First InCl₃-Catalyzed, Three-Component Coupling of Aldehydes, β-Naphthol, and 6-Amino-1,3-dimethyluracil to Functionalized Naphthopyranopyrimidines

Abstract

Indium(III) chloride was found to be a highly effective and efficient catalyst for the three-component, one-pot coupling of aldehydes, β-naphthol, and 6-amino-1,3-dimethyluracil under solvent-free conditions to give 8,10-dimethyl-12-aryl-12H-naphtho[1′,2′:5,6]pyrano[2,3-d]pyrimidine-9,11-diones in high yields for the first time. No co-catalyst or activator is required. Water and ammonia are the only byproducts in the reactions.

multicomponent reaction - one-pot synthesis - InCl₃ - naphthopyranopyrimidine

References and Notes

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General Procedure for Synthesis of 8,12-Dihydro-8,10-dimethyl-12-aryl-9 H -naphtho[1′,2′:5,6]pyrano[2,3- d ]pyrimidine-9,11-(10 H )-dione (4)
The aldehyde (1.0 mmol), 6-amino-1,3-dimethyluracil (1.2 mmol), and 2-naphthol (1.0 mmol) were ground in a mortar. The catalyst InCl₃ (35 mol%) was added to the reaction mixture and further ground nicely for additional 15 min. The whole reaction mixture was heated in an oil bath at 120 ˚C for the stipulated period of time (Table  [¹] ) till the completion of the reaction (monitored by TLC). Water (50 mL) was added to the reaction mixture to remove unreacted reactants, and the product was extracted with EtOAc (3 × 20 mL). The organic layer was dried over anhyd MgSO₄, and the solvent was evaporated under vacuum. The residue obtained was purified by column chromatography on silica gel using EtOAc-n-hexane (1:4) to afford the pure desired product. Finally the products were recrystallized from MeOH.
Spectral and Analytical Data of Some Newly Synthesized Compounds
12-(4-Methoxyphenyl)-8,12-dihydro-8,10-dimethyl-9 H -naphtho[1′,2′:5,6]pyrano[2,3- d ]pyrimidine-9,11-(10 H )-dione (4d)
White solid; R _f  = 0.40 (EtOAc-hexane, 1:4); mp 257-258 ˚C. IR (KBr): 3057, 2948, 1708, 1650, 1587, 1481
cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 8.03-7.93 (m, 3 H), 7.61-7.43 (m, 3 H), 7.24 (d, J = 7.8 Hz, 2 H), 6.74 (d, J = 7.8 Hz, 2 H), 5.61 (s, 1 H), 3.62 (s, 3 H), 3.50 (s, 3 H), 3.16 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 161.4, 157.7, 151.8, 150.1, 146.6, 135.9, 131.3, 130.3, 129.1, 128.9, 128.2, 127.0, 125.1, 123.4, 117.0, 116.3, 113.3, 90.9, 54.7, 34.7, 28.7, 27.7. MS-FAB: m/z = 401 [M + H]⁺. Anal. Calcd for C₂₄H₂₀N₂O₄: C, 71.99; H, 5.03; N, 7.00. Found: C, 71.78; H, 4.91; N, 6.88.
