Chemoselective aza-Michael addition of indoles to 2-aroyl-1,3-diarylenones

Abstract

A total of 20 examples of 2-[(1H-indol-1-yl)(aryl)methyl]-1,3-diphenylpropane-1,3-diones were efficiently synthesized by the aza-Michael addition at the N1 position of indoles with 2-aroyl-1,3-diarylenones at room temperature in the presence of potassium hydroxide. The salient features of this protocol are no transition-metal catalysts, mild conditions, high chemoselectivity, high atom economy, high yields, and a simple work-up procedure.

Keywords

2-aroyl-1 3-diarylenone atom economy aza-Michael addition chemoselectivity indoles

Introduction

The aza-Michael reaction is one of the most popular methods for carbon–nitrogen bond formation and the shortest way to prepare β-aminocarbonyl compounds, which are widely used for the synthesis of naturally occurring nitrogen-containing heterocyclic scaffolds and pharmaceuticals.^1–5 A few NH compounds including aromatic amines,⁶ aliphatic amines,^7–9 α-amino esters,¹⁰ benzotriazoles,^11,12 pyrazole,^13,14 indazole,¹⁵ piperazine,¹⁶ and urazole¹⁷ as Michael donors, and alkenyl sulfones,⁶ nitroolefins,^18,19 alkenyl benzimidazoles,²⁰ and α,β-unsaturated ketones,^21–24 acids,²⁵ esters,²⁶ amides,²⁷ and imides²⁸ as Michael acceptors were reported. However, some drawbacks still remain for these existing methods, for example, the use of transition-metal catalysts and low yields.

Indole, as a Michael donor, can be used to easily introduce a heterocycle to functionalized molecules. Meanwhile, enones, as important Michael acceptors, can participate in addition reactions. However, the reported reactions of indole with enones generally take place at the C3 or C2 positions.^29–37 There is scant literature on the aza-Michael addition reactions at the N1 position.^38,39

2-Aroyl-1,3-diarylenones have many important applications in organic synthesis.^40–43 However, to the best our knowledge, there are no reports on their use in aza-Michael addition reactions.

In this work, we report high-yielding chemoselective aza-Michael additions at the N1 position of (un)substituted indoles with 2-aroyl-1,3-diarylenones under transition-metal-free and mild conditions.

Results and discussion

Initially the reaction of 2-benzylidene-1,3-diphenylpropan-1,3-dione (1a) with unsubstituted indole was selected as the model reaction to screen for the optimum conditions (Scheme 1) (Ar = Ph; R = H). Different bases and solvents were investigated and the results are summarized in Table 1. The reaction was first tested in MeCN at room temperature in the absence of a base, but no product was detected (Table 1, entry 1). Next, 1 equiv. of Cs₂CO₃ was used as the base. After the mixture had been stirred at room temperature for 4 h, the product, 2-[(1H-indol-1-yl)(phenyl)methyl]-1,3-diphenylpropan-1,3-dione (2a), was isolated in 66% yield (Table 1, entry 2). The disappearance of NH peak of indole ring in ¹H NMR (both in CDCl₃ and DMSO-d₆) and the presence of 60.1 and 60.5 ppm (CH–CH in CDCl₃) peaks in ¹³C NMR could prove the correctness of 2a structure. Other inorganic bases, such as KOH, NaOH, K₂CO₃, and NaOAc (Table 1, entries 3–6), and organic bases, including Et₃N, 1,8-diazabicyclo[5.4.0] (DBU), 1,4-diazabicyclo[2.2.2] octane (DABCO) and 4-dimethylaminopyridine (DMAP) (Table 1, entries 7–10), were also tested for the reaction. Among these, KOH gave the best yield (78%) (Table 1, entry 3). Screening various other solvents including CH₂Cl₂, 1,4-dioxane, DMSO, EtOH, ClCH₂CH₂Cl, tetrahydrofuran (THF), PhMe, and dimethylformamide (DMF) showed that some solvents did not afford the desired product (Table 1, entries 11–14), and the others produced 2a, but in low yields (Table 1, entries 15–18). In addition, the reaction yield of 2a could be greatly improved (95%) when the amount of base was increased from 1 to 2 equiv. (Table 1, entry 19).

Scheme 1.

Aza-Michael addition of indoles to 2-aroyl-1,3-diarylenones.

Table 1.

