Synthesis of Bioderived Cinnolines and Their Flow-Based Conversion into 1,4-Dihydrocinnoline Derivatives

Published as part of the Special Section 11^th EuCheMS Organic Division Young Investigator Workshop

Abstract

Starting from phenylhydrazine and glucose, a versatile cinnoline scaffold was obtained on a multigram scale and further derivatized. A simple continuous-flow hydrogenation process permits the conversion of selected cinnolines into their 1,4-dihydrocinnoline counterparts. These products are generated in high yields and high purities with residence times of less than one minute and, along with their cinnoline precursors, are expected to serve as valuable heterocyclic building blocks for future medicinal chemistry programs.

Key words

flow synthesis - cinnolines - dihydrocinnolines - hydrogenation

• References and Notes

• 1a Taylor AP, Robinson RP, Fobian YM, Blakemore DC, Jones LH, Fadeyi O. Org. Biomol. Chem. 2016; 14: 6611
• 1b Taylor RD, MacCoss M, Lawson AD. G. J. Med. Chem. 2017; 60: 1638
• 1c Taylor RD, MacCoss M, Lawson AD. G. J. Med. Chem. 2014; 57: 5845
• 1d Baumann M, Baxendale IR. Beilstein J. Org. Chem. 2013; 9: 2265
• 2a Vinogradova OV, Balova IA. Chem. Heterocycl. Compd. 2008; 44: 501
• 2b Szumilak M, Stanczak A. Molecules 2019; 24: 2271
• 2c Lewgowd W, Stanczak A. Arch. Pharm (Weinheim, Ger.) 2007; 340: 65
• 2d Sadek KU, Mekheimer RA, Abd-Elmonem M. Mini-Rev. Org. Chem. 2019; 16: 578

