Pd-catalyzed direct C2-acylation and C2,C7-diacylation of indoles: pyrimidine as an easily removable C–H directing group

Abstract

Pyrimidine is successfully used as an easily removable C(sp²)–H directing group for the synthesis of 2-acyl indoles and 2,7-diacyl indoles through direct C–H functionalization using a Pd-catalyst from 1-(pyrimidin-2-yl)-1H-indoles and aldehydes. Easy removal of the pyrimidine directing group using EtONa in DMSO provides C2-acyl indoles.

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Introduction

Transformation of unactivated C(sp²)–H bonds to C(sp²)–C and C(sp²)-hetero atom bonds is one the most important chemical transformations in synthetic chemistry.¹ Transition metal catalysts such as Rh, Ru, Pd, Cu, Fe, etc. play vital roles in C–H bond functionalization reactions. Particularly, Pd compounds occupy a central role as a catalyst for C–H bond functionalization reactions.² The nature of the directing groups play a crucial role in the activation of unactivated C–H bonds.³ Easily removable directing groups add more advantages to C–H bond functionalization reactions.⁴ Herein, we report, direct C2-acylation and C2,C7-diacylation of N-pyrimidine substituted indoles to synthesize C2-acyl and C2,C7-diacyl indoles using a Pd-catalyst and aldehyde as an acyl source (Scheme 1).

Scheme 1 Pd-catalyzed direct C2-acylation and C2,C7-diacylation of indoles using removable pyrimidine directing group.

The direct C–H bond functionalization of indole was started with 1-(pyrimidin-2-yl)-1H-indole 1a. The initial reaction was carried out with 10 mol% of Pd(OAc)₂ in chlorobenzene at 90 °C using benzaldehyde 2a as acyl source in the presence of tert-butyl hydrogen peroxide (TBHP) oxidant.⁵ The pyrimidine group directed the acyl group to the less reactive C2 position of indole ring yielding 43% of expected selective C2-acylated product 3a (Table 1, entry 1). In this reaction, neither C3-acylation nor C7-acylation product was observed. To increase the efficiency of this pyrimidine directed C2-acylation reaction, several Pd-salts were screened and among them PdCl₂ provided a maximum of 70% isolated yield of 3a (entry 2).

Table 1 Optimization for Pd-catalyzed C2-acylation of indole using pyrimidine directing group^a

Entry	Pd salt	Oxidant	Solvent	Time (h)	Yield^b (%)
a Reaction condition: 1a (0.5 mmol), 2a (0.75 mmol), and 70% of aq. TBHP. b Isolated yield. c TBHP (5.0 equiv.).
1	Pd(OAc)2	TBHP	PhCl	24	43
2	PdCl2	TBHP	PhCl	12	70
3	Pd(CH3CN)2Cl2	TBHP	PhCl	24	47
4	Pd(PPh3)2Cl2	TBHP	PhCl	24	20
5	Pd(TFA)2	TBHP	PhCl	24	55
6	Pd2(dba)3	TBHP	PhCl	24	51
7	PdCl2	DTBP	PhCl	36	40
8	PdCl2	TBPB	PhCl	36	22
9	PdCl2	H2O2	PhCl	36	20
10	PdCl2	O2	PhCl	36	14
11	PdCl2	K2S2O8	PhCl	36	17
12	PdCl2	TBHP	THF	26	21
13	PdCl2	TBHP	DMF	36	<5
14	PdCl2	TBHP	Benzene	15	62
15	PdCl2	TBHP	Toluene	12	80
16	PdCl2	TBHP	Dioxane	24	44
17	PdCl2	TBHP	DCE	24	60
18	PdCl2	TBHP	Hexanes	24	26
19	PdCl2	TBHP	Toluene	12	67^c
20	—	TBHP	Toluene	25	00
21	PdCl2	—	Toluene	26	00

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Then the reaction was screened with several oxidants such as di-tert-butyl peroxide, tert-butyl peroxybenzoate (TBPB), H₂O₂ etc. and all of them gave inferior result compared with TBHP (entries 6–11). Solvent screening (entries 12–18) was fruitful and toluene provided a maximum of 80% isolated yield of 3a (entry 15). Increasing the quantity of TBHP reduced the efficiency of the C–H activation reaction. And the reaction without Pd-catalyst or oxidant TBHP failed to yield any 2-acylation product (entries 20 and 21).

