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Synlett 2021; 32(10): 1004-1008
DOI: 10.1055/s-0040-1720461
letter

Copper-Catalyzed Synthesis of β- and δ-Carbolines by Double N-Arylation of Primary Amines

Ban Van Phuc
a   Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
,
Ha Nam Do 
b   Faculty of Chemistry, Hanoi University of Science, Vietnam National University (VNU), 19-Le Thanh Tong, Hanoi, Vietnam
,
Nguyen Minh Quan
c   Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
,
Nguyen Ngoc Tuan
a   Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
,
Nguyen Quang An
a   Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
,
Nguyen Van Tuyen
a   Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
c   Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
,
Hoang Le Tuan Anh
d   Center for Research and Technology Transfer, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
,
Tran Quang Hung  ∗
a   Institute of Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
c   Graduate University of Science and Technology, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
,
Tuan Thanh Dang∗
b   Faculty of Chemistry, Hanoi University of Science, Vietnam National University (VNU), 19-Le Thanh Tong, Hanoi, Vietnam
,
Peter Langer  ∗
e   Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
f   Leibniz Institut für Katalyse an der Universität Rostock e.V., Albert-Einstein-Str. 3a, 18059 Rostock, Germany
› Author AffiliationsThis research is funded by the Vietnam National Foundation for Science and Technology Development (NAFOSTED, Grant Number 104.01-2020.35).
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Abstract

Two efficient and practical approaches are reported for the synthesis of β- and δ-carbolines from 3,4-dibromopyridine. The synthesis is based on site-selective Cu-catalyzed double C–N coupling reactions and subsequent annulations by twofold Pd-catalyzed C–N coupling with amines.

Key words

catalysis - heterocycles - cross-coupling - cyclizations - copper

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1720461.
  • Supporting Information


Publication History

Received: 02 February 2021

Accepted after revision: 21 March 2021

Article published online:
31 March 2021

© 2021. Thieme. All rights reserved

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  • 20 Preparation of 3-Bromo-2-(2-bromophenyl)pyridine (1a) 2,3-Dibromopyridine (2.00 g, 8.44 mmol), 2-bromophenyl boronic acid (1.70 g, 8.44 mmol), and Pd(PPh3)4 (488 mg, 0.422 mmol) were added to a 250 mL Schlenk flask. The mixture was backfilled several times with argon. To the mixture were added K2CO3 (1 M, 25 mL), 5 drops of aqueous KOH (10%) and 35 mL of THF, then backfilled several times with argon. The reaction was heated at 70 °C for 18 h. The solvent was evaporated in vacuo. The residue was extracted with ethyl acetate and water. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The yellow residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 20:1) to yield 3-bromo-2-(2-bromophenyl)pyridine (1a)17s (2.20 g, 85%) as a colorless oil.
  • 21 General Procedure for the Synthesis of 5H-Pyrido[3,2-b]indoles 3a–o 3-Bromo-2-(2-bromophenyl)pyridine (1a, 100 mg, 0.32 mmol), 4-fluoroaniline (116 mg, 0.958 mmol), copper(I) iodide (12 mg, 0.064 mmol, Aldrich, 99%), l-proline (11 mg, 0.096 mmol), and K2CO3 (132 mg, 0.958 mmol) were dissolved in DMSO (1.5 mL) and heated at 120 °C for 24 h. After cooling, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 5:1) to yield 5-(4-methylbenzyl)-5H-pyrido[3,2-b]indole (3b, 85 mg, 95%) as a white solid. 1H NMR (500 MHz, CDCl3): δ = 8.57 (s, 1 H), 8.46 (s, 1 H), 7.65 (s, 1 H), 7.56–7.50 (m, 1 H), 7.42 (d, J = 8.2 Hz, 1 H), 7.35 (d, J = 6.8 Hz, 2 H), 7.07 (d, J = 7.9 Hz, 2 H), 7.01 (d, J = 7.9 Hz, 2 H), 5.47 (s, 2 H), 2.29 (s, 3 H). 13C NMR (126 MHz, CDCl3): δ = 141.4, 137.5, 133.5, 129.6, 127.9, 126.4, 120.2, 109.3, 21.1. HRMS (ESI): m/z calcd for C19H16N2 [M + 1]+: 273.1386; found: 273.1401.
  • 22 Preparation of 3-Bromo-4-(2-bromophenyl)pyridine (1b) 3,4-Dibromopyridine (2.00 g, 8.44 mmol), 2-bromophenylboronic acid (1.70 g, 8.44 mmol), and Pd(PPh3)4 (488 mg, 0.422 mmol) were added to a 250 mL Schlenk flask. The mixture was backfilled several times with argon. To the mixture were added K2CO3 (1 M, 25 mL), 5 drops of aqueous KOH (10%), and 35 mL of THF, then backfilled several times with argon. The reaction was heated at 70 °C for 18 h. The solvent was evaporated in vacuo. The residue was extracted with ethyl acetate and water. The organic layer was dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 20:1) to yield 3-bromo-4-(2-bromophenyl)pyridine (1b)17m (2.30 g, 80%) as a colorless syrup.
  • 23 General Procedure for the Synthesis of 9H-pyrido[3,4-b]indoles 4a–h 3-Bromo-2-(2-bromophenyl)pyridine (1a, 100 mg, 0.32 mmol), 4-fluoroaniline (116 mg, 0.958 mmol), copper(I) iodide (15.4 mg, 0.08 mmol), l-proline (11 mg, 0.096 mmol), and K2CO3 (132 mg, 0.958 mmol) were dissolved in DMSO (1.5 mL) and heated at 160 °C for 24 h. After cooling, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layer was dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel, hexane/ethyl acetate = 5:1) to yield 9-phenethyl-9H-pyrido[3,4-b]indole (4e, 61 mg, 70%) as a white solid. 1H NMR (500 MHz, CDCl3): δ = 8.72 (s, 1 H), 8.43 (d, J = 4.9 Hz, 1 H), 8.14 (dt, J = 7.9, 1.0 Hz, 1 H), 7.95 (d, J = 5.2 Hz, 1 H), 7.56 (ddd, J = 8.4, 7.1, 1.2 Hz, 1 H), 7.39–7.33 (m, 1 H), 7.32–7.23 (m, 2 H), 7.25–7.20 (m, 1 H), 7.23–7.17 (m, 2 H), 7.17 (ddt, J = 7.7, 5.7, 1.6 Hz, 1 H), 7.11–7.05 (m, 2 H), 4.59 (t, J = 7.4 Hz, 2 H), 3.15 (t, J = 7.4 Hz, 2 H). 13C NMR (126 MHz, CDCl3): δ = 141.1, 138.5, 138.2, 131.7, 128.8, 128.7, 128.7, 128.6, 128.5, 126.9, 126.4, 122.0, 121.1, 119.8, 109.4, 45.3, 35.5. HRMS (ESI): m/z calcd for C19H16N2 [M + 1]+: 273.1386; found: 273.1400.