Platinum(II)-catalyzed dehydrative C3-benzylation of electron-deficient indoles with benzyl alcohols

Abstract

A synthetic strategy for the water-promoted direct dehydrative coupling of indoles with benzyl alcohols catalyzed by PtCl₂(PhCN)₂ in 1,2-dichloroethane has been developed. Water molecules significantly accelerate C–C bond formation, whereas the reaction proceeds slowly under anhydrous conditions. Comparative rate plots for reactions in the presence of H₂O and D₂O show a kinetic solvent isotope effect (KSIE) of 1.5. A Hammett study of the dehydrative reaction of para-substituted benzhydrols shows negative ρ values, indicating a build-up of cationic charge during the rate-determining sp³ C–O bond cleavage step. Our catalytic system can be used on the gram scale with simplified product isolation and catalysis is performed using 1 mol% of a Pt(II) catalyst with an additional molecule of water.

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Introduction

Compared to conventional organic solvents, water possesses very interesting properties and selectivities for chemical transformations in a wide variety of carbon–carbon bond forming reactions such as the Diels–Alder reaction, aldol reaction, Claisen rearrangement and cross-coupling reactions.^1,2 In 1991, the pioneering work of Breslow demonstrated the acceleration of Diels–Alder reactions by the hydrophobic effect in aqueous media.³ In 2005, Sharpless et al. demonstrated the rate acceleration of several “on water” reactions of water-insoluble substrates.⁴ The organic–water interface effect of dangling OH groups has been proven to enhance reaction rates. Therefore, hydrogen bonding activation and hydrophobic effects by water molecules are believed to contribute to the rate acceleration for a wide variety of organic reactions.

Indoles are valuable building blocks for pharmaceutical agents in modern drug discovery (Fig. 1).⁵ Therefore, efficient methods for the direct introduction of diverse functionalities on indole rings are gaining increasing interest. In recent years, direct dehydrative coupling reactions of indoles with relatively low toxic, inexpensive and abundantly available alcohols as coupling partners have emerged for the construction of C–C bonds due to the advantages of being a salt-free, environmentally benign and atom-economical process with water as the by-product.^6,7

Fig. 1 Representative biologically active 3-substituted indoles.

In the light of our ongoing efforts to develop dehydrative C–C bond forming reactions in water,⁸ we herein report the first examples of a Pt(II)-catalyzed direct dehydrative coupling reaction of electron-deficient indoles with benzyl alcohols in 1,2-dichloroethane (Scheme 1).⁹ In 2008, Yadav et al. reported the dehydrative benzylation of 5-nitroindole with benzylic alcohols catalyzed by phosphomolybdic acid-supported silica gel.^9c While the heterogeneous catalysts offer significant advantages (e.g. simple work-up, cleaner reaction profiles and reutilization procedures), our homogeneous platinum catalyst system could be used in simple, convenient and readily available protocols for the dehydrative benzylation.

Scheme 1 Water-promoted dehydrative C3-benzylation.

Notably, the PtCl₂(PhCN)₂ catalyst is highly effective as a Lewis acid for the activation of alcohols while Pt(II) catalysts are generally used for the π-activation of alkenes and alkynes.¹⁰ Furthermore, water molecules present in situ serve as an essential cocatalyst for achieving high catalytic activity of the Pt(II) complex under mild reaction conditions without the need for bases or other additives in the atom-economical process.

Results and discussion

Optimization of reaction conditions

Initially, electron-deficient 5-nitroindole (1a) and benzhydrol (2a) were chosen as model compounds to optimize the dehydrative reaction conditions. When using the PtCl₂(PhCN)₂ catalyst (5 mol%) at 50 °C for 16 h in 1,2-dichloroethane (DCE), the desired C3-benzylated product 3a was obtained selectively in 75% isolated yield (Table 1, entry 1). Excellent yield was achieved when the reaction was performed at 60 °C (entry 2, 96%). In contrast, no reaction occurred in the absence of the catalyst (entry 3). With regard to the platinum(II) catalyst, PtCl₂(PhCN)₂ gave the best result (entry 1 vs. entries 4–9).¹¹ Replacing DCE with CHCl₃ as a solvent resulted in almost the same yield (entry 10, 72%). In contrast, the use of CH₂Cl₂ or chlorobenzene afforded lower yields (entries 11 and 12). Other organic solvents such as toluene, EtOAc or 1,4-dioxane resulted in slightly lower yields (entries 13–15). No reaction occurred when polar organic solvents such as EtOH or DMSO¹² were used (entries 16 and 17). The use of only water as a solvent was also disfavored in this catalytic system (entry 18).