For recent examples of heterocycle syntheses based on carbohydrates, see:
• 3a El Ashry ES. H, El Kilany Y, Nahas NM. Top. Heterocycl. Chem. 2007; 7: 1
• 3b Baumann M, Baxendale IR. Org. Lett. 2014; 16: 6076
• 3c Baumann M, Baxendale IR. Eur. J. Org. Chem. 2017; 6518
• 4a Fischer E. Ber. Dtsch. Chem. Ges 1884; 17: 579
• 4b Fischer E. Ber. Dtsch. Chem. Ges. 1887; 20: 821
• 4c Fischer E. Ber. Dtsch. Chem. Ges 1894; 27: 2486
• 4d Fischer E. Ber. Dtsch. Chem. Ges. 1908; 41: 73
• 5 Mester L, El Khadem H, Horton D. J. Chem. Soc. C 1970; 2567
• 6a Barry VC, Mitchell PW. D. Nature 1955; 175: 220
• 6b Hassner A, Catsoulacos P. Tetrahedron Lett. 1967; 8: 489
• 6c Dyong I, Bertram HP. Chem. Ber. 1973; 106: 1743
• 6d Shemyakin MM, Maimind VI, Ermolaev KM, Bamdas EM. Tetrahedron 1965; 21: 2771
• 6e Simon H, Kraus A. In Synthetic Methods for Carbohydrate: ACS Symp. Ser., Vol. 39. El Khadem HS. American Chemical Society; Washington DC: 1977. Chap. 11, 188
• 7 During these studies an analogous experiment using d-fructose instead of d-glucose was performed, yielding the identical osazone species in 86% yield (see Supporting Information for details).
• 8 (1R,2S,3R)-1-Cinnolin-3-ylbutane-1,2,3,4-tetrol (9)A mixture of d-glucose (12.0 g, 66 mmol) and phenylhydrazine (39.9 g, 369 mmol) was heated in 1 M aq HCl (180 mL) at 95–100 °C for 2–3 h. After cooling to rt, the yellow precipitate of osazone 8 was collected by suction filtration and washed with cold MeCN (yield: 40–50%). The aqueous filtrate was basified to pH 11 with 8 M aq NaOH and extracted with CH₂Cl₂ (3 × 50 mL). The aqueous layer was neutralized with aq HCl, leading to slow crystallization of the desired product 9 as a beige solid (yield: ~20%); this process that could be accelerated by directing a stream of N₂ over the solution.IR (neat): 3178 (s), 2935 (w), 2832 (w), 1434 (w), 1411 (w), 1090 (s), 1046 (s) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.42 (d, J = 8.6 Hz, 1 H), 8.16 (s, 1 H), 8.06 (dd, J = 8.1, 1.3 Hz, 1 H), 7.87 (ddd, J = 8.5, 6.6, 1.6 Hz, 1 H), 7.84–7.79 (m, 1 H), 5.48 (br s, 2 H), 4.73 (br s, 1 H), 4.40 (br s, 2 H), 3.81 (d, J = 8.5 Hz, 1 H), 3.73–3.61 (m, 2 H), 3.46 (dd, J = 11.3, 6.1 Hz, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 160.5 (C), 149.8 (C), 131.5 (CH), 130.7 (CH), 129.2 (CH), 127.7 (CH), 126.3 (C), 120.9 (CH), 74.7 (CH), 71.9 (CH), 71.8 (CH), 64.1 (CH₂). HRMS (ES-TOF)⁺: m/z [M + H]⁺ calcd for C₁₂H₁₅N₂O₄: 251.1032; found: 251.1030.
• 9 Cinnoline-3-carbaldehyde (10)To a suspension of KIO₄ (3.5 equiv.) in H₂O (0.7 M) was added a mixture of glucocinnoline 9 (1.0 equiv) in CH₂Cl₂ (0.5 M). The resulting biphasic mixture was stirred vigorously at rt until the starting material was consumed (TLC; 2–3 h). Upon filtration of the organic phase through a plug of silica and evaporation, the desired aldehyde product 10 was isolated as a pale-brown solid in 75–80% yield.IR (neat): 3047 (w), 2846 (w), 1711 (s), 1479 (m), 1362 (m), 1154 (m), 766 (s), 752 (s) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 10.69 (s, 1 H), 8.65 (d, J = 9.0 Hz, 1 H), 8.49 (d, J = 1.0 Hz, 1 H), 8.05–7.98 (m, 2 H), 7.86 (ddd, J = 8.1, 7.0, 1.2 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 192.6 (CH), 151.8 (C), 149.5 (C), 133.3 (CH), 132.2 (CH), 130.1 (CH), 128.4 (CH), 125.4 (C), 122.2 (CH). HRMS (ES-TOF)⁺: m/z [M + H]⁺ calcd for C₉H₇N₂O: 159.0558; found: 159.0552.
