Directed C–H Functionalization of C3-Aldehyde, Ketone, and Acid/Ester-Substituted Free (NH) Indoles with Iodoarenes via a Palladium Catalyst System

Abstract

Pd(II)-catalyzed C–H arylations of free (NH) indoles including different carbonyl directing groups on C3-position with aryl iodides are demonstrated. Importantly, the reactions are carried out using the same catalyst system without any additional transient directing group (TDG). In this study, the formyl group as a directing group gave the C4-arylated indoles versus C2-arylation. Using this catalyst system, C–H functionalization of 3-acetylindoles provided domino C4-arylation/3,2-carbonyl migration products. This transformation involves the unusual migration of the acetyl group to the C2-position following C4-arylation in one pot. Meanwhile, migration of the acetyl group could be simply controlled and N-protected 3-acetylindoles afforded C4-arylation products without migration of the acetyl group. Functionalization of indole-3-carboxylic acid (or methyl ester) with aryl iodides using the present Pd(II)-catalyst system resulted in decarboxylation followed by the formation of C2-arylated indoles. Based on the control experiments and the literature, plausible mechanisms are proposed. The synthetic utilities of these acetylindole derivatives have also been demonstrated. Remarkably, C4-arylated acetylindoles have allowed the construction of functionalized pityiacitrin (a natural product).

Introduction

Transition-metal (TM)-catalyzed functionalization reactions through directing group-assisted C–H activation have emerged as a powerful tool for C–C and C–X bond-forming reactions, providing an atom- and step-economical strategy for organic synthesis.¹ The C–H activation, which represents a paradigmatic change in the field of synthesis of complex heterocyclic and carbocyclic molecules, allows not only specifically functionalizes of the inert C–H bonds but also provides the formation of various compounds by coupling the introduced functional groups.²

Indole core is found in numerous natural products, pharmaceuticals, materials chemistry, and other bio-relevant compounds and has been recognized as a privileged structure scaffold.³ Because of this, enormous efforts have been devoted to the construction of functionalized indoles. Due to the high nucleophilic activity of the pyrrole ring of the indole, most C–H activation reactions primarily occur at the C2 or C3 position of pyrrole moiety (Figure 1a).⁴ As opposed to these positions, C–H functionalization of the low active C4–C7 positions in the benzenoid ring is less scrutinized and remains a long-standing challenge (Figure 1a). In recent years, transition-metal-catalyzed directed C–H activation has been studied as a powerful synthetic tool to access the functionalized indoles at C4–C7 positions.⁵ Especially, Shi,⁶ You,⁷ Yu,⁸ Ackermann,⁹ and others¹⁰ pioneered the developments in benzenoid functionalization. C–H activation through C3 at the pyrrole ring of indole has two directing modes. The first is vicinal activation, in which the directing group (DG) and the target C–H bond are at vicinal positions of the indole (Figure 1b).¹¹ With this activation mode for a suitable DG at the C3-position, a metallacycle is formed after C–H activation, which leads to C2-functionalization via the resulting metal–C bond. The second directing mode for DG on the indole C3-position involves nonvicinal activation to form a metallacycle for C4-functionalization (Figure 1b).^7,11a,11b Similarly, by installing a directing group at the indole nitrogen, both C2- and C7-activation have also been enabled.^5j,11c However, both C5 and C6 positions lie even more remote from a directing group, and therefore, used strategies have mimicked those used for remote meta functionalization. These strategies include template-controlled palladium-catalyzed C–H alkenylation,⁸ C–H alkylation via σ-activation,¹² and copper-catalyzed arylation using diaryliodonium salts as the arylating agent.¹³

Figure 1.

C–H functionalization of indoles and directed C–H bond activation mode examples.

Due to the remarkable importance of C4-functionalized indoles in natural products and medicinal chemistry, researchers have concentrated on the direct diversification of relatively less explored C-4 position of indoles via C–H activation strategy. Therefore, alkenylation,^10a,14 acylation,^10c amidation,^7b,15 allylation,¹⁶ alkylation,¹⁷ borylation,^5f cyclization,¹⁸ fluoroalkylation,^6e,19 and halogenation²⁰ of indoles at C4-positions have been demonstrated using different transition-metal catalysts (such as Rh, Ir, Pd, Co, and Ru) in the presence of appropriate directing groups. Despite the importance of biaryl compounds, a limited number of arylations at the C4-position through C–H activation have been performed so far. In 2017, Shi’s group installed an elegant Pd(0)-catalyzed strategy for the C4-arylation of N-benzylindoles using a pivaloyl directing group (Scheme 1a).^13a Almost simultaneously, Yu and Zhang’s group showed a single example (in a yield of 82%) of Pd(II)-C4-arylation of N-tosyl-3-fomylindole with methyl 4-iodobenzoate, in which the formyl group was installed in the C3 position of the indole (Scheme 1a).²¹ In this work, 2-amino-2-methylpropanoic acid was used as a transient directing group. Later, Maiti and Volla’s group reported a similar transformation for the C4-arylation of unprotected 3-formylindole (single example) and N-protected (methyl, tosyl, and benzyl) 3-formylindoles with aryl iodides using glycine as an inexpensive transient directing group (Scheme 1a).^10d Yang and You’s group disclosed an iridium-catalyzed C2/C4-regioselective C–H heteroarylation of indoles with the help of a pivaloyl group at the C3-position (Scheme 1a/b).^7a The oxidants Cu(OAc)₂·H₂O and Ag₂O have been demonstrated to play a vital role in the C2/C4-regioselectivity. Recently, Punniyamurthy’s group reported the palladium-catalyzed weak chelation-assisted regioselective C4-arylation of indoles utilizing arenes as the aryl source via a twofold C–H activation/C–C bond formation (Scheme 1a).²² When using carboxylic acid as the directing group, N-heterocyclic carbene (NHC) and abnormal NHC (aNHC)-based Pd-catalyzed arylation reactions of N-alkylindole-2-carboxylic acids with aryl bromides and aryl chlorides as the coupling partners resulted in decarboxylative C2-arylation (Scheme 1c).²³ Synthesis of 2-arylindoles was also reported via a Pd-catalyzed decarboxylative strategy in water without base, oxidant, and ligand using diaryliodonium salts as the aryl partners (Scheme 1c).²⁴ Despite the above background, the examples of the directed C–H arylation of unprotected indoles remain extremely limited and include transient directing group strategies. At this point, it is important to note that An, Li, and Yang’s group recently reported C4-arylation or domino C4-arylation/3,2-carbonyl migration (via migration of acetyl substituent from the C3- to C2-indole position) of 3-acetyl indoles via the different pathways by tuning either the Pd(I)–Pd(II) pathway or Pd(II) catalysis.²⁵ Our simultaneous results complete this research, and also expand its scope, and include new findings. Herein, we now wish to report the arylations for unprotected indoles including formyl, acetyl, carboxylic acid, and methyl ester groups as a directing group at the C3-position with aryl iodides and without a transient directing group using the single Pd(II) catalyst system. With different directing groups, different pathways were observed (Scheme 1d).

Scheme 1. Transition-Metal-Catalyzed Arylation of Indoles via C–H Functionalization.

Results and Discussion

In continuation of our research interest in C–H arylation reactions,²⁶ we started our investigation, focusing on the C–H arylation reactions of unprotected indole 1a involving the formyl group at the C3-position as a directing group without a transient directing group. Initially, 1H-indole-3-carbaldehyde (1a) and iodobenzene (2a) were selected as model substrates to screen the reaction conditions (Table 1). When 10 mol % Pd(OAc)₂ was used as the catalyst and AgOAc (2 equiv) was used as the oxidant at 100 °C, among the employed solvents such as 1,1,1,3,3,3- hexafluoroisopropanol (HFIP), HOAc, 1,2-dichloroethane (DCE), N,N-dimethylformamide (DMF), toluene (Tol), trifluoroacetic acid (TFA), and 2,2,2-trifluoroethanol (TFE) (Table 1, entries 1–8), TFA gave the desired product 3aa in 23% yield (Table 1, entry 8). The yields were improved to 47 and 58% when HOAc and TFA were used as the additive, respectively (Table 1, entries 9 and 10). Entries 9 and 10 showed that the use of TFA as a co-solvent was also effective. To test the effect of the co-solvents such as DCE, N,N-dimethylacetamide (DMA), DMF, Tol, or TFE, further optimization was conducted (Table 1, entries 11–15). Under these conditions, the formation of 3aa was observed as trace amounts. To our delight, decreasing the reaction time to 3.5 h, we obtained the desired product 3aa with an 87% isolated yield (Table 1, entries 16 and 17). When the reaction was carried out at 120 °C for 3.5 h, the yield decreased (Table 1, entry 18). The reaction at 65 °C for 15 h did not give the expected increase in yield (Table 1, entry 19). Other oxidants such as Ag₂CO₃, Ag₂O, Cu(OAc)₂·H₂O, and AgTFA were also screened, but none of them achieved the same effect as silver acetate (Table 1, entries 20–23). Further experiments revealed that other palladium catalysts such as PdCl₂ and Pd(PPh₃)₂Cl₂, and Pd(TFA)₂ in HFIP (with and without TFA) were inferior to Pd(OAc)₂ (entry 24–27). Also, when the Pd(TFA)₂/AgOAc catalyst system in HFIP/TFA was used, the C4-arylation proceeded cleanly, and 3aa was isolated in 87% yield (entry 28). Based on the screening conditions described above, the use of Pd(OAc)₂ as a catalyst due to inexpensive AgOAc as an oxidant and TFA as an additive in HFIP at 100 °C was determined to be the optimal reaction conditions (entry 17).

Table 1. Optimization of Reaction Conditions^a.

entry	catalyst	oxidant	temp (°C)	solvent	additive	time (h)	yield (3aa, %)b
1–7	Pd(OAc)2	AgOAc	100	solventc		10–12	trace
8	Pd(OAc)2	AgOAc	100	TFA		10	23
9	Pd(OAc)2	AgOAc	100	HFIP	HOAc	10	47
10	Pd(OAc)2	AgOAc	100	HFIP	TFA	10	57
11–15	Pd(OAc)2	AgOAc	100	HFIP	other solventd	5	trace
16	Pd(OAc)2	AgOAc	100	HFIP	TFA	5	70
17	Pd(OAc)2	AgOAc	100	HFIP	TFA	3.5	87
18	Pd(OAc)2	AgOAc	120	HFIP	TFA	3.5	72
19	Pd(OAc)2	AgOAc	65	HFIP	TFA	15	81
20	Pd(OAc)2	Ag2CO3	100	HFIP	TFA	3.5	45
21	Pd(OAc)2	Ag2O	100	HFIP	TFA	3.5	70
22	Pd(OAc)2	Cu(OAc)2·H2O	100	HFIP	TFA	3.5	trace
23	Pd(OAc)2	AgTFA	100	HFIP		5	trace
24	PdCl2	AgOAc	100	HFIP	TFA	3.5	71
25	Pd(PPh3)2Cl2	AgOAc	100	HFIP	TFA	3.5	67
26	Pd(TFA)2	AgOAc	100	HFIP		3.5	trace
27	Pd(TFA)2	AgTFA	100	HFIP		36	74
28	Pd(TFA)2	AgOAc	100	HFIP	TFA	3.5	87

^aReaction conditions: 1a (0.40 mmol), Pd(OAc)₂ (10 mol %), 2a (0.80 mmol), oxidant (0.80 mmol), solvent (1 mL), additive (1 mL).

^bIsolated yield.

^cSolvent: HFIP, HOAc, DCE, DMA, DMF, Tol, or TFE.

^dOther solvent: DCE, DMA, DMF, Tol, or TFE.

With the optimized condition in hand, the substrate scope of this C–H arylation reaction was investigated, and the results are depicted in Scheme 2. Initially, both various electron-rich (Me, t-Bu, OMe) and electron-poor (Br, CO₂Me, COMe, and CF₃) aryl iodides 2a-l were subjected to C4 arylation with 1H-indole-3-carbaldehyde (1a) under the standard conditions. Generally, reactions of aryl iodides possessing diverse substituents at different positions of the phenyl ring proceeded smoothly, and the desired C4 arylated products 3aa-ai and 3al were obtained in good to excellent yields (Scheme 2a). ortho-Methyl group at the iodoarene is not tolerated, suggesting that a sterically crowded intermediate is being formed during the coupling (Scheme 2a). Using 1-iodo-1,3-dimethylbenzene (2k) gave a reaction mixture that could not be purified. Then, the influence of the substitution pattern at the indole ring was investigated. The coupling of iodobenzene (2a) with a variety of substituted 1H-indole-3-carbaldehydes 1b-j was tested (Scheme 2b). No arylation products 3ea-ga were obtained from 5-substituted indoles, indicating that the reaction is very sensitive to steric hindrance at this position. Conversely, substituted indoles at C2, C7, or N1 positions readily couple with iodobenzene to give the corresponding C4 arylated products 3ba-da, 3ha, and 3ia in excellent yields. Particularly noteworthy are the 7-halogen substrates in which the presence of the fluorine and bromine substituents at C7 does not hamper the arylation in the C4 position. The structures of C–H arylation products were confirmed by ¹H and ¹³C NMR spectroscopy and high-resolution mass spectrometry (HRMS). The arylation at C4-position in 1a was also assigned by a nuclear Overhauser effect (NOE) study. NOE correlations between the C2 hydrogen atom and ortho-hydrogen atoms of the C4 phenyl substituent of the aldehyde hydrogen atom within 3a (see blue arrows) support the relative arylation depicted (Scheme 2a).

Scheme 2. Substrate Scope of Iodoarenes and 3-Formylindoles.