Effect of the reaction conditions (base, solvent) on the yield of 2a.^a

Entry	Base	Solvent	Yield (%)^b
1	–	MeCN	0
2	Cs₂CO₃	MeCN	66
3	KOH	MeCN	78
4	NaOH	MeCN	16
5	K₂CO₃	MeCN	8
6	NaOAc	MeCN	0
7	Et₃N	MeCN	37
8	DBU	MeCN	50
9	DABCO	MeCN	14
10	DMAP	MeCN	12
11	KOH	CH₂Cl₂	0
12	KOH	1,4-dioxane	0
13	KOH	DMSO	0
14	KOH	EtOH	0
15	KOH	ClCH₂CH₂Cl	13
16	KOH	THF	11
17	KOH	PhMe	18
18	KOH	DMF	47
19^c	KOH	MeCN	95

Reaction conditions: 1a (0.2 mmol), indole (0.2 mmol), base (0.2 mmol), MeCN (2 mL), room temperature, 4 h.

Isolated yield.

Base (0.4 mmol).

With optimized reaction conditions in hand, the scope of aza-Michael addition of (un)substituted indoles with 2-aroyl-1,3-diarylenones in MeCN at room temperature using 2 equiv. of KOH as the base was examined. The results are summarized in Table 2. It was found that for the typical situation (R = H), a wide range of substituents on the Ar group of compounds 2, including H, Me, MeO, CF₃, F, Cl, Br, and NO₂ were tolerated (Table 2, 2a–o). The yields of the aza-Michael adducts was excellent for both electron-donating and electron-withdrawing groups. The yields for meta- and para-substituted substrates was slightly higher than those of ortho-substituted ones because of less steric hindrance. When the aromatic ring was replaced by a heteroaryl ring, such as furan, a good yield of the corresponding product was obtained (Table 2, 2p). For the substituted indoles (R = Cl, MeO), the aza-Michael additions proceeded smoothly, and gave the corresponding products in high yields (Table 2, 2q–t).

Table 2.

Synthesis of 2-[(1H-indol-1-yl)(aryl)methyl]-1,3-diphenylpropane-1,3-diones 2a–t.^a

Compound	Ar	R	Yield (%)^b
2a	C₆H₅	H	95
2b	2-MeC₆H₄	H	86
2c	3-MeC₆H₄	H	76
2d	4-MeC₆H₄	H	90
2e	2-MeOC₆H₄	H	88
2f	4-MeOC₆H₄	H	90
2g	4-F₃CC₆H₄	H	86
2h	3-FC₆H₄	H	82
2i	3-FC₆H₄	H	88
2j	2-ClC₆H₄	H	82
2k	3-ClC₆H₄	H	97
2l	4-ClC₆H₄	H	86
2m	2-BrC₆H₄	H	70
2n	3-BrC₆H₄	H	83
2o	2-O₂NC₆H₄	H	98
2p		H	86
2q	C₆H₅	5-Cl	99
2r	C₆H₅	5-MeO	92
2s	3-BrC₆H₄	5-Cl	95
2t	3-MeC₆H₄	5-MeO	85

Reaction conditions: 2-aroyl-1,3-diarylenone 1 (0.2 mmol), indole (0.2 mmol), KOH (0.4 mmol), MeCN (2 mL), room temperature, 4 h.

Isolated yield.

The synthesized products can be found applications in the important synthesis. For example, the reaction of product 2a with hydrazine hydrate in ethanol at room temperature could give 1-[(3,5-diphenyl-1H-pyrazol-4-yl)(phenyl)methyl]-1H-indole (3a) in 90% yield (Scheme 2).

Scheme 2.

Synthesis of 1-[(3,5-diphenyl-1H-pyrazol-4-yl)(phenyl)methyl]-1H-indole (3a).

In conclusion, an efficient method for the aza-Michael addition at the N1 position of indoles with 2-aroyl-1,3-diphenylenones has been developed. A series of 2-[(1H-indol-1-yl)(aryl)methyl]-1,3-diarylpropane-1,3-diones has been synthesized in high yields. The protocol tolerates a wide range of substrates, does not require transition-metal catalysts, and utilizes mild conditions. The products are obtained with high chemoselectivity, high yields, and high atom economy. This method provides an alternative for the straightforward preparation of N-heterocycle-functionalized 1,3-diones.

