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Synlett 2016; 27(18): 2606-2610
DOI: 10.1055/s-0035-1562794
letter
© Georg Thieme Verlag Stuttgart · New York

Transition-Metal-Free Cross-Dehydrogenative Coupling of Triazines with 5,7-Dihydroxycoumarins

Igor A. Khalymbadzha*
a   Department of Organic and Biomolecular Chemistry, Ural Federal University, Mira 19, 620002 Ekaterinburg, Russian Federation   Email: i.a.khalymbadzha@urfu.ru
,
Oleg N. Chupakhin
a   Department of Organic and Biomolecular Chemistry, Ural Federal University, Mira 19, 620002 Ekaterinburg, Russian Federation   Email: i.a.khalymbadzha@urfu.ru
b   Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Kovalevskoy 22, 620219 Ekaterinburg, Russian Federation
,
Ramil F. Fatykhov
a   Department of Organic and Biomolecular Chemistry, Ural Federal University, Mira 19, 620002 Ekaterinburg, Russian Federation   Email: i.a.khalymbadzha@urfu.ru
,
Valery N. Charushin
a   Department of Organic and Biomolecular Chemistry, Ural Federal University, Mira 19, 620002 Ekaterinburg, Russian Federation   Email: i.a.khalymbadzha@urfu.ru
b   Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Kovalevskoy 22, 620219 Ekaterinburg, Russian Federation
,
Alexander V. Schepochkin
b   Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Kovalevskoy 22, 620219 Ekaterinburg, Russian Federation
,
Victor G. Kartsev
c   InterBioScreen Ltd., Institutsky Prospect 7a, 142432 Chernogolovka, Russian Federation
› Author Affiliations
Further Information

Publication History

Received: 20 June 2016

Accepted after revision: 28 July 2016

Publication Date:
16 August 2016 (online)

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Abstract

A new method for the direct metal-free C–H functionalization of electron-deficient triazines with fragments of naturally occurring and synthetic 5,7-dihydroxycoumarins is reported. It has been found that the reaction of 5,7-dihydroxycoumarins with triazines proceeds under mild conditions, showing a high chemo- and regioselectivity.

Key words

C–H arylation - dehydrogenative coupling - triazines - halogen-free metal-free reaction

Supporting Information

 