After successful optimizing the reaction conditions for the synthesis of C2-acylated indole, the substrate scope of this synthetic methodology was examined and the results are summarized in Table 2. Both electron-releasing (3c) and electron-withdrawing group (3d and 3e) containing aromatic aldehydes yielded the corresponding 2-acylated products in moderate to good yields. Sterically hindered 1-naphthyl aldehyde also gave C2-acylated product in 79% yield (3b). Heteroaromatic aldehydes such as furan-2-carbaldehyde and thiophene-2-carbaldehyde also provided the corresponding C–H activation product in good yields (3f and 3i). Electron-releasing and electron-withdrawing groups at 5^th position of indole also yielded the C2-acylated product in moderate yield range (3g and 3h). Sterically hindered ortho-substituted aldehyde, aliphatic aldehyde, cyclic and α–β unsaturated aldehydes were yielded the expected acylated product in good yield (3k, 3l, 3m and 3n). When a mixture of benzaldehyde and acetaldehyde were used for acylation, only C2-benzoylated indole was selectively obtained. In this reaction condition, acylation took place neither at C2 position nor at C7 position of indole ring.

Table 2 Pd-catalyzed direct C2-acylation of indoles using removable pyrimidine directing group^a

a Reaction condition: 1a (0.5 mmol), 2a (0.75 mmol), and 70% of aq. TBHP in toluene (2 mL). All of them are isolated yield.

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Usage of excess (3 equiv.) aldehyde under same reaction conditions yielded symmetric C2,C7-diacylated product 4 through functionalization of C2 and C7 C–H bonds with good yields. Acylation of two different aldehydes (1.5 equiv. each) one after another aldehyde yielded unsymmetric diacylated products 5. These results clearly shows that in indole molecule, pyrimidine group functionalize both C2 and C7 C–H bonds whereas C2 C–H bond functionalization is more facile than C7 C–H bond of indole moiety (Scheme 2).

Scheme 2 Double C–H functionalization using pyrimidine directing group.

When pyrrole and carbazole were used instead of indole molecule, both of them gave mixture of mono and diacylated products as both the C2 and C5 C–H bonds of pyrrole and C2 and C8 C–H bonds of carbazole are identical for C–H functionalization. Using excess of benzaldehyde with N-pyrimidine protected carbazole, the reaction gave C2 and C8-dibenzoylated carbazole (7) with 65% isolated yield (Scheme 3).

Scheme 3 C–H functionalization of carbazole using pyrimidine directing group.

The pyrimidine group in acylated indole molecule could be easily removed as shown in Scheme 4.⁶ Reaction of 3a–c with EtONa in DMSO yielded 2-acylated indole 8a–c. In this C–H acylation, the palladium catalyst will coordinate with pyrimidine nitrogen before activating nearby C–H bond. In the presence of Pd catalyst and TBHP, acyl radical will be generated from aldehyde⁷ which will be attached to Pd catalyst. Reductive elimination of palladium complex should yield C2-acylated indole. In the presence of excess aldehyde, the mono acylated indole will be acylated at C7 position. This result shows that functionalization at C2 position is easier than functionalization of indole at C7 which is slightly far from indole nitrogen atom.

Scheme 4 Synthesis of 2-acyl indole by removal of pyrimidine directing group.

Conclusions

In conclusion, we have demonstrated an efficient methodology using Pd-catalyst for the synthesis of C2-acylated indole using pyrimidine as directing group. Usage of excess aldehyde provides C2,C7-diacylated indole through double C–H functionalization reaction. Easily removal of pyrimidine directing group using EtONa in DMSO yields C2-acyl indoles.

Typical experimental procedure

General considerations. All the reactions were carried out in reaction tubes. All the solvents were obtained from Merck or RANKEM chemicals. Reactions were monitored by Thin-layer Chromatography (TLC) using Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching using appropriate mixture of ethyl acetate and hexanes. PdCl₂, TBHP were purchased from Sigma Aldrich chemicals. Benzaldehyde was distilled before use. Other aldehydes were used as received. All the 2-pyrimidine indoles were prepared according to the literature procedure.⁸ Silica gel (particle size 100–200 mesh) was purchased from SRL India and used for column chromatography using hexanes and ethyl acetate mixtures as eluent. ¹H and ¹³C NMR spectra were recorded on a Bruker 400 MHz instrument. ¹H NMR spectra were reported relative to residual CHCl₃ (δ 7.26 ppm) or DMSO-d₆ (δ 2.50 ppm). ¹³C NMR were reported relative to CDCl₃ (δ 77.16 ppm) or DMSO-d₆ (δ 39.52 ppm). FT-IR spectra were recorded on a JASCO spectrometer and are reported in frequency of absorption (cm⁻¹). High resolution mass spectra (HRMS) were recorded on Q-Tof Micro mass spectrometer.

