Synthesis, Characterization, and Application of Pd(II)-NNN Pincer Complexes in Direct C–H Arylation of Heteroarenes with Aryl Bromides

Abstract

We report the synthesis, characterization, and catalytic activity of two new palladium­(II) complexes featuring benzo­[d]­oxazol-2-yl-based pincer ligands, namely, [Pd­(NNN^mor)­Cl] (C1) [Pd­(NNN^pic)­Cl] (C2), and (where NNN^mor = N-(2-(benzo­[d]­oxazol-2-yl)­phenyl)-2-morpholinoacetamide) NNN^pic = N-(2-(benzo­[d]­oxazol-2-yl)­phenyl) picolinamide. Structures of the ligands and the complexes were confirmed by FTIR, NMR and high-resolution mass spectrometry (HRMS). Further, the molecular structure of C2 in the solid state was confirmed by single-crystal X-ray diffraction. The complex showed pincer coordination mode with a distorted square planar geometry. The catalytic activity of these Pd­(II) complexes in the direct arylation of indazoles and other heteroarenes with aryl bromides has been explored, with complex C2 exhibiting better reactivity compared to complex C1. Mechanistic investigations revealed that the catalytic pathway involves a Pd^II–Pd^IV-Pd^II cycle. The results are supported by DFT calculations.

Introduction

Pincer complexes are characterized by bearing a tridentate bond in a meridional coordination mode that forms two metallacycles, where the coordinating atoms are in a coplanar conformation. The complexes are stabilized through a chelate effect. Shaw and co-workers first discovered the pincer ligand and Shaw and van Koten first used the “pincer” terminology for a tridentate meridionally chelating monoanionic ligand with a phenyl backbone. Pincer complexes have been extensively utilized as catalysts for a wide variety of organic transformations, including C–H activation due to their extraordinary chemical characteristics, such as exceptional stability, distinct reactivity, and easy functionalization. − Appropriate changes in ligand design elements offer an opportunity for improvement in structural and electronic properties of pincer complex, and thereby the catalytic activity and stability of pincer metal complexes can be tuned. Catalytic activity of palladium pincer complexes derived from phosphine- and carbene-based pincer ligands have been explored extensively for carbon–carbon and carbon-heteroatom coupling reactions. − Although these complexes exhibit exceptional catalytic efficiency, their air and moisture sensitivity make them less attractive. In recent years, palladium pincer complexes with NNN-tridentate coordination have shown comparable catalytic activity with the phosphine- and carbene-based complexes, with better stability in air and moisture sensitivity. − Hence, the design and development of low-cost and effective unsymmetrical metal pincer ligands and their metal complexes have been of great interest in the field of organometallic chemistry. − , In contrast to the well-studied pincer systems, reports are scarce on ligands where the coordination framework employs the nitrogen atom of benzoxazole as a coordinating donor. − Therefore, we decided to explore the development of a pincer complex incorporating 2-aminobenzoxazole as a key donor unit.

On the other hand, direct functionalization of C–H bonds has been recognized as an atom-economical and environmentally benign strategy in organic synthesis, as it can reduce the generation of stoichiometric metal wastes, the number of steps, and energy consumption in synthetic processes. However, due to the lesser reactivity of the C–H bond, its direct functionalization is challenging and generally involves use of catalysts such as transition metals. Among different catalysts employed for activation of the C–H bond, transition metal pincer complexes have exhibited remarkable results. Further, aryl-heteroaryl motifs are found in a variety of functional materials, pharmaceuticals, and natural products. Direct arylation of heteroarenes is one of the most straightforward, cost-effective, and environmentally appealing methods for constructing aryl-heteroaryl motifs. − In continuation of our interest in direct C–H bond functionalization of heteroarenes and exploring catalytic application of novel pincer complexes, herein, we report the synthesis and characterization of novel palladium­(II) NNN pincer complexes and their catalytic application in direct arylation of heteroarenes using aryl bromides with low loading of catalyst without the addition of any external ligand (Scheme ).

1. Synthesis of Pd­(II) NNN Pincer Complex and Application for Direct Arylation of Heteroarenes Using Aryl Bromides.

Results and Discussion

The NNN-tridentate ligand L1 was prepared by the reaction of 2-aminobenzoxazole with 2-bromoacetyl bromide, followed by reaction with morpholine. Ligand L2 was prepared by the reaction of 2-aminobenzoxazole with picolyl chloride. Next, complex C1 and C2 were prepared by the reaction of PdCl₂(CH₃CN)₂ (1.0 equiv) with L1 and L2, respectively in acetonitrile (Scheme ). Complex C2 has good solubility in solvents like CH₂Cl_2, acetonitrile, THF, DMSO, and DMF, whereas complex C1 is partially soluble in CH₂Cl₂ and CHCl₃ and has good solubility in DMF and DMSO. Both ligands (L1 and L2) and complexes (C1 and C2) are air and moisture insensitive. Structure of both ligands and complexes was confirmed by ¹H NMR, ¹³C­{¹H} NMR, HRMS, IR, and UV–visible spectra (Figures S1–S20), Supporting Information. A broad absorption band around 3217–3230 cm^–1 corresponding to the N–H stretching vibrations in the FT-IR spectra of the free ligands disappeared upon coordination with Pd­(II), suggesting the involvement of the amidic nitrogen atom in the binding to the palladium. The UV–visible spectrum of both ligands showed peaks at 249, 301, and 321 nm (L1), and peaks at 284 and 329 nm (L2), which correspond to π → π* and n → π* transitions (Figures S9 and S19). The UV–visible spectra of C1 and C2 showed an additional new band at 370 nm (for C1) and 398 nm (for C2), along with ligand bands which validate the coordination of palladium with ligands (Figures S9 and S15). Further, absence of the signals corresponding to −NH protons in the ¹H NMR of the complexes, which are observed at 12.38 (L1) and 13.77 (L2) ppm in the free ligand, indicated coordination of the amidic nitrogen with the palladium ion (Figures S1, S6, S11, and S14). Deshielding and diastereotopic behavior of the −CH₂ protons of the ligand L1 in the ¹H NMR of complex C1 also supported effective coordination of palladium to the monoanionic tridentate ligand L1 (Figure S5). In the ¹³C NMR of the complexes, the CO signals for C1 were shifted by 4.0 ppm (Figures S2 and S6) and those for C2 by 6.0 ppm (Figures S12 and S16) with respect to the corresponding CO peak in ligands. The HRMS analysis of both complexes showed a mass peak at m/z 443.0554 (for C1) corresponding to [M + H–Cl] ⁺ ion, and 421.0119 (for C2) for [M + H–Cl] ⁺ ion. (Figures S7 and S17). Subsequently, to evaluate the thermal stability of complexes C1 and C2, thermal gravimetric analysis was performed over the temperature range of 30–600 °C. The thermal analysis was conducted under a nitrogen atmosphere with constant flow rate of 20 mL/min. A heating rate of 10 °C/min was employed during the analysis. Both the complexes were thermally stable up to 300 °C. Complexes C1 and C2 exhibited one step decomposition in in the temperature range of 300–320 °C and 405–410 °C, respectively (Figures S10 and S20).

