One-Pot Synthesis of 1-Alkoxyisoquinoline Derivatives via Ru(II)-Catalyzed Aryl C−H Activation and Alkyne Annulation

Nitumoni Hazarika; Nitish Nayan Gogoi; Manashjyoti Gogoi; Nayan Ghosh; Animesh Das

doi:10.1055/a-2744-3045

Synlett, Table of Contents

Synlett
DOI: 10.1055/a-2744-3045

Letter

Alkynes In Organic Synthesis

One-Pot Synthesis of 1-Alkoxyisoquinoline Derivatives via Ru(II)-Catalyzed Aryl C−H Activation and Alkyne Annulation

Authors

Nitumoni Hazarika

¹Department of Chemistry, IIT Guwahati, Guwahati, India (Ringgold ID: RIN28678)
Nitish Nayan Gogoi

¹Department of Chemistry, IIT Guwahati, Guwahati, India (Ringgold ID: RIN28678)
Manashjyoti Gogoi

¹Department of Chemistry, IIT Guwahati, Guwahati, India (Ringgold ID: RIN28678)
Nayan Ghosh

¹Department of Chemistry, IIT Guwahati, Guwahati, India (Ringgold ID: RIN28678)
Animesh Das

¹Department of Chemistry, IIT Guwahati, Guwahati, India (Ringgold ID: RIN28678)

Abstract

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Abstract

A one-pot synthesis of 1-alkoxyisoquinolines via ruthenium(II)-catalyzed aryl C−H activation and annulation with internal alkynes has been demonstrated. The reaction involves in situ generation of a benzimidate ester by the addition of nucleophilic alcohols and it acts as an “automatic directing group” (DG^auto) for the aryl C−H activation and subsequent alkyne annulation. In contrast to conventional nitrogen-containing DG-assisted annulation approaches, this DG^auto-assisted annulation of alkynes via C−H activation is advantageous as it reduces the number of reaction steps, simplifies the experimental procedure, and allows for easier handling of the corresponding precursors. Based on preliminary experimental observations, a plausible mechanism is disclosed for this transformation. Interestingly, most of the compounds show intense fluorescence emission, and their absorption and emission spectra are also presented in this work.

Keywords

Alkynes - Annulation - Ruthenium catalysis - Heterocycles - Homogeneous catalysis

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References

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24 General procedure for the synthesis of annulated compounds (GP)

A mixture of aryl/heteroaryl nitrile 1 (0.2 m = mol, 1 equiv), alkyne 2 (0.22 mmol, 1.1 equiv), [Ru(p-cymene)Cl₂]₂ (0.005 mmol, 2.5 mol%), Cu(OAc)₂·H₂O (0.3 mmol, 1.5 equiv) was added to an oven-dried 15 mL pressure tube containing a magnetic stirring bar. Dry solvent ROH (100 equiv) was added to the tube and the mixture was stirred at 120 °C in a preheated oil bath for 8 h under air in a sealed tube. After completion of the reaction, the reaction mixture was transferred to a round-bottom flask and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using ethyl acetate and petroleum ether as the eluent to obtain the corresponding isoquinoline derivative

3,4-Diethyl-1-methoxyisoquinoline (3a)

Following the general procedure GP with compounds 1a and 2a, the title compound 3a was isolated as a colorless oil using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.7) in 94% yield (40 mg). 1H NMR (500 MHz, CDCl₃): δ 8.22 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.66–7.62 (m, 1H), 7.45–7.42 (m, 1H), 4.10 (s, 3H), 2.96 (q, J = 7.5 Hz, 2H), 2.86 (q, J = 7.5 Hz, 2H), 1.34 (t, J = 7.5 Hz, 3H), 1.24 (t, J = 7.5 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 158.6, 150.4, 137.4, 130.1, 125.0, 124.6, 122.8, 122.3, 118.5, 53.3, 28.0, 20.5, 15.3, 14.3

3,4-Diethyl-1-methoxy-6-(trifluoromethyl)isoquinoline (3b)

