Synlett 2016; 27(20): 2811-2814
DOI: 10.1055/s-0036-1588619
letter
© Georg Thieme Verlag Stuttgart · New York

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

Lisa I. Pilkington
a   School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand   eMail: d.barker@auckland.ac.nz
,
Natalie A. Haverkate
a   School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand   eMail: d.barker@auckland.ac.nz
,
Michelle van Rensburg
a   School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand   eMail: d.barker@auckland.ac.nz
,
Johannes Reynisson
a   School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand   eMail: d.barker@auckland.ac.nz
,
Euphemia Leung
b   Auckland Cancer Society Research Centre and Department of Molecular Medicine and Pathology, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
,
David Barker*
a   School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand   eMail: d.barker@auckland.ac.nz
› Institutsangaben
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Publikationsverlauf

Received: 04. August 2016

Accepted after revision: 13. September 2016

Publikationsdatum:
11. Oktober 2016 (online)


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.

Supporting Information

 
  • References and Notes

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    • 10a Arabshahi HJ, van Rensburg M, Pilkington LI, Jeon CY, Song M, Gridel L.-M, Leung E, Barker D, Vuica-Ross M, Volcho KP, Zakharenko AL, Lavrik OI, Reynisson J. Med. Chem. Commun. 2015; 6: 1987
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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.
  • 13 Vitorino P, Yeung S, Crow A, Bakke J, Smyczek T, West K, McNamara E, Eastham-Anderson J, Gould S, Harris SE, Ndubaku C, Ye W. Nature (London, U.K.) 2015; 519: 425
  • 14 Dyke HJ, Gancia E, Gazzard LJ, Goodacre SC, Lyssikatos JP, Macleod C, Williams K. WO 2009151589, 2009
  • 15 Daghish M, Schulze A, Reichelt C, Ludwig A, Leistner S, Heinicke J, Kroedel A. WO 2006100095, 2006
  • 16 Yakovlev MY, Kadushkin AV, Granik VG. Pharm. Chem. J. 1996; 30: 107
  • 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): νmax = 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): νmax = 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): νmax = 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): νmax = 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.