Table 1 Effects of catalysts and solvents^a

Entry	Pt catalyst	Solvent	T (°C)	Yield (%)
a Reaction conditions: 5-nitroindole 1a (1 mmol), Pt catalysts (0.05 mmol), benzhydrol 2a (1.2 mmol), and solvent (4 mL), 50–80 °C, 16 h under air. Yields of the isolated products are shown. b NMR yield.
1	PtCl2(PhCN)2	DCE	50	75
2	PtCl2(PhCN)2	DCE	60	96
3	None	DCE	50	0
4	PtCl2	DCE	50	0
5	PtCl2(PPh3)2	DCE	50	0
6	Pt(COD)Cl2	DCE	50	0
7	Pt(acac)2	DCE	50	0
8	Na2PtCl4·xH2O	DCE	50	Trace
9	cis-PtCl2(NH3)2	DCE	50	0
10	PtCl2(PhCN)2	CHCl3	50	72
11	PtCl2(PhCN)2	CH2Cl2	50	15^b
12	PtCl2(PhCN)2	PhCl	50	39
13	PtCl2(PhCN)2	Toluene	60	80
14	PtCl2(PhCN)2	EtOAc	60	71
15	PtCl2(PhCN)2	1,4-Dioxane	60	71
16	PtCl2(PhCN)2	EtOH	60	0
17	PtCl2(PhCN)2	DMSO	60	0
18	PtCl2(PhCN)2	Water	60	38

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Effect of water on the dehydrative reaction

To gain insight into the effect of water on the dehydrative coupling of 1a (1 mmol) with 2a in 1,2-dichloroethane, molecular sieves (4 Å MS, 160 mg) were added to the reaction mixture to scavenge the water in the dehydration step.¹³ As expected, compared to the absence of 4 Å MS, the reaction rate was significantly slower (Fig. 2).¹⁴ In contrast, the addition of water (1 mmol) led to an acceleration of the reaction rate, and the reaction proceeded to near completion within 6 h.¹⁵ The rate of the reaction was faster in the presence of H₂O than that in the presence of D₂O with a kinetic solvent isotope effect (KSIE) of 1.5 (Fig. 3).¹⁶ This low deuterium isotope value indicates that hydrogen bonding activation plays an important role in our catalytic system.^1b,17

Fig. 2 The effect of water on the dehydrative coupling. Reaction conditions: 5-nitroindole 1a (1 mmol), PtCl₂(PhCN)₂ (0.05 mmol), benzhydrol 2a (1.2 mmol), and 1,2-dichloroethane, 60 °C.

Fig. 3 Comparison of reaction rates in the presence of water and D₂O. Reaction conditions: 5-nitroindole 1a (1 mmol), PtCl₂(PhCN)₂ (0.05 mmol), benzhydrol 2a (1.2 mmol), and 1,2-dichloroethane (4 mL) with H₂O or D₂O (1 mmol), 60 °C.

Next, the same technique was used to determine the influence of the amount of water. The observed initial rate acceleration did not depend on the amount of water added, since the excess water molecules would react with the benzyl cation intermediate. Water promoted the reaction with rates in the following order: H₂O (1 mmol) > H₂O (2 mmol) > D₂O (1 mmol) > H₂O (0.5 mmol) = no additive (0.18 mmol of water molecules would be formed after 3 h) > 4 Å MS (anhydrous conditions) > H₂O (22 mmol) (Table 2, entries 1–7). Indeed, replacing 1,2-dichloroethane with only water as the solvent resulted in a lower yield (see Table 1). EtOH was found to be less effective than water (entry 2 vs. entry 8). In the absence of the Pt(II) catalyst, the addition of only water or aqueous HCl was not effective (entries 9 and 10). Other salts such as Cu(II), Ni(II) and Co(II) were less effective than Pt(II) (entries 11–13). These results indicate that the Pt(II) catalyst is highly effective for the water-promoted coupling reaction.

Table 2 Effects of the amounts of water and catalysts^a

Entry	Catalyst	Additive (mmol)	NMR yield (%)
a Reaction conditions: 1a (1 mmol), PtCl2(PhCN)2 (0.05 mmol), 2a (1.2 mmol), and 1,2-dichloroethane (4 mL), 60 °C, 3 h under air. b DCE (3.6 mL) and H2O (0.4 mL, 10% v/v) were used as solvents. c 160 mg. d HCl aq. (3 mol L^−1, 18 μL) was used.
1	PtCl2(PhCN)2	H2O (0.5)	18
2	PtCl2(PhCN)2	H2O (1)	41
3	PtCl2(PhCN)2	H2O (2)	26
4	PtCl2(PhCN)2	H2O (22)^b	7
5	PtCl2(PhCN)2	D2O (1)	22
6	PtCl2(PhCN)2	None	18
7	PtCl2(PhCN)2	4 Å MS^c	10
8	PtCl2(PhCN)2	EtOH (1)	26
9	None	H2O (1)	0
10	None	HCl aq. (1)^d	4
11	CuCl2	H2O (1)	4
12	NiCl2·6H2O	H2O (1)	0
13	CoCl2·6H2O	H2O (1)	0

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Based on the literature reports of the Shilov reaction,¹⁸ we propose a catalytic pathway for the water-promoted sp³ C–O bond activation of alcohol 2a as follows (Scheme 2). Initially, a ligand exchange of PtCl₂(PhCN)₂ with water molecules generates PtCl₂(OH₂)₂.^11,19 This aqua complex with benzhydrol (2a) is in fast equilibrium with its Lewis acid adduct A (conjugate acid). The water molecules promote the facile sp³ C–O bond cleavage, thus allowing for a much lower energy for the TS. Following bond cleavage, benzyl cation species B is formed via the rate-determining step. Shinokubo and Oshima used theoretical calculations to elucidate the importance of hydration of the hydroxy group for the smooth generation of the π-allylpalladium species for the dehydrative Tsuji–Trost reaction.²⁰ Cozzi et al. reported that the direct generation of carbocations from alcohols is driven by the hydrogen bonding activation.²¹ The kinetic solvent isotope effect (KSIE) of 1.5 is consistent with the hydrogen bonding activation pathway.

