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Synlett 2022; 33(20): 2033-2037
DOI: 10.1055/s-0041-1738758
letter

Practical Synthesis of 7-Azaserotonin and 7-Azamelatonin

Ren Fukuya
,
Koji Yamada
,
Takahide Nishi  ∗
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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0041-1738758.
  • Supporting Information


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.