Synthesis of Novel 1,2,3-Triazole-Dihydropyrimidinone Hybrids Using Multicomponent 1,3-Dipolar Cycloaddition (Click)–Biginelli Reactions: Anticancer Activity

Published as part of the ISySyCat2019 Special Issue

Abstract

In this work, 21 novel (1,4-disubstituted 1,2,3-triazole)-dihydropyrimidinone (1,2,3-trzl-DHPM) type hybrids were synthesized and characterized. These were divided into two types: hybrids A (5 in total) containing the dihydropyrimidinone heterocyclic ring decorated with a 1,4-disubstituted 1,2,3-triazole in the C-5 position [these compounds were accessed by a multicomponent copper(I)-catalyzed azide alkyne cycloaddition (CuAAC) (or click)–Biginelli reactions with satisfactory yields (39–57%)] and hybrids B (16 in total) containing two 1,2,3-triazole units in the C-5 and C-6 methyl position of the DHPM. Hybrids B were synthesized via functionalization of the C-6 methyl group of hybrids A, a multistep sequence of reactions was used that included bromination, azidation, and a CuAAC. Hybrids B were obtained in very good to excellent yields (up to 99%). Some hybrids A and B were evaluated for their antiproliferative activity against different cancer cell lines that included A549 and SW1573 (non-small-cell lung), HBL-100 and T-47D (breast), HeLa (cervix) and WiDr (colon). Three of these hybrids were potent cell proliferation inhibitors of non-small-cell lung cancer, cervix cancer, breast cancer, and colon cancer.

Key words

hybrids - 1,2,3-triazole - dihydropyrimidinone - click reaction - Biginelli reaction - one-pot - cancer - antiproliferative

