Synthesis of 1H-Indazoles via Silver(I)-Mediated Intramolecular Oxidative C-H Bond Amination.

We described a silver(I)-mediated intramolecular oxidative C-H amination that enables the construction of assorted 1H-indazoles that are widely applicable in medicinal chemistry. The developed amination was found to be efficient for the synthesis of a variety of 3-substituted indazoles that are otherwise difficult to be synthesized by other means of C-H aminations. Preliminary mechanistic studies suggested that the current amination proceeds via single electron transfer (SET) mediated by Ag(I) oxidant.

Introduction

Indazole and its derivatives are ubiquitously found in a broad spectrum of biological and pharmaceutical applications.[1] In particular, as a surrogate of indole that is a central motif in natural and synthetic pharmacophores,[2] indazole still has extensive space of derivatization to expand a new chemical territory for the acquisition of patents. Indeed, indazole moiety is found in a variety of FDA-approved drugs such as Granisetron (5-HT3 antagonist) as an antiemetic drug[3a] and Lonidamine (antiglycolytic drug) for brain tumor treatment.[3b] In addition, indazoles are also found as a core structure in tyrosine kinase inhibitors such as Axitinib, Pazopanib, and Entrectinib for renal cell carcinoma treatment[3c,3d] or for ROS-1 positive, metastatic nonsmall cell lung cancer.[3f] More recently, poly[ADP-ribose]polymerase inhibitor (PARP inhibitor) Niraparib with indazole core was FDA-approved for recurrent epithelial ovarian cancer[3e] (Scheme ).

Scheme 1

1H-Indazole Derivatives in Pharmaceutical Use

Based on this high demand of indazole derivatives in pharmaceutical chemistry, a wide range of synthetic approaches have been reported in precedent literature (Scheme ):[4] (a) [3 + 2] cycloaddition of diazomethanes with benzyne,[4a−4i] (b) diazotization or nitrosation of ortho-alkylanilines,[4j−4l] (c) intramolecular amination of ortho-haloarylhydrazones,[4m−4q] and (d) addition and cyclization of hydrazines with ortho-haloarylaldehydes or ketones.[4r−4w] More recently, as a straightforward and atom-efficient method, C–H bond functionalization has recently been developed,[5] and C–C- or C–N-bond-forming reactions in both inter-/intramolecular C–H functionalization grant access to synthetic variants of indazole moiety (Scheme ).[6]

Scheme 2

Diverse Approaches to 1H-Indozoles

Scheme 3

Synthesis of 1H-Indozoles via C–H Functionalization

Despite recent advances, a vast majority of current methods still exhibit a limited access to indazoles possessing 3-carbonyl or 3-alkenyl substituents, which have been proven to exhibit an exceptional level of pharmaceutical activity (Scheme , upper line). These considerations led us to develop a new C–H amination system that allows us to give an array of 3-substituted 1H-indazoles as a promising potential pharmacophore (Scheme ).

Results and Discussion

We commenced our study on intramolecular C–H amination via the cross-dehydrogenative coupling (CDC) strategy with α-ketoester-derived hydrazone 1a under catalytic oxidative conditions (Table ). The initial effort on the application of well-established Pd- or Cu-mediated systems[4] that are previously employed in C–H amidation/amination was totally ineffective (entries 1 and 2). During the course of investigation employing precedent CDC reaction conditions,[7] we realized that the iridium(III)-based catalyst system[8] successfully afforded the desired product (entry 3). Surprisingly, it was revealed that the amination was high-yielding in the absence of iridium catalyst (entry 4). This result differentiates the current reaction protocol from the previous example. A set of control experiments suggested that the copper species promotes the reaction, but not is not necesary for the amination (entries 5 and 6). These results imply that copper plays a role as a base additive, rather than a chemical oxidant. Not only the amount of silver(I) oxidant (entry 7) but also the choice of the counteranion (entries 8 and 9) was found to be crucial. We were pleased to see that the amination showed an excellent yield under elevated temperatures (entry 10). However, the use of silver as a catalyst by employing terminal oxidants was not efficient, showing a low catalyst turnover at the present stage (entries 11 and 12).

Table 1

Reaction Optimizationa

entry	catalyst (mol %)	additive (equiv)	oxidant (equiv)	temp (°C)	yield (%)b
1	Pd(OTf)2 (5)		Na2S2O8 (4.0)	80	n.r.
2	Cu(OAc)2 (100)	Na2CO3 (1.0)	O2 (1 atm)	80	n.r.c
3	[IrCp*Cl2]2 (5)	Cu(OAc)2 (0.5)	AgNTf2 (3.0)	25	90
4		Cu(OAc)2 (0.5)	AgNTf2 (3.0)	25	92
5			AgNTf2 (3.0)	25	73
6		NaOAc (1.0)	AgNTf2 (3.0)	25	60
7		Cu(OAc)2 (0.5)	AgNTf2 (1.0)	25	50
8		Cu(OAc)2 (0.5)	Ag2CO3 (3.0)	25	n.r.
9		Cu(OAc)2 (0.5)	AgOTf (3.0)	25	25
10		Cu(OAc)2 (0.5)	AgNTf2 (3.0)	80	97 (95)
11	AgNTf2 (20)	Cu(OAc)2 (0.5)	Na2S2O8 (4.0)	80	21
12	AgNTf2 (20)	Cu(OAc)2 (0.5)	PhI(OAc)2 (2.0)	80	22

1a (0.3 mmol), catalyst, additive and oxidant in 1,2-dichloroethane (1.0 mL) for 24 h.

Yield based on 1H NMR analysis of the crude reaction mixture using CH2Br2 as the internal standard (isolated yield in parentheses).

DMSO (2.0 mL) as a solvent.