Following the general procedure GP with compounds 1b and 2a, the title compound 3b was isolated as a colorless oil using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.8) in 92% yield (52 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.33 (d, J = 8.7 Hz, 1H), 8.14 (brs, 1H), 7.62 (dd, J = 8.7, 1.8 Hz, 1H), 4.12 (s, 3H), 2.98 (q, J = 7.5 Hz, 2H), 2.88 (q, J = 7.5 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H), 1.26 (t, J = 7.5 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃): δ 158.4, 152.3, 136.8, 131.7 (q, J = 31.9 Hz), 125.9, 125.3, 123.5, 122.8, 120.7 (q, J = 3.1 Hz), 120.4 (q, J = 4.4 Hz), 119.7, 53.5, 28.0, 20.5, 15.3, 14.1. ¹⁹F NMR (565 MHz, CDCl₃): δ −62.6. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₅H₁₇F₃NO is 284.1257; found 284.1245

6-Bromo-3,4-diethyl-1-methoxyisoquinoline (3c)

Following the general procedure GP with compounds 1c and 2a, the title compound 3c was isolated as a white solid using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.8) in 83% yield (49 mg). ¹H NMR (600 MHz, CDCl₃): δ 8.08 (d, J = 8.8 Hz, 1H), 8.00 (d, J = 1.7 Hz, 1H), 7.52–7.51 (m, 1H), 4.08 (s, 3H), 2.90 (q, J = 7.6 Hz, 2H), 2.84 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H), 1.23 (t, J = 7.6 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃): δ 158.6, 152.0, 138.8, 128.3, 126.4, 125.4, 125.3, 121.5, 116.9, 53.4, 28.0, 20.5, 15.2, 14.1. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₄H₁₇BrNO is 294.0489; found 294.0490

1-(3,4-Diethyl-1-methoxyisoquinolin-6-yl)ethan-1-one (3d)

Following the general procedure GP with compounds 1d and 2a, the title compound 3d was isolated as a light yellow oil using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.7) in 86% yield (44 mg). ¹H NMR (600 MHz, CDCl₃): δ 8.47 (brs, 1H), 8.27 (d, J = 8.6 Hz, 1H), 7.94 (dd, J = 8.6, 1.4 Hz, 1H), 4.11 (s, 3H), 3.01 (q, J = 7.6 Hz, 2H), 2.87 (q, J = 7.5 Hz, 2H), 2.73 (s, 3H), 1.34 (t, J = 7.5 Hz, 3H), 1.27 (t, J = 7.6 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃): δ 198.5, 158.4, 151.7, 137.9, 136.9, 125.2, 124.1, 123.4, 123.3, 120.4, 53.5, 28.0, 27.1, 20.5, 15.5, 14.1. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₆H₂₀NO₂ is 258.1489; found 258.1486

3,4-Diethyl-1-methoxy-6-methylisoquinoline (3e)

Following the general procedure GP with compounds 1e and 2a, the title compound 3e was isolated as a colorless oil using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.7) in 74% yield (34 mg). ¹H NMR (600 MHz, CDCl₃): δ 8.12 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.09 (s, 3H), 2.94 (q, J = 7.6 Hz, 2H), 2.85 (q, J = 7.5 Hz, 2H), 2.54 (s, 3H), 1.33 (t, J = 7.5 Hz, 3H), 1.25 (t, J = 7.6 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃): δ 158.6, 150.5, 140.1, 137.7, 127.0, 124.4, 122.1, 121.9, 116.6, 53.2, 28.0, 22.5, 20.4, 15.3, 14.3. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₅H₂₀NO is 230.1540; found 230.1543

3,4-Diethyl-1,6-dimethoxyisoquinoline (3f)

Following the general procedure GP with compounds 1f and 2a, the title compound 3f was isolated as a white solid using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.9) in 69% yield (34 mg). ¹H NMR (600 MHz, CDCl₃): δ 8.14 (d, J = 9.0 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.08–7.07 (m, 1H), 4.08 (s, 3H), 3.94 (s, 3H), 2.92 (q, J = 7.6 Hz, 2H), 2.85 (q, J = 7.5 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.25 (t, J = 7.6 Hz, 3H). ¹³C NMR (151 MHz CDCl₃): δ 161.0, 158.6, 151.2, 139.4, 126.4, 121.7, 116.2, 113.4, 102.4, 55.4, 53.1, 28.1, 20.7, 14.9, 14.2. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₅H₂₀NO₂ is 246.1489; found 246.1490