Reaction conditions: 1a (0.40 mmol), Pd(OAc)₂ (10 mol %), 2 (0.80 mmol), AgOAc (0.80 mmol), HFIP (1 mL), TFA (1 mL).

At 65 °C.

At 120 °C.

Notably, 3-acetylindole (4a) was subjected to reaction with 2a under the determined optimized reaction conditions for indole-3-aldehydes, and the desired product 5aa was obtained in 83% yields (Scheme 3a). Recently, An, Li, and Yang’s group researched the same reaction and reported this domino C4-arylation/3,2-carbonyl migration and structures of corresponding products.²⁵ The structure of products was assigned by NMR spectra and HRMS. At the ¹H NMR spectrum, the chemical shift of the C2-H (low-field) and C3-H (high-field) protons for indoles is a characteristic indication. The C3-H resonance (δ 7.34 ppm) of 5aa appeared at a lower field than the C2-H resonance (δ 7.87 ppm) of 4a. Comparison of the NMR spectra of 4a and 5aa, the disappearance of characteristic C2-H resonance, and the appearance of a new C3-H resonance at high-field indicated the formation of 5aa, which reveals that the ketone group is migrated under these conditions. Additionally, for domino C4-arylation/1,2-carbonyl migration product 5aa, structure assignment was confirmed according to NOE signals (see blue arrows) between acetyl methyl protons and C3–H/N–H protons (Scheme 3a). The evaluation of the substrate scope for this transformation is depicted in Scheme 3a. A wide variety of aryl iodides 2a-l (except 2j) were also well tolerated by the palladium catalyst to deliver domino C4-arylation/1,2-carbonyl migration products 5ab-al (except 5aj). For example, aryl iodides 2b-d with the electron-donating groups at the para and meta positions, such as methyl and tert-butyl, promoted this transformation smoothly. The corresponding products (5ab-ad) were obtained in excellent yields (74–81%). para-Methoxy-substituted iodobenzene gives the product 5af in a high yield (70%). In contrast, aryl iodides 2e and 2g-i substituted with electron-withdrawing groups, such as −Br, −COOMe, −COMe, and −CF₃, also reacted with 4a smoothly, giving the corresponding products 5ae and 5ag-ai in 53–80% yields. When ortho-methyl-substituted iodobenzene 5j was employed under standard conditions, no corresponding product 5aj was determined. This entry indicated that the steric hindrance of ortho-substitution had a significant effect on the progress of the reaction. In addition, product 5al was obtained in a low yield (53%) when the −NO₂ substitution as a strong electron-withdrawing substituent exists on the meta position. When 3,4-dimethyliodobenzene (2k) was used as a substrate, the corresponding product 5ak was obtained in good yield (73%). To further widen the scope of this domino C4-arylation/3,2-carbonyl migration strategy, 3-acetylindoles 4b-d with iodobenzene (2a) were subjected to optimized reaction conditions (Scheme 3b). Also, 3-acetyl-7-fluoro-1H-indole (4b) worked well to yield 5ba in good yield (73%). Interestingly, 3-acetyl-7-bromo-1H-indole (4c) afforded C4-arylated product 6ca (76% yield) in which the acetyl group did not migrate at 120 °C for 12 h, while domino C4-arylation/3,2-carbonyl migration product 5ca was obtained when the reaction was performed at 120 °C for 24 h. In the case of C2-protected indole, 3-acetyl-2-methyl-1H-indole (4e) provided C4-arylated product 7da with directing group removal.

Scheme 3. Substrate Scope of Iodoarenes and 3-Acetylindoles.

Reaction conditions: 1a (0.40 mmol), Pd(OAc)₂ (10 mol %), 2 (0.80 mmol), AgOAc (0.80 mmol), HFIP (1 mL), TFA (1 mL).

At 130 °C.

At 100 °C.

At 110 °C.

Shi’s group reported C4/C5-arylation (single examples) in a lower yield of an N–Bn-protected indole bearing directing groups at the C3 position, such as formyl, acetyl, and isobutyryl substituents.¹³ To confirm the importance of the NH-unprotected indoles for this unusual DG migration, we investigated the reaction between 3-acetyl-N-benzylindole 8a with a variety of aryl iodides 2a-l containing a wide variety of electron-donating or electron-withdrawing substituents under the same optimized reaction conditions (Scheme 4a). No significant electronic effect on the reaction progress was observed. Aryl iodides with substituents on meta, para-positions delivered corresponding C4-arylation products 9aa-al in good to excellent yields. But 2-iodotoluene (9j) led to a trace amount of product 9aj. Substrates 8b and 8c containing fluoro and bromo participated in C4-arylation smoothly in excellent yields (Scheme 4b). Compared to 3-acetyl-N-benzylindole (8a), 3-acetyl-N-methylindole (8e) gave C4 arylation products 9ea and 9eg in almost similar yields. However, the presence of the methyl group on the C2-position of indole led to an unpurified reaction mixture (Scheme 4b, for 9d).

Scheme 4. Substrate Scope of Iodoarenes and 3-Acetyl-N-Benzylindoles.

Reaction conditions: 1a (0.20 mmol), Pd(OAc)₂ (10 mol %), 2 (0.40 mmol), AgOAc (0.40 mmol), HFIP (1 mL), TFA (1 mL).

At 110 °C.

At 120 °C.

At 90 °C.

At 75 °C.

With the catalyst system in hand, we next examined the scope of acid/ester-directed C–H arylation with iodoarenes using N-unprotected 1H-indole-3-carboxylic acid (10a) and methyl 1H-indole-3-carboxylate (10b) (Scheme 5). First, the indole-3-carboxylic acid (10a) without substituents on position N1 with aryl iodides (2a-e and 2k) was tested. All gave the corresponding decarboxylative C2-arylation products 11a-e and 11k in high yields (75–87%) with complete site selectivity.²⁷⁻³⁰ However, the methyl 1H-indole-3-carboxylate (11b) was effective and gave the same products 11a-e and 11k successfully, but in moderate yields (60–66%). Since this catalytic process yields decarboxylative C2-arylation products, we have limited the scope of aryl iodides.

Scheme 5. Substrate Scope of Iodoarenes and 1H-Indole-3-Carboxylic Acid or Methyl 1H-Indole-3-Carboxylate.

Reaction conditions: 10a (or 10b) (0.40 mmol), Pd(OAc)₂ (10 mol %), 2 (0.80 mmol), AgOAc (0.80 mmol), HFIP (1 mL), TFA (1 mL).

For R = H.

For R = Me.

To explore the practical utility of this C(sp²)–H arylation reaction, a gram-scale reaction of 3-formylindole (1a) was carried out under the standard conditions (Scheme 6a). The desired arylation product 3aa could be obtained in 69% yield. Also, to confirm the synthetic utility of this domino C4-arylation/1,2-carbonyl migration process, a gram-scale reaction of 3-acetylindole (4a, 6.3 mmol) and iodobenzene (2a, 25.1 mmol) was conducted under the standard conditions. A total of 0.98 g of compound 5aa was obtained in a satisfying yield (65%), which was comparable with the small-scale reaction (Scheme 6b). Furthermore, the potential applications of both domino C4-arylation/1,2-carbonyl migration products and C4-arylation products as useful synthetic blocks are illustrated (Scheme 6c–e). To perform structure confirmation as well as synthetic diversification, the benzylation reaction of 5aa gave the N1-benzylated indole derivative 12 in good yields (Scheme 6c). Comparison of the NMR spectra of 12 and 9aa is important to confirm that the acetyl group does not migrate during the arylation of 3-acetyl-N-benzylindole 8a under the standard conditions. Besides C–H arylation on the C4-position of the indole ring, the bromine group on the 7-position of 5ca has a potential derivatization site. The classical palladium-catalyzed Suzuki–Miyaura coupling of 5ca with thiophene-2-boronic acid provided 13 in excellent yield (89%) (Scheme 6d).³¹ Pityiacitrin (14) is a 1-indolyl-β-carboline alkaloid isolated from various sources and has also been tested for various biological activities.³² To demonstrate utility in the synthesis of the functionalized natural product of C4-arylated acetylindoles, the synthesis of the substituted pityiacitrin starting from 9ad was carried out successfully (Scheme 6e). For this, 9ad and 5-methoxytryptamine (15) were reacted with 1.0 equiv of I₂ and 1.5 equiv of H₂O₂ in dimethyl sulfoxide (DMSO) at 100 °C for 24 h to form substituted pityiacitrin 16. The protocol involves Kornblum oxidation to form indolylglyoxal, Pictet–Spengler condensation with tryptamine to yield dihydro-β-carboline, and finally, aromatization of dihydro-β-carboline to provide the desired product 16. This one-pot process successfully led to the synthesis of structurally related analogue 17 of pityiacitrin from 5aa (Scheme 6e).

Scheme 6. Gram-Scale Reaction and Synthetic Applications.

To further understand both structure characterization and the progress of these reactions, several control experiments were performed. During arylation of 4c, product 6ca was also isolated in 76% yield (Scheme 3b). Under the standard conditions, 6ca itself provided 3,2-carbonyl migration product 5ca in 74% yield (Scheme 7a). In fact, the C–H arylation reaction of N-unprotected 3-acetylindoles 4a-d can follow two paths: respectively, migration/arylation or arylation/migration. This result strongly supports both the migration of the acetyl group after the arylation reaction and the reported results of An, Li, and Yang’s group.²⁵ To understand the mechanism of the decarboxylative arylation reaction, several control experiments were performed (Scheme 7b–e). First, indole-3-carboxylic acid (10a) (or methylindole-3-carboxylate (10b)) was subjected to standard reaction conditions without using substrate 2a, wherein we isolated 3-acylation product 18 in 75% (or 70%) yield as a sole product (Scheme 7b).³³ We first assume that indole-3-carboxylic acid yields indole (19a) via palladium-catalyzed decarboxylation. Then, product 18 is formed from the acylation of indole (19a) with TFA. In addition, when indole (19a) and 2a were reacted under the standard reaction conditions, 2-phenylindole (11a) was obtained in 70% yield (Scheme 7c). These results indicate that indole (19a) might be the key intermediate for the decarboxylative arylation reaction. Furthermore, the reaction of 2-methylindole-3-carboxylic acid (10c)³⁴ without 2a/with 2a under standard reaction conditions gave 2-methylindole (19b) via decarboxylation (Scheme 7d). But the treatment of 19b with 2a did not provide any product (Scheme 7e). These experiments showed that C–H arylation could not proceed via C2 protection under our standard conditions.

Scheme 7. Control Experiments.

To probe the role of TFA in C4-arylation, optimization experiments were carried out (Table 1, especially entries 17 and 28). The role of TFA can be categorized into two aspects: (i) Pd(OAc)₂ could be readily converted to Pd(TFA)₂ to catalyze reactions (Table 1, entries 8, 10, 16–21, 24, and 25); (ii) it may affect the reaction rate or by increasing the solubility of the reaction mixture (Table 1, entries 26–28). Based on previous reports,^25,35 our findings, and control experiments, possible catalytic mechanisms are illustrated in Scheme 8. Initially, the active catalytic species A is formed from Pd(II) catalyst (Pd(TFA)₂, a catalyst formed in situ from Pd(OAc)₂ and TFA) and 3-formylindole (1a) (or 3-acetylindole) (or 4a) in the presence of AgOAc, followed by the C–H bond activation to form the cyclometalated Pd(II) intermediate B. The intermediate B further underwent oxidative addition with aryl iodide 2 to produce diaryl Pd(IV) species C. Reductive elimination of C produced the desired C4-arylated product 3 (or 6) and regeneration of the active Pd(II) species by AgOAc to regenerate the catalytic cycle. To explain carbonyl migration, An, Li, and Yang’s group conducted many independent experiments and mechanism studies and proposed a plausible reaction pathway.²⁵ Accordingly, after the formation of Pd(II)-catalyzed C4-arylation product 6, the 3,2-carbonyl migration (or Friedel–Crafts acyl rearrangement) process takes place. The first step would be a reaction between 6 and TFA, yielding the product D and mixed (or unsymmetrical) acid anhydride Evia protonation and reverse Friedel–Crafts process. Next, TFA (or Pd(TFA)₂)-promoted intermolecular Friedel–Crafts reaction takes place between D and E to yield selectively migration product 5 through acylation rearomatization. This unusual Friedel–Crafts acyl rearrangement is not reversible. We speculate that C3-acetylated product 6 was the kinetically controlled product, whereas C2-acetylated product 5 was the thermodynamically controlled product. NH-free 3-acetylindoles underwent unusual migration of the acetyl group to the C2-position following C4-arylation in one pot, whereas N-alkylated 3-acetylindoles showed C4-arylations without migration. These results indicate that an alkyl group at the nitrogen atom of the indoles plays a crucial role to prevent the migration of the acetyl group. We believe the existence of iminium intermediate Fvia a hydrogen-bond interaction between the CF₃COO^– and the NH-free indole, which could promote both reverse Friedel–Crafts process and 1,2-acetyl migration process.

Scheme 8. Proposed Pd^II-Pd^IV Catalytic Cycle for C4-Arylation and Migration Mechanism.

Two different pathways for the formation of decarboxylative C2-arylated indoles 11, through either the C–H arylation/decarboxylation process (path 1) or the decarboxylation/C–H arylation process (path 2), could be evaluated (Scheme 9). Based on the above control results and literature reports,^26,36 a plausible reaction pathway is path 2. In this context, the mechanism involves initial palladation at C3 followed by palladium migration to C2 via the Pd(II)/Pd(IV) pathway. Accordingly, this reaction is progressing to yield aryl-palladium intermediate indole cations G and H, followed by oxidative addition of palladium(II) to the ArI. This aryl-palladium intermediate I undergoes sequential reductive elimination to afford the C2-arylated product 11 and PdIOAc or PdI₂ (from 2 turnovers). Finally, the catalytically active Pd(OAc)₂ (or Pd(TFA)₂) for the cycle is regenerated from inactive PdIOAc or PdI₂via silver salt and TFA.