With the optimized reaction conditions in hand, we next investigated the scope of the current amination (Table ). The arylhydrazones bearing electron-donating substituents at para-position (1a–1f) smoothly participated in the present amination in give good to excellent yields. It was notable to see that the substrate with unmasked amine substituent successfully converted into desired product (2f). It was also revealed that the intramolecular amination of arylhydrazones with electron-withdrawing substituents was successful (2g–2k), showing a good compatibility with halogen substituents such as F, Cl, and Br (1i–1k). Biaryl- or naphthyl-derived arylhydrazones (1l–1m) also showed good yields. The current amination took place to form a more sterically accessible C–H bond when a meta-substituted arylhydrazone was tested (2n). Disubstituted arylhydrazones (1o–1p) were also converted to the desired products in moderate yields. Notably, 1H-indazoles including amide, ketone, olefin, aryl, and even CF3 group as substituents at 3-position could be obtained under the current C–H amination protocol (2q–2u).

Table 2

Substrate Scope of 1H-Indazolesa

1 (0.3 mmol), 0.5 equiv Cu(OAc)2, and 3.0 equiv AgNTf2 in 1,2-dichloromethane (1.0 mL) at 80 °C for 24 h. Isolated yields are reported.

We subsequently investigated the substrate scope with respect to the substituents on the 1-aryl group of indazole (Table ). A wide range of functional groups on para-position was successfully applied to afford indazole products regardless of the electronic nature of the substituents (4a–4h). Substrates bearing ortho- (3i–3k) or meta- (3l–3n) substituents were also tested, albeit with somewhat diminished reaction efficiency. Besides, reaction with multisubstituted aryl rings were proven to be effective as well (4o–4q), furnishing the generality of current amination.

Table 3

Substrate Scope with Respect to 1-Aryl Substituentsa

3 (0.3 mmol), 0.5 equiv Cu(OAc)2, and 3.0 equiv AgNTf2 in 1,2-dichloromethane (1.0 mL) at 80 °C for 24 h. Isolated yields are reported.

To gain mechanistic insight for current amination, we first conducted an initial rate comparison test with deuterium-labeled substrate under standard reaction conditions (Figure A). No significant amount of primary kinetic isotope effect (KIE) value was measured (kH/kD = 1.04), implying that the C–H bond cleavage step is not involved in the rate-determining stage.

Figure 1

Preliminary mechanistic investigation.

Cyclic voltammetry (CV) data showed that the oxidation of 3e displayed two irreversible anodic waves with peak potentials of 1.5 and 2.2 V, respectively (Figure B, black line). And it was found that the second oxidation is responsible for the corresponding 1H-indazole product 4e (red line). Since the low potential threshold for an outer-sphere electron transfer event (e.g., from anode to 3e) is typically ca. 500 mV below the thermodynamic potential of the substrate,[9] this results provided a clue that the reaction can go through outer-sphere electron transfer from the employed Ag(I) oxidant (1.05 V vs Ag/AgCl)[10] to afford desired 1H-indazole products from direct oxidation of α-ketoester-derived hydrazones. In addition, the reaction efficiency was measured to be significantly dropped when (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), butylated hydroxytoluene (BHT), and 1,1-diphenylethylene (DPE) were utilized as radical scavengers, indicating that the current amination presumably proceeds via a radical intermediacy (Figure C).

Although additional mechanistic details remained unclear at the present stage, a plausible reaction pathway is depicted on the basis of the above preliminary experiments and precedent literature[6,11] (Figure D). First, an equivalent amount of silver induces proton-coupled oxidation via single electron transfer (SET) to give a nitrogen-centered radical (NCR) intermediate (II).[12] A rapid intramolecular C–N bond formation is proposed to give a subsequent radical intermediate III, which could afford the desired product IV by second SET oxidation followed by concomitant base-assisted rearomatization. According to the optimization study (Table , entry 2), Cu(II) is more likely involved in deprotonation rather than an oxidation of a substrate.

Conclusions

In conclusion, we report a new synthetic route to 1H-indazoles by intramolecular oxidative C–H amination. This silver(I)-mediated process was found to be particularly efficient for the synthesis of assorted 1H-indazoles possessing amide, ketone, ester, olefin, aryl, and even CF3 groups on 3-position that are widely applicable in medicinal chemistry. Preliminary mechanistic studies suggest that it proceeds via outer-sphere electron transfer mediated by the employed Ag(I) oxidant.

Experimental Section

General Methods

All chemicals and solvents were purchased from Sigma-Aldrich, Alfa Aesar, and TCI Chemicals unless otherwise noted. Analytical thin-layer chromatography (TLC) was performed using EMD 0.2 mm silica gel 60-F plates. Column chromatography was performed on E. Merck 60 Å silica gel (230–400 mesh). 1H NMR spectra were recorded on Bruker 300 (300 MHz). Chemical shifts were quoted in parts per million (ppm) referenced to the appropriate solvent peak or 0 ppm for TMS. 1H NMR data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet, td = triplet of doublet, m = multiplet), integration, and coupling constant (s) J in hertz (Hz). 13C NMR spectra were recorded on a Varian Gemini 500 (125 MHz). Chemical shifts were reported in ppm referenced to the center of a triplet at 77.0 ppm of chloroform-d. 19F NMR spectra were recorded on a Bruker Avance NEO 500 (471 MHz). Infrared (IR) spectra were recorded on FR-IR spectrometer. High-resolution mass spectra (HRMS) were recorded on a Varian 1200L quadrupole MS (EI) spectrophotometer. Melting points were obtained on a Mettler Toledo MP40 apparatus.

Preparation of Arylhydrazones

α-Ketoester-derived hydrazones were prepared according to the reference procedure.[13]

General Procedure for the Synthesis of 1H-Indazoles via Silver(I)-Mediated Intramolecular Oxidative C–H Amination

To a screw-capped vial with a Spinvane triangular-shaped Teflon spinbar were added arylhydrazones (0.3 mmol), AgNTf2 (0.6 mmol), Cu(OAc)2 (0.15 mmol), and 1,2-dichloroethane (1.0 mL) under atmospheric conditions. The reaction mixture was stirred in a preheated oil bath at 80 °C for 24 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography on silica gel to give the desired product.