Typical experimental procedure for C2-acylation. Indole (0.5 mmol, 97.6 mg), PdCl₂ (0.05 mmol, 8.9 mg), benzaldehyde (0.75 mmol, 76 µL), TBHP (1.5 mmol, 193 µL, 70% aq.) and toluene (2 mL) were taken in a reaction tube. The reaction mixture was heated at 90 °C. The progress of the reaction was monitored by TLC. Upon disappearance of indole, the reaction mixture was brought to room temperature. The reaction mixture was dissolved in ethyl acetate (30 mL), and washed with saturated solution of sodium bicarbonate (2 × 10 mL). The combined organic layers were dried with Na₂SO₄. The organic solvent was evaporated under reduced pressure and the resulting crude product was purified by silica gel column chromatography (hexanes–ethyl acetate) to give the desired acylation product. The product was confirmed by ¹H and ¹³C NMR, FT-IR and HRMS spectroscopic analysis.

Typical experimental procedure for C2,C7-acylation. Indole (0.5 mmol, 97.6 mg), PdCl₂ (0.05 mmol, 8.9 mg), benzaldehyde (3 equiv.), TBHP (2.5 mmol, 321 µL, 70% equiv.) and toluene (2 mL) were taken in a reaction tube. The reaction mixture was heated at 90 °C. The progress of the reaction was monitored by TLC. Upon disappearance of indole, the reaction mixture was brought to room temperature. The reaction mixture was dissolved in ethyl acetate (30 mL), and washed with saturated solution of sodium bicarbonate (2 × 10 mL). The combined organic layers were dried with Na₂SO₄. The organic solvent was evaporated under reduced pressure and the resulting crude product was purified by silica gel column chromatography (hexanes–ethyl acetate) to give the desired acylation product. The product was confirmed by ¹H and ¹³C NMR, FT-IR and HRMS spectroscopic analysis.

Typical experimental procedure for unsymmetrical acylation. Monosubstituted indole 3a (0.33 mmol, 100 mg), PdCl₂ (0.033 mmol, 5.9 mg), aldehyde (Ar″-CHO) (1.5 equiv.), TBHP (0.99 mmol, 127 µL, 70% aq.) and toluene (2 mL) were taken in a reaction tube. The reaction mixture was heated at 90 °C. The progress of the reaction was monitored by TLC. Upon disappearance of indole 3a, the reaction mixture was brought to room temperature. The reaction mixture was dissolved in ethyl acetate (30 mL), and washed with saturated solution of sodium bicarbonate (2 × 10 mL). The combined organic layers were dried with Na₂SO₄. The organic solvent was evaporated under reduced pressure and the resulting crude product was purified by silica gel column chromatography (hexanes–ethyl acetate) to give the desired acylation product. The product was confirmed by ¹H and ¹³C NMR, FT-IR and HRMS spectroscopic analysis.