Experiment

¹H NMR and ¹³C NMR spectra were obtained with a Mercury-600BB instrument using CDCl₃ or DMSO-d₆ as solvents and Me₄Si as the internal standard. High-resolution mass spectra (HRMS) (ESI) were obtained with Bruker Daltonics APEX II 47e and Orbitrap Elite mass spectrometers. Melting points were observed in an electrothermal melting point apparatus (X-5, Beijing Tech Instrument Co. Ltd, China). Unless otherwise noted, the solvents and reagents were reagent grade and were used without any further purification. Column chromatographic separations were carried out on a flash chromatographic system using silica gel (200–300 mesh), and petroleum ether (60–90 °C) and ethyl acetate as eluent. For thin layer chromatography (TLC), silica gel plates precoated with GF-254 were used. The 2-aroyl-1,3-diarylenones were prepared according to the literature procedure.⁴⁴

Preparation of 2-[(1H-indol-1-yl)(aryl)methyl]-1,3-diphenylpropan-1,3-diones (2a–t)

A mixture of 2-aroyl-1,3-diarylenone (0.2 mmol), indole (0.2 mmol) and potassium hydroxide (0.4 mmol) in acetonitrile (2 mL) were stirred at room temperature for 4 h. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was extracted with ethyl acetate (3 × 10 mL). The combined organic layer was washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated by column chromatography using petroleum ether and ethyl acetate (5:1, v/v) as eluent to give the pure product.

2-[(1H-Indol-1-yl)(phenyl)methyl]-1,3-diphenylpropane-1,3-dione (2a)

White solid (80 mg, 95%); m.p. 202–205 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.91 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 4.0 Hz, 4H), 7.28 (d, J = 7.4 Hz, 2H), 7.24–7.10 (m, 7H), 6.98 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 11.1 Hz, 1H), 6.62 (d, J = 11.1 Hz, 1H), 6.32 (d, J = 3.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 192.42, 192.23, 138.39, 136.26, 136.08, 135.86, 133.73, 133.44, 128.84, 128.76, 128.61, 128.40, 128.36, 128.26, 128.08, 127.13, 125.23, 121.88, 120.62, 119.64, 110.26, 102.91, 60.48, 60.08; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₄NO₂: 430.1802; found: 430.1803.

2-[(1H-Indol-1-yl)(o-tolyl)methyl]-1,3-diphenylpropane-1,3-dione (2b)

White solid (74 mg, 86%); m.p. 128–131 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.90 (d, J = 7.4 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.52 (dd, J = 7.9, 3.9 Hz, 2H), 7.46 (d, J = 8.7 Hz, 1H), 7.40–7.33 (m, 3H), 7.28 (d, J = 8.0 Hz, 1H), 7.17–7.10 (m, 6H), 7.00 (d, J = 3.3 Hz, 1H), 6.96–6.92 (m, 2H), 6.74 (d, J = 11.0 Hz, 1H), 6.22 (d, J = 3.2 Hz, 1H), 2.23 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 193.96, 192.03, 137.98, 136.52, 136.11, 135.93, 135.64, 133.63, 133.37, 131.63, 128.89, 128.32, 128.17, 128.13, 128.02, 127.99, 125.89, 125.48, 125.28, 121.84, 120.48, 119.46, 110.17, 103.15, 58.88, 56.76, 19.68; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₁H₂₆NO₂: 444.1958; found: 444.1956.

2-[(1H-Indol-1-yl)(m-tolyl)methyl]-1,3-diphenylpropane-1,3-dione (2c)

White solid (66 mg, 76%); m.p. 151–154 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.93 (d, J = 7.1 Hz, 2H), 7.72 (d, J = 7.0 Hz, 2H), 7.54–7.48 (m, 2H), 7.40 (q, J = 8.2 Hz, 4H), 7.25–7.20 (m, 3H), 7.17–7.11 (m, 3H), 7.09 (t, J = 7.5 Hz, 1H), 7.02–6.96 (m, 2H), 6.79 (d, J = 11.1 Hz, 1H), 6.66 (d, J = 11.1 Hz, 1H), 6.34 (d, J = 3.1 Hz, 1H), 2.19 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 192.60, 192.33, 138.52, 138.27, 136.35, 136.12, 135.91, 133.70, 133.45, 128.93, 128.83, 128.60, 128.59, 128.42, 128.36, 128.27, 125.22, 123.93, 121.88, 120.61, 119.63, 110.30, 102.90, 60.39, 60.08, 21.40; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₁H₂₆NO₂: 444.1958; found: 444.1959.

