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.

There has been extensive reporting on the significant antiproliferative activities of thienopyridine derivatives against a range of human cancer cell lines.[1] [2] [3] [4] [5] [6] [7] [8] [9] Of particular note is the potent activity of this family of compounds, with some having GI₅₀ values in the nanomolar range against triple negative breast cancer cell lines such as MDA-MB-231/468.[4] Despite these promising findings, in a recent report that includes an investigation into the in vivo activity of thienopyridines, it was noted that the poor aqueous solubility of the compounds tested was a significant factor in limiting the dose that could be tested.[10] We envisioned that the synthesis of nitrogen analogues of such a scaffold, thereby synthesizing the corresponding pyrrolo[2,3-b]quinolines, could lead to compounds with improved solubility (Figure [1]).

Previous syntheses of 3-amino-2-carboxamide pyrrolo[2,3-b]quinolines or other similar fused-ring pyrrolopyridines are unreported in the literature; we herein report the first synthesis of 3-amino-2-carboxamide pyrrolo[2,3-b]quinolines allowing the preparation of analogues of bioactive 3-amino-2-carboxamide thieno[2,3-b]quinolines.

To achieve our goal, we proposed to adapt our previously reported route towards thienopyridines; that route centers on the reaction between a bicyclic thiocarbonitrile and bromoaniline and the concomitant cyclization of the resulting condensation product, to provide the final structure.[1] [4] [6] [10] The synthesis of nitrogen analogues requires the use of chlorotetrahydroquinoline 1, which we envisioned could be coupled with a primary amine 2 to give nitrile 3 which could undergo cyclization via a Thorpe–Ziegler reaction (Scheme [1]).

Initially, we decided to test our proposed methodology on the synthesis of N-unsubstituted nitrogen analogues, containing phenyl (4a) or 2-naphthyl (4b) carboxamide. The required amines 2a,b were synthesized from the corresponding N-aryl bromoacetamides[1] 5a,b, in two steps; formation of azides 6a,b using NaN₃ in DMSO, and hydrogenation of 6a,b gave 2a,b in yields of 94% and 84%, respectively, over two steps (Scheme [2]).

Chloroquinoline 1 was formed through the chlorination, using POCl₃ of 7,[11] itself formed following literature procedures from cyclohexanone 8.[1] Amination of chloride 1 with amines 2a,b was performed in DMSO with KF (2.4 equiv) at 120 °C overnight[12] to give coupled products 3a,b, respectively. No cyclization products 4a,b were obtained. Unfortunately, despite a large number of conditions attempted to effect this cyclization to 4, including reactions with a number of different bases for extended reaction times with heating, no cyclized products were isolated from the reaction. A literature investigation provided very few examples of successful cyclization of similar cyanopyridines, and no examples without additional electron-withdrawing groups on the pyridine ring.[13] [14] [15] The Thorpe–Ziegler reaction of these compounds is proposed to be difficult due to deprotonation of the amine rather than the α-amide protons which is required for cyclization.[16]

Following the unsuccessful synthesis of the N-unsubstituted analogues 4, we wished to prepare analogues containing an N-substituent, which we hoped would allow for the cyclization to proceed. We began using a methyl substituent and methyl amines 9a–f were obtained in quantitative yields through the direct amination of bromides 5a,b prepared earlier as well as a number of other analogues 5c–f using methylamine in EtOH (Scheme [3]).[17]

Utilizing the previously optimized coupling conditions,[12] the coupled products 10 were successfully synthesized, however, once again with no cyclization products 11 seen, which is contrasting with the synthesis of thienopyridines which are often formed in a single step.[1] [4] [6] [10] Cyclization conditions were tested using 10a [18] (see Table [1] for a summary of conditions tested); heating 10a with a number of bases including NaHCO₃, Na₂CO₃, Cs₂CO₃ in various solvents did not induce cyclization, with only starting material isolated after extended reaction times. When the reaction was attempted with stronger base KO ^t Bu, after four hours at 80 °C only degradation products were seen. The reaction did not proceed at room temperature, even after five days, however, using KO ^t Bu in THF at 80 °C for just one hour, the desired substituted pyrrolo[2,3-b]quinoline 11a [19] was obtained in quantitative yield. These conditions were then repeated for the remaining nitriles 10b–f,[20] providing pyrrolo[2,3-b]tetrahydroquinolines 11b–f in 64% to quantitative yields.

We then decided to explore whether this method could be adapted to allow for other substituents attached to the nitrogen atom; 3-phenylpropylamine and 3-morpholinoamine were added to bromide 5a, giving amines 9g [21] and 9h [22] in 68% and 95% yields, respectively. These amines were coupled[12] and then cyclized[20] to provide N-3-phenylpropyl and N-3-morpholinopropyl analogues 11g and 11h, respectively.

In addition to the substitution on the aryl ring, one of the main points of variation that is extensively investigated for thienopyridines is the size of the fused nonaromatic ring. We wished to determine that if the method could be applied to the generation of nitrogen analogues of other heterocycles, thus the eight-membered bicycle 12 was formed from cyclooctanone 13 firstly by conversion into the α-hydroxymethylene salt and then its reaction with cyanoacetamide and piperidinium acetate, followed by acidification with acetic acid, to give bicyclic product 14 which was then chlorinated to provide 12. Chloride 12 was then coupled[12] with amine 9a to give 15 which was then cyclized[20] to give 16 in quantitative yield (Scheme [4]).