Scheme 2 Proposed pathway for the sp³ C–O bond cleavage.

Furthermore, Pt(II) complexes have been investigated not only for the development of synthetic methods but also as antitumor drugs. Cisplatin, cis-[PtCl₂(NH₃)₂], is activated inside the cell through the hydrolysis of the Pt–Cl bonds to form a cationic Pt(II) aqua complex, cis-[PtCl(NH₃)₂(H₂O)]⁺.²² Therefore, investigation on water-promoted reactions using our catalytic system would be important for understanding the activation process of cisplatin in the cell and rationally designing improved anticancer drugs.

Reaction scope

With the optimized conditions in hand, we examined the substrate scope of the dehydrative coupling reaction (Scheme 3). The electron-withdrawing (NO₂, CO₂H, CN and Cl) groups on the benzene ring of substituted indoles 1 were tolerated well to produce the corresponding products 3b–i in moderate to excellent yields (53–95%). Sterically demanding carboxy and phenyl groups of 2-substituted indoles were also tolerated in the direct substitution (65–74%, 3j–k). The scope of alcohols 2 was examined next with 4-nitroindole (1a) as the coupling partner. The use of benzhydryl alcohols with electron-donating methoxy and methyl groups, or electron-withdrawing fluoro, chloro and trifluoromethyl groups, resulted in excellent yields (72–98%, 3l–r). Furthermore, α-methylbenzyl alcohols, allylic alcohol, and triphenylmethanol led to the corresponding C3-benzylic and allylic products 3s–v (52–95%).

Scheme 3 Scope of indoles 1 and alcohols 2. Reaction conditions: 1 (1 mmol), PtCl₂(PhCN)₂ (0.05 mmol), 2 (1.2 mmol), and 1,2-dichloroethane (4 mL).

Hammett study

To demonstrate the electronic effect of the substituents on the rates of the sp³ C–O bond cleavage of alcohols, the relative rates of the coupling of 4-substituted benzhydrols 2X with 5-nitroindole (1a) were examined (see ESI, Scheme S2†).²³Fig. 4 shows good correlation (R² = 0.99) between the log(k_X/k_H) and the σ_p values of the respective substituents. The resulting negative ρ value of 2.9 indicates that there is a build-up of positive charge in the transition state.

Fig. 4 Hammett plots for the rate constants of benzylation by various substituted 4-benzhydrols 2X (X = OMe, Me, F and Cl groups).

Control experiments

¹H NMR study was performed to ascertain the role of the Pt(II) catalyst (Scheme 4A). Roy et al. reported that all proton signals of the C3-palladated indole complex were shifted downfield from those of free indole, except for the C3-H signal.^7c In contrast, when 5-nitroindole (1a) was treated with PtCl₂(PhCN)₂ (1 equiv.) in CDCl₃ at 60 °C, the ¹H NMR spectrum was unchanged from that of 1a. These results suggested that the Pt(II) catalyst did not interact with the electron-deficient indole 1a due to the low Lewis basicity of 1a. Interestingly, the water-promoted dehydrative coupling of 5-cyanoindole (1b) with alcohol 2a proceeded smoothly using our catalytic system, whereas the use of the PdCl₂(MeCN)₂ catalyst was less effective, clearly demonstrating the superiority of the Pt(II) catalytic system for the C3-benzylation of 1b (Scheme 4B).

Scheme 4 Control experiments.

Mechanistic considerations

On the basis of these results and our previous report, we propose a catalytic system for the water-promoted dehydrative coupling of 4-nitroindole (1a) with benzhydrol (2a) catalyzed by Pt(II) as illustrated in Scheme 5. Initially, a ligand exchange of PtCl₂(PhCN)₂ with alcohol 2a generates intermediate A (step 1: ligand exchange), and sp³ C–O bond activation occurs to generate a benzylic cation B (step 2: C–O bond cleavage). The observed negative Hammett ρ value of 2.9 in the reaction of para-substituted benzhydryl alcohols 2 clearly shows cationic charge build up during the rate-determining sp³ C–O bond cleavage (see Fig. 4). Additionally, the direct substitution of trityl alcohol affords the corresponding desired product 3u, which is in agreement with the reaction proceeding through an S_N1 reaction. Notably, the presence of a few water molecules leads to an acceleration of the dehydrative reaction rate, suggesting that the transition state TS was stabilized by water molecules. Next, the hydroxyl anion of platinum species C acts as a base to remove the acidic proton of substrate 1a, which attacks the electrophilically active benzyl cation B to afford the corresponding C3-benzylated product 3a (step 3: C3-benzylation).

Scheme 5 Proposed mechanism.