2. Synthesis of Ligand (L1 and L2) and Complexes (C1 and C2).

Single Crystal X–ray Structure

The palladium complex C2 was structurally characterized by X–ray diffraction studies, which gave the coordination of the ligand with the metal and the geometry around the metal center (Figure ). The crystal of the complex was grown by slow evaporation of the ACN/MeOH solution. The crystal data and refining parameters of C2 are shown in Table S1. As expected, the NNN palladium complex C2 has a distorted square planar geometry. NNN tridentate coordination to the palladium is through benzoxazole (N1), amido (N2), and pyridine (N3). An ionic chlorine occupied the remaining position. This chlorine atom and amidic N2 are trans in their geometry. The Pd–N1 (benzoxazole), Pd–N2 (amidic), and Pd–Cl bond length are 1.998(7), 2.037(6), and 2.316(3) Å, respectively. The bond angles around the palladium center are N1–Pd–N2 92.9° (3), N2–Pd–N3 82.0° (3), and Cl–Pd–N1 95.6° (2). The trans N3–Pd–N1 and Cl–Pd–N2 bond angles are 174.7° (3) and 171.5° (2), respectively. The bond lengths and bond angles are consistent with earlier reported amidic palladium complexes (1.980–2.058 Å). The selected bond lengths and bond angles are given below.

1.

ORTEP crystal structure diagram of complex C2 (CCDC 2384000). Thermal ellipsoids are drawn at a 50% probability level. Selected bond distances (Å) and selected bond dangles for complex C2: Pd(1)–N(1) 1.998(7); Pd(1)–Cl(1) 2.316(3); Pd(1)–N(3) 2.026(7); Pd(1)–N(2) 2.037(6); N(1)-Pd (1)-Cl (1) 95.6(2); N(1)–Pd(1)–N(2) 92.9(3); N(1)–Pd(1)–N(3) 174.7(3); N(2)–Pd(1)–Cl(1) 171.5(2); N(3)–Pd(1)–Cl(1) 89.5(2); N(3)–Pd(1)–N(2) 82.0(3).

Catalytic Activity of C2 for the Direct C–H Arylation of Heteroarenes with Aryl Bromides

Indazoles are one of the most important classes of heterocycles prevalent in a variety of biologically active compounds and pharmaceuticals. Particularly, compounds with a 3-arylindazole scaffold have been used for various therapeutic applications. For example, compound I (YC-I), a potent inhibitor of platelet aggregation, compound II (WAY-169916) is a pathway-selective NF-kB inhibitor, compound III is MEK4 inhibitor and compound IV exhibits antiangiogenetic activity (Figure ). Thus, considering their importance many synthetic methods have been developed for preparation of 3-arylindazole. −

2.

Selected bioactive 3-arylindazoles.

We optimized the reaction conditions for direct arylation of 2-indazoles by using 2-cyclohexyl-2H-indazole (1a) and 4-bromobenzonitrile (2a) as model substrates. Initially, reaction of 1a with 2a in the presence of pincer complex C2 (2 mol %) and KOAc (2 equiv) in DMA produced coupled product 3aa in 76% yield (Table , entry 1). Yield of 3aa increased to 82% on increasing the amount of KOAc to 3 equiv (Table , entry 2); however, further increase in the amount of KOAc was detrimental to the yield of 3aa. (Table , entry 3). Next, the effect of various bases such as AgOAc, NaOAc, NH₄OAc, KO^tBu, Cs₂CO₃, and K₂CO₃ was examined (Table , entries 4–9). Among all of the screened bases, KOAc was found to be the most effective for this reaction. Subsequently, the role of the solvent was examined by varying solvents such as dioxane, toluene, DMF, and DMSO (Table , entries 10–13). Among all of the varied solvents, product 3aa was obtained only in DMF (48%), and the reaction did not occur in other solvents. Replacing catalyst C2 with catalyst C1 and PdCl₂ produced the desired product in 71% and 45%, respectively (Table , entries 14 and 15). Reaction did not occur in the absence of a catalyst or base (Table , entries 16 and 17).

1. Optimization for the Reaction Conditions .

S.No.	catalyst	base	solvent	yield of 3aa (%)
1	C2	KOAc	DMA	76
2	C2	KOAc	DMA	81
3	C2	KOAc	DMA	82
4	C2	AgOAc	DMA	40
5	C2	NaOAc	DMA	59
6	C2	NH4OAc	DMA	35
7	C2	KOtBu	DMA	NR
8	C2	CS2CO3	DMA	45
9	C2	K2CO3	DMA	NR
10	C2	KOAc	Dioxane	NR
11	C2	KOAc	Toluene	NR
12	C2	KOAc	DMF	48
13	C2	KOAc	DMSO	NP
14	C1	KOAc	DMA	71
15	PdCl2	KOAc	DMA	45
16		KOAc	DMA	NR
17	C2		DMA	NR

^aReaction conditions: 1a (0.12 mmol), 2a (0.12 mmol), catalyst (2 mol %), base (3 equiv), solvent (1 mL) for 12 h at 130 °C.

^bIsolated yield.

^c3 Equiv of KOAc was used.

^d4 Equiv of KOAc was used.

Having obtained reaction conditions in hand, we examined the substrate scope of direct C3-arylation of 2H-indazoles (Table ). Initially, 2-cyclohexyl-2H-indazole (1a) was reacted with aryl bromides (2a–2g) having numerous substitution groups such as −CN, −COMe, −CHO, −COEt, and –NHCOMe under standard reaction conditions and the respective products (3aa-3ag) were furnished in good to moderate yields (65–86%). The TON and TOF for the product 3aa was found to be 43, and 4h^–1 indicating a moderately active catalytic system. In our case, ortho-substituted aryl bromides failed to react under standard reaction conditions probably due to steric hindrance. Next, 2-bromonaphthalene (2h) was reacted with 2-cyclohexyl-2H-indazole (1a) to obtain 2-cyclohexyl-3-(naphthalen-2-yl)-2H-indazole (3ah) in 72% yield. Later, different 2-alkyl-2H-indazoles (1b-1d) and 2-aryl-2H-indazoles (1e–1k) were reacted with 2a to get the corresponding arylated products 3ba-3ka in good to excellent yields (67–80%) under the standard reaction conditions. Finally, the reaction of 2-(m-tolyl)-2H-indazole (1k) with 2b and 2i afforded 1-(4-(2-(m-tolyl)-2H-indazol-3-yl)­phenyl)­ethan-1-one (3kb) and 3-phenyl-2-(m-tolyl)-2H-indazole (3ki) in 71% and 55% yields, respectively.

