and 3l, respectively. Unfortunately, other aldehydes such as acetaldehyde were not allowed for this transformation, and the starting materials were recovered completely. When we moved to employ 2-arylpyri- dine as an arene substrate (Eq. 1), indolizine products 5a~5c were also isolated in accepted yield under slightly modified reaction condition. Finally, we converted 3k to the corresponding product 6a in 78% yield via a hydrolysis and subsequent decarboxylation process (Eq. 2).

  Table 2

  

  Table 2.  Substrate scope^{a, b}

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  (1)

  (2)

  To gain more insights into the mechanism, some experiments were conducted (Scheme 2). A competition reaction was performed to determine the electronic prefe- rence of this transformation. When 1c and 1f were treated at the same time, the reaction favored the electron-rich azo-benzenes in 3.2:1 ratio (Scheme 2a), thus implying that the C—H activation step might be an electrophilic aromatic substitution process.^[9] Subsequently, the intermolecular isotope effect (K_H/K_D＝1.1) further indicated that C—H bond-breaking was not involved in the rate- limitting step of this transformation (Scheme 2b).^[10] On the basis of the above-mentioned results, a plausible mechanism is proposed in Scheme 3. First, coordination of an azo group in azobenzene 1a to a cationic Ru species to form a five-membered cobaltacycle intermediate I. Subse- quently, an insertion of C＝O to Ru—C bond of interme-diate A forms the seven-membered intermedaite II, which undergoes protonation to give the alcohol III with release of Ru catalyst. Finally, indazole 3a is obtained through an intramolecular nucleophilic substitution/cyclization process.

  Scheme 2

  

  Scheme 2.  Preliminary mechanistic studies

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  Scheme 3

  

  Scheme 3.  Proposed mechanism

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  3.   Conclusions

  In conclusion, we have developed a novel Ru(Ⅱ)- catalyzed regioselective C—H bond cycloaddition of azobenzenes with ethyl glyoxalate for the rapid assembly of 3-carboxylate indazole. This catalytic system tolerates a wide range of azobenzene substrates with high reaction efficiency. Further synthetic applications to bioactive molecules are underway in sour laboratory.

  4.   Experimental section

  4.1   General information

  The azobenzene substrates were prepared according to the previously reported procedure.^[5] Solvents were treated with 4 Å molecular sieves or sodium and distilled prior to use. Purifications of reaction products were carried out by flash chromatography using silica gel (200~300 mesh). ¹H NMR and ¹³C NMR spectra were recorded with tetramethylsilane (TMS) as internal standard at ambient temperature unless otherwise indicated on a Bruker Avance DPX 600 fourier Transform spectrometer operating at 400 MHz for ¹H NMR and 100 MHz for ¹³C NMR. High resolution mass spectra (HRMS) were recorded on an IF-TOF spectrometer (Micromass).

  4.2   General procedure for the synthesis of 3-car- boxylate indazole derivatives 3

  A 10 mL of reaction tube was charged with azobenzenes 1 (0.2 mmol), [Ru(p-cymene)Cl₂] (5 mol%), AgSbF₆ (20 mol%), NaOAc (50 mol%) and DCE (1.5 mL) under Ar atmosphere. Then ethyl glyoxalate 2a (0.4 mmol) in DCE (0.5 mL) was added in one-pot under Ar and the mixture was stirred at 100 ℃ for 24 h. The corresponding reaction mixture was filtered through a pad of Celite, washed with DCE and concetrated under reduced pressure. The residue was purified by flash chromatography on silical gel using ethyl acetate/petroleum ether (V:V＝1:8) as eluent to afford the products 3.

  Ethyl 2-phenyl-2H-indazole-3-carboxylate (3a): Brown solid, 82% yield. m.p. 80~82 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.12 (d, J＝8.3 Hz, 1H), 7.85 (d, J＝8.5 Hz, 1H), 7.52 (s, 5H), 7.41 (t, J＝7.1 Hz, 1H), 7.34 (t, J＝7.4 Hz, 1H), 4.36 (q, J＝13.1, 2H), 1.33 (t, J＝6.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 159.5, 148.4, 141.0, 129.3, 128.6, 127.1, 126.4, 125.5, 125.1, 124.01, 121.6, 118.6, 61.1, 14.1; HRMS (ESI) calcd for C₁₆H₁₅N₂O₂ [M+H]⁺ 267.1132, found 267.1135.