Typical experimental procedure for removal of pyrimidine directing group. Under N₂ atmosphere, monoacylated indole (0.41 mmol 124 mg) and sodium ethoxide (3.0 equiv.) were dissolved in DMSO (5 mL) at room temperature. Then the reaction mixture was heated upto 100 °C for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were dried with Na₂SO₄. The organic solvent was evaporated under reduced pressure and the resulting crude product was purified by silica gel column chromatography (hexanes–ethyl acetate) to give the desired acylation product. The product was confirmed by ¹H and ¹³C NMR, FT-IR and HRMS spectroscopic analysis.
Phenyl(1-(pyrimidin-2-yl)-1H-indol-2-yl)methanone 3a. Yield 80%; colorless solid; mp = 121–123 °C [122–124 °C];^9a R_f = 0.23 (hexanes : ethyl acetate 8 : 2); IR (KBr) 3408, 2327, 1655, 1570, 1523, 1426, 1277, 748, 717 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.08 (m, 1H), 7.15 (s, 1H), 7.28–7.36 (m, 1H) 7.46 (m, 3H), 7.53–7.63 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 7.6 Hz, 2H), 8.43 (d, J = 8.4, 1H), 8.65 (d, J = 4.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 114.4, 115.5, 117.4, 122.6, 122.9, 126.6, 128.1, 128.4, 129.6, 132.8, 137.3, 138.1, 138.4, 157.4, 158.0, 187.7; HRMS (ESI) calcd for C₁₉H₁₃N₃O [M + H]⁺ 300.1137; found 300.1136.
Naphthalen-1-yl(1-(pyrimidin-2-yl)-1H-indol-2-yl)methanone 3b. Yield 79%; colorless solid; mp = 136–138 °C [136–138 °C];^9a R_f = 0.25 (hexanes : ethyl acetate 8 : 2); IR (KBr) 3048, 1653, 1573, 1449, 813, 777, 751 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.95 (t, J = 4.8 Hz, 1H), 7.16 (s, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 8.4 Hz, 1H), 7.51–7.56 (m, 1H), 7.57–7.64 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 8.4 Hz), 8.53 (d, J = 4.8 Hz, 2H), 8.72 (d, J = 8.4 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 114.4, 116.3, 117.4, 122.8, 123.0, 124.3, 126.2, 126.5, 126.8, 127.7, 128.1, 128.3, 129.1, 131.2, 132.4, 133.8, 136.2, 138.6, 139.1, 157.5, 158.0, 189.0; HRMS (ESI) calcd for C₂₃H₁₅N₃O [M + H]⁺ 350.1288; found 350.1281.
(1-(Pyrimidin-2-yl)-1H-indol-2-yl)(p-tolyl)methanone 3c. Yield 64%; colorless solid; mp = 128–130 °C [121–123 °C];^9a R_f = 0.3 (hexanes : ethyl acetate 8 : 2); IR (KBr) 2924, 2856, 1643, 1570, 1434, 1282, 958, 826, 751 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 2.41 (s, 3H), 7.04 (t, J = 5.2 Hz, 1H),7.09 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.40–7.46 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 8.40 (d, J = 8.4 Hz, 1H), 8.62 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.8, 114.4, 115.0, 117.4, 122.5, 122.9, 126.4, 128.2, 129.2, 129.9, 135.6, 137.6, 138.4, 143.6, 157.5, 158.1, 187.5; HRMS (ESI) calcd for C₂₀H₁₅N₃O [M + H]⁺ 314.1281; found 314.1288.
4-(1-(Pyrimidin-2-yl)-1H-indole-2-carbonyl)benzonitrile 3d. Yield 68%; white solid; mp = 150–153 °C; R_f = 0.26 (hexanes : ethyl acetate 7 : 3); IR (KBr) 3122, 2226, 1646, 1564, 1434, 1208, 7601 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.07 (t, J = 4.4 Hz, 1H), 7.20 (s, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.44–7.52 (m, 1H), 7.68–7.76 (m, 3H), 8.01 (d, J = 8.4 Hz, 2H), 8.45 (d, J = 8.4 Hz, 1H), 8.61 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 114.7, 115.8, 116.1, 117.6, 118.2, 122.8, 123.3, 127.2, 128.1, 129.7, 132.3, 136.4, 138.5, 141.7, 157.2, 158.1, 186.0; HRMS (ESI) calcd for C₂₀H₁₂N₄O [M + H]⁺ 325.1089; found 325.1100.