8,9-Diethyl-6-methoxy-[1,3]dioxolo[4,5-f]isoquinoline (3g)

Following the general procedure GP with compounds 1g and 2a, the title compound 3g was isolated as a light yellow oil using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.8) in 63% yield (32.6 mg). ¹H NMR (600 MHz, CDCl₃): δ 7.85 (d, J = 8.7 Hz, 1H), 7.08 (d, J = 8.7 Hz, 1H), 6.11 (s, 2H), 4.06 (s, 3H), 3.02 (q, J = 7.4 Hz, 2H), 2.80 (q, J = 7.5 Hz, 2H), 1.31 (t, J = 7.5 Hz, 3H), 1.20 (t, J = 7.4 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃): δ 158.4, 151.0, 147.5, 140.8, 125.0, 120.0, 119.5, 115.5, 109.1, 101.1, 53.3, 27.4, 22.0, 16.2, 14.3. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₅H₁₈NO₃ is 260.1282; found 260.1280

3,4-Diethyl-1-methoxy-2,6-naphthyridine (3h)

Following the general procedure GP with compounds 1h and 2a, the title compound 3h was isolated as a colorless oil using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.7) in 88% yield (38 mg). ¹H NMR (600 MHz, CDCl₃): δ 9.35 (s, 1H), 8.59 (d, J = 5.5 Hz, 1H), 7.94 (d, J = 5.5 Hz, 1H), 4.10 (s, 3H), 3.04 (q, J = 7.6 Hz, 2H), 2.87 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.5 Hz, 3H), 1.28 (t, J = 7.6 Hz, 3H). ¹³C NMR (151 MHz, CdCl₃): δ 157.9, 152.4, 148.0, 143.2, 131.7, 121.8, 121.5, 116.7, 53.6, 27.7, 19.8, 15.7, 14.1. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₃H₁₇N₂O is 217.1336; found 217.1334

4,5-Diethyl-7-methoxythieno[2,3-c]pyridine (3i)

Following the general procedure GP with compounds 1i and 2a, the title compound 3i was isolated as a colorless oil using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.8) in 78% yield (34.5 mg). ¹H NMR (600 MHz, CDCl₃): δ 7.58 (d, J = 5.3 Hz, 1H), 7.35 (d, J = 5.3 Hz, 1H), 4.11 (s, 3H), 2.90 (q, J = 7.6 Hz, 2H), 2.85 (q, J = 7.5 Hz, 2H), 1.35 (t, J = 7.5 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃): δ 156.2, 151.6, 148.0, 130.5, 123.7, 122.1, 120.3, 53.3, 27.0, 22.5, 15.5, 14.4

1-Ethoxy-3,4-diethylisoquinoline (3j)

Following the general procedure GP with compounds 1a, 2a and ethanol as a solvent, the title compound 3j was isolated as a colorless oil using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.8) in 93% yield (42.6 mg). ¹H NMR (500 MHz, CDCl₃): δ 8.25 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.65–7.62 (m, 1H), 7.45–7.42 (m, 1H), 4.56 (q, J = 7.1 Hz, 2H), 2.96 (q, J = 7.5 Hz, 2H), 2.84 (q, J = 7.5 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.5 Hz, 3H), 1.24 (t, J = 7.5 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 158.3, 150.4, 137.4, 130.0, 124.8, 124.6, 122.7, 122.0, 118.5, 61.5, 28.0, 20.5, 15.3, 14.9, 14.3. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₅H₂₀NO is 230.1540; found 230.1546

3,4-Diethyl-1-(2,2,2-trifluoroethoxy)isoquinoline (3k)