  Ethyl 5-methyl-2-(p-tolyl)-2H-indazole-3-carboxylate (3b): Brown solid, 84% yield. m.p. 68~70 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.85 (s, 1H), 7.73 (d, J＝8.6 Hz, 1H), 7.39 (d, J＝7.3 Hz, 2H), 7.30 (d, J＝7.5 Hz, 2H), 7.24 (d, J＝9.1 Hz, 1H), 4.36 (q, J＝6.6 Hz, 2H), 2.50 (s, 3H), 2.44 (s, 3H), 1.34 (t, J＝6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 159.7, 147.4, 139.2, 138.7, 135.3, 129.8, 129.2, 126.1, 124.4, 119.7, 118.2, 60.9, 22.2, 21.3, 14.2; HRMS (ESI) calcd for C₁₈H₁₉N₂O₂ [M+H]⁺ 295.1631, found 295.1636.

  Ethyl 5-methoxy-2-(4-methoxyphenyl)-2H-indazole-3- carbo-xylate (3c): Brown solid, 88% yield. m.p. 88~90 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.64 (d, J＝9.1 Hz, 1H), 7.35 (d, J＝7.6 Hz, 2H), 7.26 (s, 1H), 7.01 (d, J＝9.2 Hz, 1H), 6.93 (d, J＝7.6 Hz, 2H), 4.30~4.21 (q, 2H), 3.83 (d, J＝8.6 Hz, 3H), 3.80 (s, 3H), 1.25 (t, J＝6.5 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 160.0, 159.8, 157.9, 145.0, 134.2, 127.4, 125.1, 124.1, 121.8, 119.9, 113.7, 97.9, 60.8, 55.6, 55.4, 14.2; HRMS (ESI) calcd for C₁₈H₁₉N₂O₄ [M+H]⁺ 327.1328, found 327.1332.

  Ethyl 5-chloro-2-(4-chlorophenyl)-2H-indazole-3-car- boxylate (3d): Brown solid, 77% yield. m.p. 186~188 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.08 (s, 1H), 7.77 (d, J＝9.1 Hz, 1H), 7.56~7.44 (m, 5H), 7.36 (d, J＝9.0 Hz, 1H), 4.39 (q, J＝7.0 Hz, 2H), 1.38 (t, J＝7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 159.0, 146.9, 139.1, 135.6, 131.7, 129.4, 128.9, 127.6, 124.4, 124.2, 120.5, 120.1, 61.5, 14.2; HRMS (ESI) calcd for C₁₆H₁₃Cl₂N₂O₂ [M+H]⁺ 335.0355, found 335.0359.

  Diethyl 2-(4-(ethoxycarbonyl)phenyl)-2H-indazole-3, 5 - dicarb-oxylate (3e): Brown solid, 68% yield. m.p. 139~141 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.91 (s, 1H), 8.23 (d, J＝7.3 Hz, 2H), 8.05 (d, J＝8.9 Hz, 1H), 7.86 (d, J＝8.8 Hz, 1H), 7.63 (d, J＝7.8 Hz, 2H), 4.51~4.36 (m, 6H), 1.42 (m, 9H); ¹³C NMR (101 MHz, CDCl₃) δ: 166.5, 165.6, 158.9, 149.8, 143.9, 131.6, 130.6, 130.1, 127.8, 127.3, 127.2, 126.3, 125.7, 123.4, 122.9, 118.5, 61.7, 61.4, 61.3, 14.3, 14.1; HRMS (ESI) calcd for C₂₂H₂₃N₂O₆ [M+H]⁺ 411.1501, found 411.1508.

  Ethyl 5-cyano-2-(4-cyanophenyl)-2H-indazole-3-car- boxylate (3f): Brown solid, 59% yield. m.p. 192~194 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.81 (s, 1H), 8.07 (s, 1H), 7.93 (d, J＝8.5 Hz, 1H), 7.84 (d, J＝8.6 Hz, 1H), 7.24 – 7.03 (m, 3H), 4.40 (q, 2H), 1.42 (t, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 162.5, 142.2, 141.1, 132.7, 131.4, 128.8, 127.7, 127.3, 121.9, 120.9, 119.9, 118.0, 117.9, 117.5, 117.3, 104.4, 59.6, 14.9; HRMS (ESI) calcd for C₁₈H₁₃N₄O₂ [M+H]⁺317.1064, found 317.1070.