2-[(1H-Indol-1-yl)(p-tolyl)methyl]-1,3-diphenylpropane-1,3-dione (2d)

White solid (78 mg, 90%); m.p. 201–205 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.93 (d, J = 7.5 Hz, 2H), 7.70 (d, J = 7.5 Hz, 2H), 7.53 (t, J = 7.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.42–7.37 (m, 4H), 7.24–7.16 (m, 5H), 7.13 (t, J = 7.7 Hz, 1H), 6.99 (dd, J = 19.9, 7.5 Hz, 3H), 6.79 (d, J = 11.1 Hz, 1H), 6.63 (d, J = 11.1 Hz, 1H), 6.31 (d, J = 3.2 Hz, 1H), 2.21 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 192.68, 192.26, 137.81, 136.33, 136.05, 135.90, 135.44, 133.68, 133.40, 129.45, 128.84, 128.63, 128.37, 128.26, 127.04, 125.31, 121.82, 120.59, 119.58, 110.30, 102.85, 60.52, 59.88, 20.97; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₁H₂₆NO₂: 444.1958; found: 444.1957.

2-[(1H-Indol-1-yl)(2-methoxyphenyl)methyl]-1,3-diphenylpropane-1,3-dione (2e)

White solid (80 mg, 88%); m.p. 103–106 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.90 (d, J = 7.6 Hz, 2H), 7.71 (d, J = 7.1 Hz, 2H), 7.55 (d, J = 8.3 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.42–7.34 (m, 5H), 7.28 (s, 1H), 7.23 (t, J = 7.9 Hz, 2H), 7.15–7.10 (m, 2H), 7.05 (d, J = 11.2 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.85–6.81 (m, 2H), 6.72 (d, J = 8.2 Hz, 1H), 6.29 (dd, J = 3.3, 0.8 Hz, 1H), 3.67 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 193.35, 192.29, 157.06, 136.37, 136.23, 136.20, 133.41, 133.28, 129.40, 128.65, 128.50, 128.44, 128.34, 128.23, 128.03, 126.46, 125.57, 121.59, 120.62, 120.34, 119.28, 111.33, 110.34, 102.40, 59.96, 55.69, 55.35; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₁H₂₆NO₃: 460.1907; found: 460.1905.

2-[(1H-Indol-1-yl)(4-methoxyphenyl)methyl]-1,3-diphenylpropane-1,3-dione (2f)

White solid (82 mg, 90%); m.p. 180–183 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.92 (d, J = 7.1 Hz, 2H), 7.70 (d, J = 7.5 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.44–7.37 (m, 5H), 7.22 (t, J = 8.4 Hz, 4H), 7.16 (d, J = 3.3 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 6.76 (d, J = 11.1 Hz, 1H), 6.71 (d, J = 8.7 Hz, 2H), 6.60 (d, J = 11.1 Hz, 1H), 6.31 (d, J = 3.1 Hz, 1H), 3.68 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 192.53, 192.29, 159.17, 136.34, 136.01, 135.90, 133.70, 133.40, 130.55, 128.85, 128.62, 128.38, 128.33, 128.25, 125.18, 121.82, 120.60, 119.58, 114.13, 110.31, 102.81, 60.75, 59.60, 55.16; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₁H₂₆NO₃: 460.1907; found: 460.1908.

2-[(1H-Indol-1-yl)(4-(trifluoromethyl)phenyl)methyl]-1,3-diphenylpropane-1,3-dione (2g)

White solid (84 mg, 86%); m.p. 184–186 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.92 (d, J = 7.2 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.40 (q, J = 8.6, 7.5 Hz, 7H), 7.24 (s, 2H), 7.16 (d, J = 3.4 Hz, 2H), 7.01 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 11.0 Hz, 1H), 6.62 (d, J = 11.0 Hz, 1H), 6.36 (d, J = 3.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 192.10, 192.09, 142.44, 135.96, 135.66, 134.07, 133.65, 130.40, 130.18, 128.99, 128.62, 128.48, 128.28, 127.56, 125.79 (q, J = 3.9 Hz), 125.09, 124.60, 122.79, 122.18, 120.85, 119.96, 110.02, 103.49, 60.20, 59.67; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₁H₂₃F₃NO₂: 498.1675; found: 498.1675.