2. Substrate Scope for Direct Arylation of Heterarenes,

^aReaction conditions: 1 (0.12 mmol), 2 (0.12 mmol), C2­(2 mol %), KOAc (3 equiv), DMA (1 mL) for 12h at 130 °C.

^bIsolated yield.

After exploring direct arylation of 2H-indazoles, the scope was extended to divergent heteroarenes such as 2-methylthiophene (4), furan (5), benzofuran (6), 1-methyl-1H-imidazole (7), 1,3,7-trimethyl-3,7-dihydro-1H-purine-2,6-dione (8), 1,3-dimethyl-1H-indole (9), and 2-phenylimidazo­[1,2-a]­pyridine (10). To our satisfaction, the reaction of heteroarenes (4–10) with 2a under standard reaction conditions afforded the corresponding arylated products 12–18 in moderate to good (47–69%) yields. Further, the reaction of 2-(4-methoxyphenyl)-6-methylimidazo­[1,2-a]­pyridine (11) with 2j furnished the corresponding acrylated product 19 in 51% yield.

To gain insight into the reaction mechanism of the developed direct arylation reaction, we conducted some control experiments (Scheme ). A competition experiment was conducted using 2-cyclohexyl-2H-indazole (1a) and 2-phenyl-2H-indazole (1e) with 2a under the optimized reaction conditions, as shown in (Scheme a). The findings revealed that the N-alkylated indazole exhibited higher reactivity compared to the N-aryl indazole. We conducted H-D exchange experiments. When we performed the reaction of 1a with C2 (2 mol %) in the absence of 2a and an excess amount of D₂O, 75% H/D exchange was observed at the C3-position of 1a, indicating that the C–H activation step is reversible (Scheme b). Next, a peak at m/z 620.1275 for the [M + H] ⁺ ion was observed in the HRMS analysis of the reaction mixture of 1a with C2 under standard conditions (Scheme d). On the other hand, no peak for the ion corresponding to oxidative addition of 2a to C2 was observed in the reaction mixture of 2a with C2 under standard conditions. This indicated that the C–H metalation step is involved in the reaction mechanism. To further understand the nature of the catalytic reaction (homogeneous vs heterogeneous) and the role of the catalyst, mercury poisoning and PPh₃ inhibition experiments were performed. The reaction between 1a and 2a under optimized conditions, in the presence of 100 equiv of Hg (with respect to C2), resulted in 79% yield of 3aa, while the addition of 5 equiv of PPh₃ (with respect to C2) gave 81% yield of 3aa (Scheme c). These results suggest that the catalyst remains active during the reaction without forming an amalgam with mercury or being significantly inhibited by the phosphine ligand. These results also indicate that the reaction proceeds via a homogeneous catalytic pathway in the presence of catalyst C2. In addition, this homogeneous nature is further validated by the observation that no black particles were formed during the reaction, which is generally observed in heterogeneous catalytic systems.

3. Control Experiments.

Computation Study

We identified two reaction pathways in our proposed mechanism: one proceeding from C2 → A → B and the other from C2 → B via C–H metalation. Figure (a) displays all of the optimized structures, clearly representing the molecular configurations involved in each pathway. Furthermore, Figure (b) illustrates the Gibbs free energy profile, comparing the energy changes throughout both pathways. The Gibbs free energy (ΔG) value for reactant C2 for both pathways (as shown in Figure b) is assumed to be zero. The corresponding values for the intermediates (A, A-IM1, A-IM2, C2-IM1, and C2-IM2) and the products (B + AcOH and B + HCl) are expressed relative to this baseline value. As demonstrated in Figure (b), the reactivity pattern of reaction C2 + KOAc → A + 1a → B + AcOH exhibits a significantly more stable ΔG value of +20.2 kcal/mol. This is notably more favorable compared to the second pathway, C2 + 1a → B + HCl, which has a ΔG value of +27.0 kcal/mol, indicating a higher energy barrier. With this comprehensive analysis, we can conclude that the reactivity pathway C2 → A → B is more favorable and significantly more efficient than the pathway leading from C2 to B. This insight into the mechanistic details emphasizes the importance of the chosen pathway in determining the overall reactivity and effectiveness of the reaction.

3.

(a) Optimized geometries of all the structures involved in the pathways from A → B and C2 → B in the reaction mechanism. For clarity, hydrogen atoms have been omitted. The color scheme used is as follows: palladium is represented in dark green, nitrogen in blue, oxygen in red, carbon in gray, and chlorine in green. (b) Gibbs free energy profiles for the two different pathways from A → B and C2 → B in the reaction mechanism. All the calculated ΔG energy values are in kcal/mol.

To enhance our understanding of the reactivity pattern of compound 2a with the intermediate square planar palladium complex B, we thoroughly investigated the progress of the reaction between compound 2a and the square planar palladium complex B. This intricate process unfolds in two essential steps: (a) oxidative addition and (b) reductive elimination, which facilitate the transition from square planar palladium complex B to square planar palladium complex D. As depicted in Figure , among the two transition states evaluated, TS-1 stands out with a lower energy profile, being 1 kcal/mol more stable than TS-1a, confirming that the addition of compound 2a to B proceeds via TS-1. This pathway leads to the formation of the octahedral intermediate, C, which is endergonic by 49.0 kcal/mol, as illustrated in Figure . Intermediate C is crucial in forming a C–C bond, which occurs smoothly through the transition state TS-2, with a barrier of 8.0 kcal/mol. During this reductive elimination step, we observe the brominated palladium complex D forming alongside the C–C coupled product 3aa. This transformation results in a substantial exergonic reaction, releasing 52.0 kcal/mol of energy compared to the initial reactants (B + 2a), illustrated in Figure . Additionally, Figure explicitly indicates that the energy barrier for the critical step in the reaction involving 2a with B is 57.0 kcal/mol. The transformation of brominated palladium square planar complex (D) to the original palladium square planar complex (A) is an exergonic reaction, which is 6.0 kcal/mol.

4.

Gibbs free energy profile for the reaction of B with 2a. All the calculated ΔG energy values are expressed in kcal/mol. For clarity, hydrogen atoms have been omitted. The color scheme used is as follows: palladium is represented in dark green, nitrogen in blue, oxygen in red, carbon in gray, and bromine in maroon.