Methyl-4-(1-(pyrimidin-2-yl)-1H-indole-2-carbonyl)benzoate 3e. Yield 55%; colorless solid; mp = 134–136 °C; R_f = 0.22 (hexanes : ethyl acetate 8 : 2); IR (KBr) 2938, 1723, 1653, 1569, 1438, 1287, 729 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 3.94 (s, 3H), 7.04 (t, J = 4.8 Hz, 1H), 7.16 (s, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 8.43 (d, J = 8.4 Hz, 1H), 8.60 (d, J = 4.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 52.6, 114.6, 115.8, 117.5, 122.7, 123.1, 126.9, 128.1, 129.3, 129.7, 133.5, 136.9, 138.4, 141.7, 157.2, 158.1, 166.5, 187.0; HRMS (ESI) calcd for C₂₁H₁₆N₃O₃ [M + H]⁺ 358.1192; found 358.1184.
Furan-2-yl(1-(pyrimidin-2-yl)-1H-indol-2-yl)methanone 3f. Yield 58%; light yellow solid; mp = 120–122 °C [122–124 °C];^9a R_f = 0.26 (hexanes : ethyl acetate 7 : 3); IR (KBr) 2926, 1640, 1568, 1468, 1292, 827, 793, 750 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.47 (d, J = 1.6 Hz, 1H), δ 7.03 (t, J = 4.8 Hz, 1H), δ 7.16–7.25 (m, 2H), δ 7.29 (s, 1H), δ 7.36 (t, J = 7.6 Hz, 1H), δ 7.55 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), δ 8.27 (d, J = 8.4 Hz, 1H), δ 8.61 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 112.4, 114.2, 115.4, 117.6, 119.5, 122.7, 122.9, 126.8, 128.0, 136.2, 138.7, 147.0, 152.7, 157.5, 158.2, 174.4; HRMS (ESI) calcd for C₁₇H₁₂N₃O₂ [M + H]⁺ 290.0930; found 290.0933.
(5-Methoxy-1-(pyrimidin-2-yl)-1H-indol-2-yl)(phenyl)methanone 3g. Yield 70%; colorless solid; mp = 129–131 °C [134–135 °C];^9a R_f = 0.20 (hexanes–ethyl acetate 8 : 2); IR (KBr) 2987, 2361, 1657, 1607, 1440, 1234, 804, 706 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 3.88 (s, 3H), 7.02 (t, J = 4.8 Hz, 1H), 7.05 (d, J = 0.4 Hz, 1H), 7.08 (dd, J = 9.2, 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.39–7.46 (m, 1H), 7.50–7.56 (m, 1H), 7.92–7.98 (m, 2H), 8.34 (d, J = 9.2 Hz, 1H), 8.59 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 55.8, 103.6, 115.1, 115.5, 116.6, 117.3, 128.4, 128.8, 129.6, 132.8, 133.3, 137.7, 138.2, 156.1, 157.3, 158.0, 187.8; HRMS (ESI) calcd for C₂₀H₁₆N₃O₂ [M + H]⁺ 330.1243; found 330.1230.
(5-Bromo-1-(pyrimidin-2-yl)-1H-indol-2-yl)(phenyl)methanone 3h. Yield 61%; light yellow solid; mp = 116–118 °C [120–122 °C];^9a R_f = 0.25 (hexanes : ethyl acetate); IR (KBr) 2922, 1667, 1572, 1443, 800, 713 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.02 (s, 1H), 7.04 (t, J = 8.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.50 (dd, J = 9.2, 2.0 Hz, 1H), 7.52–757 (m, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.91–7.98 (m, 2H), 8.32 (d, J = 9.2 Hz, 1H), 8.59 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 113.7, 116.0, 116.1, 117.7, 124.8, 128.5, 129.2, 129.5, 129.8, 133.0, 136.7, 137.7, 138.1, 156.9, 158.1, 187.5; HRMS (ESI) calcd for C₁₉H₁₃N₃OBr [M + H]⁺ 378.0242; found 378.0229.
(1-(Pyrimidin-2-yl)-1H-indol-2-yl)(thiophen-2-yl)methanone 3i. Yield 54%; colorless solid; mp = 144–146 °C [136–138 °C];^9a R_f = 0.20 (hexanes : ethyl acetate 8 : 2); IR (KBr) 3071, 1624, 1570, 1521, 1425, 742 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.00–7.04 (m, 1H), 7.05–7.09 (m, 1H), 7.17–7.25 (m, 2H), 7.33–7.39 (m, 1H), 7.60–7.66 (m, 2H), 7.75 (dd, J = 4, 1.2 Hz, 1H), 8.29 (dd, J = 8.4, 0.4 Hz, 1H), 8.61 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 113.7, 116.2, 116.3, 117.8, 124.9, 128.9, 129.4, 129.8, 130.9, 136.2, 136.7, 137.7, 139.5, 157.0, 158.2, 186.4; HRMS (ESI) calcd for C₁₇H₁₂N₃O [M + H]⁺ 306.0701; found 306.0711.