12-(3-Hydroxyphenyl)-8,12-dihydro-8,10-dimethyl-9 H -naphtho[1′,2′:5,6]pyrano[2,3- d ]pyrimidine-9,11-(10 H )-dione (4m) White solid; R _f  = 0.40 (EtOAc-hexane, 2:5); mp 293-294 ˚C. IR (KBr): 3409, 3054, 2951, 1708, 1642, 1590, 1478 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.95-7.82 (m, 3 H), 7.43-7.37 (m, 3 H), 7.09 (t, J = 8.1 Hz, 1 H), 6.90-6.88 (m, 2 H), 6.60 (d, J = 7.2 Hz, 1 H), 5.77 (s, 1 H), 5.23 (s, 1 H), 3.60 (s, 3 H), 3.33 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 161.9, 155.6, 152.4, 150.6, 147.2, 145.5, 131.7, 130.9, 129.6, 129.5, 128.4, 127.5, 125.5, 123.9, 120.5, 116.2, 115.3, 113.9, 106.8, 91.3, 35.7, 29.0, 28.2. MS-FAB:
m/z = 387 [M + H]⁺. Anal. Calcd for C₂₃H₁₈N₂O₄: C, 71.49; H, 4.70; N, 7.25. Found: C, 71.41; H, 4.67; N, 7.12.
12-(5-Bromo-2-hydroxyphenyl)-8,12-dihydro-8,10-dimethyl-9 H -naphtho[1′,2′:5,6]pyrano[2,3- d ]pyrimidine-9,11-(10 H )-dione (4o) White solid; R _f  = 0.40 (EtOAc-hexane, 2:3); mp 291-292 ˚C. IR (KBr): 3112, 2951, 2930, 1703, 1643, 1591, 1476 cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 9.18 (s, 1 H), 8.25-8.03 (m, 4 H), 7.83-7.77 (m, 2 H), 7.65-7.45 (m, 3 H) 6.55 (s, 1 H), 3.68 (s, 3 H), 3.35 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 161.1, 153.8, 152.7, 150.0, 146.8, 132.9, 132.6, 131.1, 130.5, 130.3, 129.3, 128.5, 127.2, 125.2, 123.5, 118.1, 116.8, 116.3, 110.1, 88.6, 30.7, 28.9, 27.7. MS-FAB: m/z = 465 [M + H]⁺. Anal. Calcd for C₂₃H₁₇BrN₂O₄: C, 59.37; H, 3.68; N, 6.02. Found: C, 59.19; H, 3.58; N, 5.91.
12-(2-Hydroxy-5-nitrophenyl)-8,12-dihydro-8,10-dimethyl-9 H -naphtho[1′,2′:5,6]pyrano[2,3- d ]pyrimidine-9,11-(10 H )-dione (4p) Yellow solid; R _f  = 0.40 (EtOAc-hexane, 2:3); mp 215-217 ˚C. IR (KBr): 3320, 2951, 2930, 1709, 1646, 1586, 1470 cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 9.66 (s, 1 H), 8.16-8.09 (m, 2 H), 7.97-7.31 (m, 5 H), 6.91-6.88 (m, 2 H), 6.10 (s, 1 H), 3.50 (s, 3 H), 3.02 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 161.2, 153.9, 152.7, 150.2, 147.3, 133.1, 131.4, 129.8, 129.2, 128.4, 127.6, 125.9, 125.5, 123.4, 122.8, 122.3, 118.9, 117.3, 116.4, 87.6, 29.6, 29.2, 27.7. MS-FAB: m/z = 432 [M + H]⁺. Anal. Calcd for C₂₃H₁₇N₃O₆: C, 64.04; H, 3.97; N, 9.74. Found: C, 63.91; H, 3.85; N, 9.72.
12-(3-Ethoxy-2-hydroxyphenyl)-8,12-dihydro-8,10-dimethyl-9 H -naphtho[1′,2′:5,6]pyrano[2,3- d ]pyrimidine-9,11-(10 H )-dione (4r) White solid; R _f  = 0.40 (EtOAc-hexane, 3:7); mp 208-209 ˚C. IR (KBr): 3225, 3061, 2963, 2928, 1702, 1671, 1590, 1482 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 9.41 (s, 1 H), 7.69-7.67 (m, 2 H), 7.46-7.15 (m, 4 H), 6.87 (t, J = 7.8 Hz, 1 H), 6.77 (d, J = 8.1 Hz, 1 H), 6.42 (d, J = 7.5 Hz, 1 H), 6.03 (s, 1 H), 4.21-4.10 (m, 2 H), 3.68 (s, 3 H), 3.30 (s, 3 H), 1.56 (t, J = 6.9 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 162.1, 153.4, 153.1, 150.1, 147.4, 139.1, 132.0, 130.1, 129.6, 129.0, 126.1, 125.9, 125.4, 123.2, 123.0, 122.4, 122.1, 111.2, 90.2, 52.1, 31.0, 28.9, 27.7, 14.8. MS-FAB:
m/z = 431 [M + H]⁺. Anal. Calcd for C₂₅H₂₂N₂O₅: C, 69.76; H, 5.15; N, 6.51. Found: C, 69.69; H, 4.92; N, 6.32.