Scale-up experiment

Finally, we examined the scalability of our catalytic system (Scheme 6). To demonstrate the utility of our efficient and simple protocol, a gram scale reaction of 1a in the presence of only 1 mol% of the Pt(II) catalyst with 1 equiv. of water was carried out. The dehydrative coupling reaction of 1a with 2a was completed in 36 h. After cooling, n-hexane was added to the reaction mixture. The precipitate was filtered to give the desired product 3a in 92% isolated yield. Notably, the developed process avoids using column chromatography. To the best of our knowledge, this is the first example of a direct dehydrative coupling reaction utilizing a Pt(II) catalyst with an additional molecule of water.

Scheme 6 Scale-up experiment.

Conclusions

We have reported an efficient new protocol for the Pt(II)-catalyzed dehydrative C–C bond formation reaction to construct 3-benzylindoles. Notably, water molecules were found to be crucial as a cocatalyst for the success of our catalytic system. Our proposed strategy was applicable to the direct C3-benzylation of electron-deficient indoles. This simple protocol can be performed under mild conditions in an atom-economical process without the need for bases or other additives, furnishing the desired products in moderate to excellent yields along with only stoichiometric amounts of water as the sole co-product.

Experimental

All of the starting materials and solvents were purchased from Sigma-Aldrich Japan (Tokyo, Japan), FUJIFILM Wako Pure Chemical Co. (Osaka, Japan), and TCI Co., Ltd (Tokyo, Japan). All commercially available reagents and solvents were used without further purification. CHROMATOREX Q-PACK SI50 (Fuji Silysia Chemical Ltd, Japan) was used for flash column chromatography. All melting points were determined using a Yanako micro melting point apparatus without correction. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on a JEOL ECS400 spectrometer. IR spectra were measured with a JASCO FT/IR-4100 spectrometer. Mass spectra were obtained using a JEOL JMS-700 MStation Mass Spectrometer.

General procedure I

A mixture of indoles 1 (0.5 mmol), PtCl₂(PhCN)₂ (11.6 mg, 0.025 mmol) and alcohols 2 (0.6 mmol) in 1,2-dichloroethane (2 mL) was heated at 60 or 90 °C under air. After cooling, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, n-hexane/EtOAc) to give the desired product 3.

General procedure II

A mixture of indoles 1 (1 mmol), PtCl₂(PhCN)₂ (23 mg, 0.05 mmol) and alcohols 2 (1.2 mmol) in 1,2-dichloroethane (4 mL) was heated at 90 °C for 17 h under air. After cooling, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, n-hexane/EtOAc) to give the desired product 3.

3-Benzhydryl-5-nitro-1H-indole 3a. Following the general procedure II, 3a was obtained as a yellow solid; yield 315 mg (96%); mp 275–278 °C [257–265 °C, lit];^9b IR (KBr) (cm⁻¹) 3304, 3025, 1625, 1500; ¹H NMR (400 MHz, CDCl₃): δ 5.71 (s, 1H), 6.76 (dd, J = 2.1, 0.9 Hz, 1H), 7.19–7.33 (m, 10H), 7.39 (d, J = 8.5 Hz, 1H), 8.09 (ddd, J = 9.0, 2.1, 0.9 Hz, 1H), 8.20 (dd, J = 1.4, 0.7 Hz, 1H), 8.32 (br, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 48.4, 111.1, 117.1, 118.0, 122.7, 126.4, 126.7, 126.9, 128.5, 128.8, 139.6, 141.7, 142.9; MS (FAB): m/z 329 [M + H]⁺.

3-Benzhydryl-4-nitro-1H-indole 3b. Following the general procedure I, 3b was obtained as a brown solid; yield 131 mg (80%); R_f = 0.5 (hexane/ethyl acetate = 2 : 1); mp 267–269 °C; IR (KBr) (cm⁻¹) 3361, 3021, 2339, 1510; ¹H NMR (400 MHz, CDCl₃): δ 6.04 (s, 1H), 6.65 (dd, J = 2.8, 1.1 Hz, 1H), 7.08–7.13 (m, 4H), 7.16–7.29 (m, 7H), 7.62 (ddd, J = 7.9, 5.8, 0.9 Hz, 2H), 8.37 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 49.3, 116.7, 117.4, 118.4, 119.9, 121.1, 126.3, 128.3, 128.8, 129.1, 139.1, 143.9, 144.1; MS (EI): m/z (%) 328 (M⁺, 21), 280 (100); HRMS (EI): m/z [M⁺] calcd for C₂₁H₁₆N₂O₂ 328.1208, found 328.1213.

3-Benzhydryl-6-nitro-1H-indole 3c. Following the general procedure I, 3c was obtained as a yellow solid; yield 123 mg (75%); mp 186–188 °C [186–190 °C, lit];^9b IR (KBr) (cm⁻¹) 3328, 3025, 1587, 1496; ¹H NMR (400 MHz, CDCl₃): δ 5.67 (s, 1H), 6.89 (dd, J = 2.5, 0.9 Hz, 1H), 7.19–7.33 (m, 11H), 7.88 (dd, J = 8.9, 2.1 Hz, 1H), 8.34 (d, J = 2.1 Hz, 1H), 8.42 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 48.5, 108.1, 115.0, 120.0, 121.1, 126.7, 128.5, 128.8, 129.7, 131.5, 135.1, 143.0, 143.4; MS (FAB): m/z 329 [M + H]⁺.