Scheme 9. Proposed Pd^II-Pd^IV Catalytic Cycle for C2-Arylation.

Conclusions

In summary, we have reported Pd(II)-catalyzed protocol for accessing arylated indole scaffolds utilizing iodoarenes as the aryl source via the C–H bond activation of N-unprotected indoles with the aid of readily accessible carbonyl directing groups (aldehyde, acetyl, carboxylic acid, and methyl ester) at the C3 position. The protocol is operationally simple and utilizes Pd(OAc)₂ as a catalyst, AgOAc as an oxidant, and TFA as an additive in HFIP at 65–120 °C. The substrate scope is broad and displays excellent selectivity (C4- arylation for 3-formylindoles and N-protected 3-acetylindoles, C4-arylation including 3,2-carbonyl migration for 3-acetylindoles, C2-arylation via decarboxylation/arylation steps for both indole-3-carboxylic acid and methylindole-3-carboxylate). Based on the control experiments and the literature, plausible mechanisms are proposed via Pd(II)/Pd(IV) catalytic cycles. To show the synthetic utility of both our catalytic system and the arylation products, gram-scale reaction and synthetic applications were performed. In this context, C4-arylated acetylindoles allowed us to construct the functionalized and structural-related analogues of pityiacitrin.

Experimental Section

General Information

Unless otherwise mentioned, all reagents and solvents from commercial sources were used without further purification. NMR spectra were recorded in CDCl₃, DMSO-d₆, or acetone-d₆ solvents at 400 MHz (¹H) and 100 MHz (¹³C), respectively. Chemical shifts (δ) are reported in parts per million (ppm), using the residual solvent peak in CDCl₃ (δ = 7.26 ppm for ¹H NMR and δ = 77.0 ppm for ¹³C NMR), DMSO-d₆ (δ = 2.50 ppm for ¹H NMR and δ = 39.4 ppm for ¹³C NMR), and acetone-d₆ (δ = 2.05 ppm for ¹H NMR and δ = 29.8 ppm for ¹³C NMR) as an internal standard, and coupling constants (J) are indicated in hertz (Hz). Signal multiplicities are abbreviated as s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, and br = broad. High-resolution mass spectrometry (HRMS) of all compounds was performed using a quadrupole time-of-flight (QTOF) spectrometry device. Column chromatography was performed using silica gel (70–230 mesh).

General Procedures

General Procedure A: Preparation of 1H-Indole-3-carbaldehydes (1b-g)³⁷

1H-Indole-3-carbaldehydes 1b-g were prepared according to the reported literature method.³⁷ Pyrophosphoryl chloride (0.9 mL, 9.4 mmol, 1.1 equiv) was added dropwise to a stirred mixture of N,N-dimethylformamide (2.8 mL, 36.7 mmol, 4.3 equiv) at 10–20 °C. To this mixture, a solution of indole substrate (8.5 mmol) in N,N-dimethylformamide (1.67 mL, 5 M for indole substrate) was added slowly, keeping the temperature at 20–30 °C. The mixture was then stirred in a preheated oil bath at 35 °C for 45 min. After completion of the reaction, the mixture was cooled to room temperature and carefully quenched with crushed ice (3.5 g). The mixture was stirred vigorously, and further crushed ice (3.5 g) was added, followed by a solution of NaOH (3.77 g, 94.3 mmol, 11 equiv) in water (10 mL). Then, the mixture was heated under reflux for 15 min, and the precipitate was filtered, washed with water (3 × 20 mL), and dried in vacuo to afford 1H-indole-3-carbaldehydes 1b-g.

General Procedure B: Preparation of 3-Acetyl-1H-indoles (4a-d)³⁸

3-Acetyl-1H-indoles 4a-d were prepared according to the reported literature method.³⁸ SnCl₄ (0.75 mL, 6 mmol, 1.2 equiv) was added dropwise into a stirred solution of 1H-indole derivative (5 mmol) in dichloromethane (10 mL, 2 M for 1H-indole derivative) at 0 °C in an inert atmosphere of N₂. The resultant mixture was warmed to room temperature and stirred for 30 min, then acetic anhydride (510 mg, 0.5 mL, 5 mmol, 1 equiv) was added, followed by nitromethane (7.5 mL), and stirred for 2 h at room temperature. After the completion of the reaction, the reaction was quenched by the addition of ice and water (20 mL), then extracted with dichloromethane (3 × 30 mL), and dried over anhydrous Na₂SO₄. The solvent was evaporated, and the crude product was then purified by silica gel chromatography to give 3-acetyl-1H-indoles.

General Procedure C: Preparation of N-Alkyl Indoles (1h-i and 8a-d)^10a

To a suspension of NaH (1.1 mmol, 1.1 equiv, 60% dispersion in mineral oil) in THF at 0 °C, a solution of 1H-3-acetylindole (or 1H-indole-3-carbaldehyde) (1 mmol) in THF (5 mL, 0.2 M for 1H-3-acetylindole or 1H-indole-3-carbaldehyde) was added dropwise. Benzyl bromide (methyl iodide for methylation) (1.1 mmol, 1.1 equiv) was then added dropwise to this solution and stirred for 12 h at room temperature. After completion, the reaction was quenched with water and extracted by EtOAc (2 × 30 mL). The combined organic phase was dried over Na₂SO₄, then concentrated under reduced pressure, and the residue was purified on silica gel column chromatography to provide the corresponding N-alkyl 3-acetyl indoles (or N-alkyl 3-carbaldehydes) indoles.

General Procedure D: C–H Arylation

The indole material 1 (or 4, or 8, or 10) (0.4 mmol), Pd(OAc)₂ (9 mg, 40 μmol, 10 mol %), and AgOAc (133 mg, 0.8 mmol, 2 equiv) were weighed in air and placed in a sealed tube (15 mL) with a magnetic stir bar. To the reaction mixture, aryl iodide 2 (0.8 mmol, 2 equiv) and HFIP/TFA (2 mL, 1:1, v/v, 0.2 M for the indole material 1 (or 4, or 8, or 10)) were added. The reaction mixture was then stirred in a preheated oil bath at 65–130 °C for 3–24 h. Upon completion, the reaction mixture was cooled to room temperature, the solvents were removed under reduced pressure, and the resulting mixture was purified by a silica gel column chromatography column to obtain the corresponding C–H arylation product using hexane/EtOAc as the eluent.

Spectral Data of Starting Materials

7-Fluoro-1H-indole-3-carbaldehyde (1b)³⁹

Off-white solid, mp: 140–141 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 12.70 (bs, NH, 1H), 9.97 (s, CHO, 1H), 8.37 (s, CH, 1H), 7.91 (d, J = 7.8 Hz, CH, 1H), 7.24–7.16 (m, CH, 1H), 7.13–7.07 (m, CH, 1H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 185.2, 149.0 (d, J = 245.2 Hz), 139.0 (s), 127.7 (d, J = 4.5 Hz), 124.7 (d, J = 13.2 Hz), 122.8 (d, J = 6.0 Hz), 118.7, 116.9 (d, J = 3.6 Hz), 108.5 (d, J = 15.9 Hz).

7-Bromo-1H-indole-3-carbaldehyde (1c)⁴⁰

Yellow solid, mp: 166–167 °C; ¹H NMR (400 MHz, Acetone-d₆): δ 11.32 (bs, NH, 1H), 10.06 (s, CHO, 1H), 8.29 (s, CH, 1H), 8.23 (d, J = 8.2 Hz, CH, 1H), 7.51–7.49 (m, CH, 1H), 7.20 (t, J = 7.8 Hz, CH, 1H). ¹³C{¹H} NMR (100 MHz, Acetone-d₆): δ 185.7, 138.5, 136.7, 127.2, 127.0, 124.5, 121.7, 120.9, 105.5.

2-Methyl-1H-indole-3-carbaldehyde (1d)⁴¹

White solid, mp: 200–201 °C; ¹H NMR (400 MHz, Acetone-d₆): δ 10.94 (bs, NH, 1H), 10.18 (s, CHO, 1H), 8.29–8.09 (m, CH, 1H), 7.52–7.34 (m, CH, 1H), 7.27–7.09 (m, CH, 2H), 2.75 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, Acetone-d₆): δ 184.6, 148.5, 136.5, 127.1, 123.6, 122.8, 121.3, 115.3, 112.0, 11.8

5-Bromo-1H-indole-3-carbaldehyde (1e)⁴⁰

White solid, mp: 204–205 °C; ¹H NMR (400 MHz, Acetone-d₆): δ 11.31 (bs, NH, 1H), 10.02 (s, CHO, 1H), 8.39 (d, J = 1.9 Hz, CH, 1H), 8.26 (s, CH, 1H), 7.53 (d, J = 8.6 Hz, CH, 1H), 7.40 (dd, J = 8.6, 2.0 Hz, CH, 1H). ¹³C{¹H} NMR (100 MHz, Acetone-d₆): δ 185.4, 139.0, 137.0, 127.3, 127.2, 124.6, 119.4, 116.1, 115.0.

5-(Benzyloxy)-1H-indole-3-carbaldehyde (1f)⁴²

Yellow solid, mp: 108–109 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 12.10 (bs, NH, 1H), 9.89 (s, CHO, 1H), 8.22 (s, CH, 1H), 7.70 (d, J = 2.5 Hz, CH, 1H), 7.52–7.46 (m, CH, 2H), 7.46–7.37 (m, CH, 3H), 7.35–7.29 (m, CH, 1H), 6.97 (dd, J = 8.7, 2.5 Hz, CH, 1H), 5.12 (s, CH₂, 2H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 184.8, 154.6, 138.5, 137.4, 132.0, 128.3, 127.6, 127.6, 124.8, 118.0, 113.8, 113.2, 104.0, 69.6.

5-Nitro-1H-indole-3-carbaldehyde (1g)⁴⁰

Yellow solid, mp: 292–293 °C; ¹H NMR (400 MHz, DMSO-d₆): δ 10.02 (s, CHO, 1H), 8.93 (s, CH, 1H), 8.56 (s, CH, 1H), 8.14 (d, J = 8.2 Hz, CH, 1H), 7.71 (d, J = 8.2 Hz, CH, 1H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 185.4, 142.7, 141.6, 140.3, 123.5, 119.0, 118.6, 117.0, 113.2.

1-Benzyl-1H-indole-3-carbaldehyde (1h)⁴⁰

White solid, mp: 107–108 °C; ¹H NMR (400 MHz, CDCl₃): δ 9.99 (s, CHO, 1H), 8.46–8.23 (m, CH, 1H), 7.70 (s, CH, 1H), 7.40–7.28 (m, CH, 6H), 7.21–7.16 (m, CH, 2H), 5.35 (s, CH₂, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 184.6, 138.6, 137.5, 135.3, 129.1, 128.4, 127.2, 125.5, 124.2, 123.1, 122.2, 118.5, 110.4, 50.9.

1-Methyl-1H-indole-3-carbaldehyde (1i)⁴⁰

Pale-brown solid, mp: 68–69 °C; ¹H NMR (400 MHz, CDCl₃): δ 9.94 (s, CHO, 1H), 8.34–8.30 (m, CH, 1H), 7.60 (s, CH, 1H), 7.41–7.28 (m, CH, 3H), 3.80 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 184.5, 139.5, 137.9, 125.2, 124.0, 122.9, 121.9, 117.9, 110.0, 33.6.

1-Tosyl-1H-indole-3-carbaldehyde (1j)⁴³

1-Tosyl-1H-indole-3-carbaldehyde (1j) were prepared according to the reported literature method.⁴¹ Purple solid, mp: 139–140 °C; ¹H NMR (400 MHz, CDCl₃): δ 10.09 (s, CHO, 1H), 8.25 (d, J = 7.3 Hz, =CH, 1H), 8.23 (s, =CH, 1H), 7.95 (d, J = 7.9 Hz, =CH, 1H), 7.87–7.82 (m, AA′ part of AA′BB′ system, =CH, 2H), 7.44–7.32 (m, =CH, 2H), 7.31–7.26 (m, BB′ part of AA′BB′ system, =CH, 2H), 2.36 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 185.4, 146.2 (2C), 136.2, 135.2, 134.4, 130.3, 127.2, 126.3, 125.1, 122.6, 122.4, 113.3, 21.6.

1-(1H-indol-3-yl)ethan-1-one (4a)^10a

White solid, mp: 189–190 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.93 (bs, NH 1H), 8.43–8.37 (m, CH, 1H), 7.87 (d, J = 3.0 Hz, CH, 1H), 7.48–7.39 (m, CH, 1H), 7.35–7.23 (m, CH, 2H), 2.56 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.2, 136.6, 132.3, 125.4, 123.6, 122.6, 122.2, 118.2, 111.7, 27.6.

1-(7-Fluoro-1H-indol-3-yl)ethan-1-one (4b)

White solid, mp: 195–196 °C: ¹H NMR (400 MHz, Acetone-d₆): δ 11.41 (bs, NH, 1H), 8.28 (d, J = 3.0 Hz, CH, 1H), 8.12 (d, J = 8.0 Hz, CH, 1H), 7.20–7.14 (m, CH, 1H), 7.01 (dd, J = 11.5, 8.0 Hz, CH, 1H), 2.50 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, Acetone-d₆): δ 193.2 (d, J = 0.9 Hz), 150.3 (d, J = 243.8 Hz), 134.5 (d, J = 17.1 Hz), 130.4 (d, J = 4.4 Hz), 125.8 (d, J = 13.4 Hz), 123.2 (d, J = 6.0 Hz), 119.3 (d, J = 1.6 Hz), 118.9 (d, J = 3.7 Hz), 108.6 (d, J = 15.8 Hz), 27.5. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₀H₉FNO: 178.0663; found: 178.0659.