Methyl 1-(4-methoxyphenyl)-1H-indazole-3-carboxylate (2a)

White solid; mp 117–119 °C; 1H NMR (CDCl3) δ 8.31 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.3 Hz, 3H), 7.46 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 8.5 Hz, 2H), 4.07 (s, 3H), 3.89 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.1, 159.4, 140.5, 136.2, 132.2, 127.5, 125.6, 124.2, 123.6, 122.3, 114.6, 110.8, 55.6, 52.1; IR (cm–1) 3027, 2957, 2841, 1716, 1517, 1475, 1436, 1408, 1301, 1244, 1193, 1124, 1058, 1020, 970, 835, 819, 790, 771, 743; HRMS (EI) calcd. For C16H14N2O3 [M]+ 282.1004, found 282.1003.

Methyl 1-(4-methoxyphenyl)-6-methyl-1H-indazole-3-carboxylate (2b)

White solid; mp 137–139 °C; 1H NMR (CDCl3) δ 8.17 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.9 Hz, 2H), 7.39 (s, 1H), 7.19 (s, 1H), 7.06 (d, J = 8.9 Hz, 2H), 4.05 (s, 3H), 3.89 (s, 3H), 2.50 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.2, 159.3, 141.1, 138.0, 136.1, 132.3, 125.9, 125.6, 122.4, 121.8, 114.6, 110.1, 55.6, 52.1, 22.0; IR (cm–1) 3030, 2962, 2918, 1711, 1517, 1451, 1398, 1302, 1249, 1209, 1160, 1138, 1103, 1059, 1022, 972, 836, 814, 759; HRMS (EI) calcd. For C17H16N2O3 [M]+ 296.1161, found 296.1158.

Methyl 6-methoxy-1-(4-methoxyphenyl)-1H-indazole-3-carboxylate (2c)

White solid; mp 218–220 °C; 1H NMR (CDCl3) δ 8.14 (d, J = 8.9 Hz, 1H), 7.59 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 8.9 Hz, 2H), 7.01 (dd, J = 9.0, 2.1 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H), 4.04 (s, 3H), 3.89 (s, 3H), 3.85 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.2, 160.2, 159.3, 141.9, 136.2, 132.3, 125.7, 123.0, 118.9, 115.7, 114.7, 91.5, 55.6, 52.1; IR (cm–1) 2958, 2843, 1714, 1624, 1509, 1467, 1432, 1407, 1355, 1273, 1172, 1126, 1084, 1038, 1017, 972, 880, 833, 821, 784; HRMS (EI) calcd. For C17H16N2O4 [M]+ 312.1110, found 312.1090.

Methyl 1-(4-methoxyphenyl)-6-phenoxy-1H-indazole-3-carboxylate (2d)

Colorless oil; 1H NMR (CDCl3) δ 8.24 (d, J = 8.9 Hz, 1H), 7.55 (d, J = 9.0 Hz, 2H), 7.35 (t, J = 8.0 Hz, 2H), 7.17–7.15 (m, 1H), 7.13–7.08 (m, 2H), 7.05–7.00 (m, 4H), 4.06 (s, 3H), 3.86 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.0, 159.3, 157.4, 156.9, 141.3, 136.3, 132.1, 129.9, 125.3, 123.7, 123.5, 120.6, 118.9, 117.2, 114.6, 99.4, 55.6, 52.1; IR (cm–1) 3255, 2953, 1709, 1547, 1482, 1459, 1444, 1317, 1270, 1241, 1197, 1166, 1117, 1059, 932, 886, 805, 766, 715; HRMS (EI) calcd. For C22H18N2O4 [M]+ 374.1267, found 374.0777.

Methyl 6-(dimethylamino)-1-(4-methoxyphenyl)-1H-indazole-3-carboxylate (2e)

Yellow solid; mp 130–132 °C; 1H NMR (CDCl3) δ 8.08 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 8.9 Hz, 2H), 6.95 (dd, J = 9.1, 2.2 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 4.03 (s, 3H), 3.88 (s, 3H), 3.02 (s, 6H); 13C NMR (125 MHz, CDC13) δ 163.4, 159.0, 150.7, 142.7, 136.1, 132.7, 125.6, 122.3, 116.4, 114.5, 113.1, 90.0, 55.6, 51.9, 40.9; IR (cm–1) 2995, 2947, 2915, 2847, 1703, 1621, 1513, 1440, 1394, 1352, 1298, 1249, 1198, 1141, 1113, 1059, 1026, 958, 849, 806, 791, 776, 746; HRMS (EI) calcd. For C18H19N3O3 [M]+ 325.1426, found 325.1418.

Methyl 6-amino-1-(4-methoxyphenyl)-1H-indazole-3-carboxylate (2f)

Brown oil; 1H NMR (CDCl3) δ 8.03 (dd, J = 8.5, 0.9 Hz, 1H), 7.57 (d, J = 8.9 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 6.77–6.73 (m, 2H), 4.02 (s, 3H), 3.87 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.3, 159.1, 146.7, 142.3, 136.3, 125.5, 123.0, 117.9, 115.3, 114.5, 92.9, 55.6, 52.0; IR (cm–1) 3373, 2953, 2843, 1714, 1627, 1480, 1323, 1196, 1123, 1054, 798, 743; HRMS (EI) calcd. For C16H15N3O3 [M]+ 297.1113, found 297.1114.

Methyl 1-(4-methoxyphenyl)-6-(methylsulfonyl)-1H-indazole-3-carboxylate (2g)

White solid; mp 206–208 °C; 1H NMR (CDCl3) δ 8.52 (d, J = 8.6 Hz, 1H), 8.27–8.26 (m, 1H), 7.87 (dd, J = 8.6, 1.5 Hz, 1H), 7.61 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 4.09 (s, 3H), 3.91 (s, 3H), 3.12 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.4, 160.1, 139.7, 139.5, 136.5, 131.2, 131.0, 127.9, 126.7, 125.7, 124.1, 121.2, 115.0, 111.7, 55.7, 52.5, 44.7; IR (cm–1) 3012, 2996, 2916, 1706, 1592, 1513, 1404, 1361, 1289, 1243, 1191, 1132, 1057, 1025, 967, 839, 835, 783, 763; HRMS (EI) calcd. For C17H16N2O5S [M]+ 360.0780, found 360.0777.