2-[(3-Fluorophenyl)(1H-indol-1-yl)methyl]-1,3-diphenylpropane-1,3-dione (2h)

White solid (77 mg, 82%); m.p. 192–195 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.92 (d, J = 7.1 Hz, 2H), 7.70 (d, J = 7.1 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.2 Hz, 5H), 7.25–7.22 (m, 2H), 7.18–7.12 (m, 3H), 7.07 (d, J = 7.4 Hz, 1H), 7.02–6.96 (m, 2H), 6.85 (t, J = 8.4 Hz, 1H), 6.78 (d, J = 11.1 Hz, 1H), 6.58 (d, J = 11.0 Hz, 1H), 6.35 (d, J = 3.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 192.10, 192.02, 162.80 (d, J = 246.0 Hz), 140.97 (d, J = 6.8 Hz), 136.05 (d, J = 6.1 Hz), 135.73, 133.92, 133.55, 130.39, 130.33, 128.93, 128.61, 128.47, 128.42, 128.27, 125.01, 122.86 (d, J = 2.9 Hz), 122.07, 120.75, 119.85, 115.13 (d, J = 21.1 Hz), 114.29 (d, J = 22.4 Hz), 110.11, 103.26, 60.36, 59.58; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₃FNO₂: 448.1707; found: 448.1707.

2-[(4-Fluorophenyl)(1H-indol-1-yl)methyl]-1,3-diphenylpropane-1,3-dione (2i)

White solid (78 mg, 88%); m.p. 183–185 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.93 (d, J = 7.1 Hz, 2H), 7.73 (d, J = 7.7 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.41 (q, J = 8.3, 7.8 Hz, 5H), 7.30–7.26 (m, 2H), 7.25–7.22 (t, J = 7.9 Hz, 2H), 7.19 (d, J = 3.2 Hz, 1H), 7.16–7.13 (m, 1H), 7.01 (t, J = 7.4 Hz, 1H), 6.88 (t, J = 8.6 Hz, 2H), 6.81 (d, J = 11.1 Hz, 1H), 6.62 (d, J = 11.1 Hz, 1H), 6.36 (d, J = 3.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 192.25, 192.20, 162.21 (d, J = 246.1 Hz), 136.15, 136.02, 135.79, 134.37 (d, J = 3.1 Hz), 133.94, 133.58, 128.95, 128.90 (d, J = 8.1 Hz), 128.63, 128.49, 128.45, 128.29, 125.01, 122.03, 120.76, 119.82, 115.73 (d, J = 21.7 Hz), 110.19, 103.17, 60.61, 59.48; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₃FNO₂: 448.1707; found: 448.1709.

2-[(2-Chlorophenyl)(1H-indol-1-yl)methyl]-1,3-diphenylpropane-1,3-dione (2j)

White solid (75 mg, 82%); m.p. 179–182 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.90 (dd, J = 8.4, 1.3 Hz, 2H), 7.67–7.63 (m, 2H), 7.55–7.49 (m, 3H), 7.38 (dd, J = 7.2, 1.3 Hz, 3H), 7.33–7.29 (m, 2H), 7.23–7.10 (m, 7H), 6.95 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 11.0 Hz, 1H), 6.29 (d, J = 3.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 193.08, 191.92, 136.09, 135.92, 135.78, 135.68, 134.97, 133.75, 133.49, 130.74, 129.39, 128.87, 128.45, 128.31, 128.13, 128.07, 127.60, 126.82, 125.25, 121.89, 120.49, 119.59, 110.47, 103.25, 59.54, 56.82; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₃ClNO_2: 464.1412; found: 464.1410.

2-[(3-Chlorophenyl)(1H-indol-1-yl)methyl]-1,3-diphenylpropane-1,3-dione (2k)

White solid (89 mg, 97%); m.p. 207–209 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.92 (d, J = 7.5 Hz, 2H), 7.71 (d, J = 7.3 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 5H), 7.28 (s, 1H), 7.25 (s, 1H), 7.24 (s, 1H), 7.19 (d, J = 6.7 Hz, 1H), 7.17 (d, J = 3.3 Hz, 1H), 7.15–7.10 (m, 3H), 7.03–6.99 (m, 1H), 6.76 (d, J = 11.1 Hz, 1H), 6.58 (d, J = 11.1 Hz, 1H), 6.36 (d, J = 3.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 192.12, 192.05, 140.45, 136.05, 136.03, 135.71, 134.73, 133.95, 133.59, 130.03, 128.94, 128.62, 128.49, 128.40, 128.37, 128.28, 127.43, 125.38, 124.92, 122.12, 120.77, 119.88, 110.09, 103.36, 60.27, 59.56; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₃ClNO₂: 464.1412; found: 464.1413.

