New Methodologies for the Synthesis of 3-Acylpyridone Metabolites

Abstract

A core isoxazolo[4,3-c]pyridin-4-one scaffold is prepared and elaborated at C-3(Me) and C-7 as a masked building block for 3-acylpyridin-2-ones related to the acylpyridone natural products

Key words

heterocycles - cycloaddition - metalation - aldol reaction - pyridone

References and Notes

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  Choudhury, A. K. unpublished results.

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13

Typical ProcedureSynthesis of 3-Methyl-7-phenyl-5 H -isoxazolo[4,3- c ]pyridin-4-one (12a)
Pd(PPh₃)₄ (4.2 mg, 0.004 mmol) was added to degassed 1,4-dioxane (10 mL), followed by iodopyridone 11 (20 mg, 0.07 mmol). The solution was purged with N₂ for 10 min at 23 ˚C. Phenylboronic acid (13 mg, 0.1 mmol) in EtOH (10 mL) and aq Na₂CO₃ (2 M, 0.02 mL, 0.14 mmol) were degassed with N₂, and added sequentially. The mixture was heated at reflux for 18 h under an N₂ atmosphere, cooled, H₂O (50 mL) added, and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO₄), filtered, and evaporated under reduced pressure to a brown oil purified by silica column chromatography eluting with EtOAc-light PE (bp 40-60 ˚C) (1:1 v/v) to leave title compound 12a, white solid (10 mg, 67%); mp 253.5-254 ˚C. IR (CH₂Cl₂): ν_max = 3245, 2959, 1676, 1629, 1404 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.86 (3 H, s, CH₃), 7.33 (1 H, d, J = 6.0 Hz, NHCH), 7.36 (1 H, t, J = 7.2 Hz, ArCH), 7.43 (2 H, m, ArCH), 7.75 (2 H, d, J = 7.2 Hz, ArCH), 8.72 (1 H, br, NH). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.0 (CH₃), 108.6, 112.5 (2 × C), 127.3, 128.0, 128.8, 129.1 (4 × CH), 133.2, 158.8, 161.7, 174.2 (4 × C). HRMS-FAB: m/z calcd for C₁₃H₁₁N₂O₂: 227.0822; found: 227.0825 [MH⁺].

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Typical ProcedureSynthesis of 3-(2-Phenylethenyl)-5 H -isoxazolo[4,3- c ]pyridin-4-one (14a)
To 3-methyl-5H-isoxazolo[4,3-c]pyridin-4-one (6, 100 mg, 0.66 mmol) in THF (20 mL) at -78 ˚C under N₂ was added BuLi (0.6 mL of a 2.5 M solution in hexanes, 1.45 mmol) and the solution stirred for 1 h before benzaldehyde (1.0 mL, 0.99 mmol) was added. Stirring was continued for 5 min at -78 ˚C, before the mixture was quenched with H₂O (20 mL), acidified with HCl (2 M, 20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO₄), filtered, and evaporated under reduced pressure to a yellow oil purified by silica column chromatography, eluting with EtOAc-light PE (bp 40-60 ˚C) (1:1 v/v) to afford hydroxy adduct 13a (106 mg, 63%), pale yellow solid; mp 180-182 ˚C. IR (CH₂Cl₂):
ν_max = 3395, 3131, 2962, 1675, 1643, 1457 cm^-¹. ^¹H NMR [400 MHz, (CD₃)₂SO]: δ = 3.55 (2 H, d, J = 7.7 Hz, CHCH ₂ ), 5.19 (1 H, m, CH₂CH), 5.74 (1 H, d, J = 4.9 Hz, CHOH), 6.38 (1 H, d, J = 7.6 Hz, NHCHCH), 7.15 (1 H, dd, J = 7.6, 5.7 Hz, NHCH), 7.39-7.46 (5 H, m, ArCH), 10.15 (1 H, br, NH). ^¹³C NMR [100 MHz, (CD₃)₂SO]: δ = 36.9 (CH₂), 70.4, 92.6 (2 × CH), 108.5 (C), 125.6, 127.3, 128.2, 134.1 (4 × CH), 144.4, 157.3, 158.9, 174.8 (4 × C). HRMS (EI):
m/z calcd for C₁₄H₁₃N₂O₃: 257.0921; found: 257.0924 [MH⁺]. To 13a (130 mg, 0.51 mmol) in PhMe (30 mL) was added TsOH (96 mg, 0.51 mmol) and the mixture heated at reflux overnight under Dean-Stark conditions. Water (20 mL) was added to the cooled mixture, and it was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO₄), filtered, and evaporated under reduced pressure to leave title compound 14a, yellow solid (86 mg, 71%); mp 217-218 ˚C. IR (CH₂Cl₂): ν_max = 3131, 2922, 1672, 1643, 1569, 1457 cm^-¹. ^¹H NMR [400 MHz, (CD₃)₂SO]: δ = 6.38, 7.15 (each 1 H, d, J = 7.5 Hz, NHCH=CH), 7.42-7.51 (3 H, m, ArCH), 7.56 (1 H, d, J = 16.4 Hz, PhCH=CH), 7.75 (2 H, m, ArCH), 8.21 (1 H, d, J = 16.4, PhCH=CH), 10.95 (1 H, br, NH). ^¹³C NMR [100 MHz, (CD₃)₂SO]: δ = 95.1 (CH), 107.8 (C), 112.6, 128.2, 128.9, 130.3 (4 × CH), 135.2 (C), 135.9, 139.9 (2 × CH), 158.3, 159.9, 171.8 (3 × C). HRMS (EI): m/z calcd for C₁₄H₁₀N₂O₂: 238.0741; found: 238.0741 [M⁺].

16

Crystallographic data for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication nos. 752383 (13a) and 752384 (19). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].