3-Benzhydryl-7-nitro-1H-indole 3d. Following the general procedure I, 3d was obtained as a yellow solid; yield 156 mg (95%); mp 194–197 °C [190–194 °C, lit];^9b IR (KBr) (cm⁻¹) 3369, 3032, 1517, 1492; ¹H NMR (400 MHz, CDCl₃): δ 5.68 (s, 1H), 6.77 (dd, J = 2.3, 1.1 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 7.19–7.34 (m, 10H), 7.54 (d, J = 7.8 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 9.72 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 48.5, 118.9, 119.4, 121.5, 126.4, 126.6, 128.1, 128.5, 128.9, 130.2, 130.8, 132.9, 143.0; MS (FAB): m/z 329 [M + H]⁺.

3-Benzhydryl-1H-indole-5-carboxylic acid 3e. Following the general procedure I, 3e was obtained as a white solid; yield 131 mg (80%); R_f = 0.75 (CHCl₃/MeOH = 4 : 1); mp 228–233 °C; IR (KBr) (cm⁻¹) 3430, 3025, 1683, 1619; ¹H NMR (400 MHz, CDCl₃): δ 5.73 (s, 1H), 6.67 (dd, J = 2.2, 1.1 Hz, 1H), 7.19–7.32 (m, 12H), 7.39 (dd, J = 8.6, 0.5 Hz, 1H), 7.93 (dd, J = 8.5, 1.6 Hz, 1H), 8.10 (t, J = 0.8, 1H), 8.17 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 48.4, 110.8, 120.6, 121.7, 123.7, 124.1, 125.3, 126.4, 126.7, 128.4, 128.9, 139.7, 143.5, 172.4; MS (FAB): m/z 328 [M + H]⁺; anal. calcd for C₂₂H₁₇NO₂: C, 80.71; H, 5.23; N, 4.28. Found: C, 80.44; H, 5.25; N, 4.29.

3-Benzhydryl-1H-indole-6-carboxylic acid 3f. Following the general procedure II, 3f was obtained as a white solid; yield 261 mg (79%); R_f = 0.75 (CHCl₃/MeOH = 4 : 1); mp >300 °C; IR (KBr) (cm⁻¹) 3373, 3026, 2875, 1661; ¹H NMR (400 MHz, DMSO-d₆): δ 5.72 (s, 1H), 6.95 (dd, J = 2.5, 0.7 Hz, 1H), 7.13–7.34 (m, 11H), 7.47 (dd, J = 8.4, 1.5 Hz, 1H), 8.01 (dd, J = 1.4, 0.7 Hz, 1H), 11.29 (d, J = 2.1 Hz, 1H), 12.48 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 47.7, 113.6, 118.1, 118.5, 119.2, 123.2, 126.1, 127.6, 128.2, 128.4, 129.5, 135.8, 143.9, 168.2; MS (EI): m/z (%) 327 (M⁺, 100); HRMS (EI): m/z [M⁺] calcd for C₂₂H₁₇NO₂ 327.1255, found 327.1258.

3-Benzhydryl-1H-indole-7-carboxylic acid 3g. Following the general procedure II, 3g was obtained as a pale brown solid; yield 225 mg (69%); R_f = 0.33 (hexane/ethyl acetate = 1 : 2); mp 208–212 °C; IR (KBr) (cm⁻¹) 3453, 3032, 2538, 1682; ¹H NMR (400 MHz, CDCl₃): δ 5.70 (s, 1H), 6.71 (dd, J = 2.0, 0.9 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 7.19–7.33 (m, 11H), 7.49 (d, J = 7.8 Hz, 1H), 7.96 (dd, J = 7.6, 0.9 Hz, 1H), 9.58 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 48.7, 111.4, 118.9, 120.2, 125.2, 125.6, 126.4, 126.8, 128.3, 128.4, 128.9, 136.9, 143.6, 172.9; MS (EI): m/z (%) 327 (M⁺, 13), 59 (100); HRMS (FAB): m/z [M⁺] calcd for C₂₂H₁₇NO₂ 327.1255, found 327.1260.

3-Benzhydryl-1H-indole-5-carbonitrile 3h. Following the general procedure II, 3h was obtained as a white solid; yield 163 mg (53%); mp 223–227 °C [226–229 °C, lit];^9b IR (KBr) (cm⁻¹) 3330, 3026, 2218, 1615; ¹H NMR (400 MHz, CDCl₃): δ 5.64 (s, 1H), 6.71 (dd, J = 2.4, 1.0 Hz, 1H), 7.17–7.34 (m, 10H), 7.40 (s, 2H), 7.55 (s, 1H), 8.26 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 48.6, 102.5, 112.0, 120.7, 121.0, 125.2, 125.6, 126.1, 126.7, 126.8, 128.5, 128.8, 138.4, 143.0; MS (FAB): m/z 309 [M + H]⁺.