1-(7-Bromo-1H-indol-3-yl)ethan-1-one (4c)⁴⁴

White solid, mp: 191–192 °C: ¹H NMR (400 MHz, DMSO-d₆): δ 12.16 (bs, NH, 1H), 8.35 (s, CH, 1H), 8.19 (d, J = 7.7 Hz, CH, 1H), 7.44 (d, J = 7.7 Hz, CH, 1H), 7.12 (t, J = 7.7 Hz, CH, 1H), 2.48 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 193.0, 135.1, 135.0, 126.9, 125.4, 123.1, 120.7, 117.6, 104.6, 27.4.

1-(2-Methyl-1H-indol-3-yl)ethan-1-one (4d)⁴⁵

Off-white solid, mp: 201–202 °C: ¹H NMR (400 MHz, CDCl₃): δ 8.70 (bs, NH, 1H), 8.03 (d, J = 7.8 Hz, CH, 1H), 7.37–7.33 (m, CH, 1H), 7.29–7.19 (m, CH, 2H), 2.76 (s, CH₃, 3H), 2.67 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.8, 143.7, 134.5, 127.0, 122.4, 122.1, 120.9, 114.7, 110.8, 31.3, 15.5.

1-(1-Benzyl-1H-indol-3-yl)ethan-1-one (8a)^10a

White solid; mp 114–115 °C: ¹H NMR (400 MHz, CDCl₃): δ 8.36–8.28 (m, CH, 1H), 7.64 (s, CH, 1H), 7.29–7.13 (m, CH, 6H), 7.08–7.04 (m, CH, 2H), 5.23 (s, CH₂, 2H), 2.41 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 193.0, 137.1, 135.8, 135.0, 129.1, 128.2, 127.0, 126.5, 123.5, 122.7 (2C), 117.5, 110.2, 50.7, 27.7.

1-(1-Benzyl-7-fluoro-1H-indol-3-yl)ethan-1-one (8b)

White solid; mp 132–133 °C: ¹H NMR (400 MHz, CDCl₃): δ 8.19 (d, J = 8.0 Hz, CH, 1H), 7.69 (s, CH, 1H), 7.41–7.29 (m, CH, 3H), 7.22–7.14 (m, CH, 3H), 6.95 (dd, J = 12.6, 7.9 Hz, CH, 1H), 5.50 (s, CH₂, 2H), 2.50 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 192.9, 149.8 (d, J = 245.5 Hz), 136.6, 136.1, 130.1 (d, J = 4.1 Hz), 129.0, 128.2, 127.0, 124.9 (d, J = 9.1 Hz), 123.1 (d, J = 6.7 Hz), 118.5 (d, J = 3.9 Hz), 118.0, 109.4 (d, J = 17.7 Hz), 53.0 (d, J = 6.1 Hz), 27.7. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₅FNO: 268.1132; found: 268.1130.

1-(1-Benzyl-7-bromo-1H-indol-3-yl)ethan-1-one (8c)

White solid; mp 154-153 °C: ¹H NMR (400 MHz, CDCl₃): δ 8.47 (dd, J = 8.0, 0.9 Hz, CH, 1H), 7.70 (s, CH, 1H), 7.43 (dd, J = 7.6, 0.8 Hz, CH, 1H), 7.36–7.29 (m, CH, 3H), 7.13 (t, J = 7.9 Hz, CH, 1H), 7.06–7.01 (m, CH, 2H), 5.85 (s, CH_2, 2H), 2.49 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 192.8, 137.8, 137.4, 133.6, 129.5, 129.1, 129.0, 127.9, 126.3, 123.9, 122.2, 117.1, 104.0, 52.2, 27.7. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₅BrNO: 328.0332; found: 328.0329.

1-(1-Benzyl-2-methyl-1H-indol-3-yl)ethan-1-one (8d)^10a

White solid; mp 96–97 °C: ¹H NMR (400 MHz, CDCl₃): δ 8.12–8.08 (m, CH, 1H), 7.39–7.31 (m, CH, 5H), 7.29 (dd, J = 7.0, 1.4 Hz, CH, 1H), 7.06 (d, J = 6.5 Hz, CH, 2H), 5.43 (s, CH₂, 2H), 2.80 (s, CH₃, 3H), 2.79 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.8, 144.9, 136.5, 136.1, 129.0, 127.8, 126.5, 125.9, 122.3, 122.1, 120.8, 114.7, 110.0, 46.4, 31.8, 12.7.

1-(1-Benzyl-2-methyl-1H-indol-3-yl)ethan-1-one (8e)^10a

White solid; mp 101–102 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.43–8.31 (m, CH, 1H), 7.67 (s, CH, 1H), 7.40–7.24 (m, CH, 3H), 3.82 (s, CH₃, 3H), 2.51 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 192.9, 137.5, 135.8, 126.2, 123.3, 122.5 (2C), 116.9, 109.6, 33.5, 27.6.

2-Methyl-1H-indole-3-carboxylic Acid (10c)³⁴

(Pink solid; mp: 174–175 °C); ¹H NMR (400 MHz, DMSO-d₆): 11.86 (bs, NH, OH, 2H), 7.94–7.89 (m, CH, 1H), 7.37–7.31 (m, CH, 1H), 7.11–7.05 (m, CH, 2H), 2.64 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 166.7, 144.3, 134.7, 127.2, 121.3, 120.6, 120.4, 111.0, 103.2, 13.7.

Spectral Data for C–H Arylation Products

4-Phenyl-1H-indole-3-carbaldehyde (3aa)

Compound 3aa was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a, 58 mg, 0.4 mmol) and iodobenzene (2a, 90 μL, 0.8 mmol) at 100 °C for 3.5 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3aa (76 mg, 87%, a brown solid, mp: 151–152 °C); ¹H NMR (400 MHz, CDCl₃): δ 10.05 (bs, NH, 1H), 9.52 (s, CHO, 1H), 8.01 (d, J = 2.6 Hz, CH, 1H), 7.57–7.51 (m, CH, 2H), 7.50–7.39 (m, CH, 4H), 7.33 (t, J = 7.5 Hz, CH, 1H), 7.20 (d, J = 7.5 Hz, CH, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 187.2, 141.9, 137.1, 135.6, 131.8, 129.0, 128.6, 127.7, 124.2, 123.9, 123.4, 119.2, 111.5. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₂NO: 222.0913; found: 222.0914.

4-(p-Tolyl)-1H-indole-3-carbaldehyde (3ab)

Compound 3ab was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a, 58 mg, 0.4 mmol) and 1-iodo-4-methylbenzene (2b, 175 mg, 0.8 mmol) at 65 °C for 15 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3ab (76 mg, 81%, a brown solid, mp: 207–208 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.52 (bs, NH, 1H), 9.02 (s, CHO, 1H), 8.02 (d, J = 3.1 Hz, CH, 1H), 7.46–7.39 (m, CH, 3H), 7.33 (t, J = 7.3 Hz, CH, 1H), 7.29–7.25 (m, BB′ part of AA′BB′ system, CH, 2H), 7.18 (dd, J = 7.1, 0.7 Hz, CH, 1H), 2.42 (s,CH_3, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 187.3, 138.9, 137.5, 137.0, 135.7, 131.2, 129.3, 128.8, 124.3, 123.9, 123.4, 119.3, 111.1, 21.3. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₄NO: 236.1070; found: 236.1071.

4-(m-Tolyl)-1H-indole-3-carbaldehyde (3ac)

Compound 3ac was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a, 58 mg, 0.4 mmol) and 1-iodo-3-methylbenzene (2c, 103 μL, 0.8 mmol) at 65 °C for 20 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3ac (65 mg, 70%, a dark brown solid, mp: 87–88 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.78 (bs, NH, 1H), 9.51 (s, CHO, 1H), 8.01 (d, J = 3.0 Hz, CH, 1H), 7.42 (d, J = 8.0 Hz, CH, 1H), 7.38–7.28 (m, CH, 4H), 7.22 (d, J = 7.0 Hz, CH, 1H), 7.18 (d, J = 6.9 Hz, CH, 1H), 2.40 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 187.4, 138.3, 137.0, 135.7, 131.3, 129.7, 128.5, 128.4, 126.0, 123.8, 123.4, 119.2, 111.3, 21.5. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₄NO: 236.1070; found: 236.1070.

4-(4-(tert-Butyl)phenyl)-1H-indole-3-carbaldehyde (3ad)

Compound 3ad was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a, 58 mg, 0.4 mmol) and 1-(tert-butyl)-4-iodobenzene (2d, 141 μL, 0.8 mmol) at 100 °C for 3 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3ad (86 mg, 78%, a dark brown solid, mp: 153–154 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.79 (bs, NH, 1H), 9.56 (s, CHO, 1H), 8.00 (d, J = 3.0 Hz, CH, 1H), 7.52–7.44 (m, CH, 4H), 7.41 (d, J = 8.0 Hz, CH, 1H), 7.30 (t, J = 7.2 Hz, CH, 1H), 7.18 (d, J = 7.2 Hz, CH, 1H), 1.37 (s, CH₃, 9H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 187.5, 150.7, 144.6, 138.8, 137.0, 135.6, 131.2, 128.6, 125.5, 124.3, 124.0, 123.4, 119.3, 117.7, 111.1, 34.6, 31.4. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₂₀NO: 278.1539; found: 278.1541.

4-(4-Bromophenyl)-1H-indole-3-carbaldehyde (3ae)

Compound 3ae was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a, 58 mg, 0.4 mmol) and 1-bromo-4-iodobenzene (2e, 226 mg, 0.8 mmol) at 100 °C for 6 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3ae (102 mg, 86%, a dark brown solid, mp: >300 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.55 (bs, NH, 1H), 9.04 (s, CHO, 1H), 8.03 (d, J = 2.7 Hz, CH, 1H), 7.64–7.56 (m, AA′ part of AA′BB′ system, CH, 2H), 7.51–7.44 (m, CH, 1H), 7.42–7.37 (m, BB′ part of AA′BB′ system, CH, 2H), 7.34 (t, J = 7.5 Hz, CH, 1H), 7.16 (d, J = 7.5 Hz, CH, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 186.2, 140.8, 137.0, 134.4, 131.7, 131.6, 130.7, 123.9, 123.7, 123.6, 121.9, 119.4, 111.5. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₁BrNO: 300.0019; found: 300.0018.

4-(4-Methoxyphenyl)-1H-indole-3-carbaldehyde (3af)

Compound 3af was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a, 58 mg, 0.4 mmol) and 1-iodo-4-methoxybenzene (2f, 187 mg, 0.8 mmol) at 100 °C for 3 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3af (88 mg, 79%, a dark brown solid, mp: 111–112 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.55 (bs, NH, 1H), 9.21 (s, CHO, 1H), 8.02 (d, J = 3.2 Hz, CH, 1H), 7.48–7.40 (m, CH, 3H), 7.32 (t, J = 7.3 Hz, CH, 1H), 7.19–7.14 (m, CH, 1H), 7.03–6.97 (m, BB′ part of AA′BB′ system, CH, 2H), 3.87 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 187.2, 159.2, 137.0, 135.4, 134.2, 131.2, 130.1, 124.4, 123.9, 123.4, 119.4, 114.0, 111.0, 55.3. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₄NO₂: 252.1019; found: 252.1019.

Methyl 4-(3-Formyl-1H-indol-4-yl)benzoate (3ag)

Compound 3ag was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a, 58 mg, 0.4 mmol) and methyl 4-iodobenzoate (2g, 210 mg, 0.8 mmol) at 100 °C for 12 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3ag (97 mg, 87%, a brown solid, mp: 190–191 °C); ¹H NMR (400 MHz, Acetone-d₆): δ 11.46 (bs, NH, 1H), 9.56 (s, CHO, 1H), 8.20 (d, J = 3.3 Hz, CH, 1H), 8.15–8.06 (m, AA′ part of AA′BB′ system, CH, 2H), 7.70–7.58 (m, CH, 3H), 7.36 (t, J = 7.4 Hz, CH, 1H), 7.17 (dd, J = 7.5, 0.8 Hz, CH, 1H), 3.92 (s,CH₃, 3H). ¹³C{¹H} NMR (100 MHz, Acetone-d₆): δ 184.6, 167.2, 148.2, 138.8, 135.2, 134.7, 130.2 (2C), 130.0, 124.2, 124.1, 124.0, 119.9, 113.1, 52.4. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₄NO₃: 280.0968; found: 280.0968.

4-(4-Acetylphenyl)-1H-indole-3-carbaldehyde (3ah)

Compound 3ah was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a, 58 mg, 0.4 mmol) and 1-(4-iodophenyl)ethan-1-one (2h, 196 mg, 0.8 mmol) at 100 °C for 3 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3ah (96 mg, 92%, a dirty white solid, mp: 220–221 °C); ¹H NMR (400 MHz, Acetone-d₆): δ 11.45 (bs, NH, 1H), 9.56 (s, CHO, 1H), 8.19 (d, J = 3.2 Hz, CH, 1H), 8.14–8.03 (m, AA′ part of AA′BB′ system, CH, 2H), 7.70–7.60 (m, CH, 3H), 7.36 (t, J = 7.4 Hz, CH, 1H), 7.19–7.14 (m, CH, 1H), 2.65 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, Acetone-d₆): δ 197.7, 184.7, 148.2, 138.8, 137.1, 135.2, 134.5, 130.2, 129.1, 124.2, 124.1, 124.0, 119.8, 113.1, 26.8. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₄NO₂: 264.1019; found: 264.1024.

