An Efficient Protocol for Multicomponent Stereoselective Synthesis of 3-Amino-2(1H)-pyridinones Using CeCl₃˙7H₂O/NaI as a Reaction Promoter

Abstract

An efficient and convenient diastereoselective synthesis of 3-amino-2(1H)-pyridinones by CeCl₃˙7H₂O/NaI-promoted [3+2+1] three-component coupling reactions of chalcones, 2-phen­yl-1,3-oxazolon-5-one, and amines is reported. The protocol involves sequential Michael addition, condensation, ring transformation, and acid hydrolysis. Operational simplicity, ambient temperature, high yields, and diastereoselectivity are the key features of the present synthetic protocol. The reaction is an excellent illustration of Ce(III)-catalyzed C-C and C-N bond formations in a one-pot procedure

multicomponent reaction - Lewis acid - chalcones - heterocycles - stereoselective synthesis

References and Notes

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33

General Procedure for the Synthesis of 3-Benzamido-2 (1 H )-pyridinones 5 A mixture of 1,3-oxazolon-5-one 1 (5 mmol), chalcone 2 (5 mmol), amine 3 (5 mmol), CeCl₃˙7H₂O (1 mmol), and NaI (1 mmol) in EtOH (25 mL) was stirred at r.t. for 3-5 h. After completion of the reaction, as indicated by TLC (hexane-EtOAc, 8:2, v/v), the solvent was evaporated under reduced pressure, the residue thus obtained extracted with Et₂O (3 × 15 mL). The extract was evaporated to leave the crude product which was recrystallized from EtOH to afford a distereomeric mixture (>96:<4; in the crude products the ratio was >94:6 as indicated by ^¹H NMR spectroscopy). The product on second recrystallization from EtOH furnished analytically pure pale yellow crystal of a single diastereomer 4, which was assigned the trans stereochemistry on the basis of ^¹H NMR spectra. Characterization Data for Representative Compounds Compound 7 (Ar^¹ = Ar^² = R = Ph): pale yellow crystals; yield 82%; mp 124-125 ˚C. IR (KBr): ν_max = 3340, 3023, 1745, 1642, 1605, 1585, 1455, 755, 712 cm.^-¹. ^¹H NMR (400 MHz, DMSO-d ₆ and D₂O-TMS): δ = 3.99 (d, 1 H, J = 10.0 Hz, 3-H), 4.19 (dd, 1 H, J = 10.0, 5.9 Hz, 4-H), 5.93 (d, 1 H, J = 5.9 Hz, 5-H), 7.10-7.70 (m, 20 H_arom). ^¹³C NMR(100 MHz, DMSO-d ₆): δ = 39.9, 59.0, 114.2, 117.6, 119.0, 120.1, 121.3, 124.0, 125.2, 126.4, 127.5, 128.5, 129.6, 130.8, 132.0, 133.1, 134.2, 135.5, 137.4, 143.4, 172.6, 174.2. MS (EI): m/z = 444 [M⁺]. Anal. Calcd for C₃₀H₂₄N₂O₂: C, 81.06; H, 5.44; N, 6.30. Found: C, 80.70; H, 5.74; N, 6.10.
Compound 7 (Ar^¹ = 4-MeOC₆H₄; Ar^² = R = Ph): pale yellow crystals; yield 80%; mp 133-134 ˚C. IR (KBr): 3340, 3021, 1742, 1640, 1600, 1582, 1400, 752, 710 cm.^-¹. ^¹H NMR (400 MHz, DMSO-d ₆ and D₂O-TMS): δ = 3.79 (s, 3 H, OMe), 4.01 (d, 1 H, J = 10.0 Hz, 3-H), 4.18 (dd, 1 H, J = 10.0, 5.9 Hz, 4-H), 5.99 (d, 1 H, J = 5.9 Hz, 5-H), 7.18-7.99 (m, 19 H_arom). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 39.2, 56.0, 59.2, 114.0, 117.5, 119.2, 120.3, 122.4, 124.0, 125.1, 126.2, 127.3, 128.3, 129.4, 130.5, 131.6, 132.9, 134.0, 135.2, 137.5, 143.9, 172.9, 174.8. MS (EI):
m/z = 474 [M⁺]. Anal. Calcd for C₃₁H₂₆N₂O₃: C, 78.46; H, 5.52; N, 5.90. Found: C, 78.81; H, 5.30; N, 5.56.

34

General Procedure for the Synthesis of 3-Amino-2 (1 H )-Pyridinone 4
Compound 5 (2.0 mmol) was refluxed in H₂SO₄-H₂O (15 mL, 4:3, v/v) for 30 min in an oil bath. The reaction mixture was cooled, filtered, and the desired product 4 was precipitated by adding concentrated NH₄OH (d = 0.88) under ice cooling and recrystallized from EtOH to afford an analytically pure sample of 4 (Table  [¹] ).
Characterization Data for Representative Compounds Compound 4 (Table  [²] , entry 1): pale yellow crystals; yield 90%; mp 135-134 ˚C. IR (KBr): 3342, 3011, 1699, 1608, 1540, 1430, 749, 703 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆ and D₂O-TMS): δ = 3.96 (d, 1 H, J = 9.9 Hz, 3-H), 4.15 (dd, 1 H, J = 9.9, 5.9 Hz, 4-H), 5.90 (d, 1 H, J = 5.9 Hz, 5-H), 7.19-7.90 (m, 15 H_arom). ^¹³C NMR(100 MHz, DMSO-d ₆ ): δ = 39.7, 58.5, 114.0, 120.0, 122.1, 125.0, 126.2, 127.4, 128.7, 129.8, 130.8, 131.9, 133.0, 134.7, 141.0, 143.0, 172.6. MS (EI): m/z = 340 [M⁺]. Anal. Calcd for C₂₃H₂₀N₂O: C, 81.15; H, 5.92; N, 8.23. Found: C, 80.83; H, 5.62; N, 8.43.
Compound 4 (Table  [²] , entry 7): pale yellow crystals; yield 87%; mp 140-141 ˚C. IR (KBr): ν_max = 3340, 3021, 1742, 1640, 1600, 1582, 1400, 752, 710 cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆ and D₂O-TMS): δ = 3.78 (s, 3 H, OMe), 3.98 (d, 1 H, J = 9.9 Hz, 3-H), 4.13 (dd, 1 H, J = 9.9, 5.9 Hz, 4-H), 5.92 (d, 1 H, J = 5.9 Hz, 5-H), 7.19-7.86 (m, 14 H_arom). ^¹³C NMR (100 MHz, DMSO-d ₆ ): δ = 39.2, 55.6, 58.3, 114.1, 120.2, 122.0, 125.1, 126.3, 127.5, 128.5, 129.8, 130.9, 132.0, 133.6, 134.8, 141.2, 144.0, 172.4. MS (EI): m/z = 370 [M⁺]. Anal. Calcd for C₂₄H₂₂N₂O₂: C, 77.81; H, 5.99; N, 7.56. Found: C, 78.12; H, 6.29; N, 7.26.