2-[(4-Chlorophenyl)(1H-indol-1-yl)methyl]-1,3-diphenylpropane-1,3-dione (2l)

White solid (79 mg, 86%); m.p. 189–192 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.91 (d, J = 7.1 Hz, 2H), 7.69 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.43–7.36 (m, 5H), 7.24–7.20 (m, 4H), 7.16 (d, J = 8.5 Hz, 2H), 7.15–7.11 (m, 2H), 6.99 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 11.1 Hz, 1H), 6.57 (d, J = 11.1 Hz, 1H), 6.33 (d, J = 3.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 192.17, 192.10, 137.01, 136.07, 135.96, 135.72, 133.96, 133.56, 128.96, 128.63, 128.62, 128.50, 128.46, 128.43, 128.26, 125.06, 122.05, 120.76, 119.83, 110.12, 103.24, 60.42, 59.50; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₃ClNO₂: 464.1412; found: 464.1414.

2-[(2-Bromophenyl)(1H-indol-1-yl)methyl]-1,3-diphenylpropane-1,3-dione (2m)

White solid (71 mg, 70%); m.p. 204–206°C; ¹H NMR (600 MHz, CDCl₃): δ 7.89 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 7.7 Hz, 2H), 7.56 (d, J = 8.3 Hz, 1H), 7.51 (q, J = 7.7 Hz, 3H), 7.37 (q, J = 7.8, 7.0 Hz, 3H), 7.30 (d, J = 7.9 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.7 Hz, 2H), 7.14–7.10 (m, 3H), 7.07 (t, J = 7.7 Hz, 1H), 6.95–6.92 (m, 1H), 6.66 (d, J = 10.9 Hz, 1H), 6.29 (d, J = 3.4 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 193.18, 191.94, 137.36, 136.10, 135.91, 135.64, 134.15, 133.72, 133.47, 129.62, 128.87, 128.41, 128.27, 128.06, 127.71, 127.41, 125.52, 125.24, 121.84, 120.45, 119.57, 110.78, 103.35, 59.58, 59.12; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₃BrNO₂: 508.0907; found: 508.0908.

2-[(3-Bromophenyl)(1H-indol-1-yl)methyl]-1,3-diphenylpropane-1,3-dione (2n)

White solid (82 mg, 83%); m.p. 204–206 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.92 (d, J = 7.5 Hz, 2H), 7.71 (d, J = 7.5 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.45–7.39 (m, 6H), 7.28 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.7 Hz, 3H), 7.17–7.13 (m, 2H), 7.05 (t, J = 7.9 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 11.0 Hz, 1H), 6.58 (d, J = 11.1 Hz, 1H), 6.36 (d, J = 3.3 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 192.12, 192.02, 140.67, 136.05, 136.03, 135.72, 133.95, 133.59, 131.30, 130.33, 130.28, 128.94, 128.62, 128.49, 128.40, 128.28, 125.83, 124.87, 122.90, 122.13, 120.77, 119.88, 110.08, 103.38, 60.28, 59.51; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₃BrNO₂: 508.0907; found: 508.0906.

2-[(1H-Indol-1-yl)(3-nitrophenyl)methyl]-1,3-diphenylpropane-1,3-dione (2o)

Pale yellow solid (92 mg, 98%); m.p. 95–97 °C; ¹H NMR (600 MHz, CDCl₃): δ 8.22 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.94 (d, J = 7.5 Hz, 2H), 7.74 (s, 2H), 7.65 (d, J = 7.2 Hz, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.43–7.34 (m, 6H), 7.24 (d, J = 6.7 Hz, 3H), 7.17–7.12 (m, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.73–6.67 (m, 1H), 6.38 (d, J = 3.1 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 192.09, 191.82, 148.30, 140.68, 135.95, 135.79, 135.58, 134.21, 133.81, 133.76, 129.89, 129.04, 128.65, 128.57, 128.51, 128.35, 124.80, 123.16, 122.34, 121.79, 120.96, 120.12, 109.89, 103.90, 60.37, 59.46; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₃N₂O₄: 475.1652; found: 475.1651.

