Synthesis of 3-Amino-2-carboxamide Tetrahydropyrrolo[2,3-b]quinolines

Abstract

This article communicates the first synthesis of 3-amino-2-carboxamide pyrrolo[2,3-b]quinolines and fused-ring pyrrolopyridines in an efficient synthesis via a Thorpe–Ziegler transformation. The reported synthetic route allows for a wide range of nitrogen analogues of thienopyridines – compounds which have potent bioactivities but poor aqueous solubility.

Key words

pyrrolo[2,3-b]quinolines - Thorpe–Ziegler - pyrrolo[2,3-b]pyridines - thieno[2,3-b]pyridines - heterocycles

• References and Notes

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• 12 General Procedure for the Coupling of Carbonitrile and Amine A mixture of carbonitrile (1 equiv) and amine (1 equiv) were dissolved in DMSO, and KF (2.4 equiv) was added under an atmosphere of N₂. The mixture was heated at 120 °C overnight, before cooling to r.t. The reaction was diluted with EtOAc, before being quenched with H₂O. The mixture was then extracted with EtOAc (2×), and the combined organic extracts were washed with H₂O (5×), brine, dried (MgSO₄), and the solvent removed in vacuo to give the crude product, which was then purified using flash chromatography to give the desired product.
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• 17 General Procedure for the Synthesis of N-Methyl Phenylacetamides Methylamine in 33% EtOH (55 equiv) was added to the N-aryl bromoacetamide (1 equiv). The mixture was stirred at r.t. overnight and solvent removed in vacuo to give the desired compound. The resulting phenylacetamides were used in the next reaction without further purification.
• 18 2-[(3-Cyano-5,6,7,8-tetrahydroquinolin-2-yl)(methyl)-amino]-N-phenylacetamide (10a) The reaction was carried out following the general procedure using carbonitrile 1 (0.100 g, 0.520 mmol), 9a (80.0 mg, 0.520 mmol), KF (73.0 mg, 1.26 mmol), and dry DMSO (2.5 mL) and purified with flash chromatography (n-hexanes–EtOAc = 2:1) to give the title compound 10a (85.0 mg, 51%) as a white solid; mp 159–161 °C. IR (ATR): ν_max = 3268, 3093, 2933, 2211, 1672, 1547, 1415, 1251, 1209 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.79–1.90 (4 H, m, H-6 and H-7), 2.67 (2 H, t, J = 5.4 Hz, H-5), 2.83 (2 H, t, J = 5.4 Hz, H-8), 3.41 (3 H, s, NCH₃), 4.26 (2 H, s, NCH₂C=O), 7.07–7.11 (1 H, m, H-4′), 7.32 (2 H, m, H-3′), 7.49–7.53 (2 H, m, H-2′), 7.53 (1 H, s, H-4), 9.17 (1 H, br s, NH). ¹³C NMR (100 MHz, CDCl₃): δ = 22.5 (C-6 and C-7), 27.2 (C-5), 33.0 (C-8), 40.0 (NCH₃), 57.5 (NCH₂C=O), 91.5 (C-3), 118.2 (CN), 119.6 (C-2′), 123.7 (C-4a), 124.2 (C-4′), 129.0 (C-3′), 137.9 (C-1′), 144.8 (C-4), 157.4 (C-2), 160.6 (C-8a) 168.5 (C=O). MS (ESI⁺): m/z (%) = 343 (100) [MH⁺], 321 (5). HRMS (ESI⁺): m/z calcd for C₁₉H₂₀N₄NaO: 343.1529; found: 343.1524.
