Synthesis of Eleven-Membered Cyclic Urea Fused Quinazolinones

Abstract

Straightforward synthesis of quinazolinones having N-fused medium-sized ring urea was accomplished. Key intermediates were tert-butyl {2-[4-oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamates derived from copper-catalyzed domino reaction of tert-butyl [2-(2-iodobenzamido)ethyl]carbamates and cyclic enaminones. Steric hindrance of cyclic enaminones played an important role in the formation of quinazolinone ring. The eleven-membered ring urea moiety was readily achieved by direct cyclization using 1,1′-carbonyldiimidazole (CDI) of diamino intermediate generated by readily reductive amination and deprotection of tert-butyl {2-[4-oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamates.

Key words

tricyclic quinazolinones - copper-catalyzed domino reaction - C–N bond formation - medium-sized ring heterocycles - cyclic ureas

Publication History

Received: 14 February 2022

Accepted after revision: 09 March 2022

Accepted Manuscript online:
09 March 2022

Article published online:
20 April 2022

• References and Notes

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• 10 General Procedure B: Synthesis of Quinazolinones Prepared according to modified procedure reported by Songsichan.⁴ A sealed tube equipped with a magnetic stirring bar was charged with 2-iodobenzamides 1 (0.5 mmol), cyclic enaminones 2 (0.6 mmol), CuI (5 mol%), 1,2-trans-diaminocyclohexane (10 mol%), and K₃PO₄ (1.25 mmol) in THF (2.5 mL). The resulting mixture was stirred at 90 °C for 15 h. After that, the resulting mixture was cooled to room temperature, quenched with sat. NH₄Cl, and extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (CH₂Cl₂/EtOAc, 5:1) to provide quinazolinone products 3.
• 11 Analytical Data for tert-Butyl {2-[4-Oxo-2-(4-oxopentyl)quinazolin-3(4H)-yl]ethyl}carbamate 3a Prepared according to general procedure B. Yield 88% as a white solid. ¹H NMR (300 MHz, CDCl₃): δ = 8.22 (d, J = 7.6 Hz, 1 H), 7.71 (t, J = 7.6 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H), 5.24 (br s, 1 H), 4.27 (t, J = 6.2 Hz, 2 H), 3.48 (q, J = 6.2 Hz, 2 H), 2.92 (t, J = 6.8 Hz, 2 H) 2.66 (t, J = 6.8 Hz, 2 H), 2.28–2.04 (m, 5 H), 1.38 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 208.3, 162.6, 156.4, 156.2, 147.2, 134.2, 126.9, 126.6, 126.4, 120.3, 79.6, 43.1, 42.4, 39.2, 33.8, 30.0, 28.3, 21.0. IR (thin film): ν = 3258, 2935, 1710, 1666, 1593, 1366, 1250, 1170, 774 cm^–1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₀H₂₇N₃O₄: 396.1899; found: 396.1899.
• 12 General Procedure C: Synthesis of Quinazolinone-Fused Eleven-Membered Ring Ureas To a solution of quinazolinone 3 (0.6 mmol) and benzylamine (0.9 mmol) in CH₂Cl₂ (6 mL) was added sodium triacetoxyborohydride (STABH, 1.2 mmol) and acetic acid (18.0 μL). The resulting mixture was stirred at room temperature under a N₂ atmosphere for 24 h. After that, the resulting mixture was quenched by adding 1.0 N NaOH and extracted with CH₂Cl₂ (3 × 10.0 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated. Then, to the crude mixture in CH₂Cl₂ (3.0 mL) was added trifluoroacetic acid (3.0 mL). The mixture was stirred at room temperature under a N₂ atmosphere for 2 h. After that, the resulting mixture was quenched by adding 1.0 N NaOH and extracted with CH₂Cl₂ (3 × 10.0 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to give amine crude. Then, the crude mixture in t-BuOH (30.0 mL) was stirred at room temperature. CDI (0.72 mmol) was added in the reaction mixture at room temperature and stirred at room temperature for 18 h. After that, t-BuOH was evaporated in vacuo. The resulting mixture was quenched with sat. NH₄Cl and extracted with EtOAc (3 × 10.0 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (EtOAc/MeOH, 9:1) to provide quinazolinone-fused eleven-membered-ring ureas 5.
• 13 Analytical Data for 5-Benzyl-6-methyl-2,3,6,7,8,9-hexahydro-[1,3,6]triazacycloundecino[7,6-b]quinazoline-4,15(1H,5H)-dione (5a) Prepared according to general procedure C. Yield 60% as a white solid. ¹H NMR (300 MHz, CDCl₃ + CD₃OD 2 drops): δ = 8.25 (d, J = 7.5 Hz, 1 H), 7.71 (t, J = 7.5 Hz, 1 H), 7.59 (d, J = 7.5 Hz, 1 H), 7.43 (t, J = 7.5 Hz, 1 H), 7.42–7.45 (m, 5 H), 4.78 (d, J = 14.7 Hz, 1 H), 4.58 (d, J = 14.4 Hz, 1 H), 4.45 (m, 1 H), 4.30 (d, J = 14.7 Hz, 1 H), 4.20–4.05 (m, 2 H), 3.53–3.38 (m, 1 H), 3.36–3.20 (m, 1 H), 2.96–2.80 (m, 1 H), 2.63–2.52 (m, 1 H), 2.45–2.28 (m, 1 H), 1.70–1.52 (m, 1 H), 1.51–1.38 (m, 1 H), 1.20–1.11 (m, 1 H), 1.07 (d, J = 6.9 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃ + CD₃OD 2 drops): δ = 162.7, 158.2, 158.0, 147.3, 139.0, 134.5, 129.0, 128.6 (3 C), 127.7, 126.8 (2 C), 126.5, 120.2, 54.5, 52.8, 43.8, 40.3, 31.4, 30.8, 24.5, 20.1. IR (thin film): ν = 3351, 2931, 1661, 1537, 1453, 1305, 1167, 769, 728, 698 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₆N₄O₂: 391.2129; found: 391.2129.