Based on the control experiment results, DFT analysis, and literature reports, a plausible mechanism for the developed direct arylation is proposed in Scheme . During the initial phase of the catalysis cycle, KOAc transformed catalyst C2 into active catalyst A by substituting chlorine with an acetate group, and formation of A was confirmed with the HRMS peaks at m/z 481.0160 corresponding to [M + H] ⁺. In the next step, C–H metalation at C3-position of 2-cyclohexyl-2H-indazole (1a) takes place, leading to the formation of intermediate B, which was confirmed with the HRMS peak at m/z 620.1333 for [M + H]⁺ ion, similar to the earlier reported examples, which supports C–H metalation. − Further, the intermediate B undergoes oxidative addition with 4-bromobenzonitrile (2a) to give the intermediate C, which was validated with an HRMS peak at m/z 820.0764 corresponding to [M + H] ⁺ ion. This intermediate C undergoes reductive elimination to produce product 3aa and species D, which in the presence of KOAc regenerates the catalyst in its active form A.

4. Plausible Mechanism.

Conclusions

The new structurally characterized unsymmetrical NNN palladium pincer complexes C1 and C2 are active precatalysts for the C–H arylation of substituted 2H-indazoles by using 4-bromobenzonitrile under optimized reaction conditions. The complex C2 was found to be a better precatalyst than complex C1, which shows the superiority of these classes of NNN pincer catalysts, which can easily prepare stable catalysts. The substrate scope of aryl bromide and heteroarenes elaborated with the most active precatalyst complex C2, which concluded that the reaction conditions are sustainable with various substituents on both reactants. DFT calculation on the arylation reaction strongly supports a Pd­(II)/Pd­(IV)/Pd­(II) redox, which involves the C–H metalation followed by the oxidative addition of aryl bromide to the NNN Pd­(II) species, and the subsequent reductive elimination of the coupled product.

Experimental Section

General

All reagents and solvents were purchased from commercially available sources and used without further purification. Thin-layer chromatography (TLC) was performed on 0.25 mm silica gel 60-F254 and was visualized using a UV lamp. The products were purified by column chromatography over silica gel (100–200 mesh) using ethyl acetate/hexanes as the eluent. The absorption spectra were measured on a JASCO V-650 UV–visible spectrophotometer. IR spectra were taken on a Nicolet Protége 460 FT-IR spectrometer on KBr pellets. The ¹H and ¹³C­{¹H} NMR spectra were recorded on a Bruker Advance 400 spectrometer using CDCl₃ or DMSO-d ₆ as the solvent, and chemical shifts (δ) are reported in parts per million (ppm). The chemical multiplicities were reported as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and combinations of them as well. HRMS data were recorded on a Q-TOF LC-MS spectrometer in positive electrospray ionization (ESI) mode. Melting points were determined in open capillary tubes on the EZ-Melt automated melting point apparatus and were uncorrected. Single-crystal X-ray diffraction data were collected on a Rigaku Oxford XtaLAB AFC12 (RINC) Kappa dual-source diffractometer

Synthesis of Ligand (L1)

A mixture of morpholine (3 equiv) and N-(2-(benzo­[d]­oxazol-2-yl) phenyl)-2-bromoacetamide (1 equiv) in acetone was refluxed overnight. After cooling to room temperature, the mixture was diluted with water and extracted twice with ethyl acetate (EtOAc). The organic layer was washed once with brine, dried over sodium sulfate (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to afford the desired ligand L1 as a white solid in 74% yield. mp:148–150 °C; ¹H NMR (400 MHz, CDCl₃) δ 12.38 (s, 1H), 8.98 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 7.8 Hz, 1H), 7.89–7.80 (m, 1H), 7.70–7.63 (m, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.47–7.41 (m, 2H), 7.25 (d, J = 7.5 Hz, 1H), 3.98 (s, 4H), 3.36 (s, 2H), 2.74 (s, 4H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 170.1, 161.7, 149.5, 141.4, 138.5, 132.7, 128.8, 125.6, 124.9, 123.3, 120.8, 119.6, 113.7, 110.8, 66.8, 63.6, 53.9; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₉H₂₀N₃O₃ ⁺ 338.1505; Found 338.1509.

Synthesis of Ligand (L2)

Pyridine-2-carboxylic acid (0.500 g, 4.06 mmol) and DCM (5 mL) were taken in an oven-dried 10 mL round-bottom flask. DMF (4–5 drops) was added to the mixture and stirred at 0 °C for 5 min, followed by dropwise addition of oxalyl chloride (0.41 mL, 4.87 mmol). The reaction mixture was stirred at room temperature for 4 h. After completion, the excess oxalyl chloride was removed under a vacuum to obtain picolyl chloride. Next, picolyl chloride was dissolved in DCM (5 mL) and cooled to 0 °C. To the solution were added DMAP (0.052 g, 0.5 mmol), Et₃N (0.6 mL, 5 mmol), and 2-(benzo­[d]­oxazol-2-yl) aniline (449 mg, 2.33 mmol). The reaction mixture was stirred at room temperature overnight. After completion, as indicated by TLC, the solvent was evaporated and extracted with ethyl acetate (2 × 20 mL). The reaction mixture was washed with 2 N HCl (20 mL) and brine solution (20 mL), and dried over Na₂SO₄. The solvent was evaporated under reduced pressure, and crude product was purified by column chromatography to afford the ligand L2 as white solid in 82% (620 mg) yield; mp; 165–167 °C; ¹H NMR (400 MHz, CDCl₃) δ 13.77 (s, 1H), 9.15–9.10 (m, 1H), 8.91–8.85 (m, 1H), 8.38–8.28 (m, 2H), 7.98–7.93 (m, 1H), 7.92–7.87 (m, 1H), 7.68–7.60 (m, 2H), 7.58–7.53 (m, 1H), 7.46–7.41 (m, 2H), 7.32–7.27 (m, 2H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 164.1, 161.8, 150.9, 149.5, 148.5, 141.4, 138.8, 137.4, 132.6, 128.6, 126.4, 125.6, 124.7, 123.3, 122.9, 120.8, 119.9, 114.3, 110.6; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₁₉H₁₄N₃O₂ ⁺ 316.1086; Found 316.1079.