4-(4-(Trifluoromethyl)phenyl)-1H-indole-3-carbaldehyde (3ai)

Compound 3ai was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a, 58 mg, 0.4 mmol) and 1-iodo-4-(trifluoromethyl)benzene (2i, 117 μL, 0.8 mmol) at 100 °C for 15 h and purified by silica gel column chromatography (70:30 hexane/ethyl acetate): 3ai (95 mg, 83%, a dark brown solid, mp: 190–191 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.53 (bs, NH, 1H), 9.03 (s, CHO, 1H), 8.04 (d, J = 3.1 Hz, CH, 1H), 7.79–7.70 (m, AA′ part of AA′BB′ system, CH, 2H), 7.66–7.62 (m, BB′ part of AA′BB′ system, CH, 2H), 7.50 (d, J = 7.6 Hz, CH, 1H), 7.37 (t, J = 7.6 Hz, CH, 1H), 7.19 (d, J = 7.6 Hz, CH, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 185.9, 145.6, 137.1, 134.2, 132.4, 129.8 (q, J = 32.6 Hz), 129.4, 126.9 (q, J = 272.2 Hz), 125.4 (q, J = 3.4 Hz), 124.1, 123.6, 123.5, 119.2, 111.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₁F₃NO: 290.0787; found: 290.0792.

4-(3-Nitrophenyl)-1H-indole-3-carbaldehyde (3al)

Compound 3al was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a, 58 mg, 0.4 mmol) and 1-iodo-3-nitrobenzene (2l, 199 mg, 0.8 mmol) at 120 °C for 16 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3ab (72 mg, 68%, a yellow solid, mp: 187–188 °C); ¹H NMR (400 MHz, Acetone-d₆): δ 11.54 (bs, NH, 1H), 9.65 (s, CHO, 1H), 8.30 (d, J = 3.3 Hz, CH, 1H), 8.29–8.24 (m, CH, 2H), 7.94–7.81 (m, CH, 1H), 7.72 (t, J = 7.9 Hz, CH, 1H), 7.69–7.66 (m, CH, 1H), 7.40 (t, J = 7.4 Hz, CH, 1H), 7.27–7.21 (m, CH, 1H). ¹³C{¹H} NMR (100 MHz, Acetone-d₆): δ 183.8, 148.7, 145.0, 139.3, 138.1, 136.2, 134.2, 129.8, 124.9, 124.8, 124.3, 123.2, 122.6, 120.1, 113.4. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₁N₂O₃: 267.0764; found: 267.0765.

7-Fluoro-4-phenyl-1H-indole-3-carbaldehyde (3ba)

Compound 3ba was synthesized by following general procedure D using 7-fluoro-1H-indole-3-carbaldehyde (1b, 65 mg, 0.4 mmol) and iodobenzene (2a, 90 μL, 0.8 mmol) at 100 °C for 5 h and purified by silica gel column chromatography (70:30 hexane/ethyl acetate): 3ba (85 mg, 90%, a purple solid, mp: 114–115 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.48 (bs, NH, 1H), 9.21 (s, CHO, 1H), 8.03 (d, J = 3.0 Hz, C, 1H), 7.51–7.40 (m, CH, 5H), 7.12–7.02 (m, CH, 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 187.1, 149.2 (d, J = 246.3 Hz), 141.1, 132.2, 131.5 (d, J = 3.8 Hz), 129.1, 128.6, 127.8, 127.3 (d, J = 4.3 Hz), 125.2 (d, J = 13.8 Hz), 124.0 (d, J = 6.2 Hz), 119.7 (d, J = 1.1 Hz), 108.1 (d, J = 16.0 Hz). HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₁FNO: 240.0819; found: 240.0820.

7-Bromo-4-phenyl-1H-indole-3-carbaldehyde (3ca)

Compound 3ca was synthesized by following general procedure D using 7-bromo-1H-indole-3-carbaldehyde (1c, 45 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and iodobenzene (2a, 90 μL, 0.8 mmol) at 100 °C for 5 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3ca (50 mg, 84%, a dark brown solid, mp: >300 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.46 (bs, NH, 1H), 9.15 (s, CHO, 1H), 8.07 (d, J = 2.9 Hz, CH, 1H), 7.58–7.37 (m, CH, 6H), 7.07 (d, J = 7.8 Hz, B part of AB system, CH, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 186.7, 140.8, 135.3, 135.2, 130.9, 128.9, 128.7, 128.0, 125.7, 125.2, 124.8, 120.5, 104.6. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₁BrNO: 300.0019; found: 300.0018.

2-Methyl-4-phenyl-1H-indole-3-carbaldehyde (3da)

Compound 3da was synthesized by following general procedure D using 2-methyl-1H-indole-3-carbaldehyde (1d, 58 mg, 0.4 mmol) and iodobenzene (2a, 90 μL, 0.8 mmol) at 100 °C for 3.5 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3da (77 mg, 82%, a pale-brown solid, mp: 190–191 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.54 (bs, NH, 1H), 8.66 (s, CHO, 1H), 7.54–7.49 (m, CH, 2H), 7.48–7.34 (m, CH, 3H), 7.31–7.27 (m, CH, 2H), 7.13 (dd, J = 7.4, 0.7 Hz, CH, 1H), 2.78 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 187.9, 145.4, 142.2, 135.1, 134.8, 128.9, 128.6, 127.6, 125.7, 123.8, 122.6, 114.4, 110.4, 29.7. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₄NO: 236.1070; found: 236.1070.

1-Benzyl-4-phenyl-1H-indole-3-carbaldehyde (3ha)

Compound 3ha was synthesized by following general procedure D using 1-benzyl-1H-indole-3-carbaldehyde (1h, 47 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and iodobenzene (2a, 45 μL, 0.4 mmol) at 100 °C for 3 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3ha (52 mg, 84%, a pale-brown solid, mp: 171–172 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.45 (s, CHO, 1H), 7.96 (s, CH, 1H), 7.53 (d, J = 7.0 Hz, CH, 2H), 7.50–7.40 (m, CH, 3H), 7.39–7.28 (m, CH, 5H), 7.25–7.16 (m, CH, 3H), 5.38 (s, CH₂ 2H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 186.3, 141.9, 137.5, 136.0, 135.3, 134.2, 129.2, 129.1, 128.6, 128.4, 127.8, 127.4, 125.3, 123.9, 123.2, 118.4, 110.0, 51.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₂H₁₈NO: 312.1383; found: 312.1382.

1-Methyl-4-phenyl-1H-indole-3-carbaldehyde (3ia)

Compound 3ia was synthesized by following general procedure D using 1-methyl-1H-indole-3-carbaldehyde (1i, 64 mg, 0.4 mmol) and iodobenzene (2a, 90 μL, 0.8 mmol) at 65 °C for 3 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 3ia (76 mg, 81%, a yellow oil); ¹H NMR (400 MHz, CDCl₃): δ 9.35 (s, CHO, 1H), 7.82 (s, CH, 1H), 7.42 (d, J = 7.4 Hz, CH, 2H), 7.37 (t, J = 7.4 Hz, CH, 2H), 7.34–7.27 (m, CH, 3H), 7.11 (dd, J = 6.0, 2.0 Hz, CH, 1H), 3.80 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 186.2, 141.9, 137.9, 135.8, 134.8, 129.0, 128.6, 127.7, 125.0, 123.8, 123.0, 118.0, 109.4, 33.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₄NO: 236.1070; found: 236.1070.

1-(4-Phenyl-1H-indol-2-yl)ethan-1-one (5aa)

Compound 5aa was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and iodobenzene (2a, 90 μL, 0.8 mmol) at 120 °C for 7 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5aa (78 mg, 83%, a yellow solid, mp: 188–189 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.14 (bs, NH, 1H), 7.69–7.65 (m, CH, 2H), 7.53 (t, J = 7.6 Hz, CH, 2H), 7.46–7.39 (m, CH, 3H), 7.34 (d, J = 1.8 Hz, CH, 1H), 7.22 (dd, J = 5.9, 2.2 Hz, CH, 1H), 2.58 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.8, 140.4, 138.0, 137.0, 135.6, 128.8, 128.7, 127.5, 126.6, 126.2, 120.6, 111.4, 109.7, 25.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₄NO: 236.1070; found: 236.1070.

1-(4-(p-Tolyl)-1H-indol-2-yl)ethan-1-one (5ab)

Compound 5ab was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and 1-iodo-4-methylbenzene (2b, 175, 0.8 mmol) at 130 °C for 7 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5ab (81 mg, 81%, a dirty white solid, mp: 185–186 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.46 (bs, NH, 1H), 7.62–7.56 (m, AA′ part of AA′BB′ system, CH, 2H), 7.45–7.39 (m, BB′ part of AA′BB′ system, 2H), 7.38–7.32 (m, CH, 3H), 7.20 (t, J = 4.1 Hz, CH, 1H), 2.59 (s, CH₃, 3H), 2.47 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.6, 138.0, 137.5, 137.3, 137.0, 135.5, 129.5, 128.6, 126.7, 126.2, 120.5, 111.1, 109.7, 25.9, 21.3. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₆NO: 250.1226; found: 250.1226.

1-(4-(m-Tolyl)-1H-indol-2-yl)ethan-1-one (5ac)

Compound 5ac was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and 1-iodo-3-methylbenzene (2c, 103 μL, 0.8 mmol) at 120 °C for 7 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5ac (74 mg, 74%, a pale-yellow solid, mp: 110–111 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.59 (bs, NH, 1H), 7.51–7.47 (m, CH, 2H), 7.45–7.38 (m, CH, 3H), 7.35 (d, J = 1.9 Hz, CH, 1H), 7.25 (d, J = 7.4 Hz, CH, 1H), 7.20 (dd, J = 6.3, 1.9 Hz, CH, 1H), 2.60 (s, CH₃, 3H), 2.47 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.7, 140.4, 138.4, 138.0, 137.2, 135.6, 129.5, 128.6, 128.3, 126.6, 126.2, 125.9, 120.6, 111.3, 109.7, 26.0, 21.6. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₆NO: 250.1226; found: 250.1226.

1-(4-(4-(tert-Butyl)phenyl)-1H-indol-2-yl)ethan-1-one (5ad)

Compound 5ad was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and 1-(tert-butyl)-4-iodobenzene (2d, 142 μL, 0.8 mmol) at 120 °C for 8 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5ad (89 mg, 76%, a brown solid, mp: 209-210 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.38 (bs, NH, 1H), 7.67–7.60 (m, AA′ part of AA′BB′ system, CH, 2H), 7.59–7.54 (m, BB′ part of AA′BB′ system, 2H), 7.45–7.39 (m, CH, 3H), 7.22 (dd, J = 4.6, 3.5 Hz, CH, 1H), 2.60 (s, CH₃, 3H), 1.43 (s, CH₃, 9H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.6, 150.5, 137.9, 137.4, 136.9, 135.5, 128.4, 126.7, 126.2, 125.7, 120.5, 111.0, 109.8, 34.7, 31.4, 25.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₂₂NO: 292.1696; found: 292.1696.

1-(4-(4-Bromophenyl)-1H-indol-2-yl)ethan-1-one (5ae)

Compound 5ae was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and 1-bromo-4-iodobenzene (2e, 227 mg, 0.8 mmol) at 100 °C for 13 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5ae (101 mg, 80%, a white solid, mp: 198–199 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.14 (bs, NH, 1H), 7.68–7.61 (m, AA′ part of AA′BB′ system, CH, 2H), 7.56–7.51 (m, BB′ part of AA′BB′ system, CH, 2H), 7.45–7.40 (m, CH, 2H), 7.27 (d, J = 1.9 Hz, CH, 1H), 7.18 (dd, J = 4.7, 3.4 Hz, CH, 1H), 2.58 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.5, 139.3, 137.8, 135.8, 135.7, 131.9, 130.3, 126.6, 125.9, 121.7, 120.6, 111.7, 109.0, 25.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₃BrNO: 314.0175; found: 314.0174.

1-(4-(4-Methoxyphenyl)-1H-indol-2-yl)ethan-1-one (5af)

Compound 5af was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and 1-iodo-4-methoxybenzene (2f, 188 mg, 0.8 mmol) at 120 °C for 5 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5af (74 mg, 70%, a pale-yellow solid, mp: 196–197 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.34 (bs, NH, 1H), 7.66–7.56 (m, AA′ part of AA′BB′ system, CH, 2H), 7.46–7.37 (m, CH, 2H), 7.34 (d, J = 1.5 Hz, CH, 1H), 7.17 (dd, J = 5.8, 2.2 Hz, CH, 1H), 7.14–7.03 (m, CH, BB′ part of AA′BB′ system, 2H), 3.90 (s, CH₃, 3H), 2.59 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.6, 159.2, 138.0, 136.7, 135.5, 132.9, 129.8, 126.7, 126.2, 120.3, 114.2, 110.8, 109.7, 55.4, 25.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₆NO₂: 266.1176; found: 266.1175.