2-[Furan-2-yl(1H-indol-1-yl)methyl]-1,3-diphenylpropane-1,3-dione (2p)

White solid (71 mg, 86%); m.p. 115–119 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.99 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.55 (t, J = 7.9 Hz, 2H), 7.44–7.41 (m, 3H), 7.38 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 3.3 Hz, 1H), 7.24 (dd, J = 1.9, 0.9 Hz, 1H), 7.23–7.18 (m, 3H), 7.02 (t, J = 7.4 Hz, 1H), 6.81 (d, J = 10.8 Hz, 1H), 6.71 (d, J = 10.8 Hz, 1H), 6.33 (d, J = 3.1 Hz, 1H), 6.26 (d, J = 3.3 Hz, 1H), 6.21 (dd, J = 3.4, 1.9 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 192.00, 191.91, 150.92, 142.26, 136.11, 135.82, 135.70, 133.73, 133.48, 128.85, 128.62, 128.41, 128.38, 128.31, 126.09, 121.96, 120.72, 119.72, 110.69, 110.11, 108.77, 103.00, 59.08, 54.19; HRMS (ESI): m/z [M+H]⁺ calcd for C₂₈H₂₂NO₃: 420.1594; found: 420.1595.

2-[(5-Chloro-1H-indol-1-yl)(phenyl)methyl]-1,3-diphenylpropane-1,3-dione (2q)

White solid (92 mg, 99%); m.p. 194–196 °C; ¹H NMR (600 MHz, DMSO-d₆): δ 8.16 (d, J = 3.2 Hz, 1H), 8.11 (d, J = 7.6 Hz, 2H), 8.07 (d, J = 7.7 Hz, 2H), 7.79 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 7.3 Hz, 2H), 7.56–7.51 (m, 2H), 7.44–7.36 (m, 6H), 7.19 (t, J = 7.7 Hz, 2H), 7.13 (dd, J = 8.8, 2.1 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.57 (d, J = 11.1 Hz, 1H), 6.36 (d, J = 3.3 Hz, 1H); ¹³C NMR (150 MHz, DMSO-d₆): δ 192.86, 192.51, 138.54, 135.97, 135.85, 134.85, 134.56, 134.50, 129.35, 129.29, 129.23, 129.18, 128.84, 128.45, 128.23, 127.95, 124.46, 121.82, 119.82, 112.30, 102.40, 60.28, 59.25; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₂ClNO₂: 464.1412; found: 464.1413.

2-[(5-Methoxy-1H-indol-1-yl)(phenyl)methyl]-1,3-diphenylpropane-1,3-dione (2r)

Pale yellow solid (84 mg, 92%); m.p. 216–218 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.89 (d, J = 7.6 Hz, 2H), 7.71 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.3 Hz, 1H), 7.42–7.37 (m, 3H), 7.30–7.26 (m, 3H), 7.23 (d, J = 7.9 Hz, 2H), 7.19 (t, J = 7.5 Hz, 2H), 7.16–7.12 (m, 2H), 6.85 (d, J = 2.5 Hz, 1H), 6.78 (dd, J = 9.0, 2.5 Hz, 1H), 6.72 (d, J = 11.1 Hz, 1H), 6.59 (d, J = 11.1 Hz, 1H), 6.24 (d, J = 3.2 Hz, 1H), 3.76 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 192.40, 192.21, 154.06, 138.41, 136.29, 135.92, 133.69, 133.41, 131.42, 128.82, 128.74, 128.60, 128.40, 128.26, 128.05, 127.07, 125.92, 112.09, 110.97, 102.47, 102.43, 60.59, 60.30, 55.77; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₁H₂₆NO₃: 460.1907; found: 460.1907.