• 10 Cinnoline Enone Adducts 11a–f; General ProcedureA solution of NaOH (1 equiv) in 50:50 EtOH–H₂O (0.5 M) was added to a mixture of cinnoline-3-carbaldehyde (10; 1 equiv) and the appropriate acetophenone (1 equiv) in MeCN (0.5 M). The mixture was stirred at rt, leading to precipitation within 1 h of the desired product, which was isolated by suction filtration.(2E)-3-Cinnolin-3-yl-1-(4-methoxyphenyl)prop-2-en-1-one (11a)Yellow solid; yield: 240 mg (79%); mp 164 °C (dec). IR (neat): 2988 (m), 1660 (m), 1596 (s), 1305 (m), 1261 (s), 1163 (s), 1021 (s), 825 (s), 740 (s), 597 (m) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.62 (d, J = 15.3 Hz, 1 H), 8.59–8.56 (m, 1 H), 8.16 (d, J = 8.8 Hz, 2 H), 8.01 (d, J = 15.3 Hz, 1 H), 7.90 (d, J = 0.8 Hz, 1 H), 7.89–7.83 (m, 2 H), 7.80–7.74 (m, 1 H), 6.99 (d, J = 8.9 Hz, 2 H), 3.89 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 188.3 (C), 163.8 (C), 150.3 (C), 149.7 (C), 139.2 (CH), 131.7 (CH), 131.2 (2CH), 131.1 (CH), 130.7 (C), 130.2 (CH), 127.1 (CH), 126.3 (CH), 125.9 (C), 123.4 (CH), 114.0 (2CH), 55.5 (CH₃). HRMS (ES-TOF)⁺: m/z [M + Na]⁺ calcd for C₁₈H₁₄N₂NaO₂: 313.0953; found: 313.0951.(2E)-1-(1,3-Benzodioxol-5-yl)-3-cinnolin-3-ylprop-2-en-1-one (11b)Beige solid; yield: 227 mg (75%); IR (neat): 3058 (w), 1664 (m), 1622 (m), 1598 (m), 1579 (m), 1506 (s), 1441 (s), 1358 (s), 1269 (s), 1094 (s), 1033 (s), 734 (s) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.62 (d, J = 8.3 Hz, 1 H), 8.60 (d, J = 15.1 Hz, 1 H), 8.04 (d, J = 15.1 Hz, 1 H), 7.94 (s, 1 H), 7.93–7.88 (m, 2 H), 7.86–7.79 (m, 2 H), 7.65 (d, J = 1.8 Hz, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 6.10 (s, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 188.0 (C), 152.2 (C), 150.3 (C), 149.6 (C), 148.5 (C), 139.5 (CH), 132.7 (C), 131.8 (CH), 131.2 (CH), 130.2 (CH), 127.1 (CH), 126.2 (CH), 125.9 (C), 125.4 (CH), 123.5 (CH), 108.5 (CH), 108.1 (CH), 102.0 (CH₂). HRMS (ES-TOF)⁺: m/z [M + H]⁺ calcd for C₁₈H₁₃N₂O₃: 305.0926; found: 305.0925.
• 11a Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 117: 11796
• 11b Dallinger D, Kappe CO. Curr. Opin. Green Sustainable Chem. 2017; 7: 6
• 11c Jensen KF. AIChE J. 2017; 63: 858
• 11d Fitzpatrick DE, Ley SV. Tetrahedron 2018; 74: 3087
• 11e Baumann M, Baxendale IR. Beilstein J. Org. Chem. 2015; 11: 1194
• 11f Lummiss JA. M, Morse PD, Beingessner RL, Jamison TF. Chem. Rec. 2017; 17: 667
• 11g Bogdan AR, Dombrowski AW. J. Med. Chem. 2019; 62: 6422
• 11h Movsisyan M, Delbeke EI. P, Berton JK. E. T, Battilocchio C, Ley SV, Stevens CV. Chem. Soc. Rev. 2016; 45: 4892
• 11i Baumann M. Org. Biomol. Chem. 2018; 16: 5946
• 12a Bryan MC, Wernick D, Hein CD, Petersen JV, Eschelbach JW, Doherty EM. Beilstein J. Org. Chem. 2011; 7: 1141