• 19 3-Amino-1-methyl-N-phenyl-5,6,7,8-tetrahydro-1H-pyrrolo[2,3-b]quinoline-2-carboxamide (11a) The reaction was carried out following the general procedure using 10a (0.100 g, 0.310 mmol), KO ^t Bu (40.0 mg, 0.310 mmol) and THF (2 mL) to give the title compound 11a (90.0 mg, 90%) as a dark brown solid; mp 102–105 °C. IR (ATR): ν_max = 3282, 2930, 1728, 1598, 1443, 1259 cm^–1. ¹H NMR (400 MHz, (CD₃)₂CO): δ = 1.73–1.82 (4 H, m, H-6 and H-7), 2.64–2.70 (4 H, m, H-5 and H-8), 3.42 (3 H, s, NCH₃), 4.40 (2 H, s, NH₂), 7.04 (1 H, t, J = 7.4 Hz, H-4′), 7.28 (2 H, t, J = 7.4 Hz, H-3′), 7.58 (1 H, s, H-4), 7.63 (2 H, d, J = 7.4 Hz, H-2′), 9.30 (1 H, br s, NH). ¹³C NMR (100 MHz, (CD₃)₂CO): δ = 23.39 and 23.41 (C-6 and C-7), 27.6 (C-5), 33.6 (C-8), 40.3 (NCH₃), 119.6 (C-3a), 120.2 (C-2), 120.3 (C-2′), 122.9 (C-3), 124.2 (C-3′), 129.5 (C-4), 129.6 (C-4′), 140.1 (C-4a), 145.3 (C-1′), 157.8 (C-9a), 161.0 (C-8a), 168.8 (C=O). MS (ESI⁺): m/z (%) = 321 (20) [MH⁺], 218 (100). HRMS (ESI⁺): m/z calcd for C₁₉H₂₁N₄O: 321.1710; found 321.1706.
• 20 General Procedure for the Synthesis of Pyrrolo[2,3-b]quinolines Uncyclized nitrile (1 equiv) was dissolved in dry THF and KO ^t Bu (1.2 equiv) added under an atmosphere of N₂. The mixture was heated at 70 °C until completion, monitored by TLC, then cooled to r.t. before being quenched with H₂O and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried (MgSO₄), and the solvent removed in vacuo to give the desired compound.
• 21 N-Phenyl-2-[(3-phenylpropyl)amino]acetamide (9g) The reaction was carried out following the general procedure using 2-bromo-N-phenylacetamide (5a, 1.00 g, 4.67 mmol) and 3-phenylpropylamine (2.53 g, 18.7 mmol) in EtOH (25 mL) to give the title compound 9g (0.856 g, 68%) as an orange oil. IR (ATR): ν_max = 3285, 3026, 2858, 1667, 1600, 1442, 1252 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.81–1.90 (2 H, m, H-2), 1.92 (1 H, s, NH), 2.68–2.73 (4 H, m, H-1 and H-3), 3.36 (2 H, s, NCH₂C=O), 7.09 (1 H, t, J = 7.4 Hz, H-4′), 7.11–7.35 (7 H, m, H-3′ and ArH), 7.58 (2 H, d, J = 7.4 Hz, H-2′), 9.30 (1 H, s, NH). ¹³C NMR (100 MHz, CDCl₃): δ = 31.7 (C-2), 33.5 (C-3), 49.8 (C-1), 53.0 (NCH₂C=O), 119.4 (C-2′), 124.0 (C-4′), 126.0 (ArCH), 128.3 (ArCH), 128.4 (ArCH), 129.0 (ArCH), 137.6 (C-1′), 141.5 (C-1′′), 169.8 (C=O). MS (ESI⁺): m/z (%) = 269 (100) [MH⁺], 148 (65). HRMS (ESI⁺): m/z calcd for C₁₇H₂₁N₂O: 269.1648; found [MH⁺]: 269.1651.
• 22 2-[(3-Morpholinopropyl)amino]-N-phenylacetamide (9h) The reaction was carried out following the general procedure using 2-bromo-N-phenylacetamide (5a, 0.700 g, 2.59 mmol) and 3-morpholinopropylamine (2.24 g, 15.5 mmol) in EtOH (10 mL) to give the title compound 9h (0.791 g, quant.) as an orange oil. IR (ATR): ν_max = 3285, 2944, 2855, 1674, 1600, 1442, 1254, 1115 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.69–1.74 (3 H, m, H-2 and NH), 2.41–2.45 (6 H, m, H-3, NCH ₂CH₂O), 2.71–2.75 (2 H, m, H-1), 3.36 (2 H, s, NCH₂C=O), 3.68–3.71 (4 H, m, NCH₂CH ₂O), 7.09 (1 H, t, J = 7.4 Hz, H-4′), 7.32 (2 H, t, J = 7.4 Hz, H-3′), 7.56 (2 H, d, J = 7.4 Hz, H-2′), 9.30 (1 H, s, NH). ¹³C NMR (100 MHz, CDCl₃): δ = 26.6 (C-2), 48.9 (C-1), 53.1 (NCH₂C=O), 53.8 (NCH₂CH₂O), 57.1 (C-3), 67.0 (NCH₂ CH₂O), 119.4 (C-2′), 124.1 (C-4′), 129.0 (C-3′), 137.6 (C-1′), 169.9 (C=O). MS (ESI⁺): m/z (%) = 278 (100) [MH⁺], 128 (55). HRMS (ESI⁺): m/z calcd for C₁₅H₂₄N₃O₂: 278.1863; found [MH⁺]: 278.1860.