Synthesis of the First Representatives of Thieno[3,2-c][1,7]naphthyridine Derivatives Based on 3-Amino-6-methyl-4-(2-thienyl) pyridin-2(1H)-one

Abstract

A one-pot method for obtaining novel thieno[3,2-c][1,7]naphthyridine derivatives based on the reaction of 3-amino-4-(thien-2-yl)pyridin-2(1H)-one with aromatic aldehydes in 80% ­phosphoric acid at 130 °C has been developed. The formation of the thieno[3,2-c][1,7]naphthyridine ring was due to the intermediate generation of the corresponding azomethine, which underwent intra­molecular cyclization with electrophilic attack of the β-carbon atom of the thiophene core under Pictet–Spengler conditions. The isolated 5,7-dihydrothieno[3,2-c][1,7]naphthyridin-4(3H)-ones underwent oxidative aromatization in air to give thieno[3,2-c][1,7]naphthyridin-6(7H)-ones. A two-step synthesis of thieno[3,2-c][1,7]naphthyridines involving the isolation of the intermediate imine did not lead to a significant increase in the product yield.

Key words

naphthyridines - aminothienylpyridinones - thienonaphthyr­idinones - cyclization - Pictet–Spengler reaction - oxidative aromatization

• References and Notes

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• 21 3-[(1E)-Benzylideneamino)-6-methyl-4-(2-thienyl)pyridin-2(1H)-one (13a); Typical Procedure for 13a–e A mixture of 3-amino-6-methyl-4-(2-thienyl)pyridin-2(1H)-one 9 (206 mg, 1 mmol), PhCHO (1.5 mmol), and a catalytic amount of HCO₂H in i-PrOH (10 mL) was refluxed for 1–3 h, then cooled. The precipitated imine 13a was collected by filtration and washed with hexane to give yellow crystals; yield: 216 mg (74%); mp 231–233°С (i-PrOH–CHCl₃). ¹H NMR (400 MHz, СDCl₃): δ = 2.38 (s, 3 H, 6-CH₃), 6.57 (s, 1 H, H-5), 7.13 (dd, ³ J = 5.2 Hz, ³ J = 4.1 Hz, 1 H, Н-4 Th), 7.50–7.51 (m, 3 H, H-3′,4′,5′ Ph), 7.58 (dd, ³ J = 5.5 Hz, ⁴ J = 1.1 Hz, 1 H, H-5 thienyl), 7.62 (dd, ³ J = 3.8 Hz, ⁴ J = 1.1 Hz, 1 H, H-3 thienyl), 8.02–8.04 (m, 2 H, H-2′,6′ Ph), 9.57 (s, 1 H, N=CH–), 12.42 (br s, 1 H, NH). ¹³C NMR (100 MHz, СDCl₃): δ = 18.9 (6-CH₃), 105.1 (C-5), 126.4, 128.1, 128.6 (C-3′,5′ Ph), 129.4 (C-2′,6′-Ph), 129.5, 131.0, 132.0, 137.3 (2 C), 138.1, 139.8 (C-6), 160.7 (С-2), 163.2 (N=CH–). 8-Methyl-4-phenyl-5,7-dihydrothieno[3,2-c]-1,7-naphthyridin-6(4H)-one (11a); Typical Procedure for 11a, 11b, and 11e A mixture of thienylpyridinone 9 (206 mg, 1.0 mmol) and PhCHO (1.5 mmol) in 80% phosphoric acid (5 mL) was heated at 120–130 °C for 10 h. The mixture was then cooled, poured onto crushed ice, and neutralized with 1 M NaOH. The resulting solid was collected by filtration and crystallized from DMF–1,4-dioxane (1:2) to give a pale-yellow powder; yield: 159 mg (54%); mp 302–304 °C. IR (KBr): 1638 (С=O), 3168 (N–H) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.31 (s, 3 H, 8-CH₃), 3.55 (s, 1 H, H-4), 6.53 (s, 1 H, H-9), 7.52–7.58 (m, 3 H, Н-3′,4′,5′ Ar), 7.72 (d, J = 5.5 Hz, 1 H, H-3), 7.86 (d, J = 6.9 Hz, 2 Н, Н-2′,Н-6′ Ph), 8.15 (d, J = 5.5 Hz, 1 H, H-2), 11.70 (br s, 1 Н, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 18.7 (CH₃), 66.3 (C-4), 97.9 (C-9), 124.2 (C-3), 128.4 (C-2′,6′ Ph), 128.9 (C-4′ Ph), 129.1 (C-3′,5′ Ph), 129.3 (C-1′ Ph), 131.6 (C-2), 133.7, 134.9, 139.2, 141.8, 143.2, 161.2 (C-6). Anal. Calcd for C₁₇H₁₄N₂OS: C, 69.36; H, 4.79; N, 9.52. Found: C, 68.94; H, 4.36; N, 9.18. 8-Methyl-4-phenylthieno[3,2-c]-1,7-naphthyridin-6(7H)-one (12a); Typical Procedure for 12a–e A mixture of thienylpyridinone 9 (206 mg, 1.0 mmol) and PhCHO in PA (5 mL) was heated at 120–130 °C for 18–20 h. The mixture was then cooled, poured onto crushed ice, and neutralized with 1 M NaOH. The resulting solid was collected by filtration and crystallized from DMF–1,4-dioxane (1:2) to give a pale-yellow powder; yield: 158 mg (54%); mp 302–304 °С. IR (KBr): 1643 (С=O), 3449 (N–H) cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.31 (s, 3 H, 8-CH₃), 6.54 (s, 1 H, H-9), 7.52–7.58 (m, 3 H, Н-3′,4′,5′ Ph), 7.71 (d, J = 5.5 Hz, 1 H, H-3), 7.85 (d, J = 6.7 Hz, 2 Н, Н-2′,6′ Ph), 8.15 (d, J = 5.5 Hz, 1 H, H-2), 11.75 (br s, 1 Н, NH). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 18.8 (CH₃), 98.0 (С-9), 124.3 (С-3), 128.5 (С-2′,6′ Ph), 129.0 (С-4′ Ph), 129.1 (С-3′,5′ Ph), 129.4, 131.8 (С-2), 133.75, 135.0, 139.3, 141.9, 143.3, 152.0 (С-4), 161.3 (С-6). Anal. Calcd for C₁₇H₁₂N₂OS: C, 69.84; H, 4.14; N, 9.58. Found: C, 70.25; H, 4.44; N, 9.36.