• 12b Saaby S, Rahbek Knudsen K, Ladlow M, Ley SV. Chem. Commun. 2005; 2909
• 12c Rahbek Knudsen K, Holden J, Ley SV, Ladlow M. Adv. Synth. Catal. 2007; 349: 535
• 12d Jones RV, Godorhazy L, Varga N, Szalay D, Urge L, Darvas F. J. Comb. Chem. 2006; 8: 110
• 12e Viviano M, Glasnov TN, Reichart B, Tekautz G, Kappe CO. Org. Process Res. Dev. 2011; 15: 858
• 12f Dalla-Vechia L, Reichart B, Glasnov T, Miranda LS. M, Kappe CO, de Souza RO. M. A. Org. Biomol. Chem. 2013; 11: 6806
• 12g Baumann M, Baxendale IR, Hornung CH, Ley SV, Rojo MV, Roper KA. Molecules 2014; 19: 9736
• 12h Fabry DC, Heddrich S, Sugiono E, Liauw MA, Rueping M. React. Chem. Eng. 2019; 4: 1486
• 13 CCDC 1959846 and 1959846 contain the supplementary crystallographic data for compounds 12a and 12c. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 14 1,4-Dihydrocinnolines 12a–fA 0.25 M stock solution of the appropriate substrate 11a–f in 1:1 EtOH–EtOAc was prepared and passed through an H-Cube Mini flow reactor equipped with a suitable catalyst cartridge (10% Pd/C, 50 mm, rt) at a flow rate of 1 mL/min. The solvent was evaporated from the resulting solution and residual solvent was removed in vacuo before ¹H NMR analysis.3-(1,4-Dihydrocinnolin-3-yl)-1-(4-methoxyphenyl)propan-1-one (12a)Beige solid; yield: 135 mg (92%); IR (neat): 3303 (m), 2922 (m), 1673 (s), 1596 (s), 1487 (s), 1306 (m), 1261 (s), 1210 (s), 1164 (s), 1023 (m), 984 (m), 836 (s), 749 (s) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.97 (d, J = 9.0 Hz, 2 H), 7.21 (s, 1 H), 7.10 (td, J = 7.7, 1.5 Hz, 1 H), 7.03–7.00 (m, 1 H), 6.94–6.88 (m, 3 H), 6.65 (dd, J = 7.8, 1.1 Hz, 1 H), 3.85 (s, 3 H), 3.31 (s, 2 H), 3.28–3.23 (m, 2 H), 2.73 (dd, J = 7.9, 6.5 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 197.7 (C), 163.4 (C), 145.7 (C), 140.2 (C), 130.3 (2CH), 130.0 (C), 127.6 (CH), 127.0 (CH), 122.1 (CH), 116.2 (C), 113.7 (2CH), 111.7 (CH), 55.4 (CH₃), 34.1 (CH₂), 30.5 (CH₂), 30.2 (CH₂). HRMS (ES-TOF)⁺: m/z [M + H]⁺ calcd for C₁₈H₁₉N₂O₂: 295.1447; found: 295.1438. X-ray data for C₁₈H₁₈N₂O₂: space group P21/c; a = 15.4438(2) Å, b = 4.67192(6) Å, c = 21.2967(3) Å, β = 106.399(2)°.1-(1,3-Benzodioxol-5-yl)-3-(1,4-dihydrocinnolin-3-yl)propan-1-one (12b)Beige solid; yield: 132 mg, 87%. IR (neat): 3365 (m), 2903 (m), 1673 (m), 1600 (m), 1503 (m), 1485 (m), 1442 (s), 1250 (s), 1037 (m), 933 (m), 753 (m) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.60 (dd, J = 8.1, 1.7 Hz, 1 H), 7.46 (d, J = 1.8 Hz, 1 H), 7.18 (s, 1 H), 7.10 (td, J = 7.6, 1.5 Hz, 1 H), 7.01 (d, J = 7.4 Hz, 1 H), 6.91 (td, J = 7.4, 1.2 Hz, 1 H), 6.83 (d, J = 8.1 Hz, 1 H), 6.65 (dd, J = 8.0, 1.2 Hz, 1 H), 6.02 (s, 2 H), 3.31 (s, 2 H), 3.25–3.20 (m, 2 H), 2.72 (t, J = 7.1 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 197.2 (C), 151.6 (C), 148.1 (C), 145.5 (C), 140.2 (C), 131.8 (C), 127.6 (CH), 127.0 (CH), 124.3 (CH), 122.2 (CH), 116.2 (CH), 111.7 (CH), 107.9 (CH), 107.8 (CH), 101.8 (CH₂), 34.2 (CH₂), 30.5 (CH₂), 30.2 (CH₂). HRMS (ES-TOF)⁺: m/z [M + H]⁺ calcd for C₁₈H₁₇N₂O₃: 309.1234; found: 309.1239.