  Ethyl 7-methyl-2-(o-tolyl)-2H-indazole-3-carboxylate (3g): Brown solid, 80% yield. m.p. 74~76 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J＝8.4 Hz, 1H), 7.42 (dd, J＝10.5, 4.2 Hz, 1H), 7.38~7.26 (m, 4H), 7.18 (d, J＝6.8 Hz, 1H), 4.30 (q, 2H), 2.69 (s, 3H), 2.01 (s, 3H), 1.27 (t, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 159.4, 148.8, 140.8, 135.0, 130.5, 129.6, 128.9, 127.0, 126.3, 126.1, 125.7, 123.3, 119.0, 60.9, 17.1, 17.0, 14.0; HRMS (ESI) calcd for C₁₈H₁₉N₂O₂ [M+H]⁺ 295.1446, found 295.1453.

  Ethyl 6-methyl-2-(m-tolyl)-2H-indazole-3-carboxylate (3h): Brown solid, 83% yield. m.p. 85~87 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.99 (d, J＝8.6 Hz, 1H), 7.58 (s, 1H), 7.41~7.26 (m, 4H), 7.17 (d, J＝8.6 Hz, 1H), 4.35 (q, J＝7.0 Hz, 2H), 2.49 (s, 3H), 2.43 (s, 3H), 1.33 (t, J＝7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 159.5, 149.0, 141.0, 138.7, 137.0, 130.0, 128.4, 128.3, 126.8, 124.9, 123.5, 122.4, 121.0, 116.8, 61.0, 22.1, 21.3, 14.2; HRMS (ESI) calcd for C₁₈H₁₉N₂O₂ [M+H]⁺295.1508, found 295.1514.

  Ethyl 2-(3, 5-dimethylphenyl)-4, 6-dimethyl-2H-indazo- le-3-carboxylate (3i): Brown solid, 78% yield. m.p. 67~69 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.38 (s, 1H), 7.26 (s, 1H), 7.12 (s, 2H), 6.85 (s, 1H), 4.25 (q, J＝7.1 Hz, 2H), 2.61 (s, 3H), 2.42 (s, 3H), 2.37 (s, 6H), 1.13 (t, J＝7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 165.8, 142.0, 132.4, 131.2, 130.0, 123.3, 121.9, 119.1, 115.8, 104.3, 98.2, 60.8, 17.9, 17.5, 13.7, 11.0; HRMS (ESI) calcd for C₂₀H₂₃N₂O₂ [M+H]⁺ 323.1791, found 323.1795.

  Ethyl 2-(3-methoxy-5-methylphenyl)-2H-indazole-3- carboxylate (3j): Brown solid, 76% yield. m.p. 95~97 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 7.73 (d, J＝9.2 Hz, 1H), 7.33 (dt, J＝30.7, 9.0 Hz, 5H), 7.09 (d, J＝9.0 Hz, 1H), 4.38 (q, 2H), 3.92 (s, 3H), 2.45 (s, 3H), 1.32 (t, J＝6.7 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 159.8, 157.9, 145.1, 139.1, 138.7, 129.1, 126.0, 125.1, 121.9, 120.0, 97.9, 60.8, 55.4, 21.3, 14.2; HRMS (ESI) calcd for C₁₈H₁₉- N₂O₃ [M+H]⁺ 311.1338, found 311.1342.

  Methyl 2-phenyl-2H-indazole-3-carboxylate (3k): Brown solid, 74% yield. m.p. 79~81 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.11 (d, J＝8.2 Hz, 1H), 7.86 (d, J＝8.3 Hz, 1H), 7.53 (s, 5H), 7.42 (t, J＝7.2 Hz, 1H), 7.35 (t, J＝7.2 Hz, 1H), 3.92 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ: 160.0, 148.4, 140.9, 129.4, 128.7, 127.1, 126.33, 125.6, 124.83 123.9, 121.5, 118.6, 52.0; HRMS (ESI) calcd for C₁₅H₁₃N₂O₂ [M+H]⁺ 253.1901, found 253.1908.