The methods reported here allow the synthesis of pyrrolo[2,3-b]tetrahydroquinolines and fused-ring pyrrolopyridines in an efficient synthesis that allows for several points of variation on the structure, including the size of the nonaromatic fused ring, substitution on the pyrrolic nitrogen, and substitution on the aryl ring. This methodology allows for the synthesis of novel analogues of thieno[2,3-b]pyridine compounds with additional substitution on the pyrrolo nitrogen. These additional substituents could incorporate functionalities that allow for improved solubility and/or bioactivity; we are currently investigating the effect of these changes, and results will be reported in due course.

Acknowledgment

We wish to acknowledge the Auckland Medical Research Foundation and the University of Auckland for funding for this work.

• References and Notes

• 1 Leung E, Pilkington LI, van Rensburg M, Jeon CY, Song M, Arabshahi HJ, De Zoysa GH, Sarojini V, Denny WA, Reynisson J, Barker D. Bioorg. Med. Chem. 2016; 24: 1142
  CrossrefPubMedSearch in Google Scholar
• 2 Reynisson J, Court W, O’Neill C, Day J, Patterson L, McDonald E, Workman P, Katan M, Eccles SA. Bioorg. Med. Chem. 2009; 17: 3169
  CrossrefPubMedSearch in Google Scholar
• 3 Feng L, Reynisdóttir I, Reynisson J. Eur. J. Med. Chem. 2012; 54: 463
  CrossrefPubMedSearch in Google Scholar
• 4 Leung E, Hung JM, Barker D, Reynisson J. Med. Chem. Comm. 2014; 5: 99
  CrossrefSearch in Google Scholar
• 5 Arabshahi HJ, Leung E, Barker D, Reynisson J. Med. Chem. Comm. 2014; 5: 186
  CrossrefSearch in Google Scholar
• 6 Hung JM, Arabshahi HJ, Leung E, Reynisson J, Barker D. Eur. J. Med. Chem. 2014; 86: 420
  CrossrefPubMedSearch in Google Scholar
• 7 Deng XQ, Wang HY, Zhao YL, Xiang ML, Jiang PD, Cao ZX, Zheng YZ, Luo SD, Yu LT, Wei YQ, Yang SY. Chem. Biol. Drug Des. 2008; 71: 533
  CrossrefPubMedSearch in Google Scholar
• 8 Zeng XX, Zheng RL, Zhou T, He HY, Liu JY, Zheng Y, Tong AP, Xiang ML, Song XR, Yang SY, Yu LT, Wei YQ, Zhao YL, Yang L. Bioorg. Med. Chem. Lett. 2010; 20: 6282
  CrossrefSearch in Google Scholar
• 9 Zhou R, Huang WJ, Guo ZY, Li L, Zeng XR, Deng YQ, Hu FY, Tong AP, Yang L, Yang YL. Oncol. Rep. 2012; 28: 225
  PubMedSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 10b Reynisson J, Jaiswal JK, Barker D, D’Mello A, Denny SW. A, Baguley BC, Leung EY. Cancer Cell Int. 2016; 16: 18
  CrossrefPubMedSearch in Google Scholar
• 11 Dabaeva VV, Bagdasaryan MR, Noravyan AS, Dzhagatspanyan IA, Nazaryan IM, Akopyan AG. Pharm. Chem. J. 2015; 49: 587
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 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.

• References and Notes

• 1 Leung E, Pilkington LI, van Rensburg M, Jeon CY, Song M, Arabshahi HJ, De Zoysa GH, Sarojini V, Denny WA, Reynisson J, Barker D. Bioorg. Med. Chem. 2016; 24: 1142
  CrossrefPubMedSearch in Google Scholar
• 2 Reynisson J, Court W, O’Neill C, Day J, Patterson L, McDonald E, Workman P, Katan M, Eccles SA. Bioorg. Med. Chem. 2009; 17: 3169
  CrossrefPubMedSearch in Google Scholar
• 3 Feng L, Reynisdóttir I, Reynisson J. Eur. J. Med. Chem. 2012; 54: 463
  CrossrefPubMedSearch in Google Scholar
• 4 Leung E, Hung JM, Barker D, Reynisson J. Med. Chem. Comm. 2014; 5: 99
  CrossrefSearch in Google Scholar
• 5 Arabshahi HJ, Leung E, Barker D, Reynisson J. Med. Chem. Comm. 2014; 5: 186
  CrossrefSearch in Google Scholar
• 6 Hung JM, Arabshahi HJ, Leung E, Reynisson J, Barker D. Eur. J. Med. Chem. 2014; 86: 420
  CrossrefPubMedSearch in Google Scholar
• 7 Deng XQ, Wang HY, Zhao YL, Xiang ML, Jiang PD, Cao ZX, Zheng YZ, Luo SD, Yu LT, Wei YQ, Yang SY. Chem. Biol. Drug Des. 2008; 71: 533
  CrossrefPubMedSearch in Google Scholar
• 8 Zeng XX, Zheng RL, Zhou T, He HY, Liu JY, Zheng Y, Tong AP, Xiang ML, Song XR, Yang SY, Yu LT, Wei YQ, Zhao YL, Yang L. Bioorg. Med. Chem. Lett. 2010; 20: 6282
  CrossrefSearch in Google Scholar
• 9 Zhou R, Huang WJ, Guo ZY, Li L, Zeng XR, Deng YQ, Hu FY, Tong AP, Yang L, Yang YL. Oncol. Rep. 2012; 28: 225
  PubMedSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 10b Reynisson J, Jaiswal JK, Barker D, D’Mello A, Denny SW. A, Baguley BC, Leung EY. Cancer Cell Int. 2016; 16: 18
  CrossrefPubMedSearch in Google Scholar
• 11 Dabaeva VV, Bagdasaryan MR, Noravyan AS, Dzhagatspanyan IA, Nazaryan IM, Akopyan AG. Pharm. Chem. J. 2015; 49: 587
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 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.

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