2-[(3-Bromophenyl)(5-chloro-1H-indol-1-yl)methyl]-1,3-diphenylpropane-1,3-dione (2s)

White solid (102 mg, 95%); m.p. 145–147 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.91 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 7.0 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.45–7.38 (m, 4H), 7.37 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.27–7.24 (m, 2H), 7.21 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 3.3 Hz, 1H), 7.10 (d, J = 9.1 Hz, 1H), 7.06 (t, J = 7.9 Hz, 1H), 6.70 (d, J = 11.1 Hz, 1H), 6.56 (d, J = 11.2 Hz, 1H), 6.29 (d, J = 3.2 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃): δ 191.99, 191.93, 140.30, 135.92, 135.58, 134.45, 134.07, 133.79, 131.51, 130.40, 130.26, 129.32, 128.99, 128.60, 128.59, 128.28, 126.26, 125.71, 125.60, 123.02, 122.46, 120.17, 111.10, 103.06, 60.10, 59.66; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₂BrClNO₂: 542.0517; found: 542.0518.

2-[(5-Methoxy-1H-indol-1-yl)(m-tolyl)methyl]-1,3-diphenylpropane-1,3-dione (2t)

Pale yellow solid (80 mg, 85%); m.p. 167–168 °C; ¹H NMR (600 MHz, CDCl₃): δ 7.91 (d, J = 7.6 Hz, 2H), 7.73 (d, J = 7.5 Hz, 2H), 7.54–7.49 (m, 1H), 7.43–7.33 (m, 4H), 7.23 (d, J = 7.8 Hz, 2H), 7.17 (d, J = 3.3 Hz, 1H), 7.13–7.06 (m, 3H), 6.96 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.9, 2.5 Hz, 1H), 6.71 (d, J = 11.1 Hz, 1H), 6.62 (d, J = 11.1 Hz, 1H), 6.25 (d, J = 3.1 Hz, 1H), 3.77 (s, 3H), 2.19 (s, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 192.57, 192.31, 154.05, 138.50, 138.27, 136.35, 135.95, 133.68, 133.44, 131.46, 128.91, 128.81, 128.78, 128.58, 128.43, 128.28, 128.19, 125.88, 123.86, 112.08, 111.00, 102.45, 102.41, 60.45, 60.30, 55.79, 21.39; HRMS (ESI): m/z [M+H]⁺ calcd for C₃₂H₂₈NO₃: 474.2064; found: 474.2065.

Preparation of 1-[(3,5-diphenyl-1H-pyrazol-4-yl)(phenyl)methyl]-1H-indole (3a)

2-[(1H-Indol-1-yl)(phenyl)methyl]-1,3-diphenylpropane-1,3-dione (2a) (0.1 mmol) was dissolved in 2 mL of ethanol and then hydrazine hydrate (0.4 mmol) was added. The mixture was stirred at 50 °C for 7 h. The reaction progress was monitored by TLC. After the completion of the reaction, the resulting mixture was extracted with ethyl acetate (3 × 10 mL), and the extract was washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated by column chromatography using petroleum ether and ethyl acetate (2:1 v/v) as eluent to give the pure product. The analytical data are given below.

Light yellow solid (38 mg, 90%); m.p. 244–246 °C; ¹H NMR (600 MHz, DMSO-d₆): δ 13.35 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.23 (s, 2H), 7.18–7.11 (m, 6H), 7.06 (d, J = 3.3 Hz, 1H), 7.05–6.95 (m, 7H), 6.90 (d, J = 10.9 Hz, 2H), 6.67 (d, J = 7.5 Hz, 2H), 6.43–6.40 (m, 1H); ¹³C NMR (150 MHz, DMSO-d₆): δ 140.22, 135.84, 129.08 (4C), 128.94, 128.66 (5C), 128.47, 128.37, 127.41, 127.39, 127.23, 121.82, 121.14, 119.95, 114.01, 110.56, 101.52, 55.58. HRMS (ESI): m/z [M+H]⁺ calcd for C₃₀H₂₄N₃ 426.1965; found: 426.1968.

Supplemental Material

Supporting_Information-revised – Supplemental material for Chemoselective aza-Michael addition of indoles to 2-aroyl-1,3-diarylenones

Supplemental material, Supporting_Information-revised for Chemoselective aza-Michael addition of indoles to 2-aroyl-1,3-diarylenones by Zheng Li, Aizhen Yang, Xiaolong Ma and Zhenrong Liu in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors thank the National Natural Science Foundation of China (21462038) for the financial support of this work.

ORCID iD

Zheng Li

Supplemental material

Supporting information for ¹H NMR and ¹³C NMR spectra of products 2a–t and 3a is available.

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