Synthesis of Pd-Complex (C1)

A round-bottom flask fitted with a condenser was charged with L1 (43 mg, 0.126 mmol), PdCl₂(CH₃CN)₂ (32 mg, 0.126 mmol), and acetonitrile (4 mL). The mixture was stirred for 180 min while refluxing. After the completion of the reaction, as monitored by TLC, the reaction mixture was cooled and concentrated in a rotary evaporator. The residue was washed with cold n-pentane to give C1 as a white solid in 76% yield (46 mg). mp; 223–225 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.87–8.84 (m, 1H), 8.47 (d, J = 8.5 Hz, 1H), 8.08 (dd, J = 8.0, 1.4 Hz, 1H), 7.60–7.55 (m, 1H), 7.52–7.46 (m, 1H), 7.46–7.39 (m, 2H), 7.18–7.12 (m, 1H), 4.22 (s, 2H), 4.13–4.05 (m, 2H), 3.97–3.92 (m, 4H), 3.00–2.92 (m, 2H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 174.1, 159.3, 149.8, 144.3, 138.7, 133.7, 129.4, 126.7, 125.5, 123.4, 122.61, 122.1, 115.2, 110.6, 65.5, 61.5, 58.3; HRMS (ESI) m/z: [M + H–Cl] ⁺ Calcd for C₁₉H₁₉N₃O₃Pd⁺ 443.0461; Found 443.0551.

Synthesis of Pd-Complex (C2)

A round-bottom flask fitted with a condenser was charged with L2 (40 mg, 0.126 mmol), PdCl₂(CH₃CN)₂ (32 mg, 0.126 mmol), and acetonitrile (4 mL). The mixture was stirred for 180 min while refluxing. After the completion of the reaction, as monitored by TLC, the reaction mixture was cooled and concentrated using a rotary evaporator. The residue was washed with cold n-pentane to give C2 as an orange solid in 91% (52 mg) yield. mp: 246–248 °C; ¹H NMR (400 MHz, DMSO-d ₆) δ 8.99 (d, J = 4.4 Hz, 1H), 8.85 (d, J = 7.9 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.28 (t, J = 6.9 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 7.3 Hz, 1H), 7.85–7.78 (m, 2H), 7.51–7.40 (m, 3H), 7.11 (t, J = 7.0 Hz, 1H); ¹³C­{¹H} NMR (100 MHz, DMSO-d ₆) δ 170.5, 160.1, 154.2, 149.9, 149.6, 148.6, 142.23 142.22, 139.4, 134.1, 130.4, 128.7, 127.3, 127.2, 125.7 123.0, 121.8, 114.5, 111.8; HRMS (ESI) m/z: [M + H–Cl] ⁺ Calcd for C₁₉H₁₃N₃O₂Pd⁺ 421.0037; Found 421.0119.

Experimental Procedure for Poisoning Experiments

An oven-dried pressure tube was charged with 1a (0.12 mmol, 1.0 equiv), 2a (0.12 mmol, 1.0 equiv), KOAc (0.37 mmol, 3.0 equiv), C2 (1.1 mg, 0.002 mmol), poisoning reagent (Hg/C2, 100:1 or PPh₃/C2, 5:1), and DMA (1 mL). The tube was closed with a septum, and the reaction mixture was stirred at 130 °C for 12 h. After the completion of the reaction, the reaction mixture was cooled to room temperature, and then the reaction mixture was poured into water (5 mL) and extracted with the organic layer was separated and dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The resulting crude was purified by column chromatography (silica gel 100–200 mesh) using EtOAc/hexane as an eluent to afford the corresponding product 3aa in 79% yield (for Hg) and 81% yield (for PPh₃).

Representative Procedure for the Direct C–H Arylation of Heteroarenes

An oven-dried pressure tube with a septum was charged with indazole derivative/heteroarene (1a) (0.12 mmol, 1.0 equiv), aryl bromide (2a) (0.12 mmol, 1.0 equiv), KOAc (0.37 mmol, 3.0 equiv), C2 (1.1 mg, 0.002 mmol), and DMA (1 mL). The resulting reaction mixture was stirred at 130 °C for 12 h. After the completion of the reaction, the reaction mixture was cooled to room temperature, and then the reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (3 × 5 mL). The organic layer was separated and dried over anhydrous Na₂SO₄, filtered, and concentrated under a vacuum. The resulting crude was purified by column chromatography (silica gel 100–200 mesh) using EtOAc/hexane as an eluent to afford the corresponding arylated heteroarene as the final product.

4-(2-Cyclohexyl-2H-indazol-3-yl)­benzonitrile (3aa)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a white solid in 86% (32 mg); mp = 177–179 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.94 – 7.86 (m, 2H), 7.82–7.79 (m, 1H), 7.67–7.61 (m, 2H), 7.54–7.51 (m, 1H), 7.39–7.32 (m, 1H), 7.18–7.09 (m, 1H), 4.43–4.35 (m, 1H), 2.36–2.34 (m 2H), 2.09–1.90 (m, 4H), 1.79–1.74 (m, 1H), 1.46–1.30 (m, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 147.0, 134.8, 132.9, 132.9, 130.3, 126.3, 122.6, 121.1, 119.3, 118.43, 117.7, 112.3, 59.6, 33.8, 25.6, 25.0; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₀H₂₀N₃ ⁺ 302.1652; Found 302.1675.

1-(4-(2-Cyclohexyl-2H-indazol-3-yl)­phenyl)­ethan-1-one (3ab)

The compound was purified by column chromatography (EtOAc/hexanes,1:19 v/v) to provide the product as a yellow solid in 71% (28 mg); mp = 143–145 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.7 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.37–7.31 (m, 1H), 7.15–7.09 (m, 1H), 4.49–4.40 (m, 1H) 2.73 (s, 3H), 2.41–2.20 (m, 2H), 2.05–1.93 (m, 4H), 1.73 (s, 1H), 1.46–1.25 (m, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 197.4, 147.9, 136.8, 134.7, 133.6, 129.8, 129.0, 126.1, 122.1, 121.1, 119.7, 117.5, 59.4, 33.7, 26.7, 25.6, 25.08; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₁H₂₃N₂O⁺ 319.1805; Found 319.1810.

4-(2-Cyclohexyl-2H-indazol-3-yl)­benzaldehyde (3ac)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a white solid in 68% (26 mg); mp = 160–162 °C; ¹ H NMR (400 MHz, CDCl₃) δ 10.16 (s, 1H), 8.11 (d, J = 7.6 Hz, 2H), 7.81 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.19–7.07 (m, 1H), 4.49–4.42 (m, 1H), 2.36–2.26 (m, 2H), 2.15–1.86 (m, 4H), 1.74 (s, 1H), 1.48–1.24 (m, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 191.6 148.0, 136.1, 135.9 133.4, 130.36, 130.27, 126.2, 122.4, 121.0, 119.6, 117.6, 59.5, 33.7, 25.6, 25.0; HRMS (ESI) m/z: [M + H]+ Calcd for C₂₂H₂₁N₂O⁺ 305.1648; Found 305.1656.