3-Benzhydryl-5-chloro-1H-indole 3i. Following the general procedure II, 3i was obtained as an amorphous solid; yield 229 mg (72%); R_f = 0.14 (hexane/ethyl acetate = 2 : 1); IR (KBr) (cm⁻¹) 3425, 3062, 3025, 2869, 1657, 1594; ¹H NMR (400 MHz, CDCl₃): δ 5.61 (s, 1H), 6.59 (s, 1H), 7.07–7.34 (m, 13H), 7.97 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 48.6, 112.1, 119.3, 119.7, 122.5, 125.1, 125.4, 126.4, 128.1, 128.4, 128.9, 135.0, 143.5; MS (FAB): m/z 319 [M + 2]⁺, 317 [M]⁺; HRMS (FAB): m/z [M⁺] calcd for C₂₁H₁₆ClN 317.0968, found 317.0972.

3-Benzhydryl-1H-indole-2-carboxylic acid 3j. Following the general procedure II, 3j was obtained as a white solid; yield 241 mg (74%); mp 246–248 °C [245–248 °C, lit];^9b IR (KBr) (cm⁻¹) 3410, 3028, 2575, 1670; ¹H NMR (400 MHz, CDCl₃): δ 6.74 (s, 1H), 6.90 (ddd, J = 8.5, 7.1, 0.9 Hz, 1H), 7.03 (dd, J = 8.2, 0.7 Hz, 1H), 7.18–7.31 (m, 12H), 7.34 (d, J = 8.2, 1H), 8.88 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 47.1, 112.0, 120.5, 122.6, 123.7, 125.9, 126.3, 127.3, 128.2, 128.4, 129.3, 136.7, 143.1, 166.5; MS (FAB): m/z 328 [M + H]⁺.

3-Benzhydryl-1-methyl-2-phenyl-1H-indole 3k. Following the general procedure I, 3k was obtained as a white solid; yield 121 mg (65%); R_f = 0.64 (hexane/ethyl acetate = 8 : 1); mp 165–168 °C; IR (KBr) (cm⁻¹) 3059, 2937, 1598; ¹H NMR (400 MHz, CDCl₃): δ 3.59 (s, 3H), 5.53 (s, 1H), 6.93 (ddd, J = 8.0, 7.1, 0.9 Hz, 1H), 7.10–7.35 (m, 15H), 7.39–7.45 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 30.9, 48.1, 109.3, 115.2, 119.2, 121.2, 121.4, 125.9, 126.9, 128.0, 128.3, 128.3, 129.1, 130.8, 131.9, 137.4, 139.0, 144.4; MS (FAB): m/z 373 [M]⁺, HRMS (FAB): m/z [M⁺] calcd for C₂₈H₂₃N 373.1825, found 373.1831.

3-[Bis(4-methoxyphenyl)methyl]-5-nitro-1H-indole 3l^9a. Following the general procedure I, 3l was obtained as a brown solid; yield 165 mg (86%); mp 226–231 °C; IR (KBr) (cm⁻¹) 3288, 2831, 1619, 1508; ¹H NMR (400 MHz, CDCl₃): δ 3.79 (s, 6H), 5.60 (s, 1H), 6.74 (d, J = 2.1 Hz, 1H), 6.83 (d, J = 8.7 Hz, 4H), 7.11 (d, J = 8.7 Hz, 4H), 7.34 (d, J = 8.9 Hz, 1H), 8.08 (dd, J = 8.9, 2.3 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H), 8.30 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 46.7, 55.3, 111.0, 113.9, 117.2, 117.9, 123.4, 126.4, 126.8, 129.8, 136.5, 139.7, 141.6, 158.2; MS (FAB): m/z 389 [M + H]⁺.

3-[Bis(4-chlorophenyl)methyl]-5-nitro-1H-indole 3m. Following the general procedure I, 3m was obtained as a yellow solid; yield 194 mg (98%); R_f = 0.37 (hexane/ethyl acetate = 2 : 1); mp 285–289 °C; IR (KBr) (cm⁻¹) 3287, 1489; ¹H NMR (400 MHz, CDCl₃): δ 5.66 (s, 1H), 6.73 Hz, (1H), 7.11 (d, J = 8.5 Hz, 4H), 7.24–7.33 (m, 4H), 7.42 (d, J = 9.2 Hz, 1H), 8.11 (dd, J = 8.9, 2.1 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.38 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 47.1, 111.3, 116.9, 118.3, 121.7, 126.1, 126.9, 128.8, 130.1, 132.8, 139.6, 141.0, 141.8; MS (EI): m/z (%) 400 (M⁺ + 4, 10), 398 (M⁺ + 2, 59), 396 (M⁺, 89), 366 (100); HRMS (EI): m/z [M⁺] calcd for C₂₁H₁₄Cl₂N₂O₂ 396.0430, found 396.0431.

