Practical Synthesis of 7-Azaserotonin and 7-Azamelatonin

Abstract

A practical method for synthesizing 7-azaserotonin and 7-azamelatonin was developed by using 3-bromo-5-methoxy-1-tosyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ol as a starting material. This compound is a useful reactant for the formal C3-electrophilic reaction. The lactone derivative obtained by the reaction with Meldrum’s acid was used as a key intermediate, in which the C₂ unit was introduced into the 7-azaindole skeleton.

Key words

azaserotonin - azamelatonin - medicinal chemistry

Publication History

Received: 19 August 2022

Accepted after revision: 06 September 2022

Article published online:
18 October 2022

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• 19 (3aR*,8aR*)-5-Methoxy-8-tosyl-3,3a,8,8a-tetrahydro-2H-furo[3′,2′:4,5]pyrrole[2,3-b]pyridin-2-one (10b): Typical ProcedureEt₃N (1.89 mL, 13.6 mmol) was added to a solution of compound 8b (1.80 g, 4.51 mmol) and Meldrum’s acid (1.95 g, 13.5 mmol) in EtOAc (80 mL), and the mixture was stirred at 80 °C for 6 h. The mixture was then diluted with brine and extracted with EtOAc. The organic layer was dried (MgSO₄) and concentrated in vacuo, and the residue was purified by flash column chromatography [silica gel, hexane–EtOAc (5:1 to 1:2)] to give a white solid; yield: 889mg (55%); mp 148–149 °C.¹H NMR (500 MHz, CDCl₃): δ = 8.10 (d, J = 8.6 Hz, 2 H), 7.86 (d, J = 2.9 Hz, 1 H), 7.30 (d, J = 8.6 Hz, 2 H), 7.05 (dd, J = 2.9 and 1.2 Hz, 1 H), 6.74 (d, J = 6.3 Hz, 1 H), 4.16 (m, 1 H), 3.78 (s, 3 H), 3.10 (dd, J = 18.3 and 10.3 Hz, 1 H), 2.69 (dd, J = 18.3 and 1.7 Hz, 1 H), 2.39 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 173.1, 153.4, 147.8, 144.8, 136.0, 134.1, 129.5, 128.7, 124.6, 121.4, 92.5, 56.4, 39.1, 33.7, 21.8. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₆N₂NaO₅S: 383.0678; found: 383.0691.3-(2-Aminoethyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (7-Azaserotonin) (3): Typical ProcedureCompound 14d (400 mg, 1.16 mmol) was treated with Cs₂CO₃ (1.13 g, 3.47 mmol) in THF (20 mL) and MeOH (10 mL) at 80 °C for 24h. The solvent was removed in vacuo, and the residue was diluted with brine and extracted with EtOAc. The organic layer was then dried (MgSO₄) and concentratedin vacuo.The residue was dissolved in DCE (5 mL), and a 1.0 M solution of BBr₃ in ­CH₂Cl₂ (9.26 mL, 9.26 mmol) was added dropwise at –78 °C. The mixture was stirred overnight at rt, then diluted with H₂O and neutralized with 10% NaOH. The solvent was removed in vacuo, and the residue was purified by preparative TLC [CHCl₃–MeOH–aq. NH₃ (10:4:1)] to give a pale-brown amorphous solid; yield: 178 mg (87%).¹H NMR (500 MHz, CD₃OD): δ = 7.85 (d, J = 2.3 Hz, 1 H), 7.46 (d, J = 2.3 Hz, 1 H), 7.28 (s, 1 H), 3.21 (t, J = 7.5 Hz, 2 H), 3.05 (t, J = 7.5 Hz, 2 H). ¹³C NMR (125 MHz, CD₃OD): δ = 148.1, 143.1, 131.5, 125.2, 120.6, 112.7, 107.5, 39.6, 23.1. HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₂N₃O: 178.0980; found: 178.0976. N-[2-(5-Methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide (7-Azamelatonin) (4): Typical ProcedureCs₂CO₃ (547 mg, 1.68 mmol) was added to a solution of compound 15d (217 mg, 0.56 mmol) in THF (18 mL) and MeOH (9 mL), and the mixture was stirred at 80°C for 24h. The solvent was removed in vacuo, and the residue was diluted with brine (50 mL) and then extracted with EtOAc. The organic layer was dried (MgSO₄) and concentratedin vacuo, and the residue was crystallized from i-Pr₂O to give a white solid; yield: 115 mg (88%); mp 165–167 °C.¹H NMR (500 MHz, CDCl₃): δ = 9.95 (br s, 1 H), 8.07 (d, J = 2.3 Hz, 1 H), 7.41 (d, J = 2.3 Hz, 1 H), 7.14 (d, J = 2.3 Hz, 1 H), 5.67 (br s, 1 H), 3.88 (s, 3 H), 3.56 (q, J = 6.9 Hz, 2 H), 2.92 (t, J = 6.9 Hz, 2 H), 1.93 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 170.2, 151.3, 144.3, 133.9, 123.4, 119.8, 111.3, 110.1, 56.6, 39.8, 25.6, 23.5. HRMS (ESI): calcd for C₁₂H₁₅N₃NaO₂ [M+Na]+ 256.1062; found, 256.1050.