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

• References and Notes

• 1a Fozard JR, Kalkman HO. Curr. Opin. Neurol. Neurosurg. 1992; 5: 595
• 1b Barnes NM, Sharp T. Neuropharmacology 1999; 38: 1083
• 1c Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois J.-M, Nomikos GG, Greengard P. Science 2006; 311: 77
• 2a Martin GR, Humphrey PP. A. Neuropharmacology 1994; 33: 261
• 2b Boess FG, Martin IL. Neuropharmacology 1994; 33: 275
• 2c Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, Saxena PR, Humphrey PP. Pharmacol. Rev. 1994; 46: 157
• 2d Villalón CM, de Vries P, Saxena PR. Drug Discovery Today 1997; 2: 294
• 3a Flaugh ME, Mullen DL, Fuller RW, Mason NR. J. Med. Chem. 1988; 31: 1746
• 3b Malleron JL, Guérémy C, Mignani S, Peyronel JF, Truchon A, Blanchard JC, Doble A, Laduron P, Piot O, Zundel J.-L, Betachart J, Canard H, Chaillou P, Ferris O, Huon C, Just B, Kerphirique R, Martin B, Mouton P, Renaudon A. J. Med. Chem. 1993; 36: 1194
• 3c Mattson RJ, Catt JD, Denhart DJ, Deskus JA, Ditta JL, Higgins MA, Marcin LR, Sloan CP, Beno BR, Gao Q, Cunningham MA, Mattson GK, Molski TF, Taber MT, Lodge NJ. J. Med. Chem. 2005; 48: 6023
• 4a Cassone VM. Trends Neurosci. 1990; 13: 457
• 4b Shochat T, Haimov I, Lavie P. Ann. Med. (Abingdon U. K.) 1998; 30: 109
• 5 Oishi A, Cecon E, Jockers R. Int. Rev. Cell Mol. Biol. 2018; 338: 59
• 6a Uchikawa O, Fukatsu K, Tokunoh R, Kawada M, Matsumoto K, Imai Y, Hinuma S, Kato K, Nishikawa H, Hirai K, Miyamoto M, Ohkawa S. J. Med. Chem. 2002; 45: 4222
• 6b Uchiyama M, Hamanuma M, Kuwano T, Nishiyama H, Nagata H, Uchimura N. Sleep Med. 2011; 12: 119
• 6c Kuriyama A, Honda M, Hayashino Y. Sleep Med. 2014; 15: 385
• 7a Lavedan C, Forsberg N, Gentile AJ. Neuropharmacology 2015; 91: 142
• 7b Keating GM. CNS Drugs 2016; 30: 461
• 8 Wu P.-W, Hsieh W.-T, Cheng Y.-M, Wei C.-Y, Chou P.-T. J. Am. Chem. Soc. 2006; 128: 14426
• 9 Wu P.-W, Cheng Y.-M, Hsieh W.-T, Wang Y.-H, Wei C.-Y, Chou P.-T. ChemMedChem 2007; 2: 1071
• 10 Mazéas D, Guillaumet G, Viaud M.-C. Heterocycles 1999; 50: 1065
• 11 Abe T, Suzuki T, Anada M, Matsunaga S, Yamada K. Org. Lett. 2017; 19: 4275
• 12 Yamada K, Mishima N, Saito K, Nishi T. Tetrahedron 2021; 97: 132404
• 13 Abe T, Yamada K. Org. Lett. 2018; 20: 1469
• 14 Dumas AM, Fillion E. Acc. Chem. Res. 2010; 43: 440
• 15 Barl NM, Malakhov V, Mathes C, Lustenburger P, Knochel P. Synthesis 2015; 47: 692
• 16 Chen D, Chen Y, Ma Z, Zou L, Li J, Li Y. J. Org. Chem. 2018; 83: 6805
• 17 Staudinger H, Mater J. Helv. Chim. Acta 1919; 2: 635
• 18 Bajwa JS, Chen G.-P, Prasad K, Repić O, Blacklock TJ. Tetrahedron Lett. 2006; 47: 6425
• 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.