Dimethyl 1-(4-methoxyphenyl)-1H-indazole-3,6-dicarboxylate (2h)

White solid; mp 196–198 °C; 1H NMR (CDCl3) δ 8.35 (d, J = 7.0 Hz, 1H), 8.34 (s, 1H), 8.03 (d, J = 9.5 Hz, 1H), 7.63 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 4.08 (s, 3H), 3.96 (s, 3H), 3.91 (s, 3H); 13C NMR (125 MHz, CDC13) δ 166.8, 162.7, 159.7, 140.1, 136.2, 131.7, 129.3, 126.7, 125.7, 124.0, 122.3, 114.8, 113.2, 55.7, 52.5, 52.3; IR (cm–1) 2955, 2840, 1714, 1518, 1442, 1412, 1294, 1259, 1238, 1196, 1130, 1087, 1063, 1025, 985, 966, 825, 797, 765, 734; HRMS (EI) calcd. For C18H16N2O5 [M]+ 340.1059, found 340.1059.

Methyl 6-fluoro-1-(4-methoxyphenyl)-1H-indazole-3-carboxylate (2i)

White solid; mp 139–141 °C; 1H NMR (CDCl3) δ 8.26 (dd, J = 8.9, 5.2 Hz, 1H), 7.58 (d, J = 8.9 Hz, 2H), 7.28–7.24 (m, 2H), 7.14 (td, J = 9.0, 2.2 Hz, 1H), 7.06 (d, J = 8.9 Hz, 2H), 4.06 (s, 3H), 3.89 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.7, 162.8, 161.7, 159.5, 140.9 (d, J = 12.7 Hz) 136.4, 131.9, 125.4, 123.9 (d, J = 10.9 Hz), 121.0, 114.8, 113.6 (d, J = 25.7 Hz), 96.6 (d, J = 26.9 Hz), 55.6, 52.2; 19F NMR (471 MHz, CDC13) δ −112.4; IR (cm–1) 3080, 3051, 2948, 2846, 1715, 1626, 1520, 1502, 1471, 1443, 1408, 1304, 1250, 1199, 1177, 1111, 1062, 1033, 959, 826, 807, 795; HRMS (EI) calcd. For C16H13FN2O3 [M]+ 300.0910, found 300.0880.

Methyl 6-chloro-1-(4-methoxyphenyl)-1H-indazole-3-carboxylate (2j)

White solid; mp 156–158 °C; 1H NMR (CDCl3) δ 8.23 (d, J = 8.7 Hz, 1H), 7.61–7.57 (m, 3H), 7.33 (dd, J = 8.7, 1.7 Hz, 1H), 7.07 (d, J = 8.9 Hz, 2H), 4.06 (s, 3H), 3.90 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.7, 159.6, 140.9, 136.4, 134.1, 131.7, 125.6, 124.7, 123.3, 122.7, 114.8, 110.6, 55.7, 52.3; IR (cm–1) 3014, 2988, 2954, 2836, 1734, 1706, 1609, 1517, 1484, 1431, 1395, 1306, 1256, 1195, 1178, 1126, 1056, 1022, 975, 938, 824, 809, 799, 789, 735; HRMS (EI) calcd. For C16H13ClN2O3 [M]+ 316.0615, found 316.0613.

Methyl 6-bromo-1-(4-methoxyphenyl)-1H-indazole-3-carboxylate (2k)

White solid; mp 158–160 °C; 1H NMR (CDCl3) δ 8.17 (d, J = 8.7 Hz, 1H), 7.79 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 4.06 (s, 3H), 3.90 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.7, 159.6, 141.2, 136.4, 131.7, 127.3, 125.6, 123.5, 123.0, 122.1, 114.8, 113.7, 55.7, 52.3; IR (cm–1) 3077, 3015, 2953, 2835, 1735, 1708, 1607, 1517, 1481, 1392, 1306, 1257, 1194, 1177, 1126, 1048, 1021, 826, 808, 798, 785; HRMS (EI) calcd. For C16H13BrN2O3 [M]+ 360.0110, found 360.0104.

Methyl 1-(4-methoxyphenyl)-6-phenyl-1H-indazole-3-carboxylate (2l)

White solid; mp 131–133 °C; 1H NMR (CDCl3) δ 8.35 (d, J = 8.5 Hz, 1H), 7.75 (s, 1H), 7.67–7.62 (m, 5H), 7.47 (t, J = 8.7 Hz, 1H), 7.41–7.36 (m, 1H), 7.07 (d, J = 8.8 Hz, 2H), 4.08 (s, 3H), 3.90 (s, 3H); 13C NMR (125 MHz, CDC13) δ163.1, 159.4, 141.2, 140.8, 136.2, 132.2, 128.9, 127.8, 127.7, 125.7, 123.9, 123.4, 122.5, 114.7, 108.8, 55.6, 52.2; IR (cm–1) 3088, 3026, 2999, 2960, 2843, 1129, 1614, 1516, 1467, 1427, 1403, 1259, 1233, 1186, 1169, 1130, 1061, 1018, 969, 899, 846, 798, 714; HRMS (EI) calcd. For C22H18N2O3 [M]+ 358.1317, found 358.1317.