• References and Notes

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• 11 General Procedure for One-Pot Syntheses of Hybrids A1–5 The reaction was carried out in a Biotage microwave reactor in a 20 mL vial equipped with a magnetic stirring bar. The reagents were added in the following order: CuI (45 mg, 0.24 mmol, 5 mol%), acetonitrile (MeCN, 3 mL) , DIPEA (34 μL, 0.2 mmol, 4%), acetic acid (11 μL, 0.2 mmol, 4%), phenylacetylene 2 (0.55 mL, 5 mmol, 1 equiv), 1-azidopropan-2-one (1, 500 mg, 5 mmol, 1 equiv) dissolved in 2 mL of MeCN. The benzaldehyde derivative 4a–e (5 mmol, 1 equiv) and the urea 5 (363 mg, 6 mmol, 1.2 equiv) were added immediately. The sealed-vial was placed in the reactor under the following conditions: 24 h, 90 °C, pre-stirring 60 s, normal adsorption. When the reaction was complete, the reaction mixture was poured onto 100 mL of ice-water, and after 2 h, the precipitated product was filtered off. Purification was achieved through crystallization. Compound A1: beige solid (949 mg, yield 57%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.69 (s, 3 H), 5.36 (s, 1 H, CH), 7.15 (d, J = 7 Hz, 2 H, Har), 7.24–7.34 (m, 4 H, Har), 7.42 (t, J = 8 Hz, 2 H, Har), 7.69 (s, 1 H, CHtrzl), 7.77 (d, J = 7.2 Hz, 2 H, Har), 8.46 (s, 1 H, NH), 8.89 (S, 1 H, NH) ppm. ¹³C-APT-NMR (100 MHz, DMSO-d ₆): δ = 14.6, 58.7, 108.0, 123.9, 125.6, 127.1, 128.4, 128.4, 129.0, 129.4, 130.8, 133.3, 142.6, 146.2, 152.4 ppm. HRMS (ESI-TOF): m/z calcd for C₁₉H₁₇N₅ONa [M + Na]⁺: 354.1325; found: 354.1335.
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• 15 General Procedure for the Synthesis of Brominated Intermediates 7a–e To a 50 mL round-bottom flask with a magnetic stirring bar, hybrids A1–5 (1 equiv), CH₂Cl₂ (15 mL), and TBABr₃ (1.5 equiv) were added. The mixture was stirred for 2 h. For the workup, a small amount of Na₂SO₃ was added to the reaction mixture, and it was extracted with a solution of sat. aq NaHCO₃. The organic layer was dried with MgSO₄, filtered, and concentrated under vacuum. The mixture was purified by column chromatography. Compound 7a: white solid (121 mg, yield 49%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.91 and 4.02 (2d, J = 11 Hz, 2 H, BrCH₂), 5.40 (d, J = 2 Hz, 1 H, CH-DHPM), 7.17 (d, J = 7 Hz, 2 H, Har), 7.25–7.35 (m, 4 H, Har), 7.44 (d, J = 7.5 Hz, 2 H, Har), 7.78 (d, J = 7 Hz, 2 H, Har), 7.86 (s, 1 H, Htrzl), 8.61 (s, 1 H, NH), 9.16 (d, J = 2 Hz, 1 H, NH) ppm. ¹³C APT NMR (100 MHz, DMSO-d ₆): δ = 24.54, 58.02, 110.11, 122.81, 125.20, 126.63, 128.20, 128.23, 128.72, 128.98, 130.04, 132.83, 141.31, 146.14, 151.82 ppm. HRMS (ESI-TOF): m/z calcd for C₁₉H₁₆BrN₅O [M + H]⁺: 410.0610; found: 410.0619.
• 16 General Procedure for the Synthesis of Azide Intermediates 8a–e The reaction was carried out in a Biotage microwave reactor in a 5 mL vial equipped with a magnetic stirrer. Added to the vial were the 1,2,3-trzl-DHPM-Br (7a–e), DMF (3 mL), and NaN₃ (1.5 equiv). The sealed vial was placed in the reactor under the following conditions: 30 min, 60 °C, pre-stirring 60 s, normal adsorption. When the reaction was complete, H₂O (5 mL) was added to the reaction mixture, and it was extracted with AcOEt. The organic layer was dried with MgSO4, filtered, and concentrated under vacuum. The crude product was purified by column chromatography and characterized. Compound 8a: white solid (135 mg, yield 88%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.82 and 3.91 (2 d, J = 14 Hz, 2 H, CH₂), 5.47 (d, J = 2 Hz, 1 H, CH-DHPM), 7.19 (d, J = 7 Hz, 2 H, Har), 7.25–7.37 (m, 4 H, Har), 7.43 (t, J = 7.6 Hz, 2 H, Har), 7.79 (d, J = 9 Hz, 2 H, Har), 7.88 (br s, 1 H, Htrzl), 8.63 (s, 1 H, NH), 9.24 (d, J = 2 Hz, 1 H, NH) ppm. ¹³C APT NMR (100 MHz, DMSO-d ₆): δ = 46.52, 58.02, 110.61, 123.10, 125.18, 126.66, 128.16, 128.22, 128.68, 128.96, 130.12, 130.96, 141.41, 146.27, 151.79 ppm. HRMS (ESI-TOF): m/z calcd for C₁₉H₁₆N₈ONa [M + Na]⁺: 395.1339; found: 395.1347.
• 17 General Procedure for the Synthesis of Hybrids B1–16 The reaction was carried out in a Biotage microwave reactor in a 3 mL vial equipped with a magnetic stirring bar. To the vial, CuSO₄·5H₂O (5 mol%), l-ascorbic acid (20 mol%), DMF (3 mL), 1,2,3-trzl-DHPM-N₃ (8a–e, 1 equiv) and alkyne 2, 9, 10, or 11 (1 equiv) were added. The sealed vial was placed in the reactor under the following conditions: 10 min, 90 °C, pre-stirring 60 s, normal adsorption. When the reaction was complete, AcOEt (5 mL) and H₂O (5 mL) were added to the reaction mixture, and this was extracted with AcOEt. The organic phase was collected and dried with MgSO₄, filtered, and concentrated under vacuum. The crude product was purified by recrystallization. Compound B1: beige solid (179 mg, yield 94%). Overall yield for the three-step reactions was 41%. ¹H NMR (400 MHz, DMSO-d ₆): δ = 5.01 and 5.14 (2 d, J = 15 Hz, 2 H, CH₂), 5.49 (d, J = 2 Hz, 1 H, CH-DHPM), 7.21–7.35 (m, 7 H, Har), 7.40–7.45 (m, 4 H, Har), 7.75 (d, J = 7.6 Hz, 2 H, Har), 7.80 (d, J = 8 Hz, 2 H, Har), 7.90 (s, 1 H, Htrzl), 8.43 (s, 1 H, Htrzl), 8.62 (s, 1 H, NH), 9.22 (d, J = 2 Hz, 1 H, NH) ppm. ¹³C APT NMR (100 MHz, DMSO-d ₆): 46.30, 58.19, 111.36, 121.97, 123.18, 125.19, 126.74, 128.01, 128.16, 128.26, 128.70, 128.96, 130.06, 130.09, 130.44, 141.31, 146.06, 146.24, 151.65 ppm. HRMS (ESI-TOF): m/z calcd for C₂₇H₂₂N₈ONa [M + Na]⁺: 497.1809; found: 497.1820.