For alternative routes to 1,4-dihydrocinnolines, see:
• 15a Besford LS, Malcolm BJ. J. Chem. Soc. 1964; 4037
• 15b Hazard R, Tallec A. Bull. Soc. Chim. Fr. 1976; 433
• 15c Frontana-Uribe BA, Moinet C, Toupet L. Eur. J. Org. Chem. 1999; 419
• 15d Somei M, Ura K. Chem. Lett. 1978; 7: 707
• 15e Hasegawa K, Kimura N, Arai S, Nishida A. J. Org. Chem. 2008; 73: 6363
• 16 1,4-Dihydrocinnolines 13 and 14a–d; General ProcedureA stock 0.25 M solution of substrate 10 in 1:1 EtOH–EtOAc was prepared and passed through an H-Cube Mini flow reactor equipped with a suitable catalyst cartridge (10% Pd/C, 50 mm, rt) at a flow rate of 1 mL min^–1. The solvent was evaporated from the resulting solution and residual solvent was removed in vacuo before ¹H NMR analysis. In case of the reductive amination products 14, the desired amine component (1.1 equiv) was added to the stock solution of aldehyde 10, and the mixture was stirred at 50 °C for 30 min before passing it through the H-Cube Mini reactor under similar conditions to those described above.1,4-Dihydrocinnoline-3-carbaldehyde (13) Yellow solid; yield: 140 mg (87%); IR (neat): 3266 (m), 3016 (w), 2818 (w), 1649 (s), 1579 (m), 1481 (m), 1349 (m), 1254 (m), 1178 (s), 722 (m) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.46 (s, 1 H), 8.27 (s, 1 H), 7.14 (td, J = 7.5, 1.6 Hz, 1 H), 7.06 (dd, J = 7.3, 1.5 Hz, 1 H), 7.04–6.98 (m, 1 H), 6.71 (d, J = 8.2 Hz, 1 H), 3.62 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 190.6 (CH), 141.4 (C), 136.5 (C), 129.0 (CH), 127.7 (CH), 124.8 (CH), 116.8 (C), 112.7 (CH), 21.9 (CH₂). HRMS (ES-TOF): m/z [M + H]⁺ calcd for C₉H₉N₂O: 161.0715; found: 161.0714. (1,4-Dihydrocinnolin-3-ylmethyl)(4-fluorobenzyl)amine (14a)Yellow oil: yield: 104 mg (78%). IR (neat): 3291 (m), 2839 (m), 1597 (m), 1507 (s), 1475 (s), 1344 (m), 1253 (s), 1155 (m), 1092 (m), 823 (s), 751 (s) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.32–7.28 (m, 3 H), 7.13 (t, J = 7.5 Hz, 1 H), 7.03 (d, J = 7.6 Hz, 1 H), 7.00 (t, J = 8.4 Hz, 2 H), 6.94 (t, J = 7.3 Hz, 1 H), 6.70 (d, J = 7.9 Hz, 1 H), 3.78 (s, 2 H), 3.45 (s, 2 H), 3.32 (s, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 162.0 (CF, d, J = 245 Hz), 144.8 (C), 140.2 (C), 135.7 (C), 129.8 (2CH, d, J = 8 Hz), 127.7 (CH), 127.1 (CH), 122.4 (CH), 116.1 (C), 115.2 (2CH, d, J = 21 Hz), 111.8 (CH), 53.4 (CH₂), 52.6 (CH₂), 28.2 (CH₂). ¹⁹F NMR (471 MHz, CDCl₃): δ = –116.0. HRMS (ES-TOF)⁺: m/z [M + H]⁺ calcd for C₁₆H₁₇FN₃: 270.1407; found: 270.1395.