(4-Chlorophenyl)(1-(pyrimidin-2-yl)-1H-indol-2-yl)methanone 3j. Yield 54%; colorless solid; mp = 144–146 °C [136–138 °C];^9a R_f = 0.20 (hexanes : ethyl acetate 8 : 2); IR (KBr) 3072, 1623, 1569, 1520, 1426, 741 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.00–7.04 (m, 1H), 7.05–7.08 (m, 1H), 7.17–7.24 (m, 2H), 7.34–7.39 (m, 1H), 7.60–7.65 (m, 2H), 7.75 (dd, J = 4, 1.2 Hz, 1H), 8.29 (dd, J = 8.4, 0.4 Hz, 1H), 8.61 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 113.7, 116.2, 116.3, 117.8, 124.9, 128.9, 129.4, 129.8, 130.9, 136.2, 136.7, 137.7, 139.5, 157.0, 158.2, 186.4; HRMS (ESI) calcd for C₁₇H₁₂N₃O [M + H]⁺ 306.0701; found 306.0711.
(1-(Pyrimidin-2-yl)-1H-indol-2-yl)(o-tolyl)methanone 3k. Yield 60%; colorless solid; mp = 124–126 °C; R_f = 0.20 (hexanes : ethyl acetate 8 : 2); IR (KBr) 3050, 1653, 1540, 1520, 1450, 756 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 2.59 (s, 3H), 7.11 (s, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.24–7.33 (m, 2H), 7.37 (td, J = 6, 1.2 Hz, 1H), 7.43–7.49 (m, 1H), 7.56–7.61 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.69 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 20.5, 114.1, 116.3, 117.7, 122.8, 122.9, 125.2, 126.9, 128.0, 130.1, 131.2, 131.3, 138.3, 138.8, 138.9, 157.6, 158.1, 189.4; HRMS (ESI) calcd for C₂₀H₁₅N₃O [M + H]⁺ 314.1284; found 314.1288.
1-(1-(Pyrimidin-2-yl)-1H-indol-2-yl)hexan-1-one 3l. Yield 61%; liquid; R_f = 0.34 (hexanes : ethyl acetate 8 : 2); IR (KBr) 3069, 1640, 1558, 1510, 1458, 860, 790, 756 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 0.82 (t, J = 7.2 Hz, 3H), 1.23–1.36 (m, 4H), 1.63–1.74 (m, 2H), 2.84 (t, J = 7.2 Hz, 2H), 7.12 (t, J = 4.8 Hz, 1H), 7.14–7.19 (m, 1H), 7.21 (s, 1H), 7.27–7.33 (m, 1H), 7.59–7.62 (m, 1H), 7.89–7.92 (m, 1H), 8.68 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 14.1, 22.6, 24.5, 31.6, 40.6, 113.3, 113.5, 118.3, 122.7, 122.8, 126.8, 127.6, 138.1, 139.3, 158.0, 158.1, 158.4, 194.1; HRMS (ESI) calcd for C₁₈H₁₉N₃O [M + H]⁺ 294.1597; found 294.1601.
Cyclohex-3-en-1-yl(1-(pyrimidin-2-yl)-1H-indol-2-yl)methanone 3m. Yield 51%; colourless solid; mp = 122–124 °C R_f = 0.23 (hexanes : ethyl acetate 8 : 2); IR (KBr) 3040, 1655, 1556, 1515, 1470, 1100, 840, 800, 745 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.73–1.87 (m, 1H), 2.08–2.23 (m, 3H), 2.27–2.37 (m, 1H), 2.40–2.52 (m, 1H), 3.26–3.35 (m, 1H), 5.80 (s, 2H), 7.21 (t, J = 4.8 Hz, 1H), 7.28 (t, J = 7.6 Hz, 2H), 7.42 (td, J = 7.2, 1.2 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.80 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 25.0, 25.9, 28.0, 44.8, 113.0, 113.8, 118.1, 122.7, 122.8, 125.9, 126.7, 126.7, 127.9, 137.7, 139.1, 158.0, 158.3, 197.3; HRMS (ESI) calcd for C₁₉H₁₇N₃O [M + H]⁺ 304.1450; found 304.1446.
(E)-1-(1-(Pyrimidin-2-yl)-1H-indol-2-yl)but-2-en-1-one 3n. Yield 45%; light yellow solid; mp = 123–125 °C; R_f = 0.30 (hexanes : ethyl acetate 6 : 4); IR (KBr) 3100, 3020, 1665, 1585, 1520, 1426, 1010, 860, 756 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 2.00 (d, J = 6.8 Hz, 3H), 6.71 (d, J = 15.6 Hz, 1H), 6.97–7.09 (m, 1H), 7.21 (t, J = 4.8 Hz, 1H), 7.28 (t, J = 8.0 Hz, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.79 (d, J = 4.8 Hz, 2H); ¹³C NMR 18.6, 113.6, 114.3, 118.1, 122.7, 126.7, 127.8, 130.3, 138.0, 139.2, 144.4, 157.9, 158.3, 184.1; HRMS (ESI) calcd for C₁₆H₁₃N₃O [M + H]⁺ 264.1137; found 264.1129.