Following the general procedure GP with compounds 1a, 2a, and 2,2,2-trifluoroethan-1-ol (TFE) as a solvent, the title compound 3k was isolated as a colorless oil using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.7) in 96% yield (54.4 mg). ¹H NMR (500 MHz, CDCl₃): δ 8.27 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.71–7.67 (m, 1H), 7.51–7.48 (m, 1H), 4.96 (q, J = 8.7 Hz, 2H), 2.98 (q, J = 7.6 Hz, 2H), 2.86 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 7.5 Hz, 3H), 1.26 (t, J = 7.6 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 156.1, 149.9, 137.8, 130.6, 125.5, 124.4, 124.2, 122.9, 117.8, 62.1 (q, J = 35.8 Hz), 27.7, 20.5, 15.2, 14.1. ¹⁹F NMR (565 MHz, CDCl₃) δ −73.6. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₅H₁₇F₃NO is 284.1257; found 284.1260

1-Methoxy-3,4-dipropylisoquinoline (3l)

Following the general procedure GP with compounds 1a and 2b, the title compound 3l was isolated as a colorless oil using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.9) in 87% yield (42.3 mg). ¹H NMR (600 MHz, CDCl₃): δ 8.23 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.65–7.62 (m, 1H), 7.45–7.43 (m, 1H), 4.10 (s, 3H), 2.92–2.89 (m, 2H), 2.83–2.80 (m, 2H), 1.87–1.80 (m 2H), 1.68–1.61 (m, 2H), 1.08 (t, J = 7.3 Hz, 3H), 1.03 (t, J = 7.4 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃): δ 158.4, 149.5, 137.7, 130.0, 124.9, 124.5, 123.0, 121.4, 118.4, 53.3, 36.8, 29.6, 24.2, 23.0, 14.7, 14.4. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₆H₂₂NO is 244.1696; found 244.1699

1-Methoxy-3,4-diphenylisoquinoline (3m)

Following the general procedure GP with compounds 1a and 2c, the title compound 3m was isolated as a pale yellow solid using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.7) in 81% yield (50.4 mg). ¹H NMR (600 MHz, CDCl₃): δ 8.33 (d, J = 8.1 Hz, 1H), 7.57–7.52 (m, 3H), 7.44–7.42 (m, 2H), 7.38–7.33 (m, 3H), 7.25–7.23 (m, 2H), 7.21–7.17 (m, 3H), 4.23 (s, 3H). ¹³C NMR (151 MHz, CDCl₃): δ 159.7, 147.0, 141.0, 138.6, 138.1, 131.8, 130.5, 128.5, 127.6, 127.1, 127.1, 126.3, 125.6, 125.0, 124.1, 118.6, 53.8

3,4-Bis(4-bromophenyl)-1-methoxyisoquinoline (3n)

Following the general procedure GP with compounds 1a and 2d, the title compound 3n was isolated as a white solid using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.8) in 77% yield (72.2 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.34–8.31 (m, 1H), 7.61–7.55 (m, 2H), 7.53–7.48 (m, 3H), 7.36–7.34 (m, 2H), 7.29–7.26 (m, 2H), 7.11–7.09 (m, 2H), 4.20 (s, 4H). ¹³C NMR (126 MHz, CDCl₃): δ 160.0, 145.9, 139.6, 138.1, 136.8, 133.4, 132.1, 131.9, 131.0, 130.9, 126.7, 125.2, 124.2, 123.8, 121.7, 121.6, 118.7, 53.9. HRMS (ESI) m/z: [M+H]⁺ calcd for C₂₂H₁₆Br₂NO is 469.9573; found 469.9566

3,4-Bis(4-(tert-butyl)phenyl)-1-methoxyisoquinoline (3o)

Following the general procedure GP with compounds 1a and 2e, the title compound 3o was isolated as a yellow solid using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.8) in 83% yield (70.3 mg). ¹H NMR (500 MHz, CDCl₃): δ 8.31 (d, J = 8.2 Hz, 1H), 7.60–7.54 (m, 2H), 7.52–7.49 (m, 1H), 7.39–7.36 (m, 4H), 7.19–7.15 (m, 4H), 4.23 (s, 3H), 1.37 (s, 9H), 1.28 (s, 9H). ¹³C NMR (126 MHz, CDCl₃): δ 159.5, 150.0, 149.8, 146.7, 138.8, 138.0, 135.1, 131.4, 130.3, 130.0, 126.1, 125.8, 125.3, 124.8, 124.4, 123.9, 118.4, 53.7, 34.7, 34.6, 31.6, 31.4. HRMS (ESI) m/z: [M+H]⁺ calcd for C₃₀H₃₄NO is 424.2635; found 424.2636