  Phenyl(2-phenyl-2H-indazol-3-yl)methanone (3l): Bro- wn solid, 32% yield. m.p. 153~155 ℃; ¹H NMR (400 MHz, ) δ: 7.89~7.85 (m, 3H), 7.60 (t, J＝7.5 Hz, 1H), 7.55~7.52 (m, 2H), 7.47~7.35 (m, 7H), 7.19~7.16 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ: 168.9, 138.9, 132.5, 130.3, 126.9, 125.9, 124.0, 123.3, 123.2, 122.9, 121.7, 120.5, 120.1, 119.3, 116.5, 114.9; HRMS (ESI) calcd for C₂₀H₁₅N₂O [M+H]⁺ 299.3208, found 299.3213.

  Ethyl pyrido[2, 1-a]isoindole-6-carboxylate (5a): Yellow solid, 36% yield. m.p. 65~67 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.98 (d, J＝6.6 Hz, 1H), 8.27 (d, J＝8.5 Hz, 1H), 8.10 (ddt, J＝12.0, 8.2, 1.1 Hz, 2H), 7.55 (m, 1H), 7.29~7.27 (m, 1H), 7.27~7.25 (m, 1H), 7.21 (td, J＝6.9, 1.5 Hz, 1H), 4.51 (q, 2H), 1.52 (t, J＝7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 150.1, 126.3, 124.8, 122.5, 122.1, 117.3, 116.6, 115.9, 115.6, 114.9, 114.0, 113.9, 103.3, 67.6, 31.9; HRMS (ESI) calcd for C₁₅H₁₄NO₂ [M+H]⁺ 240.3609, found 240.3612.

  Ethyl 8-methoxypyrido[2, 1-a]isoindole-6-carboxylate (5b): Yellow solid, 27% yield. m.p. 94~96 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.88 (s, 1H), 8.00~7.91 (m, 2H), 7.60 (s, 1H), 7.25 (m, 1H), 7.12 (td, J＝7.0, 1.4 Hz, 1H), 6.90 (dd, J＝8.8, 2.3 Hz, 1H), 4.49 (q, J＝7.1 Hz, 3H), 3.95 (s, 3H), 1.51 (t, J＝7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 150.1, 148.3, 126.5, 122.3, 117.8, 116.7, 113.4, 112.9, 111.1, 110.9, 103.1, 99.0, 67.5, 64.2, 31.9; HRMS (ESI) calcd for C₁₆H₁₆NO₃ [M+H]⁺ 270.1681, found 270.1685.

  Ethyl 8-acetylpyrido[2, 1-a]isoindole-6-carboxylate (5c): Yellow solid, 21% yield. m.p. 113~115 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 9.90 (d, J＝6.7 Hz, 1H), 8.85 (s, 1H), 8.11~8.07 (m, 2H), 7.79 (dd, J＝8.6, 1.5 Hz, 1H), 7.33~7.27 (m, 1H), 7.24 (td, J＝6.9, 1.5 Hz, 1H), 4.51 (q, J＝7.1 Hz, 2H), 2.72 (s, 3H), 1.54 (t, J＝7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ: 179.0, 149.7, 129.2, 125.7, 123.9, 122.1, 118.1, 117.6, 116.2, 115.7, 115.2, 114.6, 114.5, 104.1, 67.9, 41.4, 31.8; HRMS (ESI) calcd for C₁₇H₁₅NO₃ [M+H]⁺ 282.1131, found 282.1134.

  2-Phenyl-2H-indazole (6a): Yellow solid, 36% yield. m.p. 83~85 ℃; ¹H NMR (500 MHz, CDCl₃) δ: 8.43 (s, 1H), 7.93 (d, J＝7.7 Hz, 2H), 7.83 (d, J＝8.8 Hz, 1H), 7.73 (d, J＝8.5 Hz, 1H), 7.55 (t, J＝7.9 Hz, 2H), 7.42 (t, J＝7.4 Hz, 1H), 7.38~7.33 (m, 1H), 7.15 (dd, J＝8.0, 7.0 Hz, 1H); ¹³C NMR (126 MHz, CDCl₃) δ: 149.8, 140.5, 129.6, 127.9, 126.8, 122.8, 122.4, 121.0, 120.4, 120.4, 118.0; MS (ESI) m/z: 195.09.

