Synlett
DOI: 10.1055/s-0039-1690752
letter
© Georg Thieme Verlag Stuttgart · New York

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

Jonathan Devlin
,
Richard Clogher
,
School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland   Email: marcus.baumann@ucd.ie
› Author Affiliations
This work was generously supported by seed funding provided by University College Dublin (SF1606 and SF1609).
Further Information

Publication History

Received: 21 October 2019

Accepted after revision: 03 November 2019

Publication Date:
12 November 2019 (online)


Published as part of the Special Section 11th 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.

Supporting Information

 
  • References and Notes

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  • 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 11af; 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.
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  • 14 1,4-Dihydrocinnolines 12afA 0.25 M stock solution of the appropriate substrate 11af 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:
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  • 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.