Methyl 1-(4-methoxyphenyl)-1H-benzo[f]indazole-3-carboxylate (2m)

White solid; mp 160–162 °C; 1H NMR (CDCl3) δ 8.29 (d, J = 8.9 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.57–7.49 (m, 4H), 7.37–7.32 (m, 1H), 7.10 (d, J = 8.9 Hz, 2H), 4.07 (s, 3H), 3.95 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.3, 160.6, 137.9, 136.4, 134.0, 133.2, 129.1, 128.7, 126.7, 126.4, 125.5, 121.8, 121.6, 120.7, 119.5, 114.7, 55.7, 52.1; IR (cm–1) 3003, 2954, 2903, 2841, 1714, 1605, 1515, 1478, 1460, 1440, 1385, 1326, 1251, 1171, 1119, 1103, 1055, 1028, 980, 835, 822, 788, 692; HRMS (EI) calcd. For C20H16N2O3 [M]+ 332.1161, found 332.1160.

Methyl 5-methoxyl-1-(4-methoxyphenyl)-1H-indazole-3-carboxylate (2n)

White solid; mp 173–175 °C; 1H NMR (CDCl3) δ 7.64 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 9.2 Hz, 1H), 7.11 (dd, J = 9.2, 2.4 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 4.05 (s, 3H), 3.93 (s, 3H), 3.88 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.4, 159.3, 156.8, 125.3, 120.0, 114.6, 111.9, 100.8, 55.8, 55.6, 52.0; IR (cm–1) 3018, 2950, 2831, 1701, 1619, 1518, 1498, 1479, 1459, 1442, 1408, 1348, 1309, 1270, 1252, 1193, 1171, 1161, 1141, 1105, 1052, 1019, 975, 884, 877, 833, 797, 697; HRMS (EI) calcd. For C17H16N2O4 [M]+ 312.1110, found 312.1085.

Methyl 5,6-dimethoxyl-1-(4-methoxyphenyl)-1H-indazole-3-carboxylate (2o)

White solid; mp 177–179 °C; 1H NMR (CDCl3) δ 7.61 (s, 1H), 7.58 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 6.91 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H). 3.91 (s, 3H), 3.88 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.6, 159.4, 151.4, 148.3, 136.2, 135.4, 132.3, 125.6, 118.1, 114.7, 100.8, 91.7, 56.3, 56.2, 55.6, 52.1, 50.8; IR (cm–1) 2953, 2837, 1722, 1632, 1515, 1494, 1463, 1436, 1427, 1399, 1352, 1284, 1247, 1192, 1159, 1135, 1111, 1056, 1032, 1012, 977, 868, 830, 796, 783, 744, 703; HRMS (EI) calcd. For C18H18N2O5 [M]+ 342.1216, found 342.1224.

Methyl 1-(4-methoxyphenyl)-6,7-dihydro-1H-[1,4]dioxino[2,3-f]indazole-3-carboxylate (2p)

White solid; mp 199–201 °C; 1H NMR (CDCl3) δ 7.72 (s, 1H), 7.60 (d, J = 9.0 Hz, 2H), 7.09 (s, 1H), 7.05 (d, J = 9.0 Hz, 2H), 4.34 (s, 4H), 4.05 (s, 3H), 3.89 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.2, 159.1, 145.6, 142.3, 136.3, 135.5, 132.5, 125.1, 119.1, 114.6, 107.6, 97.2, 64.6, 64.1, 55.6, 52.0; IR (cm–1) 3072, 2957, 2874, 1172, 1635, 1607, 1589, 1569, 1509, 1483, 1456, 1440, 1420, 1399, 1388, 1334, 1292, 1268, 1245, 1220, 1183, 1157, 1123, 1106, 1069, 1057, 1033, 1022, 969, 936, 909, 874, 862, 832, 796, 783, 726, 707, 692; HRMS (EI) calcd. For C18H16N2O5 [M]+ 340.1059, found 340.1054.

1-(4-Methoxyphenyl)-N-methyl-1H-indazole-3-carboxamide (2q)

Yellow solid; mp 127–129 °C; 1H NMR (CDCl3) δ 8.47 (d, J = 8.2 Hz, 1H), 7.65–7.55 (m, 3H), 7.50–7.39 (m, 1H), 7.39–7.28 (m, 1H), 7.12–7.03 (m, 2H), 3.90 (s, 3H), 3.07 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.2, 159.1, 140.6, 138.9, 132.5, 127.5, 125.0, 123.4, 123.1, 114.7, 110.3, 55.6, 25.7; IR (cm–1) 3348, 3061, 2969, 1734, 1647, 1535, 1508, 1488, 1448, 1434, 1405, 1370, 1297, 1249, 1199, 1173, 1155, 1130, 1106, 1087, 1030, 1009, 996, 944, 851, 827, 806, 797, 789, 772, 742, 690, 670; HRMS (EI) calcd. For C16H15N3O2 [M]+ 281.1164, found 281.1147.

(1-(4-Methoxyphenyl)-1H-indazole-3-yl)(phenyl)methanone (2r)

Yellow oil; 1H NMR (CDCl3) δ 8.56 (d, J = 7.9 Hz, 1H), 8.42 (d, J = 7.4 Hz, 2H), 7.70–7.66 (m, 3H), 7.59 (d, J = 7.1 Hz, 1H), 7.55–7.47 (m, 3H), 7.42 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 3.89 (s, 3H); 13C NMR (125 MHz, CDC13) δ 188.6, 159.3, 143.1, 140.1, 137.9, 132.5, 130.7, 128.2, 127.6, 125.2, 124.1, 123.4, 114.8, 110.6, 55.7; IR (cm–1) 3055, 2834, 1636, 1596, 1574, 1512, 1465, 1404, 1300, 1279, 1246, 1200, 1177, 1157, 1132, 1106, 1082, 1027, 967, 884, 831, 802, 760, 745, 708, 687; HRMS (EI) calcd. For C21H16N2O2 [M]+ 328.1212, found 328.1183.

