Expedient Copper-Free One-Pot Alkynylation–Cyclization Sequence for the Preparation of 2-Substituted 7-Azaindoles

Dedicated to Prof. Dr. Matthias M. Wagner on the occasion of his 50th birthday

Abstract

2-Substituted 7-azaindoles are rapidly and efficiently prepared in a one-pot copper-free alkynylation–cyclization sequence starting from 2-aminopyridyl halides and terminal alkynes. Most importantly the amino nitrogen atom neither requires activation nor protection throughout the sequence.

Key words

7-azaindoles - heterocycles - alkynylation - cyclization - one-pot reaction

• References and Notes


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• 9 Typical Procedure for the Synthesis of 2-Phenyl-1H-pyrrolo[2,3-b]pyridine (4a): In a flame-dried Schlenk tube under nitrogen atmosphere, 3-bromopyridine-2-amine (1a; 173 mg, 1.00 mmol), Pd(PPh₃)₂Cl₂ (17.5 mg, 0.025 mmol), and (1-Ad)₂PBn·HBr (22.6 mg, 0.050 mmol) were dissolved in anhyd DMSO (1.50 mL). Phenylacetylene (2a; 122 mg, 1.20 mmol) and DBU (457 mg, 3.00 mmol) were added via syringe and the reaction mixture was stirred in a preheated oil bath at 100 °C until complete conversion of compound 1a (monitored by TLC). Then, KOt-Bu (281 mg, 2.5 mmol) and anhyd DMSO (1.00 mL) were added and the mixture was stirred at 100 °C until completion of the reaction (monitored by TLC). After cooling to r.t., de-ionized H₂O (2.00 mL) was added and the aqueous layer was extracted three times with EtOAc. The combined organic phases were first washed twice with de-ionized H₂O and then dried with anhyd Na₂SO₄. The solvents were removed under reduced pressure. The residue was adsorbed onto Celite^® and purified by column chromatography on a SNAP 100 g cartridge (EtOAc–n-hexane 33%) using a Biotage SP-1 flash chromatography purification system to give pure compound 4a as a colorless solid; yield: 173 mg (89%); mp 204.3 °C; R_f 0.54 (EtOAc–n-hexane, 1:1). IR (ATR): 1456 (m), 1281 (m), 750 (s), 685 (m), 675 (m), 648 (m), 625 (m) cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 6.79 (s, 1 H), 7.10 (dd, J = 4.8, 7.7 Hz, 1 H), 7.40 (t, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.92 (d, J = 7.8 Hz, 2 H), 7.96 (d, J = 7.7 Hz, 1 H), 8.31 (d, J = 4.8 Hz, 1 H), 12.94 (br s, 1 H). ¹³C NMR (150 MHz, CDCl₃ ): δ = 97.4 (CH), 116.1 (CH), 122.4 (C_quat), 126.0 (CH), 128.2 (CH), 128.7 (CH), 129.0 (CH), 132.5 (C_quat), 139.7 (C_quat), 142.1 (CH), 150.1 (C_quat). MS (EI+, 70 eV): m/z (%) = 195 (14), 194 (100) [M]⁺, 193 (14), 192 (6), 167 (7), 166 (8), 139 (5), 97 (7), 91 (8). Anal. Calcd for C₁₃H₁₀N₂ (194.2): C, 80.39; H, 5.19; N, 14.42. Found: C, 80.16; H, 4.92; N, 14.21.