(1-(Pyrimidin-2-yl)-1H-indole-2,7-diyl)bis(phenylmethanone) 4a. Yield 72%; light yellow solid; mp = 160–161 °C; R_f = 0.25 (hexanes : ethyl acetate 7 : 3); IR (KBr) 3042, 1645, 1562, 1443, 863, 717 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.96 (t, J = 4.8 Hz, 1H), 7.19 (s, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.37–7.40 (m, 2H), 7.41–7.44 (m, 2H), 7.45–7.48 (m, 2H), 7.49–7.53 (m, 1H), 7.54–7.59 (m, 1H), 7.78–7.82 (m, 2H), 7.86 (dd, J = 8.0, 1.2 Hz, 2H), 7.98 (dd, J = 8.0, 1.2 Hz, 2H), 8.34 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 114.8, 118.9, 121.4, 125.6, 125.9, 127.8, 128.3, 128.5, 128.8, 129.9, 130.1, 132.8, 133.0, 135.2, 137.3, 137.7, 137.7, 157.6, 157.9, 187.1, 195.4; HRMS (ESI) calcd for C₂₆H₁₈N₃O₂ [M + H]⁺ 404.1399; found 404.1392.
(1-(Pyrimidin-2-yl)-1H-indole-2,7-diyl)bis(p-tolylmethanone) 4b. Yield 52%; white solid mp = 179–180 °C R_f = 0.26 (hexanes : ethyl acetate 7 : 3); IR (KBr) 3036, 1650, 1602, 1427, 1276, 1214, 749, 700 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 2.34 (s, 3H), 2.36 (s, 3H), 2.36 (s, 3H), 6.91 (t, J = 4.8 Hz, 1H), 7.09 (s, 1H), 7.13 (d, J = 8.0 Hz, 2H), 7.17–7.22 (m, 3H), 7.31 (dd, J = 7.2, 1.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.77 (dd, J = 8.0, 1.2 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 8.29 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.8, 114.5, 118.9, 121.3, 125.4, 126.1, 127.6, 128.8, 129.1, 129.2, 130.2, 130.4, 135.1, 135.2, 137.4, 143.7, 143.9, 157.7, 157.9, 186.9, 195.3; HRMS (ESI) calcd for C₂₈H₂₂N₃O₂ [M + H]⁺ 432.1712; found 432.1709.
(1-(Pyrimidin-2-yl)-1H-indole-2,7-diyl)bis(cyclohexylmethanone) 4c. Yield 50%; white solid; mp = 163–165 °C R_f = 0.26 (hexanes–ethyl acetate 7 : 3); IR (KBr) 3058, 1656, 1573, 1428, 1350, 1214, 1150, 835, 720 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 1.3–1.24 (m, 3H), 1.25–1.45 (m, 4H), 1.47–1.60 (m, 4H), 1.69–1.90 (m, 5H), 1.96–2.12 (m, 5H), 2.68 (tt, J = 11.6, 3.6 Hz, 1H), 3.08 (tt, J = 11.2, 3.6 Hz, 1H), 7.19 (t, J = 4.8 Hz, 1H), 7.36–7.47 (m, 2H), 7.85–7.92 (m, 1H), 8.69 (d, J = 8.4, Hz) 8.74 (d, J = 4.8, Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 26.0, 26.1, 26.2, 29.0, 29.1, 50.3, 51.6, 116.0, 118.0, 121.0, 121.3, 124.2, 125.5, 126.7, 135.9, 140.6, 156.9, 158.1, 201.9, 202.2; HRMS (ESI) calcd for C₁₈H₁₉N₃O [M + H]⁺ 294.1597; found 294.160.
4-(2-Benzoyl-1-(pyrimidin-2-yl)-1H-indole-7-carbonyl)benzonitrile 5a. Yield 64%; white solid; mp = 190–191 °C R_f = 0.26 (hexanes–ethyl acetate 7 : 3); IR (KBr) 2924, 2231, 1656, 1573, 1428, 1255, 1214, 718 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.00 (t, J = 4.8 Hz, 1H), 7.21 (s, 1H), 7.29–7.37 (m, 2H), 7.45–7.51 (m, 2H), 7.60 (tt, J = 7.6, 1.2 Hz, 1H), 7.70–7.76 (m, 2H), 7.89–7.95 (m, 3H), 7.96–8.01 (m, 2H), 8.35 (t, J = 4.8 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 114.8, 116.1, 118.2, 119.0, 121.7, 125.0, 126.3, 127.5, 128.6, 129.2, 129.9, 130.3, 132.3, 134.8, 137.6, 137.8, 141.1, 157.3, 157.8, 187.2, 193.6; HRMS (ESI) calcd for C₂₇H₁₇N₄O₂ [M + H]⁺ 429.1352; found 429.1355.