(E)-1-(4-Methoxyphenyl)-3-(prop-1-en-1-yl)-1H-indazole (2s)

Colorless oil; 1H NMR (CDCl3) δ 7.85 (d, J = 7.2 Hz, 2H), 7.43–7.37 (m, 4H), 7.32–7.28 (m, 1H), 6.99 (d, J = 8.9 Hz, 2H), 6.50 (s, 1H), 3.86 (s, 3H), 2.33 (s, 3H); 13C NMR (125 MHz, CDC13) δ 159.1, 151.1, 140.3, 133.4, 128.6, 127.7, 126.6, 125.7, 114.2, 103.8, 55.6, 12.4; IR (cm–1) 3058, 3013, 2912, 2835, 1611, 1551, 1508, 1466, 1453, 1439, 1411, 1365, 1302, 1251, 1175, 1135, 1112, 1082, 1041, 1022, 1003, 972, 951, 840, 826, 798, 764, 735, 716, 693, 658; HRMS (EI) calcd. For C17H163N2O [M]+ 264.1263, found 264.1282.

1-(4-Methoxyphenyl)-3-phenyl-1H-indazole (2t)

White solid; mp 126–128 °C; 1H NMR (CDCl3) δ 8.09 (d, J = 8.2 Hz, 1H), 8.07–8.01 (m, 2H), 7.72–7.63 (m, 3H), 7.59–7.50 (m, 2H), 7.49–7.40 (m, 2H), 7.34–7.27 (m, 1H), 7.12–7.03 (m, 2H), 3.90 (s, 3H); 13C NMR (125 MHz, CDC13) δ 158.5, 145.5, 140.6, 133.4, 133.2, 128.8, 128.2, 127.7, 126.9, 124.8, 122.7, 121.7, 121.5, 114.6, 110.5, 55.6; IR (cm–1) 3044, 2837, 1601, 1519, 1508, 1470, 1446, 1419, 1398, 1362, 1348, 1309, 1296, 1251, 1227, 1173, 1126, 1113, 1098, 1072, 1025, 992, 940, 847, 830, 809, 779, 770, 750, 741, 727, 700, 667; HRMS (EI) calcd. For C20H16N2O [M]+ 300.1263, found 300.1257.

1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-indazole (2u)

White solid; mp 70–72 °C; 1H NMR (CDCl3) δ 7.91 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 9.0 Hz, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 9.0 Hz, 2H), 3.89 (s, 3H); 13C NMR (125 MHz, CDC13) δ 159.3, 140.2, 132.1, 127.9, 125.3, 123.1, 120.3, 114.8, 110.9, 55.7; 19F NMR (471 MHz, CDC13) δ −60.7; IR (cm–1) 3065, 2850, 1588, 1518, 1497, 1467, 1427, 1409, 1347, 1301, 1282, 1248, 1175, 1151, 1116, 1027, 1007, 946, 828, 772, 756, 739, 681; HRMS (EI) calcd. For C15H11F3N2O [M]+ 292.0823, found 292.0822.

Methyl 1-(p-tolyl)-1H-indazole-3-carboxylate (4a)

White solid; mp 119–121 °C; 1H NMR (CDCl3) δ 8.32 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.47 (t, J = 7.6 Hz, 1H), 7.40–7.34 (m, 3H), 4.07 (s, 3H), 2.45 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.1, 140.3, 138.1, 136.7, 136.4, 130.1, 127.5, 124.4, 123.8, 123.6, 122.3, 110.9, 52.1, 21.2; IR (cm–1) 2949, 2921, 1708, 1516, 1473, 1439, 1407, 1351, 1249, 1194, 1170, 1118, 1056, 970, 829, 789, 770, 751; HRMS (EI) calcd. For C16H14N2O2 [M]+ 266.1055, found 266.1048.

Methyl 1-(4-isopropylphenyl)-1H-indazole-3-carboxylate (4b)

White solid; mp 92–94 °C; 1H NMR (CDCl3) δ 8.32 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 7.7 Hz, 1H), 7.42–7.36 (m, 3H), 4.07 (s, 3H), 3.08–2.94 (m, 1H), 1.31 (d, J = 6.9 Hz, 6H); 13C NMR (125 MHz, CDC13) δ 163.1, 149.0, 140.3, 137.0, 136.4, 127.5, 124.4, 123.9, 123.6, 122.3, 111.0, 52.1, 33.9, 24.0; IR (cm–1) 3059, 2955, 2866, 1718, 1605, 1515, 1474, 1435, 1404, 1360, 1258, 1193, 1170, 1164, 1123, 1052, 854, 835, 787, 770, 754; HRMS (EI) calcd. For C18H18N2O2 [M]+ 294.1368, found 294.1366.

Methyl 1-phenyl-1H-indazole-3-carboxylate (4c)

White solid; mp 71–73 °C; 1H NMR (CDCl3) δ 8.32 (d, J = 8.1 Hz, 1H), 7.76–7.70 (m, 3H), 7.56 (t, J = 7.8 Hz, 2H), 7.51–7.35 (m, 3H), 4.07 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.1, 140.2, 139.2, 136.7, 129.6, 128.1, 127.7, 124.5, 123.9, 123.8, 122.4, 110.9, 52.2; IR (cm–1) 3006, 2953, 1727, 1597, 1476, 1458, 1409, 1364, 1257, 1169, 1127, 1075, 1058, 969, 863, 755, 722; HRMS (EI) calcd. For C15H12N2O2 [M]+ 252.0899, found 252.0927.

Methyl 1-(4-(trifluoromethoxyl)phenyl)-1H-indazole-3-carboxylate (4d)

White solid; mp 68–70 °C; 1H NMR (CDCl3) δ 8.34 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.5 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.44–7.39 (m, 3H), 4.08 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.8, 148.3, 140.1, 137.7, 137.2, 128.0, 125.1, 124.5, 123.9, 122.6, 122.1, 120.4 (q, J = 256.4 Hz), 110.5, 52.2; 19F NMR (471 MHz, CDC13) δ −58.0; IR (cm–1) 3053, 2954, 1729, 1511, 1478, 1408, 1253, 1222, 1194, 1152, 1123, 1044, 969, 951, 921, 860, 808, 789, 749; HRMS (EI) calcd. For C16H11F3N2O3 [M]+ 336.0722, found 336.0727.