3-[Bis(4-fluorophenyl)methyl]-5-nitro-1H-indole 3n. Following the general procedure I, 3n was obtained as a yellow solid; yield 178 mg (98%); R_f = 0.34 (hexane/ethyl acetate = 2 : 1); mp 264–270 °C; IR (KBr) (cm⁻¹) 3288, 1606, 1506; ¹H NMR (400 MHz, CDCl₃): δ 5.68 (s, 1H), 6.72 (t, J = 1.1 Hz, 1H), 7.00 (t, J = 8.0 Hz, 4H), 7.15 (dd, J = 8.4, 5.3 Hz, 4H), 7.41 (d, J = 9.4 Hz, 1H), 8.11 (dd, J = 9.0, 1.4 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.37 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 46.9, 111.2, 115.5 (J_CF = 22.0 Hz), 116.9, 118.2, 122.4, 126.2, 126.8, 130.2 (J_CF = 8.6 Hz), 138.5 (J_CF = 2.9 Hz), 139.7, 141.8, 161.7 (J_CF = 245.4 Hz); MS (FAB): m/z 365 [M + H]⁺; HRMS (FAB): m/z [M + H]⁺ calcd for C₂₁H₁₄F₂N₂O₂ 365.1098, found 365.1101.

3-[(4-Methoxyphenyl)(phenyl)methyl]-5-nitro-1H-indole 3o. Following the general procedure I, 3o was obtained as a yellow solid; yield 147 mg (82%); R_f = 0.31 (hexane/ethyl acetate = 2 : 1); mp 214–218 °C; IR (KBr) (cm⁻¹) 3271, 3025, 2837, 2359, 1624; ¹H NMR (400 MHz, CDCl₃): δ 3.79 (s, 3H), 5.66 (s, 1H), 6.75 (t, J = 1.1 Hz, 1H), 6.84 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 7.17–7.33 (m, 5H), 7.38 (d, J = 8.9 Hz, 1H), 8.09 (dd, J = 8.8, 2.1 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 8.32 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 47.6, 55.3, 111.0, 113.9, 117.2, 118.0, 123.0, 126.4, 126.6, 126.8, 128.5, 128.7, 129.8, 135.1, 139.7, 141.6, 143.3, 158.3; MS (EI): m/z (%) 358 (M⁺, 100); HRMS (EI): m/z [M⁺] calcd for C₂₂H₁₈N₂O₃ 358.1313, found 358.1318.

5-Nitro-3-[phenyl(p-tolyl)methyl]-1H-indole 3p. Following the general procedure I, 3p was obtained as a yellow solid; yield 158 mg (92%); R_f = 0.4 (hexane/ethyl acetate = 2 : 1); mp 265–270 °C; IR (KBr) (cm⁻¹) 3296, 3025, 1509; ¹H NMR (400 MHz, CDCl₃): δ 2.33 (s, 3H), 5.67 (s, 1H), 6.76 (t, J = 1.1 Hz, 1H), 7.10 (s, 4H), 7.19–7.33 (m, 5H), 7.38 (d, J = 8.9 Hz, 1H), 8.08 (dd, J = 8.9, 2.1 Hz, 1H), 8.20 (d, J = 1.8 Hz, 1H), 8.31 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 21.0, 48.0, 111.0, 117.2, 118.0, 122.8, 126.6, 126.8, 128.5, 128.7, 128.8, 129.2, 136.2, 139.6, 140.0, 141.7, 143.2; MS (EI): m/z (%) 342 (M⁺, 100); HRMS (EI): m/z [M⁺] calcd for C₂₂H₁₈N₂O₂ 342.1364, found 342.1369.

3-[(4-Chlorophenyl)(phenyl)methyl]-5-nitro-1H-indole 3q. Following the general procedure I, 3q was obtained as a yellow solid; yield 163 mg (90%); R_f = 0.4 (hexane/ethyl acetate = 2 : 1); mp 259–261 °C; IR (KBr) (cm⁻¹) 3306, 1489; ¹H NMR (400 MHz, CDCl₃): δ 5.68 (s, 1H), 6.74 (t, J = 1.1 Hz, 1H), 7.11–7.21 (m, 4H), 7.23–7.35 (m, 5H), 7.40 (d, J = 8.9 Hz, 1H), 8.10 (dd, J = 9.4, 2.1 Hz, 1H), 8.19 (d, J = 2.1 Hz, 1H), 8.36 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 47.8, 111.2, 117.0, 118.1, 122.1, 126.3, 126.9, 128.7, 128.7, 128.7, 130.2, 132.5, 139.6, 141.5, 141.8, 142.4; MS (EI): m/z (%) 364 (M⁺ + 2, 34), 362 (M⁺, 100), HRMS (EI): m/z [M⁺] calcd for C₂₁H₁₅ClN₂O₂ 362.0819, found 362.0823.

5-Nitro-3-{phenyl[3-(trifluoromethyl)phenyl]methyl}-1H-indole 3r. Following the general procedure I (the reaction was conducted at 90 °C), 3r was obtained as a yellow solid; yield 143 mg (72%); R_f = 0.4 (hexane/ethyl acetate = 2 : 1); mp 206–208 °C; IR (KBr) (cm⁻¹) 3310, 1625; ¹H NMR (400 MHz, DMSO-d₆): δ 6.06 (s, 1H), 7.06 (d, J = 2.3 Hz, 1H), 7.20–7.40 (m, 5H), 7.50–7.65 (m, 5H), 7.98 (dd, J = 9.2, 1.8 Hz, 1H), 8.14 (d, J = 2.3 Hz, 1H), 11.8 (brs, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 47.3, 112.8, 116.4, 117.3, 120.3, 123.8 (q, J_CF = 3.8 Hz), 124.8 (q, J_CF = 272.2 Hz), 125.4 (q, J_CF = 3.8 Hz), 126.2, 127.2, 128.8, 129.0, 129.2, 129.6 (q, J_CF = 31.6 Hz), 130.1, 133.2, 140.3, 140.8, 143.4, 145.7; MS (FAB): m/z 397 [M + H]⁺; anal. calcd for C₂₂H₁₅F₃N₂O₂: C, 66.67; H, 3.81; N, 7.07. Found: C, 66.45; H, 3.89; N, 6.97.