Methyl 4-(2-Acetyl-1H-indol-4-yl)benzoate (5ag)

Compound 5ag was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and methyl 4-iodobenzoate (2g, 210 mg, 0.8 mmol) at 110 °C for 15 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5ag (82 mg, 70%, a white solid, mp: 190–191 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.53 (bs, NH, 1H), 8.42–7.96 (m, AA′ part of AA′BB′ system, CH, 2H), 7.95–7.67 (m, BB′ part of AA′BB′ system, CH, 2H), 7.52–7.40 (m, CH, 2H), 7.32 (s, CH, 1H), 7.24 (d, J = 6.8 Hz, CH, 1H), 3.98 (s, CH₃, 3H), 2.60 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.6, 167.0, 145.0, 137.9, 135.8, 135.8, 130.0, 129.1, 128.7, 126.6, 126.0, 120.9, 112.1, 109.0, 52.2, 25.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₆NO₃: 294.1125; found: 294.1124.

1-(4-(2-Acetyl-1H-indol-4-yl)phenyl)ethan-1-one (5ah)

Compound 5ah was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and 1-(4-iodophenyl)ethan-1-one (2h, 198 mg, 0.8 mmol) at 120 °C for 7 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5ah (59 mg, 53%, a white solid, mp: 223–224 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.53 (bs, NH, 1H), 8.42–7.96 (m, AA′ part of AA′BB′ system, CH, 2H), 7.95–7.67 (m, BB′ part of AA′BB′ system, CH, 2H), 7.52–7.40 (m, CH, 2H), 7.32 (s, CH, 1H), 7.24 (d, J = 6.8 Hz, CH, 1H), 3.98 (s, CH₃, 3H), 2.60 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.6, 167.0, 145.0, 137.9, 135.8, 135.8, 130.0, 129.1, 128.7, 126.6, 126.0, 120.9, 112.1, 109.0, 52.2, 25.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₆NO₂: 278.1176; found: 278.1182.

1-(4-(4-(Trifluoromethyl)phenyl)-1H-indol-2-yl)ethan-1-one (5ai)

Compound 5aa was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and 1-iodo-4-(trifluoromethyl)benzene (2i, 118 μL, 0.8 mmol) at 110 °C for 20 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5ai (83 mg, 68%, a white solid, mp: 216-217 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.56 (bs, NH, 1H), 7.82–7.75 (m, CH, 4H), 7.50 (d, J = 7.5 Hz, CH, 1H), 7.45 (t, J = 7.5 Hz, CH, 1H), 7.30 (d, J = 1.1 Hz, CH, 1H), 7.23 (d, J = 7.5 Hz, CH, 1H), 2.61 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.6, 144.0, 137.9, 135.9, 135.4, 129.5 (q, J = 32.4 Hz), 129.0, 126.6, 126.0, 125.7 (q, J = 3.8 Hz), 121.6 (q, J = 272.4 Hz), 120.9, 112.2, 108.8, 25.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₃F₃NO: 304.0944; found: 304.0944.

1-(4-(3,4-Dimethylphenyl)-1H-indol-2-yl)ethan-1-one (5ak)

Compound 5aa was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and 4-iodo-1,2-dimethylbenzene (2k, 114 μL, 0.8 mmol) at 120 °C for 6 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5ak (77 mg, 73%, a brown solid, mp: 180–181 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.41 (bs, NH, 1H), 7.47–7.40 (m, CH, 4H), 7.37 (d, J = 2.0 Hz, CH, 1H), 7.31 (d, J = 7.6 Hz, CH, 1H), 7.23–7.18 (m, CH, 1H), 2.60 (s, CH₃, 3H), 2.40 (s, CH₃, 3H), 2.38 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.6, 138.0, 137.9, 137.2, 137.0, 136.0, 135.5, 129.98, 129.96, 126.6, 126.2, 126.2, 120.4, 110.9, 109.7, 25.9, 20.0, 19.6. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₈H₁₈NO: 264.1383; found: 264.1382.

1-(4-(3-Nitrophenyl)-1H-indol-2-yl)ethan-1-one (5al)

Compound 5al was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a, 64 mg, 0.4 mmol) and 1-iodo-3-nitrobenzene (2l, 200 mg, 0.8 mmol) at 100 °C for 15 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5al (59 mg, 53%, a yellow solid, mp: 210–211 °C); ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (bs, NH, 1H), 8.42 (s, CH, 1H), 8.28 (d, J = 7.8 Hz, CH, 1H), 8.16 (d, J = 7.8 Hz, CH, 1H), 7.83 (t, J = 7.8 Hz, CH, 1H), 7.54 (d, J = 7.7 Hz, CH, 1H), 7.48 (s, CH, 1H), 7.42 (t, J = 7.7 Hz, CH, 1H), 7.28 (d, J = 7.7 Hz, CH, 1H), 2.56 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 190.3, 148.3, 141.4, 138.2, 136.5, 134.8, 133.1, 130.4, 125.7, 124.8, 122.7, 122.1, 120.3, 113.1, 107.7, 26.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₃N₂O₃281.0921; found: 281.0920.

1-(7-Fluoro-4-phenyl-1H-indol-2-yl)ethan-1-one (5ba)

Compound 5ba was synthesized by following general procedure D using 1-(7-fluoro-1H-indol-3-yl)ethan-1-one (4b, 71 mg, 0.4 mmol) and iodobenzene (2a, 90 μL, 0.8 mmol) at 120 °C for 18 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 5ba (74 mg, 73%, an orange solid, mp: 164–165 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.31 (bs, NH, 1H), 7.62 (d, J = 7.2 Hz, CH, 2H), 7.52 (t, J = 7.6 Hz, CH, 2H), 7.46–7.40 (m, CH, 1H), 7.34–7.31 (m, CH, 1H), 7.14–7.10 (m, CH, 2H), 2.59 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.2, 149.2 (d, J = 247.0 Hz), 139.7, 136.2, 133.0 (d, J = 4.0 Hz), 129.2 (d, J = 5.2 Hz), 128.8, 128.7, 127.5, 126.4 (d, J = 14.8 Hz), 120.6 (d, J = 5.6 Hz), 110.8 (d, J = 16.0 Hz), 109.7, 26.0. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₃FNO: 254.0976; found: 254.0976.

1-(7-Bromo-4-phenyl-1H-indol-2-yl)ethan-1-one (5ca)

Compound 5ca was synthesized by following general procedure D using 1-(7-bromo-1H-indol-3-yl)ethan-1-one (4c, 71 mg, 0.3 mmol), AgOAc (100 mg, 0.6 mmol), Pd(OAc)₂ (7 mg, 30 μmol, 10 mol %), and iodobenzene (2a, 60 μL, 0.6 mmol) at 120 °C for 24 h and purified by silica gel column chromatography (85:15 hexane/ethyl acetate): 5ca (69 mg, 74%, a pale-brown solid, mp: 125–126 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.21 (bs, NH, 1H), 7.64 (d, J = 8.0 Hz, CH, 2H), 7.59–7.50 (m, CH, 3H), 7.48–7.42 (m, CH, 1H), 7.38 (d, J = 1.7 Hz, CH, 1H), 7.14–7.08 (m, CH, 1H), 2.59 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.2, 139.5, 136.4, 136.4, 135.9, 128.9, 128.7, 128.7, 127.8, 127.0, 121.7, 110.1, 104.5, 25.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₃BrNO: 314.0175; found: 314.0175.

1-(7-Bromo-4-phenyl-1H-indol-3-yl)ethan-1-one (6ca)

Compound 6ca was synthesized by following general procedure D using 1-(7-bromo-1H-indol-3-yl)ethan-1-one (4c, 71 mg, 0.3 mmol), AgOAc (100 mg, 0.6 mmol), Pd(OAc)₂ (7 mg, 30 μmol, 10 mol %), and iodobenzene (2a, 60 μL, 0.6 mmol) at 120 °C for 20 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 6ca (71 mg, 76%, a brown solid, mp: 162–163 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.01 (bs, NH, 1H), 7.79 (d, J = 2.9 Hz, CH, 1H), 7.49 (d, J = 7.9 Hz, A part of AB system, CH, 1H), 7.45–7.33 (m, CH, 5H), 7.09 (d, J = 7.9 Hz, B part of AB system, CH, 1H), 2.07 (s, CH_3, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.2, 142.0, 136.0, 135.8, 131.2, 128.6, 128.1, 127.2, 125.9, 125.1, 123.6, 121.9, 104.1, 29.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₆H₁₃BrNO: 314.0175; found: 314.0175.

2-Methyl-4-phenyl-1H-indole (7da)

Compound 7da was synthesized by following general procedure D using 1-(2-methyl-1H-indol-3-yl)ethan-1-one (4d, 69 mg, 0.4 mmol) and iodobenzene (2a, 90 μL, 0.8 mmol) at 120 °C for 13 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 7da (66 mg, 80%, a brown solid, mp: 96–97 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.78 (bs, NH, 1H), 7.64–7.57 (m, CH, 2H), 7.38 (t, J = 7.6 Hz, CH, 2H), 7.30–7.23 (m, CH, 1H), 7.18–7.03 (m, CH, 3H), 6.32 (s, CH, 1H), 2.32 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 141.5, 136.5, 135.5, 133.4, 128.8, 128.4, 127.3, 126.8, 121.3, 119.6, 109.5, 100.0, 13.8. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₅H₁₄N: 208.1121; found: 208.1120.

1-(1-Benzyl-4-phenyl-1H-indol-3-yl)ethan-1-one (9aa)

Compound 9aa was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and iodobenzene (2a, 45 μL, 0.4 mmol) at 100 °C for 5 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9aa (58 mg, 89%, a white solid, mp: 132–133 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.71 (s, CH, 1H), 7.47–7.42 (m, CH, 4H), 7.42–7.29 (m, CH, 6H), 7.24–7.18 (m, CH, 3H), 5.37 (s, CH₂, 2H), 2.00 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.0, 143.0, 138.0, 136.8, 135.8, 134.6, 129.1, 128.7, 128.2, 128.0, 127.1, 127.0, 124.1, 123.6, 123.3, 119.9, 109.3, 50.8, 29.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₀NO: 326.1539; found: 326.1539.

1-(1-Benzyl-4-phenyl-1H-indol-3-yl)ethan-1-one (9ab)

Compound 9ab was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and 1-iodo-4-methylbenzene (2b, 87 mg, 0.4 mmol) at 100 °C for 5.5 h and purified by silica gel column chromatography (85:15 hexane/ethyl acetate): 9ab (59 mg, 87%, a white solid, mp: 125–126 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.68 (s, CH, 1H), 7.36–7.31 (m, CH, 5H), 7.30–7.27 (m, CH, 2H), 7.24–7.16 (m, CH, 5H), 5.34 (s, CH₂, 2H), 2.40 (s, CH₃, 3H), 1.98 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.3, 140.1, 138.0, 136.8, 136.6, 135.8, 134.5, 129.1, 128.8, 128.6, 128.2, 127.1, 124.1, 123.6, 123.3, 120.0, 109.1, 50.8, 29.3, 21.3. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₂NO: 340.1696; found: 340.1695.

1-(1-Benzyl-4-(m-tolyl)-1H-indol-3-yl)ethan-1-one (9ac)

Compound 9ac was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and 1-iodo-3-methylbenzene (2c, 51 μL, 0.4 mmol) at 100 °C for 5.5 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9ac (57 mg, 85%, a pale-brown solid, mp: 115–116 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.60 (s, 1H), 7.29–7.19 (m, 7H), 7.17–7.08 (m, 5H), 5.27 (s, 2H), 2.31 (s, 3H), 1.88 (s, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.4, 142.8, 137.9, 137.7, 136.8, 135.8, 134.3, 129.3, 129.0, 128.2, 128.0, 127.8, 127.1, 125.8, 123.9, 123.6, 123.3, 120.0, 109.2, 50.8, 29.2, 21.5. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₂NO: 340.1696; found: 340.1696.

1-(1-Benzyl-4-(4-(tert-butyl)phenyl)-1H-indol-3-yl)ethan-1-one (9ad)

Compound 9ad was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and 1-(tert-butyl)-4-iodobenzene (2d, 71 μL, 0.4 mmol) at 100 °C for 5.5 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9ad (68 mg, 90%, a white solid, mp: 166–167 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.66 (s, CH, 1H), 7.47–7.40 (m, CH, 4H), 7.39–7.29 (m, CH, 5H), 7.24–7.19 (m, CH, 3H), 5.35 (s, CH₂, 2H), 1.79 (s, CH₃, 3H), 1.38 (s, CH₃, 9H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 195.9, 150.2, 139.9, 137.9, 136.4, 135.8, 133.8, 129.0, 128.4, 128.2, 127.2, 125.3, 123.8, 123.7, 123.2, 120.5, 109.2, 50.8, 34.6, 31.4, 29.6. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₇H₂₈NO: 382.2165; found: 382.2165.

1-(1-Benzyl-4-(4-bromophenyl)-1H-indol-3-yl)ethan-1-one (9ae)

Compound 9ae was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and 1-bromo-4-iodobenzene (2e, 113 mg, 0.4 mmol) at 100 °C for 6 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9ae (64 mg, 79%, a pale-brown solid, mp: 145–146 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.75 (s, CH, 1H), 7.55–7.50 (m, AA′ part of AA′BB′ system, CH, 2H), 7.39–7.24 (m, CH, 7H), 7.20–7.13 (m, CH, 3H), 5.39 (s, CH₂, 2H), 2.17 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 192.7, 142.0, 138.1, 135.7, 135.7, 135.5, 130.9, 130.3, 129.1, 128.3, 127.0, 124.5, 123.5, 123.2, 120.9, 119.2, 109.6, 50.8, 28.8. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₁₉BrNO: 404.0645; found: 404.0644.