Methyl 1-(4-(trifluoromethyl)phenyl)-1H-indazole-3-carboxylate (4e)

White solid; mp 100–102 °C; 1H NMR (CDCl3) δ 8.34 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.83 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 7.7 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 4.08 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.8, 142.1, 140.0, 137.8, 129.7 (q, J = 33.0 Hz), 128.3, 126.8 (q, J = 3.6 Hz), 124.8, 124.2, 123.5, 122.8, 110.6, 52.3; 19F NMR (471 MHz, CDC13) δ −62.5; IR (cm–1) 2956, 1739, 1611, 1483, 1319, 1248, 1157, 1116, 1104, 1066, 1013, 969, 843, 789, 772, 766; HRMS (EI) calcd. For C16H11F3N2O2 [M]+ 320.0773, found 320.0771.

Methyl 1-(4-fluorophenyl)-1H-indazole-3-carboxylate (4f)

White solid; mp 140–142 °C; 1H NMR (CDCl3) δ 8.33 (d, J = 8.1 Hz, 1H), 7.77–7.68 (m, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.26 (t, J = 8.5 Hz, 2H), 4.07 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.0, 162.0 (d, J = 247.2 Hz), 140.3, 136.8, 135.3 (d, J = 3.5 Hz), 127.8, 125.8 (d, J = 8.9 Hz), 124.4, 123.8, 122.5, 116.5 (d, J = 22.6 Hz), 110.6, 52.2; 19F NMR (471 MHz, CDC13) δ −112.9; IR (cm–1) 3056, 2967, 1711, 1511, 1474, 1423, 1403, 1252, 1198, 1153, 1123, 1060, 972, 846, 810, 790, 738; HRMS (EI) calcd. For C15H11FN2O2 [M]+ 270.0805, found 270.0803.

Methyl 1-(4-chlorophenyl)-1H-indazole-3-carboxylate (4g)

White solid; mp 131–133 °C; 1H NMR (CDCl3) δ 8.33 (d, J = 8.1 Hz, 1H), 7.75–7.64 (m, 3H), 7.55–7.48 (m, 3H), 7.40 (t, J = 7.5 Hz, 1H), 4.08 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.9, 140.1, 137.8, 137.1, 133.7, 129.7, 128.0, 124.9, 124.5, 123.9, 122.6, 110.6, 52.3; IR (cm–1) 2993, 2919, 2850, 1709, 1493, 1474, 1408, 1350, 1248, 1194, 1168, 1119, 1090, 1083, 1009, 968, 835, 791, 744, 735; HRMS (EI) calcd. For C15H11ClN2O2 [M]+ 286.0509, found 286.0508.

Methyl 1-(4-bromophenyl)-1H-indazole-3-carboxylate (4h)

White solid; mp 110–112 °C; 1H NMR (CDCl3) δ 8.33 (d, J = 8.1 Hz, 1H), 7.71–7.63 (m, 5H), 7.51 (t, J = 7.7 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 4.08 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.9, 140.1, 138.3, 137.2, 132.7, 128.0, 125.2, 124.6, 124.0, 122.6, 121.6, 110.6, 52.3; IR (cm–1) 3080, 3051, 2946, 1715, 1586, 1481, 1447, 1418, 1343, 1246, 1199, 1169, 1120, 1069, 1057, 835, 820, 792, 771, 743; HRMS (EI) calcd. For C15H11BrN2O2 [M]+ 330.0004, found 330.0001.

Methyl 1-(2-methoxyphenyl)-1H-indazole-3-carboxylate (4i)

White solid; mp 166–168 °C; 1H NMR (CDCl3) δ 8.30 (d, J = 7.9 Hz, 1H), 7.51–7.44 (m, 2H), 7.42–7.33 (m, 2H), 7.24 (s, 1H), 7.13–7.09 (m, 2H), 4.05 (s, 3H), 3.76 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.2, 154.6, 142.0, 136.5, 130.6, 129.0, 127.5, 127.1, 123.6, 123.3, 121.9, 120.9, 112.2, 111.4, 55.8, 52.1; IR (cm–1) 3073, 2969, 2841, 1729, 1598, 1507, 1478, 1432, 1405, 1244, 1193, 1163, 1142, 1124, 1115, 1066, 953, 810, 789, 769; HRMS (EI) calcd. For C16H14N2O3 [M]+ 282.1004, found 282.1003.

Methyl 1-(o-tolyl)-1H-indazole-3-carboxylate (4j)

White solid; mp 77–79 °C; 1H NMR (CDCl3) δ 8.32 (d, J = 7.7 Hz, 1H), 7.46–7.35 (m, 6H), 7.23 (d, J = 8.3 Hz, 1H), 4.06 (s, 3H), 2.08 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.2, 141.7, 137.4, 136.2, 135.9, 131.3, 129.7, 127.7, 127.5, 126.8, 123.5, 123.4, 122.1, 110.6, 52.1, 17.7; IR (cm–1) 3057, 2944, 1706, 1495, 1472, 1441, 1403, 1251, 1210, 1193, 1132, 1115, 1060, 986, 776, 751, 729; HRMS (EI) calcd. For C16H14N2O2 [M]+ 266.1055, found 266.1046.

Methyl 1-(2-fluorophenyl)-1H-indazole-3-carboxylate (4k)

White solid; mp 95–97 °C; 1H NMR (CDCl3) δ 8.32 (d, J = 8.8 Hz, 1H), 7.69–7.63 (m, 1H), 7.54–7.47 (m, 2H), 7.42–7.30 (m, 4H), 4.07 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.9, 157.5, 155.5, 141.6, 137.6, 130.6 (d, J = 7.7 Hz), 128.6, 127.8, 126.7 (d, J = 11.9 Hz), 125.0 (d, J = 3.8 Hz), 123.8, 122.2, 117.0 (d, J = 19.3 Hz), 110.9 (d, J = 4.3 Hz), 52.2; 19F NMR (471 MHz, CDC13) δ −120.2; IR (cm–1) 3010, 2959, 1720, 1509, 1440, 1404, 1250, 1222, 1195, 1177, 1126, 1098, 1060, 1028, 827, 808, 768; HRMS (EI) calcd. For C15H11FN2O2 [M]+ 270.0805, found 270.0818.