  • References and Notes

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  • 15 General Procedure for the Addition of 5,7-Dihydroxycoumarins 5a–e to Triazines 6a and 6b (Procedure A) To a MeOH solution (15 mL) or suspension of 5 (1 mmol) and 6a or 6b (1 mmol), BF3·OEt2 (1 mL) was carefully added. The mixture was heated under reflux with stirring for 4 h, while ­dissolution of the starting materials, followed by precipitation of product (for 7a–e), was observed. In the case of products 8a–e the reaction mixture was poured into sat. aq NaHCO3 (50 mL). The precipitate was filtered off, refluxed with acetone, and dried at 100 °C. 5-(5,7-Dihydroxy-4-methyl-2-oxo-2H-chromen-8-yl)-6-phenyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (7a) Yield 310 mg, 85%; white powder, mp 290–292 °C (dec.). 1H NMR (400 MHz, DMSO-d 6): δ = 2.48 (d, 4 J = 1 Hz, 3 H, CH3), 5.87 (d, 4 J = 1 Hz, 1 H, C3′H), 6.20 (s, 1 H, C5H), 6.29 (s, 1 H, C6′H), 6.94 (br s, 1 H, N4H), 7.22–7.25 (m, 3 H, HPh), 7.55–7.57 (m, 2 H, HPh), 10.05 (s, 1 H, N2H), 10.56 (br s, 1 H, OH), 10.76 (br s, 1 H, OH) ppm. 13C NMR (100 MHz, DMSO-d 6): δ = 23.6 (CH3), 45.8 (C5), 95.4 (C6′), 101.9 (C4a′), 106.6 (C8′), 108.6 (C3′), 125.0 (Co), 128.1 (C m ), 128.4 (C p ), 135.3 (C i ), 139.0 (C6), 149.7 (C3), 155.2 (C4′), 157.3 (C5′), 158.0 (C8a′), 159.3 (C7′), 160.0 (C2′) ppm. IR: 1696, 1664, 1550, 1356 cm–1. Anal. Calcd for C19H15N3O5: C, 62.46; H, 4.14; N, 11.50. Found: C, 62.40; H, 3.99; 11.67. 5,7-Dihydroxy-4-methyl-8-(3-(methylthio)-2,5-dihydro-1,2,4-triazin-5-yl)-chromen-2(2H)-one (8a) Yield 249 mg, 78%; pale beige powder, mp 235–237 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 2.33 (s, 3 H, SCH3), 2.51 (s, 3 H, CH3), 4.71 (s, 1 H, C5′H), 5.87 (s, 1 H, C3H), 6.32 (s, 1 H, C6H), 6.81 (s, 1 H, C6′H), 10.55 (br s, 1 H, NH), 11.01 (br s, 1 H, OH), 11.40 (br s, 1 H, OH) ppm. 13C NMR (100 MHz, DMSO-d 6): δ = 13.1 (SCH3), 23.7 (CH3), 51.8 (C5), 99.4 (C6′), 102.3 (C4a′), 102.7 (C8′), 108.7 (C3′), 140.9 (C6), 154.1 (C8a′), 155.2 (C5′), 155.3 (C3), 157.1 (C4′), 159.6 (C2′), 160.5 (C7′) ppm. IR: 1721, 1686, 1601, 1567, 1360 cm–1. Anal. Calcd for C14H13N3O4S: C, 52.66; H, 4.10; N, 13.16. Found: C, 52.73; H, 4.28; N, 13.13.
  • 17 General Procedure for the Addition of 5,7-Dihydroxycoumarins 5a–e to Triazine 6c (Procedure B) To AcOH (15 mL) 5a–e (1 mmol), 6c (1 mmol), and MsOH (1 mL) were added. The mixture was allowed to stand for 24–72 h at r.t., while precipitation of product was observed. The precipitate was filtered off, washed with acetone, and dried at 100 °C yielding pure 9a–e.8-(3,6-Diphenyl-2,5-dihydro-1,2,4-triazin-5-yl)-5,7-dihydroxy-4-methyl-2H-chromen-2-one Methanesulfonate (9a) Yield 469 mg, 90%; pale yellow needles, mp 233–235 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 2.36 (s, 3 H, CH3SO3 –), 2.46 (s, 3 H, CH3), 5.93 (s, 1 H, C3′H), 6.44 (s, 1 H, C6′H), 6.66 (s, 1 H, C5H), 7.38–7.48 (m, 3 H, H p + H o ), 7.63–7.67 (m, 2 H, H m ), 7,75–7.85 (m, 5 H, Ph), 11.01 (s, 1 H, C5′OH), 11.08 (s, 1 H, NH), 11.44–11.54 (br s, 1 H, C7′OH), 13.44 (s, 1 H, NH) ppm. 13C NMR (100 MHz, DMSO-d 6): δ = 23.7 (CH3), 39.5 (CH3SO3 -), 42.4 (C5), 99.5 (C6′), 102.9 (C4a′), 105.0 (C8′), 109.3 (C3′), 125.1 (C i ), 125.9 (C m ), 128.1 (C o ), 128.7 (C o ), 129.3 (C m ), 131.3 (C p ), 132.8 (C6), 134.1 (Cp), 148.8 (C i ), 152.7 (C3), 154.8 (C8a′), 155.6 (C4′), 158.9 (C5′), 158.9 (C2′), 159.4 (C7′) ppm. IR: 1696, 1603, 1558, 1189 cm–1. Anal. Calcd for C26H23N3O7S: C, 59.88; H, 4.45; N, 8.06. Found: C, 59.79; H, 4.40; N, 8.14.
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  • 19 General Procedure for the Addition of 5,7-Dihydroxycoumarins 5a–e to Triazine 10 (Procedure C) 5,7-Dihydroxycoumarin 5a–e (1 mmol) and triazine 10 (1 mmol) were dissolved in TFA (10 mL) and CHCl3 (10 mL), and the reaction solution was heated under reflux for 4 h. Then to the reaction mixture was added 2-PrOH (15 mL), the mixture was cooled, and the precipitate was filtered off. The product 11a–e was recrystallized from 1,4-dioxane and dried at 100 °C for 4 h. 6-(5,7-Dihydroxy-4-methyl-2-oxo-2H-chromen-8-yl)-1,3,5-triazin-2,4-dione (11a) Yield 168 mg, 55%; pinkish powder, mp 289–291 °C (dec.). 1H NMR (400 MHz, DMSO-d 6): δ = 2.51 (s, 3 H, CH3), 5.90 (s, 1 H, C3′H), 6.11 (s, 1 H, C6H), 6.36 (s, 1 H, C6′H), 7.52 (s, 2 H, N1H, N5H), 9.12 (s, 1 H, N3H), 10.65 (s, 1 H, OH), 10.70 (br s, 1 H, OH) ppm. 13C NMR (100 MHz, DMSO-d 6): δ = 23.7 (CH3), 55.4 (C6), 99.1 (C6′), 101.8 (C4a′), 106.2 (C8′), 108.7 (C3′), 152.2 (C2, C4), 154.2 (C8a′), 155.3 (C4′), 157.6 (C5′), 159.4 (C7′), 160.0 (C2′) ppm. IR: 1704, 1664, 1610, 1575, 1360 cm–1. Anal. Calcd for C13H11N3O6: C, 51.15; H, 3.63; N, 13.77. Found: C, 51.19; H, 3.58; N, 13.69.
  • 20 General Procedure for the Oxidation of Dihydroadducts To a solution of 8a–e (0.5 mmol) in AcOH (5 mL) was added an acetone solution (4 mL) of chloranil (0.5 mmol, 123 mg). The reaction mixture was heated at 40 °C for 24 h, cooled, diluted with acetone (10 mL) to complete formation of the precipitate, and the precipitate was filtered off and washed with acetone to give pure 15a–e. 5,7-Dihydroxy-4-methyl-8-(3-(methylthio)-1,2,4-triazin-5-yl)-chromen-2(2H)-one (15a) Yield 212 mg, 67%; yellow powder, mp > 300 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 2.53 (s, 3 H, CH3), 2.63 (s, 3 H, SCH3), 5.96 (C3H), 6.46 (s, 1 H, C6H), 9.34 (s, 1 H, C6′H), 11.1–11.5 (br s, 2 H, 2 OH) ppm. 13C NMR (100 MHz, DMSO-d 6): δ = 13.2 (SCH3), 23.7 (CH3), 99.1 (C6′), 101.1 (C8′), 102.6 (C4a′), 109.6 (C3′), 147.3 (C6), 153.3 (C5), 154.9 (C8a′), 155.0 (C4′), 158.9 (C2′), 160.2, 160.4 (C7′, C5′), 171.8 (C3) ppm. IR: 1740, 1483, 1404, 1285 cm–1. Anal. Calcd for C14H11N3O4S: C, 52.99; H, 3.49; N, 13.24. Found: C, 53.05; H, 3.46; N, 13.30.