1-Methoxy-4-methyl-3-phenylisoquinoline (3p) + 1-Methoxy-3-methyl-4-phenylisoquinoline (3p′)

Following the general procedure GP with compounds 1a and 2f, the title compounds 3p+3p′ (4:1) were isolated as a yellow solid using silica gel column chromatography with ethyl acetate/petroleum ether (v/v = 1/100, R _f = 0.4) in 79% combined yield (39.4 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.30 (d, J = 8.2 Hz, 1H, major, 80%), 7.96 (d, J = 8.5 Hz, 1H, major, 80%), 7.93–7.91 (m, 1H, minor, 20%), 7.75–7.71 (m, 1H, major), 7.69–7.63 (m, 2H, major + m, 1H, minor), 7.57–7.53 (m, 1H, major), 7.49–7.45 (m, 2H, major + 3H, minor), 7.42–7.37 (m, 1H, major + 4H, minor), 4.13 (s, 3H, major, 80%), 4.05 (s, 3H, minor, 20%), 2.58 (s, 3H, minor, 20%), 2.56 (s, 3H, major, 80%). ¹³C NMR (126 MHz, CDCl₃): δ 158.7, 147.9, 141.6, 138.8, 138.7, 130.5, 130.2, 130.0, 129.1, 128.3, 128.0, 127.6, 127.5, 127.3, 126.3, 126.0, 124.5, 123.7, 122.9, 118.8, 117.4, 53.6, 53.5, 15.9, 15.3. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₇H₁₆NO is 250.1227; found 250.1217

4,5,9,10-Tetraethyl-7-methoxyimidazo[1,2-a]pyrido[3,4-g]quinoline (4)

A mixture of 4-(1H-imidazol-1-yl)benzonitrile 1j (34 mg, 0.2 mmol), alkyne 2a (41 mg, 0.5 mmol), [Ru(p-cymene)Cl₂]₂ (12 mg, 0.02 mmol), Cu(OAc)₂·H₂O (160 mg, 0.8 mmol), Pivalic acid (41 mg, 0.4 mmol) was added to an oven-dried 50 mL pressure tube containing a magnetic stirring bar. Dry MeOH (100 equiv) was added to the tube and the mixture was stirred at 130 °C for 24 h under air. After completion of the reaction, the reaction mixture was transferred to a round-bottom flask and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on neutral alumina using ethyl acetate/petroleum ether (v/v = 1/20, R _f = 0.8) as eluent to obtain pure 4 as a brown solid in 72% yield (52 mg). ¹H NMR (600 MHz, CDCl₃): δ 8.85 (s, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 7.63 (s, 1H), 4.18 (s, 3H), 3.18–3.15 (m, 4H), 3.07 (q, J = 7.6 Hz, 2H), 2.90 (q, J = 7.5 Hz, 2H), 1.40–1.36 (m, 8H), 1.34–1.32 (m, 4H). ¹³C NMR (151 MHz, CDCl₃): δ 158.9, 151.2, 144.9, 135.8, 134.4, 133.6, 131.9, 129.1, 122.6, 122.0, 121.2, 116.2, 111.8, 107.2, 53.6, 28.1, 21.5, 21.2, 20.8, 15.2, 15.2, 14.5, 14.2. HRMS (ESI) m/z: [M+H]⁺ calcd for C₂₃H₂₈N₃O is 362.2227; found 362.2230

4,5-Diethylimidazo[1,2-a]quinoline-7-carbonitrile (5)