1-(4-(2-Cyclohexyl-2H-indazol-3-yl)­phenyl)­propan-1-one (3ad)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a white solid in 73% (30 mg); mp = 141–143 °C; ¹ H NMR (400 MHz, CDCl₃) δ 8.19 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 4.45–4.42 (m, 1H), 3.12 (q, J = 7.2, 2H), 2.30–2.10 (m, 2H), 2.20–1.89 (m, 4H), 1.74 (s, 1H), 1.41–1.30 (m, 6H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 200.2, 147.9, 136.6, 134.5, 133.7, 129.9, 128.7, 126.1, 122.1, 121.0, 119.8, 117.5, 59.4, 33.7, 32.0, 25.65, 25.0, 8.26; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₂H₂₅N₂O⁺ 333.1961; found 333.1926.

N-(4-(2-Cyclohexyl-2H-indazol-3-yl)­phenyl)­acetamide (3ae)

The compound was purified by column chromatography (EtOAc/hexanes, 1:4 v/v) to provide the product as a white solid in 63% (26 mg); mp = 170–172 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.80–7.70 (m, 3H), 7.54–7.51 (m, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.43 (s, 1H), 7.33–7.29 (m, 1H), 7.09–7.03 (m, 1H), 4.53–4.34 (m, 1H), 2.38–2.16 (m, 5H), 2.07–1.89 (m, 4H) 1.73 (s, 1H), 1.42–1.29 (m, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 168.4, 147.8, 138.24, 134.4, 130.5, 125.0, 125.9, 121.5, 121.0, 120.2, 120.1, 117.3, 59.0, 33.8, 25.6, 25.1, 24.7; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₁H₂₄N₃O⁺ 334.1914; found 334.1902.

1-(3-(2-Cyclohexyl-2H-indazol-3-yl)­phenyl)­ethan-1-one (3af)

The compound was purified by column chromatography (EtOAc/hexanes, 1:9 v/v) to provide the product as a yellow solid in 61% (25 mg); mp = 115–117 °C; ¹H NMR (400 MHz, CDCl₃ ¹H NMR) δ 8.12 (s, 2H), 7.84–7.66 (m, 3H), 7.54 (d, J = 8.2 Hz, 1H), 7.41–7.30 (m, 1H), 7.11 (t, J = 7.2 Hz, 1H), 4.46–4.34 (m, 1H), 2.70 (s, 3H), 2.31 (q, J = 11.3 Hz, 2H), 2.13–1.90 (m, 4H), 1.73 (s, 1H), 1.47–1.23 (m, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 197.4, 147.8, 137.8, 134.1, 133.7, 130.7, 129.6, 129.4, 128.4, 126.1, 122.0, 121.0, 119.7, 117.5, 59.3, 33.7, 26.7, 25.6, 25.0; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₁H₂₃N₂O⁺ 319.1805; found 319.1799.

2-Cyclohexyl-3-(p-tolyl)-2H-indazole (3ag)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a yellow solid in 63% (23 mg); mp = 138–140 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.40 (s, 4H), 7.33–7.29 (m, 1H), 7.07 (t, J = 7.5 Hz, 1H), 4.49–4.43 (m, 1H), 2.50 (s, 3H), 2.09–1.08 (m, 4H), 1.93 (d, J = 10.7 Hz, 2H), 1.73 (s, 1H), 1.48–1.21 (m, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 147.8, 138.7, 135.0, 129.8, 129.7, 127.1, 125.9, 121.3, 120.9, 120.3, 117.2, 58.0, 33.7, 25.7, 25.1, 21.4; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₂₃N₂ ⁺ 291.1856; found 291.1836.

2-Cyclohexyl-3-(naphthalen-1-yl)-2H-indazole (3ah)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a yellow solid in 72% (29 mg); mp = 141–143 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.72–7.62 (m, 1H), 7.62–7.52 (m, 2H), 7.50–7.41 (m, 2H), 7.39–7.31 (m, 1H), 7.26 (s, 1H), 7.06–6.95 (m, 1H), 4.22–3.98 (m, 1H), 2.41–2.10 (m, 2H), 2.08–1.91 (m, 2H), 1.90–1.74 (m, 2H), 1.61 (s, 1H), 1.41–0.98 (m, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 148.0, 133.7, 133.2, 132.8, 129.7, 129.1, 128.4, 127.6, 126.9, 126.5, 125.9, 125.5, 125.4, 122.3, 121.3, 120.4, 117.40, 59.4, 34.0, 33.1, 25.5, 25.0; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₃H₂₃N₂ ⁺ 377.1856; found 377.1850.

4-(2-Propyl-2H-indazol-3-yl)­benzonitrile (3ba)

The compound was purified by column chromatography (EtOAc/hexanes, 1:9 v/v) to provide the product as a yellow solid in 80% (32 mg); mp = 143–145 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.90–7.86 (m, 2H), 7.79–7.76 (m, 1H), 7.69–7.65 (m, 2H), 7.55–7.53 (m, 1H), 7.38–7.34 (m, 1H), 7.17–7.13 (m, 1H), 4.41 (t, J = 7.4 Hz, 2H), 1.38–1.30 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 148.1, 134.7, 133.6, 132.9, 130.2, 126.5, 122.8, 121.4, 119.4, 118.4, 117.6, 112.4, 52.6, 24.1, 11.1; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₇H₁₆N₃ ⁺ 261.1339; found 261.1330.

4-(2-Butyl-2H-indazol-3-yl)­benzonitrile (3ca)

The compound was purified by column chromatography (EtOAc/hexanes, 1:9 v/v) to provide the product as a yellow solid in 76% (30 mg); mp = 88–90 °C; ¹H NMR (400 MHz, CDCl₃) 7.89–7.87 (m, 2H), 7.79–7.76 (m, 1H), 7.68–7.65 (m, 2H), 7.55–7.53 (m, 1H), 7.38–7.32 (m, 1H), 7.17–7.13 (m, 1H) δ 4.45 (t, J = 7.4 Hz, 2H), 2.03–1.91 (m, 2H), 1.42–1.18 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 148.1, 134.7, 133.6, 132.9, 130.2, 126.5, 122.8, 121.3, 119.3, 118.4, 117.6, 112.4, 50.8, 32.8, 19.8, 13.5; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₁₈N₃ ⁺ 276.1495; found 276.1485.

4-(2-(Cyclopropylmethyl)-2H-indazol-3-yl)­benzonitrile (3da)

The compound was purified by column chromatography (EtOAc/hexanes, 1:9 v/v) to provide the product as a yellow solid in 74% (29 mg); mp = 138–140 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.88 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 7.2 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 4.35 (d, J = 6.8 Hz, 2H), 1.38–1.30 (m, 1H), 0.57 (q, J = 6.1 Hz, 2H), 0.29 (q, J = 5.3 Hz, 2H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 148.1, 134.8, 133.3, 132.8, 130.3, 126.5, 122.8, 121.6, 119.4, 118.4, 117.7, 112.4, 55.7, 12.0, 4.24; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₈H₁₆N₃ ⁺ 274.1339; found 274.1330.