1-(1-Benzyl-4-(4-methoxyphenyl)-1H-indol-3-yl)ethan-1-one (9af)

Compound 9af was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and 1-iodo-4-methoxybenzene (2f, 113 mg, 0.4 mmol) at 100 °C for 5.5 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9af (57 mg, 80%, a brown solid, mp: 132–133 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.70 (s, CH, 1H), 7.40–7.37 (m, AA′ part of AA′BB′ system, CH, 2H), 7.36–7.28 (m, CH, 5H), 7.22–7.16 (m, CH, 3H), 7.05–6.87 (m, BB′ part of AA′BB′ system, CH, 2H), 5.36 (s, CH₂, 2H), 3.86 (s, CH₃, 3H), 2.01 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.6, 158.8, 138.0, 136.4, 135.8, 135.5, 134.4, 129.7, 129.1, 128.2, 127.1, 124.0, 123.7, 123.3, 120.1, 113.6, 109.0, 55.2, 50.8, 29.4. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₂₂NO₂: 356.1645; found: 356.1645.

Methyl 4-(3-Acetyl-1-benzyl-1H-indol-4-yl)benzoate (9ag)

Compound 9ag was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and methyl 4-iodobenzoate (2g, 105 mg, 0.4 mmol) at 110 °C for 10 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9ag (62 mg, 81%, a brown solid, mp: 165–166 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.18–8.04 (m, AA′ part of AA′BB′ system, CH, 2H), 7.78 (s, CH, 1H), 7.55–7.41 (m, BB′ part of AA′BB′ system, CH, 2H), 7.42–7.27 (m, CH, 5H), 7.25–7.15 (m, CH, 3H), 5.39 (s, CH₂, 2H), 3.93 (s, CH₃, 3H), 2.18 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 192.4, 167.2, 147.8, 138.1, 135.9, 135.7, 135.5, 129.1, 129.1, 128.7, 128.4, 128.3, 127.0, 124.5, 123.4, 123.2, 119.2, 109.9, 52.0, 50.9, 28.6. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₂₂NO₃: 384.1594; found: 384.1595.

1-(4-(3-Acetyl-1-benzyl-1H-indol-4-yl)phenyl)ethan-1-one (9ah)

Compound 9ah was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (98 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and 1-(4-iodophenyl)ethan-1-one (2h, 87 mg, 0.4 mmol) at 120 °C for 6 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9ah (58 mg, 80%, a brown solid, mp: 92–93 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.05–7.97 (m, AA′ part of AA′BB′ system, CH, 2H), 7.85 (s, CH, 1H), 7.53–7.41 (m, BB′ part of AA′BB′ system, CH, 2H), 7.41–7.30 (m, CH, 5H), 7.24–7.14 (m, CH, 3H), 5.41 (s, CH₂, 2H), 2.65 (s, CH₃, 3H), 2.25 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 198.1, 192.5, 148.1, 138.2, 136.0, 135.8, 135.6, 135.3, 129.1(2C), 128.8, 128.3, 127.9, 127.0, 124.7, 123.5, 123.1, 118.9, 110.1, 50.9, 26.6. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₂₂NO₂: 368.1645; found: 368.1666.

1-(1-Benzyl-4-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)ethan-1-one (9ai)

Compound 9ai was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and 1-iodo-4-(trifluoromethyl)benzene (2i, 59 μL, 0.4 mmol) at 100 °C for 5.5 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9ai (60 mg, 77%, a white solid, mp: 169–170 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.80 (s, CH, 1H), 7.70–7.63 (m, AA′ part of AA′BB′ system, CH, 2H), 7.55–7.46 (m, BB′ part of AA′BB′ system, CH, 2H), 7.42–7.30 (m, CH, 5H), 7.25–7.15 (m, CH, 3H), 5.41 (s, CH₂, 2H), 2.21 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 192.1, 146.7, 138.1, 135.7(2C), 135.6, 129.1, 128.9, 128.7 (q, J = 32.4 Hz), 128.3, 127.0, 124.7, 124.6 (q, J = 3.4 Hz), 124.3 (q, J = 272.4 Hz), 123.5, 123.2, 119.0, 110.0, 50.9, 28.5. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₄H₁₉F₃NO: 394.1413; found: 394.1413.

1-(1-Benzyl-4-(3,4-dimethylphenyl)-1H-indol-3-yl)ethan-1-one (9ak)

Compound 9ak was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and 4-iodo-1,2-dimethylbenzene (2k, 57 μL, 0.4 mmol) at 100 °C for 4 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9ak (49 mg, 70%, a yellow gum); ¹H NMR (400 MHz, CDCl₃): δ 7.65 (s, CH, 1H), 7.34–7.27 (m, CH, 3H), 7.26–7.24 (m, CH, 1H), 7.23–7.19 (m, CH, 2H), 7.18–7.11 (m, CH, 5H), 5.33 (s, CH₂, 2H), 2.28 (s, CH₃, 3H), 2.26 (s, CH₃, 3H), 1.92 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.7, 140.4, 137.9, 136.7, 136.3, 135.9, 135.3, 134.2, 129.8, 129.5, 129.1, 128.2, 127.1, 126.1, 123.9, 123.6, 123.3, 120.1, 109.0, 50.8, 29.4, 19.9, 19.7. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₅H₂₄NO: 354.1852; found: 354.1852.

1-(1-Benzyl-4-(3-nitrophenyl)-1H-indol-3-yl)ethan-1-one (9al)

Compound 9al was synthesized by following general procedure D using 1-(1-benzyl-1H-indol-3-yl)ethan-1-one (8a, 50 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and 1-iodo-3-nitrobenzene (2l, 100 mg, 0.4 mmol) at 100 °C for 48h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate): 9al (37 mg, 51%, a yellow solid, mp: 135–136 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.25–8.19 (m, CH, 2H), 7.85 (s, CH, 1H), 7.73–7.70 (m, CH, 1H), 7.56 (t, J = 7.9 Hz, CH, 1H), 7.41–7.33 (m, CH, 5H), 7.24–7.18 (m, CH, 3H), 5.44 (s, CH₂, 2H), 2.34 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 191.5, 147.5, 144.7, 138.3, 136.6, 135.6, 134.8, 134.7, 129.3, 128.5, 128.3, 127.0, 125.0, 124.0, 123.8, 123.3, 121.7, 118.6, 110.4, 51.1, 28.3. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₁₉N₂O₃: 371.1390; found: 371.1389.

1-(1-Benzyl-7-fluoro-4-phenyl-1H-indol-3-yl)ethan-1-one (9ba)

Compound 9ba was synthesized by following general procedure D using 1-(1-benzyl-7-fluoro-1H-indol-3-yl)ethan-1-one (8b, 54 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and iodobenzene (2a, 45 μL, 0.4 mmol) at 90 °C for 6 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9ba (57 mg, 83%, a dirty white solid, mp: 112–113 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.64 (s, CH, 1H), 7.44–7.31 (m, CH, 8H), 7.22 (d, J = 6.6 Hz, CH, 2H), 7.10–6.98 (m, CH, 2H), 5.54 (s, CH₂, 2H), 1.97 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.1, 149.5 (d, J = 245.2 Hz), 142.2, 136.6, 135.5, 132.6 (d, J = 3.8 Hz), 129.0, 128.6, 128.20, 128.17, 127.1, 127.0, 126.9 (d, J = 5.0 Hz), 125.5 (d, J = 9.9 Hz), 124.2 (d, J = 6.7 Hz), 120.6, 109.2 (d, J = 18.1 Hz), 53.0 (d, J = 6.9 Hz), 29.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₁₉FNO: 344.1445; found: 344.1447.

1-(1-Benzyl-7-bromo-4-phenyl-1H-indol-3-yl)ethan-1-one (9ca)

Compound 9ca was synthesized by following general procedure D using 1-(1-benzyl-7-bromo-1H-indol-3-yl)ethan-1-one (8c, 66 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and iodobenzene (2a, 45 μL, 0.4 mmol) at 75 °C for 5 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9ca (63 mg, 78%, a pale-brown solid, mp: 130–131 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.62 (s, CH, 1H), 7.50 (d, J = 7.9 Hz, A part of AB system, CH, 1H), 7.45–7.28 (m, CH, 8H), 7.08 (d, J = 6.9 Hz, CH, 2H), 7.04 (d, J = 7.9 Hz, B part of AB system, CH, 1H), 5.90 (s, CH₂, 2H), 1.95 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 194.2, 142.0, 137.5, 136.9, 136.1, 134.1, 128.9 (2C), 128.4, 128.3, 127.9, 127.3, 126.5, 126.4, 124.9, 120.1, 103.2, 52.3, 29.3. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₁₉BrNO: 404.0645; found: 404.0644.

1-(1-Methyl-4-phenyl-1H-indol-3-yl)ethan-1-one (9ea)

Compound 9ea was synthesized by following general procedure D using 1-(1-methyl-1H-indol-3-yl)ethan-1-one (8e, 70 mg, 0.4 mmol) and iodobenzene (2a, 90 μL, 0.8 mmol) at 100 °C for 5 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9ea (79 mg, 80%, a yellow gum); ¹H NMR (400 MHz, CDCl₃): δ 7.67 (s, CH, 1H), 7.45–7.32 (m, CH, 7H), 7.23 (d, J = 6.9 Hz, CH, 1H), 3.86 (s, CH₃, 3H), 2.02 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 193.6, 143.1, 138.4, 136.7, 135.6, 128.7, 128.0, 126.9, 124.1, 123.3, 123.2, 119.2, 108.7, 33.6, 29.0. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₇H₁₆NO: 250.1226; found: 250.1226.

Methyl 4-(3-Acetyl-1-methyl-1H-indol-4-yl)benzoate (9eg)

Compound 9eg was synthesized by following general procedure D using 1-(1-methyl-1H-indol-3-yl)ethan-1-one (8e, 70 mg, 0.2 mmol) and methyl 4-iodobenzoate (2g, 210 mg, 0.8 mmol) at 100 °C for 8 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate): 9eg (100 mg, 82%, off-white solid, mp: 149–150 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.13–8.03 (m, AA′ part of AA′BB′ system, CH, 2H), 7.73 (s, CH, 1H), 7.49–7.42 (m, BB′ part of AA′BB′ system, CH, 2H), 7.40–7.32 (m, CH, 2H), 7.25–7.19 (m, CH, 1H), 3.92 (s, CH₃, 3H), 3.89 (s, CH₃, 3H), 2.18 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 192.0, 167.2, 147.9, 138.5, 136.3, 135.8, 129.1, 128.7, 128.3, 124.4, 123.3, 122.9, 118.5, 109.3, 52.0, 33.7, 28.5. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₁₉H₁₈NO₃: 308.1281; found: 308.1281.

2-Phenyl-1H-indole (11a)²⁷

Compound 11a was synthesized by following general procedure D using 1-1H-indole-3-carboxylic acid (10a, 65 mg, 0.4 mmol) and iodobenzene (2a, 90 μL, 0.8 mmol) at 120 °C for 3 h and purified by silica gel column chromatography (95:5 hexane/ethyl acetate): 11a (66 mg, 85%, off-white solid, mp: 188–189 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.34 (bs, NH, 1H), 7.67 (t, J = 6.6 Hz, CH, 3H), 7.49–7.39 (m, CH, 3H), 7.34 (t, J = 7.3 Hz, CH, 1H), 7.22 (t, J = 7.4 Hz, CH, 1H), 7.15 (t, J = 7.5 Hz, CH, 1H), 6.85 (d, J = 1.3 Hz, CH, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 137.9, 136.8, 132.4, 129.3, 129.0, 127.7, 125.2, 122.4, 120.7, 120.3, 110.9, 100.0.

2-(p-Tolyl)-1H-indole (11b)²⁷

Compound 11b was synthesized by following general procedure D using 1-1H-indole-3-carboxylic acid (10a, 65 mg, 0.4 mmol) and 1-iodo-4-methylbenzene (2b, 175 mg, 0.8 mmol) at 120 °C for 3 h and purified by silica gel column chromatography (95:5 hexane/ethyl acetate): 11b (62 mg, 75%, a white solid, mp: 214–215 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.30 (bs, NH, 1H), 7.63 (d, J = 7.7 Hz, CH, 1H), 7.60–7.54 (m, CH, 2H), 7.39 (d, J = 8.0 Hz, CH, 1H), 7.28–7.24 (m, CH, 2H), 7.22–7.17 (m, CH, 1H), 7.15–7.10 (m, CH, 1H), 6.80 (d, J = 1.5 Hz, CH, 1H), 2.40 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 138.1, 137.7, 136.7, 129.7, 129.6, 129.4, 125.1, 122.1, 120.5, 120.2, 110.8, 99.4, 21.2.

2-(m-Tolyl)-1H-indole (11c)²⁸

Compound 11c was synthesized by following general procedure D using 1-1H-indole-3-carboxylic acid (10a, 64 mg, 0.4 mmol) and 1-iodo-3-methylbenzene (2c, 102 μL, 0.8 mmol) at 120 °C for 3 h and purified by silica gel column chromatography (95:5 hexane/ethyl acetate): 11c (65 mg, 78%, a white solid, mp: 128–129 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.32 (bs, NH, 1H), 7.65 (d, J = 7.7 Hz, CH, 1H), 7.54–7.46 (m, CH, 2H), 7.41 (d, J = 8.0 Hz, CH, 1H), 7.35 (t, J = 7.6 Hz, CH, 1H), 7.23–7.18 (m, CH, 1H), 7.18–7.12 (m, CH, 2H), 6.84 (d, J = 1.3 Hz, CH, 1H), 2.44 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 138.7, 138.1, 136.8, 132.3, 129.3, 129.0, 128.6, 125.9, 122.3, 122.3, 120.6, 120.2, 110.9, 99.9, 21.6.