  Supporting Information The kinetic isotope effect (KIE) experiments and the ¹H NMR and ¹³C NMR spectra of all products. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
• 1. [1]

     (a) De Angelis, M.; Stossi, F.; Carlson, K. A.; Katzenellenbogen, B. S.; Katzenellenbogen, K. A. J. Med. Chem. 2005, 48, 1132.
     (b) A Haddadin, M. J.; Conrad, W. E.; Kurth, M. J. Mini-Rev. Med. Chem. 2012, 12, 1293.
     (c) Hu, J.-T.; Cheng, Y.-F.; Yang, Y.-Q.; Rao, Y. Chem. Commun. 2011, 47, 10133.
     (d) Magano, J.; Waldo, M.; Greene, D.; Nord, E. Org. Process Res. Dev. 2008, 12, 877.
     

  2. [2]

     (a) De Lena, M.; Lorusso, V.; Latorre, A.; Fanizza, G.; Gargano, G.; Caporusso, L.; Guida, M.; Catino, A.; Crucitta, E.; Sambiasi, D.; Mazzei, A. Eur. J. Cancer 2001, 37, 364.
     (b) Atta-ur-Rahman; Malik, S.; Cun-heng, H.; Clardy, J. Tetrahedron Lett. 1985, 26, 2759.
     (c) 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. WO 2012051659, 2011.
     (d) Steffan, R. J.; Matelan, E. M. WO 2006050006, 2006.
     

  3. [3]

     (a) Luo, G.; Chen, L.; Dubowchik, G. J. Org. Chem. 2006, 71, 5392.
     (b) Unsinn, A.; Knochel, P. Chem. Commun. 2012, 48, 2680.
     (c) Bunnell, A.; Yang, C.; Petrica, A.; Soth, M. J. Synth. Commun. 2006, 36, 285.
     

  4. [4]

     For selected reviews, see: (a) Ackermann, C. Acc. Chem. Res. 2014, 47, 281.
     (b) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651.
     (c) Huang, Z.; Lim, H, N.; Mo, F.; Young, M. C.; Dong, G. Chem. Soc. Rev. 2015, 44, 7764.
     (d) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X. Chem. Soc. Rev. 2015, 44, 291.
     (e) Chen, Z.; Wang, B.; Zhang, J.; Yu, W.; Liu, Z.; Zhang, Y. Org. Chem. Front. 2015, 2, 1107.
     (f) Song, G.; Li, X. Acc. Chem. Res. 2015, 48, 1007.
     (g) Zhang, F.; Spring, D. R. Chem. Soc. Rev. 2014, 43, 6906.
     (h) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369.
     (Ⅰ) Chen, X., Bai, L.; Zeng, W. Chin. J. Org. Chem. 2018, 38, 1859(in Chinese).
     (陈训, 白丽丽, 曾伟, 有机化学, 2018, 38, 1859.)
     (j) Zhang, Z.; Butt, N. A.; Zhou, M.; Liu, D.; Zhang, W. Chin. J. Chem. 2018, 36, 443.
     (k) Jeong, T.; Han, S. H.; Han, S.; Sharma, S.; Park, J.; Lee, J.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Org. Lett. 2016, 18, 232.
     (l) Chen, W.; Yang, W.; Wu, R.; Yang, D. Green Chem. 2018, 20, 2512.
     (m) Yang, W.; Chen, Y.; Yao, Y.; Yang, X.; Lin, Q.; Yang, D. J. Org. Chem. 2019, 84, 11080.
     (n) Yao, Y.; Yang, W.; Lin, Q.; Yang, W.; Li, H.; Wang, L.; Gu, F.; Yang D. Org. Chem. Front.. 2019, 6, 3360.
     

  5. [5]

     Lian, Y.; Bergman, R. G.; Lavis, L. D.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 7122. doi: 10.1021/ja402761p
     

  6. [6]

     (a) Hummel, J. R.; Ellman, J. A. J. Am. Chem. Soc. 2015, 137, 490.
     (b) Geng, X.; Wang, C. Org. Lett. 2015, 17, 2434.
     

  7. [7]

     (a) T. Gensch, M. N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc. Rev. 2016, 45, 2900.
     (b) Suzuki, C.; Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Adv. Synth. Catal. 2014, 356, 1521.
     (c) Itoh, M.; Hashimoto, Y.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2013, 78, 8098.
     (d) Suzuki, C.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2013, 15, 3990.
     (e) Kong, D.; Lu, G.; Wu, M.; Shi, Z.; Lin, Q. ACS Sustainable chem. Eng. 2017, 5, 3465.
     (f) De Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Ackermann, L. Adv. Synth. Catal. 2014, 356, 1461.
     (g) Zhang, Y.; Yang, Z.; Yu, X.; Cheng, X.; Li, W.; Guo, L.; Hai, L.; Guo, L.; Wu, Y. Chin. J. Org. Chem. 2018, 38, 3211(in Chinese).
     (张勇, 杨中振, 余昕玲, 程旭, 李伟剑, 郭令妹, 海俐, 郭丽, 吴勇, 有机化学, 2018, 38, 3211.)
     (h) Xu, W.; Wang, N.; Zhang, M.; Shi, D. Chin. J. Org. Chem. 2019, 39, 1735(in Chinese).
     (徐文韬, 王宁, 张梦烨, 史达清, 有机化学, 2019, 39, 1735.)
     