4-(2-Phenyl-2H-indazol-3-yl)­benzonitrile (3ea)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a yellow solid in 78% (30 mg); mp = 88–90 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.86 (d, J = 8.4 Hz, 1H), 7.73–7.69 (m, 3H), 7.50 (d, J = 8.4 Hz, 2H), 7.48–7.39 (m, 6H), 7.24 (dd, J = 8.6, 6.6 Hz, 1H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 149.1, 139.8, 134.5, 133.0, 132.6, 130.03, 129.4, 128.0, 127.3, 126.0, 123.7, 121.0, 119.6, 118.43, 118.24, 111.8; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₀H₁₄N₃ ⁺ 296.1182; found 296.1172.

4-(2-(p-Tolyl)-2H-indazol-3-yl)­benzonitrile (3fa)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a white solid in 70% (26 mg); mp = 110–112 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.8 Hz, 1H), 7.72–7.69 (m, 3H), 7.50–7.48 (m, 2H), 7.44–7.40 (m, 1H), 7.32–7.30 (m, 2H), 7.25–7.21 (m, 3H), 2.43 (s, 3H). ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ: 149.0, 139.0, 137.2, 134.6, 132.93, 132.52, 130.0, 129.9, 127.1, 125.8, 123.6, 121.8, 119.6, 118.48, 118.19, 111.6, 21.2. HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₁H₁₆N₃ ⁺ 310.1339; found 310.1328.

4-(2-(4-Methoxyphenyl)-2H-indazol-3-yl)­benzonitrile (3ga)

The compound was purified by column chromatography (EtOAc/hexanes, 1:9 v/v) to provide the product as a yellow solid in 69% (25 mg); mp = 160–162 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.8 Hz, 1H), 7.72–7.69 (m, 3H), 7.50 (d, J = 8.4 Hz, 2H), 7.44–7.40 (m, 1H), 7.36–7.32 (m, 2H), 7.25–7.21 (m, 1H), 6.95 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 159.8, 148.9, 134.6, 132.9, 132.7, 132.5, 129.0, 127.2, 127.1, 123.5, 121.7, 119.6, 118.4, 118.2, 114.5, 111.6, 55.6; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₁H₁₆N₃O⁺ 326.1288; found 326.1278.

4-(2-(4-Bromophenyl)-2H-indazol-3-yl)­benzonitrile (3ha)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a yellow solid in 67% (23 mg); 110–112 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 149.2, 138.7, 134.2, 133.0, 132.7, 132.6, 130.05, 127.60, 127.41, 123.0, 122.88, 122.1, 119.6, 118.29, 118.20, 112.13; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₀H₁₃BrN₃ ⁺ 374.0287; found 374.0259.

4-(2-(4-Fluorophenyl)-2H-indazol-3-yl)­benzonitrile (3ia)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a yellow solid in 69% (26 mg); mp = 161–163 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.85–7.83 (m, 1H), 7.74–7.69 (m, 3H), 7.50–7.48 (m, 2H), 7.44–7.40 (m, 3H), 7.26–7.22 (m, 1H), 7.17–7.13 (m, 2H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 162.4 (d, J = 249 Hz) 149.1, 135.8 (d, J = 3.0 Hz), 134.2, 133.0 (d, J = 26 Hz), 1131.3 (d, J = 264 Hz) 127.9, 127.8 (d, J = 9 Hz), 127.5, 123.9, 121.9 119.6 118.31, 118.17 116.43 (d, J = 23 Hz) 112.01; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₁₃FN₃ ⁺ 314.1088; found 314.1082.

4-(2-(4-Chlorophenyl)-2H-indazol-3-yl)­benzonitrile (3ja)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a yellow solid in 69% (25 mg); mp = 112–115 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, J = 8.8 Hz, 1H), 7.74 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.45–7.37 (m, 5H), 7.24 (t, J = 7.6 Hz, 1H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 149.2, 138.2, 134.8, 134.2, 133.0, 132.7, 130.0, 129.6, 127.5, 127.1, 123.9, 122.0, 119.6, 118.2, 118.2, 112.1; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₀H₁₃ClN₃ ⁺ 330.0793; found 330.0790.

4-(2-(m-Tolyl)-2H-indazol-3-yl)­benzonitrile (3ka)

The compound was purified by column chromatography (EtOAc/hexanes,1:19 v/v) to provide the product as a white solid in 75% (28 mg); mp = 118–120 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.82–7.85 (m, 1H), 7.72–7.67 (m, 3H), 7.52–7.46 (m, 2H), 7.44–7.38 (m, 1H), 7.36 (d, J = 0.8 Hz, 1H), 7.30–7.24 (m, 2H), 7.24–7.18 (m, 1H), 7.08–7.04 (m, 1H), 2.39 (s, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 149.0, 139.79, 139.62, 134.5, 133.0, 132.5, 130.0, 129.7, 129.0, 127.2, 126.5, 123.6, 123.1, 121.8, 119.6, 118.4, 118.2, 111.7, 21.4; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₁H₁₆N₃ ⁺ 310.1339; found 310.1336.

1-(4-(2-(m-Tolyl)-2H-indazol-3-yl)­phenyl)­ethan-1-one (3kb)

The compound was purified by column chromatography (EtOAc/hexanes, 1:95 v/v) to provide the product as a white solid in 71% (28 mg); mp = 120–122 °C; ¹ H NMR (400 MHz, CDCl₃) δ 8.00 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.7 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.46–7.36 (m, 2H), 7.28–7.14 (m, 3H), 7.10 (d, J = 6.8 Hz, 1H), 2.65 (s, 3H), 2.40 (s, 3H). ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 197.4, 149.0, 139.9, 139.6, 136.2, 134.6, 133.0, 129.6, 129.4, 128.8, 128.7, 127.1, 126.5, 123.2, 123.1, 121.9, 120.0, 118.0, 26.7, 21.3; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₂H₁₉N₂O⁺ 326.1492; found 326.1489.

3-Phenyl-2-(m-tolyl)-2H-indazole (3ki)

The compound was purified by column chromatography (EtOAc/hexanes, 1:95 v/v) to provide the product as a white solid in 55% (19 mg); mp = 118–120 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 8.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.47–7.35 (m, 7H), 7.27–7.11 (m, 4H), 2.39 (s, 3H). ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ: 148.9, 140.1, 139.3, 135.4, 130.0, 129.7, 129.0, 128.6, 128.6, 128.3, 127.0, 16.56, 123.13, 122.5, 121.7, 120.6, 117.8, 21.4. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₀H₁₇N₂ ⁺ 285.1386; found 285.1384.