2-(4-(tert-Butyl)phenyl)-1H-indole (11d)²⁷

Compound 11d was synthesized by following general procedure D using 1-1H-indole-3-carboxylic acid (10a, 64 mg, 0.4 mmol) and 1-(tert-butyl)-4-iyodobenzen (2d, 90 μL, 0.8 mmol) at 120 °C for 3 h and purified by silica gel column chromatography (95:5 hexane/ethyl acetate): 11d (87 mg, 87%, a white solid, mp: 251–252 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.32 (bs, NH, 1H), 7.66–7.59 (m, CH, 3H), 7.48 (d, J = 8.4 Hz, CH, 2H), 7.40 (d, J = 7.9 Hz, CH, 1H), 7.22–7.16 (m, CH, 1H), 7.16–7.09 (m, CH, 1H), 6.81 (d, J = 1.5 Hz, CH, 1H), 1.37 (s, CH_3, 9H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 150.9, 138.0, 136.7, 129.6, 129.4, 126.0, 124.9, 122.1, 120.5, 120.2, 110.8, 99.5, 34.7, 31.3.

2-(4-Bromophenyl)-1H-indole (11e)²⁹

Compound 11e was synthesized by following general procedure D using 1-1H-indole-3-carboxylic acid (10a, 64 mg, 0.4 mmol) and 1-bromo-4-iodobenzene (2e, 227 mg, 0.8 mmol) at 120 °C for 3 h and purified by silica gel column chromatography (95:5 hexane/ethyl acetate): 11e (90 mg, 84%, a white solid, mp: 209–210 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.29 (bs, CH, 1H), 7.63 (d, J = 7.9 Hz, CH, 1H), 7.59–7.55 (m, CH, 2H), 7.54–7.50 (m, CH, 2H), 7.40 (d, J = 8.1 Hz, CH, 1H), 7.24–7.19 (m, CH, 1H), 7.16–7.11 (m, CH, 1H), 6.83–6.82 (m, CH, 1H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 136.9, 136.7, 132.2, 131.3, 129.2, 126.6, 122.8, 121.5, 120.8, 120.5, 111.0, 100.6.

2-(3,4-Dimethylphenyl)-1H-indole (11k)³⁰

Compound 11k was synthesized by following general procedure D using 1-1H-indole-3-carboxylic acid (10a, 64 mg, 0.4 mmol) and 4-iodo-1,2-dimethylbenzene (2k, 114 μL, 0.8 mmol) at 120 °C for 3 h and purified by silica gel column chromatography (95:5 hexane/ethyl acetate): 11k (74 mg, 83%, a white solid, mp: 142–143 °C); ¹H NMR (400 MHz, CDCl₃): δ 8.29 (bs, NH, 1H), 7.66 (d, J = 7.4 Hz, CH, 1H), 7.47 (s, CH, 1H), 7.44–7.38 (m, CH, 2H), 7.25–7.12 (m, CH, 3H), 6.81 (s, CH, 1H), 2.36 (s, CH₃, 3H), 2.33 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 138.2, 137.3, 136.7, 136.4, 130.3, 130.0, 129.4, 126.5, 122.6, 122.1, 120.5, 120.2, 110.8, 99.3, 20.0, 19.6.

Gram-Scale Reaction and Synthetic Applications

(a). Gram-Scale Reaction of 3aa

Compound 3aa (1.05 g, 69%) was synthesized by following general procedure D using 1H-indole-3-carbaldehyde (1a) (1.0 g, 6.9 mmol), Pd(OAc)₂ (154 mg, 0.69 mmol, 10 mol %), AgOAc (2.3 g, 13.8 mmol, 2 equiv), and iodobenzene (2a) (1.54 mL, 13.8 mmol, 2 equiv) at 100 °C for 4 h and purified by silica gel column chromatography (80:20 hexane/ethyl acetate).

(b). Gram-Scale Reaction of 5aa

Compound 5aa (960 mg, 65%) was synthesized by following general procedure D using 1-(1H-indol-3-yl)ethan-1-one (4a) (1.0 g, 6.3 mmol), Pd(OAc)₂ (141 mg, 0.63 mmol, 10 mol %), AgOAc (2.1 g, 0.8 mmol, 2 equiv), and iodobenzene (2a) (1.4 mL, 12.6 mmol, 2 equiv) at 120 °C for 10 h and purified by silica gel column chromatography (90:10 hexane/ethyl acetate).

(c). N-Benzylation Reaction of 5aa

1-(1-Benzyl-4-phenyl-1H-indol-2-yl)ethan-1-one (12)

Compound 12 (80 mg, 82%) was prepared starting from 5aa (71 mg, 0.3 mmol) according to the General Procedure C. Yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.61 (dd, J = 8.1, 1.1 Hz, CH, 2H), 7.45 (t, J = 7.6 Hz, CH, 2H), 7.42 (s, CH, 1H), 7.39–7.33 (m, CH, 1H), 7.33–7.27 (m, CH, 2H), 7.20–7.11 (m, CH, 4H), 7.04–6.97 (m, CH, 2H), 5.81 (s, CH₂, 2H), 2.49 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 191.3, 140.5, 140.3, 138.3, 136.9, 134.7, 128.9, 128.8, 128.6, 127.6, 127.2, 126.6, 126.5, 124.6, 120.8, 112.5, 110.0, 48.4, 28.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₃H₂₀NO: 326.1539; found: 326.1539.

(d). Cross-Coupling of 2-Thienyl Boronic Acid and 5ca(31)

1-(4-Phenyl-7-(thiophen-2-yl)-1H-indol-2-yl)ethan-1-one (13)

To a solution of 1-(7-bromo-4-phenyl-1H-indol-2-yl)ethan-1-one (5ca, 63 mg, 0.2 mmol) and thiophen-2-ylboronic acid (31 mg, 0.24 mmol, 1.2 equiv) in DME/water (15 mL, 2:1 v/v, 0.013 M for 5ca) was added Na₂CO₃ (42 mg, 0.4 mmol, 2 equiv). After degassing, Pd(PPh₃)₄ (12 mg, 10 μmol) was added and the mixture was boiled in a preheated oil bath at 100 °C for 18 h. Then, the mixture was cooled to room temperature and the solution was extracted with CH₂Cl₂ (3 × 30 mL). The organic phase was combined, washed with water (3 × 20 mL), dried with Na₂SO₄, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (EtOAc/hexane, 1:9) to afford 13 as a red solid (41 mg, 85% yield, mp: 163-164 °C); ¹H NMR (400 MHz, CDCl₃): δ 9.45 (bs, NH, 1H), 7.73–7.69 (m, CH, 2H), 7.59–7.53 (m, CH, 3H), 7.49–7.39 (m, CH, 4H), 7.27 (d, J = 7.6 Hz, CH, 1H), 7.23 (dd, J = 5.0, 3.6 Hz, CH, 1H), 2.59 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 190.2, 140.0, 139.9, 136.6, 136.0, 135.2, 128.82, 128.75, 128.2, 127.7, 126.8, 126.1, 125.5, 125.0, 121.1, 118.6, 109.8, 25.9. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₀H₁₆NOS: 318.0947; found: 318.0947.

(e). Construction of Functionalized Natural Product

(1-Benzyl-4-(4-(tert-butyl)phenyl)-1H-indol-3-yl)(6-methoxy-9H-pyrido[3,4-b]indol-1-yl)methanone (16)

Compounds 16 and 17 were prepared according to the method reported in the literature.^32b 3-Acetylindole derivative 9ad (57 mg, 0.15 mmol), 5-methoxytryptamine (15, 28 mg, 0.15 mmol, 1 equiv), I₂ (30 mg, 0.12 mmol, 0.8 equiv), hydrogen peroxide (30% aqueous solution, 1.5 equiv), and DMSO (2 mL, 2 M for 9ad) were placed in a sealed tube (15 mL) with a magnetic stir bar. The resulting mixture was stirred in a preheated oil bath at 110 °C for 5 h, monitoring the reaction by TLC. Once the reaction was complete, the mixture was cooled to rt, diluted with water (50 mL), and then the reaction mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with 10% Na₂S₂O₃ solution, and then with brine, dried over anhydrous Na₂SO₄, and evaporated. The residue was purified by column chromatography on silica gel (80:20 hexane/ethyl acetate) to give 16 (63 mg, 75%, yellow solid, mp: 269-270 °C); ¹H NMR (400 MHz, CDCl₃): δ 10.04 (bs, NH, 1H), 8.40–8.30 (m, CH, 2H), 7.90 (d, J = 5.0 Hz, CH, 1H), 7.50 (d, J = 2.4 Hz, CH, 1H), 7.36–7.27 (m, CH, 7H), 7.26–7.14 (m, CH, 5H), 7.10 (d, J = 8.3 Hz, CH, 2H), 5.42 (s, CH₂, 2H), 3.89 (s, CH₃, 3H), 1.07 (s, CH₃, 9H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 189.9, 154.3, 148.9, 139.8, 138.1, 137.6, 137.3, 137.2, 136.7, 136.7, 136.1, 135.8, 130.8, 129.0, 128.1, 127.9, 127.2, 125.3, 124.4, 123.9, 123.3, 121.2, 118.7, 117.5, 116.4, 112.6, 109.1, 103.7, 56.1, 51.0, 34.2, 31.2. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₃₈H₃₄N₃O₂: 564.2646; found: 564.2645.

(6-Methoxy-9H-pyrido[3,4-b]indol-1-yl)(4-phenyl-1H-indol-2-yl)methanone (17)

Compound 17 was was synthesized starting from 5aa (48 mg, 0.25 mmol) (prepared according to the literature procedure^32b). The residue was purified by column chromatography on silica gel (80:20 hexane/ethyl acetate) to give 17 (86 mg, 83%, yellow solid, mp: >300 °C); ¹H NMR (400 MHz, CDCl₃): δ 12.18 (bs, NH, 1H), 10.54 (bs, NH, 1H), 8.58 (d, J = 4.8 Hz, CH, 1H), 8.13 (d, J = 4.8 Hz, CH, 1H), 7.96 (s, CH, 1H), 7.77 (d, J = 7.2 Hz, CH, 2H), 7.62–7.41 (m, CH, 7H), 7.29–7.20 (m, CH, 2H), 3.93 (s, CH₃, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 182.3, 154.7, 140.6, 138.4, 137.5, 137.4, 137.1, 136.8, 136.6, 136.0, 131.8, 128.9, 128.6, 127.4, 126.4, 125.6, 121.0, 120.3, 119.3, 118.6, 112.9, 111.7, 111.3, 103.8, 56.1. HRMS (ESI-TOF) m/z: [M + H]⁺ calcd for C₂₇H₂₀N₃O₂: 418.1550; found: 418.1552.

Control Experiments

a. 3,2-Carbonyl Migration from 6ca

1-(7-Bromo-4-phenyl-1H-indol-2-yl)ethan-1-one (5ca)

Compound 6ca (63 mg, 0.2 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and AgOAc (67 mg, 0.4 mmol, 2 equiv) were weighed in air and placed in a sealed tube (15 mL) with a magnetic stir bar. To the reaction mixture, HFIP/TFA (2 mL, 1:1, v/v) was added. The reaction mixture was then heated to 120 °C for 10 h under vigorous stirring. Upon completion, the reaction mixture was cooled to room temperature, the solvents were removed under reduced pressure, and the resulting mixture was purified by a silica gel column chromatography column to give 5ca (46 mg, 74%) using hexane/EtOAc (85:15 hexane/ethyl acetate).

b. Reaction under Standard Conditions without 2a

2,2,2-Trifluoro-1-(1H-indol-3-yl)ethan-1-one (18)³³

Reaction of 10a (or 10b) under standard condition without 2a gave the compound 18. 2,2,2-trifluoro-1-(1H-indol-3-yl)ethan-1-one (18) (63 mg, 75% (or 59 mg, 70%), white solid, mp 153–154 °C); ¹H NMR (400 MHz, DMSO-d₆): δ 12.72 (bs, NH, 1H), 8.51–8.47 (m, CH, 1H), 8.24–8.16 (m, CH, 1H), 7.62–7.56 (m, CH, 1H), 7.38–7.27 (m, CH, 2H). ¹³C{¹H} NMR (100 MHz, DMSO-d₆): δ 174.1 (q, J = 33.8 Hz), 137.6 (q, J = 4.8 Hz), 136.6, 125.7, 124.3, 123.4, 121.1, 116.9 (q, J = 291.7 Hz), 113.0, 108.8.

c. Reaction under Standard Conditions of 19a and 2a

Compound 11a (27 mg, 70%) was synthesized by following general procedure D using 1H-indole (19a, 24 mg, 0.2 mmol), AgOAc (67 mg, 0.4 mmol), Pd(OAc)₂ (5 mg, 20 μmol, 10 mol %), and iodobenzene (2a, 45 μL, 0.4 mmol) at 120 °C for 3 h and purified by silica gel column chromatography (95:15 hexane/ethyl acetate).

d. Reaction under Standard Conditions of 10c without 2a/with 2a

2-Methyl-1H-indole (19b)⁴⁶

(Red solid; mp: 59–60 °C); ¹H NMR (400 MHz, CDCl₃): δ 7.75 (bs, NH, 1H), 7.56 (d, J = 7.6 Hz, CH, 1H), 7.28 (d, J = 7.9 Hz, CH, 1H), 7.18–7.09 (m, CH, 2H), 6.25 (s, CH, 1H), 2.44 (s, CH, 3H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ 136.1, 135.2, 129.1, 121.0, 119.7 (2C), 110.3, 100.4, 13.8.

e. Reaction under Standard Conditions of 19b and 2a

In the reaction of 19b and 2a under standard conditions, no products were observed.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.2c00716.

• NMR and HRMS spectra of compounds (PDF)

The authors declare no competing financial interest.