  8. [8]

     白丽丽, 王颖, 王烁今, 孔杜林, 付艳, 彭德乾, 文丽君, 陈训, 有机化学, 2018, 38, 3242.Bai, L.; Wang, Y.; Wang, S.; Kong, D.; Fu, Y.; Peng, D.; Wen, L.; Chen, X. Chin. J. Org. Chem. 2018, 38, 3242(in Chinese).
     

  9. [9]

     (a) Li, B.; Xu, H.; Wang, H.; Wang, B. ACS Catal. 2016, 6, 3856.
     (b) Huang, X.; Huang, J.; Du, C.; Zhang, X.; Song, F.; You, J. Angew. Chem., Int. Ed. 2013, 52, 12970.
     (c) Thirunavukkarasu, V. S.; Raghuvanshi, K.; Ackermann, L. Org. Lett. 2013, 15, 3286.
     

  10. [10]

      (a) Chen, X.; Hu, X.; Deng, Y.; Jiang, H.; Zeng, W. Org. Lett. 2016, 18, 4742.
      (b) Jeon, B.; Yeon, U.; Son, J. Y.; Lee, P. H. Org. Lett. 2016, 18, 4610.
      

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  Figure 1  Selected bioactive indazole compounds

  下载: 全尺寸图片 幻灯片
  

  Scheme 1  Indazole synthesis via C—H functionalization

  下载: 全尺寸图片 幻灯片
  

  Scheme 2  Preliminary mechanistic studies

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  Scheme 3  Proposed mechanism

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of the reaction parameters^a

  Entry	Catalyst	Additive	Solvent	Yieldb/%
  1	[Ru(p-cymene)Cl2]	None	Dioxane	24
  2	[Ru(p-cymene)Cl2]	NaOAc	Dioxane	51
  3	[Ru(p-cymene)Cl2]	KOAc	Dioxane	46
  4	[Ru(p-cymene)Cl2]	LiOAc	Dioxane	47
  5	[Ru(p-cymene)Cl2]	CsOAc	Dioxane	40
  6	[Ru(p-cymene)Cl2]	AgOAc	Dioxane	38
  7	[Ru(p-cymene)Cl2]	PivOH	Dioxane	41
  8	[Ru(p-cymene)Cl2]	AcOH	CH3CN	26
  9	[Ru(p-cymene)Cl2]	NaOAc	Toluene	Trace
  10	[Ru(p-cymene)Cl2]	NaOAc	THF	48
  11	[Ru(p-cymene)Cl2]	NaOAc	TFE	21
  12	[Ru(p-cymene)Cl2]	NaOAc	MeOH	Trace
  13	[Ru(p-cymene)Cl2]	NaOAc	DCE	64
  14	[Ru(p-cymene)Cl2]	NaOAc	DCE	76c
  15	[Ru(p-cymene)Cl2]	NaOAc	DCE	82d
  16	RuCl2(PPh3)4	NaOAc	DCE	0
  17	Ru3(CO)12	NaOAc	DCE	0
  18	RuHCl(CO)(PPh3)3	NaOAc	DCE	0
  a Unless otherwise noted, all the reactions were carried out using azobenzenes (1a, 0.20 mmol) and ethyl glyoxalate (2a, 0.40 mmol) with catalysts (5 mol%) in the presence of AgSbF6 (20 mol%) and additive (50 mol%) in solvent (2.0 mL) at 80 ℃ for 12 h under Ar in a sealed reaction tube, followed by flash chromatography on SiO2. b Isolated yield. c The reaction temperature is 100 ℃. d The reaction time is 24 h. TFE＝2, 2, 2-trifluoroethanol.

  下载: 导出CSV

  Table 2.  Substrate scope^{a, b}

  下载: 导出CSV
•