(2-Benzoyl-1-(pyrimidin-2-yl)-1H-indol-7-yl)(p-tolyl)methanone 5b. Yield 68%; light yellow solid; mp = 179–180 °C R_f = 0.26 (hexanes : ethyl acetate 7 : 3); IR (KBr) 2925, 1649, 1570, 1422, 1262, 747, 716 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 2.34 (s, 3H), 6.92 (t, J = 4.8 Hz, 1H), 7.12 (s, 1H), 7.14 (d, J = 8.0 Hz, 2H), 7.17–7.23 (m, 1H), 7.32 (dd, J = 7.2, 1.2 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 6.8 Hz, 2H), 8.30 (d, J = 4.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 21.8, 114.9, 119.0, 121.4, 125.5, 126.1, 127.8, 128.4, 128.5, 128.8, 129.1, 130.0, 130.2, 130.4, 133.1, 135.1, 135.3, 137.2, 137.8, 143.7, 157.7, 158.0, 187.1, 195.2; HRMS (ESI) calcd for C₂₇H₂₀N₃O₂ [M + H]⁺ 418.1556; found 418.1572.
(9-(Pyrimidin-2-yl)-9H-carbazole-1,8-diyl)bis(phenylmethanone) 7. Yield 62%; light yellow solid; mp = 160–162 °C; R_f = 0.28 (hexanes : ethyl acetate 7 : 3); IR (KBr) 3090, 1670, 1530, 1510, 1434, 1208, 854, 800, 760 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.72 (t, J = 5.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 4H), 7.42–7.49 (m, 4H), 7.50–7.52 (m, 2H), 7.83 (d, J = 7.2 Hz, 4H), 7.96 (d, J = 4.8 Hz, 2H), 8.27 (d, J = 7.6 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 118.0, 122.1, 122.2, 126.7, 127.6, 128.0, 128.3, 129.9, 134.5, 136.9, 137.9, 156.6, 156.8, 194.7; HRMS (ESI) calcd for C₃₀H₁₉N₃O₂ [M + H]⁺ 454.1556; found 454.1551.
(1H-Indol-2-yl)(phenyl)methanone 8a. Yield 75%; white solid; mp = 145–146 °C [149–150 °C];^9b R_f = 0.26 (hexanes : ethyl acetate 9 : 1); IR (KBr) 3354, 1620, 1517, 1260, 1125, 736, 680 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 7.14–7.21 (m, 2H), 7.35–7.42 (m, 1H), 7.47–7.59 (m, 3H), 7.60–7.67 (m, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.98–8.1 (m, 2H), 9.56 (bs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 112.4, 113.0, 121.2, 123.4, 126.7, 127.9, 128.6, 129.4, 132.5, 134.5, 137.7, 138.2, 187.4; HRMS (ESI) calcd for C₁₅H₁₂NO [M + H]⁺ 222.0919; found 222.0917.
(1H-Indol-2-yl)(naphthalen-1-yl)methanone 8b. Yield 73%; light yellow solid; mp = 144–145 °C [150–151 °C];^9c R_f = 0.26 (hexanes : ethyl acetate 9 : 1); IR (KBr) 3327, 1614, 1520, 783, 746 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 6.98 (dd, J = 2.0, 0.8 Hz, 1H), 7.13–7.19 (m, 1H), 7.35–7.42 (m, 1H), 7.52 (dd, J = 8.4, 0.8 Hz, 1H), 7.54–7.60 (m, 3H), 7.66 (dd, J = 8.0, 0.8 Hz, 1H), 7.90 (dd, J = 7.2, 1.2 Hz, 1H) 7.92–7.98 (m, 1H), 8.05 (d, J = 8.4 Hz, 1H), 8.28–8.34 (m, 1H), 9.75 (bs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 112.5, 113.9, 121.2, 123.5, 124.5, 125.7, 126.7, 126.9, 127.5, 127.7, 127.9, 128.5, 131.0, 131.7, 134.0, 135.8, 136.2, 138.2, 189.0; HRMS (ESI) calcd for C₁₉H₁₄NO [M + H]⁺ 272.1075; found 272.1077.
(1H-Indol-2-yl)(p-tolyl)methanone 8c. Yield 71%; light yellow solid; mp = 174–176 °C [187–188 °C];^9d R_f = 0.26 (hexanes–ethyl acetate 9 : 1); IR (KBr) 3350, 1616, 1515, 1261, 825, 750 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 2.48 (s, 3H), 7.14–7.20 (m, 2H), 7.32–7.41 (m, 3H), 7.50 (dd, J = 8.4, 0.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.94 (dd, J = 8.4, 1.6 Hz, 2H), 9.54 (bs, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 21.8, 112.3, 112.5, 121.1, 123.3, 126.5, 127.9, 129.3, 134.7, 135.5, 137.6, 143.3, 187.1; HRMS (ESI) calcd for C₁₆H₁₄NO [M + H]⁺ 236.1075; found 236.1071.

Acknowledgements

We thank DST (Project no. SB/S1/OC-72/2013) and DST nano mission (SR/NM/NS-1034/2012(G)) for financial support. G.K thanks for UGC, New Delhi for Senior Research fellowship.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Copy of all the compounds ¹H and ¹³C spectra. See DOI: 10.1039/c4ra15162c

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