3-[1-(4-Methoxyphenyl)ethyl]-5-nitro-1H-indole 3s. Following the general procedure II, 3s was obtained as a yellow solid; yield 268 mg (90%); R_f = 0.29 (hexane/ethyl acetate = 2 : 1); mp 188–191 °C; IR (KBr) (cm⁻¹) 3308, 2956, 1623; ¹H NMR (400 MHz, CDCl₃): δ 1.69 (d, J = 7.1 Hz, 3H), 3.78 (s, 3H), 4.36 (q, J = 7.1 Hz, 1H), 6.84 (d, J = 8.7 Hz, 2H), 7.15 (dd, J = 2.3, 0.9 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.9 Hz, 1H), 8.07 (dd, J = 8.9, 2.1 Hz, 1H), 8.33 (brs, 1H), 8.34 (d, J = 2.1 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 22.5, 35.9, 55.3, 111.0, 113.9, 117.1, 117.8, 123.8, 124.6, 126.3, 128.2, 137.8, 139.6, 141.5, 158.1; MS (FAB): m/z (%) 297 [M + H]⁺, HRMS (FAB): m/z [M + H]⁺ calcd for C₁₇H₁₆N₂O₃ 297.1235, found 297.1239.

5-Nitro-3-(1-phenylethyl)-1H-indole 3t. Following the general procedure II, 3t was obtained as a yellow solid; yield 138 mg (52%); R_f = 0.45 (hexane/ethyl acetate = 2 : 1); mp 137–144 °C; IR (KBr) (cm⁻¹) 3297, 3025, 2869, 1625; ¹H NMR (400 MHz, CDCl₃): δ 1.72 (d, J = 7.1 Hz, 3H), 4.40 (q, J = 7.1 Hz, 1H), 7.15–7.33 (m, 6H), 7.36 (d, J = 8.9 Hz, 1H), 8.07 (dd, J = 8.9, 2.3 Hz, 1H), 8.33 (d, J = 2.1 Hz, 1H), 8.35 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 22.3, 36.7, 111.0, 117.0, 117.8, 124.0, 124.2, 126.3, 126.4, 127.3, 128.6, 139.6, 141.5, 145.7; MS (FAB): m/z (%) 267 [M + H]⁺, HRMS (FAB): m/z [M + H]⁺ calcd for C₁₆H₁₄N₂O₂ 267.1130, found 267.1140.

(E)-3-(1,3-Diphenylallyl)-5-nitro-1H-indole 3u²⁴. Following the general procedure I, 3u was obtained as a yellow solid; yield 161 mg (90%); mp 181–185 °C; IR (KBr) (cm⁻¹) 3304, 3025, 2357, 1514; ¹H NMR (400 MHz, CDCl₃): δ 5.16 (d, J = 7.3 Hz, 1H), 6.43 (d, J = 15.7 Hz, 1H), 6.70 (dd, J = 15.9, 7.1 Hz, 1H), 7.09 (dd, J = 2.3, 0.9 Hz, 1H), 7.19–7.42 (m, 11H), 8.10 (dd, J = 9.0, 2.3 Hz, 1H), 8.38 (brs, 1H), 8.39 (d, J = 2.3 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 45.8, 111.1, 117.1, 118.0, 121.5, 125.6, 126.2, 126.4, 126.9, 127.5, 128.3, 128.6, 128.7, 131.3, 131.5, 137.1, 139.6, 141.7, 142.4; MS (FAB): m/z 355 [M + H]⁺.

5-Nitro-3-trityl-1H-indole 3v. Following the general procedure I, 3u was obtained as a yellow solid; yield 192 mg (95%); mp >300 °C [298 °C, lit];²⁵ IR (KBr) (cm⁻¹) 3401, 3057, 1507; ¹H NMR (400 MHz, CDCl₃): δ 7.06 (d, J = 2.3 Hz, 1H), 7.16–7.30 (m, 15H), 7.36 (d, J = 8.9 Hz, 1H), 7.59 (d, J = 1.8 Hz, 1H), 8.01 (dd, J = 9.3, 2.3 Hz, 1H), 8.33 (brs, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 59.3, 111.1, 117.7, 119.7, 126.5, 127.2, 127.7, 128.0, 126.9, 130.5, 139.8, 141.5, 145.7; MS (FAB): m/z 405 [M + H]⁺.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the JSPS KAKENHI Grant Number 19K07003.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra for all compounds. See DOI: 10.1039/c9qo00831d

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