4-(5-Methylthiophen-2-yl)­benzonitrile (12)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a yellow solid in 48% (24 mg); mp = 134–136 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.64 (s, 4H), 7.25 (d, J = 3.6 Hz, 1H), 6.82–6.78 (m, 1H), 2.56 (s, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 142.2, 139.6, 138.9, 132.7, 126.8, 125.53, 125.14, 119.0, 109.9, 15.6; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₂H₁₀NS⁺ 200.0528; found 200.0537.

4-(Furan-2-yl)­benzonitrile (13)

The compound was purified by column chromatography (EtOAc/hexanes, 1:19 v/v) to provide the product as a yellow solid in 47% (31 mg); mp = 123–125 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.4 Hz, 2H), 7.75 (t, J = 10.1 Hz, 3H), 7.68–7.51 (m, 1H), 6.98 (s, 1H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 152.8, 133.9, 132.8, 129.3, 126.5, 124.2, 118.8, 110.0, 110.6. HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₁₁H₈NO⁺ 170.0600; found 170.0599.

4-(Benzofuran-2-yl)­benzonitrile (14)

The compound was purified by column chromatography (EtOAc/hexanes, 1:9 v/v) to provide the product as a yellow solid in 48% (22 mg); mp = 175–177 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.21 (s, 1H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 155.3, 153.6, 134.4, 132.6, 128.7, 125.6, 125.1, 123.5, 121.5, 118.8, 111.5, 111.4, 104.3; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₁₅H₁₀NO⁺ 220.0757; found 219.0684.

4-(1-Methyl-1H-imidazol-2-yl)­benzonitrile (15)

The compound was purified by column chromatography (EtOAc/hexanes, 2:3 v/v) to provide the product as a yellow solid in 53% (29 mg); mp = 140–142 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 8.4 Hz, 2H), 7.61 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.25 (s, 1H), 3.75 (s, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 134.4, 132.6, 131.7, 129.0, 129.8 128.4, 118.5, 111.4, 32.9; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₁H₁₀N₃ ⁺ 184.0869; found 184.0860.

4-(1,3,7-Trimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)­benzonitrile (16)

The compound was purified by column chromatography (EtOAc/hexanes, 3.7 v/v) to provide the product as a yellow solid in 69% (26 mg); mp = 90–92 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.87 (q, J = 7.6 Hz, 4H), 4.14 (s, 3H), 3.65 (s, 3H), 3.46 (s, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 161.9, 155.6, 151.6, 149.6, 148.3, 132.7, 129.7, 118.0, 114.0, 109.2, 34.1, 29.1, 28.1; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₅H₁₄N₅O₂ ⁺ 296.1142; found 296.1139.

4-(1,3-Dimethyl-1H-indol-2-yl)­benzonitrile (17)

The compound was purified by column chromatography (EtOAc/hexanes, 1.19 v/v) to provide the product as a yellow solid in 66% (28 mg); mp = 176–177 °C; ¹ H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.3 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.24–7.16 (m, 1H), 3.66 (s, 3H), 2.33 (s, 3H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 137.8, 137.0, 135.5, 132.2, 131.1, 128.3, 122.8, 119.62, 119.24, 118.8, 111.2, 110.4, 109.5, 31.2, 9.45; HRMS (ESI) m/z: [M + H]⁺ Calcd for C₁₇H₁₅N₂ ⁺ 247.1230; found 247.1223.

4-(2-Phenylimidazo­[1,2-a]­pyridin-3-yl)­benzonitrile (18)

The compound was purified by column chromatography (EtOAc/hexanes, 1:4 v/v) to provide the product as a yellow solid in 67% (26 mg); mp = 165–167 °C; ¹ H NMR (400 MHz, CDCl₃) δ 8.07 (d, J = 6.9 Hz, 1H), 7.86–7.81 (m, 3H), 7.65–7.57 (m, 4H), 7.37–7.33 (m, 4H), 6.92–6.88 (m, 1H); ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ 145.0, 134.3, 133.3, 132.6, 131.1, 129.3, 128.7, 128.5, 128.4, 126.2, 122.9, 119.1, 118.4, 117.7, 113.6, 112.5; HRMS (ESI) m/z: [M + H] ⁺ Calcd for C₂₀H₁₄N₃ ⁺ 296.1182; found 296.1169.

3-(3-Chloro-4-methylphenyl)-2-(4-methoxyphenyl)-5-methyl-2H-indazole (19)

The compound was purified by column chromatography (EtOAc/hexanes, 1:4 v/v) to provide the product as an off white solid in 51% yield (19 mg); mp = 157–159 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 7.0 Hz, 1H), 7.61 (d, J = 8.7 Hz, 2H), 7.47 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 6.86 (d, J = 8.7 Hz, 2H), 6.59 (d, J = 6.5 Hz, 1H), 3.82 (s, 3H), 2.49 (s, 3H), 2.43 (s, 3H). ¹³C­{¹H} NMR (100 MHz, CDCl₃) δ: 159.12, 145.30, 142.24, 136.65, 135.69, 135.29, 132.02, 130.81, 129.37, 129.22, 129.16, 126.69, 122.32, 118.24, 115.77, 114.90, 113.77, 55.24, 21.37, 20.11. HRMS (ESI) m/z: [M + H]⁺ Calcd for C₂₂H₂₀ClN₂O⁺ 363.1259; found 363.1261.

Computational Study

All theoretical calculations are performed through density functional theory (DFT) − based on methods and the software package used is Gaussian 16. The geometry optimizations were conducted using the range-separated hybrid functional ωB97XD. The LANL2DZ basis set was strategically chosen for the heavy atoms Pd and Br, while the 6–31G (d, p) basis set was implemented for the remaining atoms: C, H, N, O, Cl, and K. To account for solvent effects accurately, the Polarizable Continuum Model, specifically the Integral Equation Formalism variant (i.e., IEFPCM) , was utilized, with a dielectric constant (ε) of 37.78 for the solvent DMF. The contributions of internal energy and entropy were determined through frequency calculations performed on the optimized structures at 298.15 K. It was confirmed that the optimized transition state structures exhibit exactly one imaginary frequency, which aligns with the expected normal vibration mode. In contrast, all other intermediates were confirmed to show zero imaginary frequencies. Furthermore, through intrinsic reaction coordinate (IRC) analysis it was verified that transition states effectively connect the relevant reactants and products. As a result, the energies depicted in the figures are presented as Gibbs free energy changes (ΔG), reflecting the thermodynamic stability of the systems studied.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.6c00038.

• Details of characterization data, copies of ¹H NMR, ¹³C­{¹H} NMR of L1, L2, C1, C2, 3aa-3kb, and 12 −18, single crystal X-ray data of C2, and in situ HRMS reports of reaction intermediates (PDF)

• 2384000 CIF C2 (CIF)

The authors declare no competing financial interest.