A mixture of 1j (68 mg, 0.4 mmol), alkyne 2a (33 mg, 0.4 mmol), [Ru(p-cymene)Cl₂]₂ (12 mg, 0.02 mmol), Cu(OAc)₂·H₂O (160 mg, 0.8 mmol), and Pivalic acid (82 mg, 0.8 mmol) was added to an oven-dried pressure tube containing a magnetic stirring bar. Dry DCE (2.5 mL) was added to the tube and the mixture was stirred at 130 °C in a preheated oil bath for 24 h under air. After completion of the reaction, the reaction mixture was transferred to a round-bottom flask and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on neutral alumina using ethyl acetate/petroleum ether (v/v = 1/10, R _f = 0.6) as eluent to obtain pure 5 as a brown oil in 61% yield (61 mg). ¹H NMR (400 MHz, CDCl₃): δ 8.29 (d, J = 1.3 Hz, 1H), 8.02–8.01 (m, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.80 (dd, J = 8.6, 1.5 Hz, 1H), 7.68 (brs, 1H), 3.16 (q, J = 7.5 Hz, 2H), 3.05 (q, J = 7.6 Hz, 2H), 1.37–1.30 (m, 6H). ¹³C NMR (101 MHz, CDCl₃): δ 144.6, 134.1, 133.1, 133.0, 131.6, 130.8, 129.8, 123.9, 118.9, 116.7, 111.5, 108.5, 21.6, 21.0, 15.1, 14.3. HRMS (ESI) m/z: [M+H]⁺ calcd for C₁₆H₁₆N₃ is 250.1339; found 250.1338

4,5-Diethyl-7-methoxy-9,10-diphenylimidazo[1,2-a]pyrido[3,4-g]quinoline (6)

A mixture of 5 (50 mg, 0.2 mmol), alkyne 2c (39 mg, 0.22 mmol), [Ru(p-cymene)Cl₂]₂ (3 mg, 0.005 mmol), and Cu(OAc)₂·H₂O (60 mg, 0.3 mmol) was added to an oven-dried pressure tube containing a magnetic stirring bar. Dry MeOH (100 equiv) was added to the tube and the mixture was stirred at 120 °C in a preheated oil bath for 8 h under air. After completion of the reaction, the reaction mixture was transferred to a round-bottom flask and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on neutral alumina using ethyl acetate/petroleum ether (v/v = 1/10, R _f = 0.6) as eluent to obtain pure 6 as a brown gum in 65% yield (59 mg). ¹H NMR (600 MHz, CDCl₃): δ 8.94 (s, 1H), 7.94 (s, 1H), 7.72 (d, J = 1.3 Hz, 1H), 7.51 (d, J = 1.3 Hz, 1H), 7.48–7.47 (m, 2H), 7.44–7.41 (m, 3H), 7.32–7.31 (m, 2H), 7.22–7.20 (m, 3H), 4.31 (s, 3H), 3.21 (q, J = 7.6 Hz, 2H), 3.16 (q, J = 7.6 Hz, 2H), 1.43 (t, J = 7.6 Hz, 3H), 1.38 (t, J = 7.6 Hz, 3H). ¹³C NMR (151 MHz, CDCl₃): δ 159.9, 147.3, 144.7, 140.7, 137.8, 137.0, 134.2, 133.7, 131.9, 131.8, 130.5, 129.9, 128.8, 127.7, 127.6, 127.4, 124.1, 123.1, 122.0, 116.1, 112.0, 110.2, 54.1, 21.6, 21.2, 15.2, 14.5. HRMS (ESI) m/z: [M+H]⁺ calcd for C₃₁H₂₈N₃O is 458.2227; found 458.2231

Synthesis of [Ru(p-cymene)(OAc)₂]

A mixture of [RuCl₂(p-cymene)]₂ (184 mg, 0.3 mmol, 1 equiv) and silver acetate (225 mg, 1.35 mmol, 4.5 equiv) in toluene (4.0 mL) was stirred at room temperature for 12 h in a round-bottom flask. The reaction mixture was filtered through celite to remove AgCl and was evaporated to dryness under reduced pressure. The residue was recrystallized from diethyl ether/pet ether (1:1, v/v) and dried in vacuo to give yellow needles of the product (174 mg, 82%)

¹H NMR (600 MHz, CDCl₃): δ 5.76 (brs, 2H), 5.55 (brs, 2H), 2.87–2.83 (m, 1H), 2.24 (s, 3H), 1.92 (s, 6H), 1.35 (d, J = 6.9 Hz, 6H). ¹³C NMR (151 MHz, CDCl₃): δ 184.6, 98.2, 79.0, 77.9, 31.5, 23.9, 22.6, 18.6

Supplementary Material

Supplementary Material (PDF) (opens in new window)