Methyl 1-(m-tolyl)-1H-indazole-3-carboxylate (4l)

Colorless oil; 1H NMR (CDCl3) δ 8.32 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.57–7.35 (m, 5H), 7.23 (s, 1H), 4.07 (s, 3H), 2.46 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.1, 140.2, 139.8, 139.1, 136.5, 129.2, 128.8, 127.6, 124.6, 123.7, 122.4, 120.8, 111.0, 52.2, 21.4; IR (cm–1) 3031, 2951, 1713, 1608, 1591, 1477, 1438, 1407, 1348, 1252, 1214, 1166, 1123, 1062, 1011, 936, 846, 788, 749, 694; HRMS (EI) calcd. For C16H14N2O2 [M]+ 266.1055, found 266.1048.

Methyl 1-(3-(trifluoromethyl)phenyl)-1H-indazole-3-carboxylate (4m)

White solid; mp 83–85 °C; 1H NMR (CDCl3) δ 8.35 (d, J = 8.1 Hz, 1H), 8.05 (s, 1H), 7.99–7.96 (m, 1H), 7.74–7.70 (m, 3H), 7.57–7.51 (m, 1H), 7.46–7.40 (m, 1H), 4.09 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.7, 140.0, 139.7, 137.6, 132.2 (q, J = 32.8 Hz), 130.2, 128.2, 126.6, 124.6, 124.5 (q, J = 3.9 Hz), 124.1, 123.5 (q, J = 271.0 Hz), 122.7, 120.6 (q, J = 3.8 Hz), 110.4, 52.3; 19F NMR (471 MHz, CDC13) δ −62.7; IR (cm–1) 2956, 1711, 1595, 1484, 1445, 1414, 1318, 1271, 1243, 1199, 1170, 1103, 1061, 933, 886, 828, 792, 756, 696; HRMS (EI) calcd. For C16H11F3N2O2 [M]+ 320.0773, found 320.0790.

Methyl 1-(3-bromophenyl)-1H-indazole-3-carboxylate (4n)

White solid; mp 113–115 °C; 1H NMR (CDCl3) δ 8.33 (d, J = 8.1 Hz, 1H), 7.95 (t, J = 2.0 Hz, 1H), 7.77–7.67 (m, 2H), 7.63–7.48 (m, 2H), 7.48–7.38 (m, 2H), 4.08 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.8, 140.3, 140.1, 137.3, 131.0, 130.8, 128.1, 126.8, 124.6, 124.0, 123.1, 122.6, 122.1, 110.7, 52.3; IR (cm–1) 3054, 2951, 1724, 1709, 1590, 1486, 1470, 1436, 1409, 1250, 1196, 1185, 1123, 1063, 986, 875, 786, 761, 749, 696; HRMS (EI) calcd. For C15H11BrN2O2 [M]+ 330.0004, found 329.9999.

Methyl 1-(2,5-dimethylphenyl)-1H-indazole-3-carboxylate (4o)

White solid; mp 108–110 °C; 1H NMR (CDCl3) δ 8.32 (d, J = 7.8 Hz, 1H), 7.46–7.34 (m, 2H), 7.28–7.20 (m, 4H), 4.06 (s, 3H), 2.37 (s, 3H), 2.02 (s, 3H); 13C NMR (125 MHz, CDC13) δ 163.2, 141.6, 137.2, 136.7, 136.1, 132.4, 131.1, 130.4, 128.3, 127.4, 123.4, 122.1, 110.7, 52.1, 20.7, 17.2; IR (cm–1) 3053, 3004, 2954, 2918, 1714, 1508, 1495, 1476, 1438, 1403, 1250, 1217, 1187, 1172, 1151, 1142, 1122, 1112, 1055, 1002, 933, 828, 796, 772, 752; HRMS (EI) calcd. For C17H16N2O2 [M]+ 280.1212, found 280.1211.

Methyl 1-(3-chloro-4-methylphenyl)-1H-indazole-3-carboxylate (4p)

White solid; mp 94–96 °C; 1H NMR (CDCl3) δ 8.32 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 2.2 Hz, 1H), 7.72–7.36 (m, 1H), 7.55–7.48 (m, 2H), 7.42–7.37 (m, 2H), 4.08 (s, 3H), 2.47 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.9, 140.1, 137.9, 136.9, 136.0, 135.1, 131.5, 127.9, 124.5, 124.3, 123.9, 122.5, 121.8, 110.7, 52.2, 19.8; IR (cm–1) 3058, 2984, 2948, 1711, 1604, 1493, 1476, 1443, 1409, 1247, 1210, 1192, 1119, 1063, 943, 863, 839, 817, 796, 737; HRMS (EI) calcd. For C16H13ClN2O2 [M]+ 300.0666, found 300.0651.

Methyl 1-(3,5-dichlorophenyl)-1H-indazole-3-carboxylate (4q)

White solid; mp 148–150 °C; 1H NMR (CDCl3) δ 8.33 (d, J = 8.1 Hz, 1H), 7.59–7.47 (m, 4H), 7.41 (t, J = 7.5 Hz, 1H), 7.29 (s, 1H), 4.07 (s, 3H); 13C NMR (125 MHz, CDC13) δ 162.7, 141.5, 137.7, 137.1, 133.4, 131.5, 130.9, 130.1, 130.0, 127.9, 123.9, 123.5, 122.4, 110.9, 52.3; IR (cm–1) 3077, 2957, 1719, 1588, 1489, 1439, 1341, 1250, 1197, 1143, 1122, 1064, 942, 867, 831, 805, 789, 745, 679; HRMS (EI) calcd. For C15H10Cl2N2O2 [M]+ 320.0119, found 320.0093.