Efficient Synthesis of Functionalized 2-Carbamoylpyran-4-ones by Ring-Transformation of 5-Alkylidene-2,5-dihydropyrrol-2-ones

Abstract

Functionalized 2-carbamoylpyran-4-ones were prepared by acid-mediated ring-transformations of readily available 5-alkyl­idene-3-arylamino-2,5-dihydropyrrol-2-ones.

cyclizations - dianions - domino reactions - heterocycles - pyran-4-ones - rearrangements

References

1 Römpp Lexikon Naturstoffe   Fugmann B. Lane-Fugmann S. Steglich W. Thieme; Stuttgart: 1997. 

2a Feist H. Justus Liebigs Ann. Chem.  1890,  257:  258 

2b Feist H. Chem. Ber.  1895,  28:  1823 

2c Lehmann K. Grabow J. Chem. Ber.  1935,  68:  704 

2d Heyns C. Vogelsang F. Chem. Ber.  1954,  87:  1440 

2e Hauser CR. Harris TM. J. Am. Chem. Soc.  1958,  80:  6360 

2f Yamamoto M. Sugiyama N. Bull. Chem. Soc. Jpn.  1975,  48:  508 

2g Review: Harris TM. Harris CM. Tetrahedron  1977,  33:  2159 

2h Griffin DA. Leeper FJ. Staunton J. J. Chem. Soc., Perkin Trans. 1  1984,  1035 

2i Yamamoto M. Iwasa S. Takatsuki K. Yamada K. J. Org. Chem.  1986,  51:  346 

2j Yamaguchi M. Shibato K. Nakashima H. Minami T. Tetrahedron  1988,  44:  4767 

3a Langer P. Döring M. Synlett  2001,  1437 

3b Anders JT. Görls H. Langer P. Eur. J. Org. Chem.  2004,  1897 

4 For a review of cyclizations of oxalic acid-bis(imidoyl) dichlorides, see: Langer P. Döring M. Eur. J. Org. Chem.  2002,  221 

5

General Procedure for the Synthesis of 5-Alkylidene-3-arylamino-2,5-dihydropyrrol-2-ones ( 3): [3] A THF solution of LDA was prepared by addition of n-BuLi (3.05 mL, 4.4 mmol, 1.5 M solution in n-hexane) to a THF solution (40 mL) of diisopropylamine (0.45 g, 0.62 mL, 4.4 mmol) at 0 °C. To the LDA solution was added the dicarbonyl compound 1 (2.0 mmol) at 0 °C. The solution was stirred at 0 °C for 60 min and was subsequently cooled to -78 °C and transferred to a THF solution (40 mL) of the oxalic acid-bis(arylimidoyl)dichloride 2 (2.0 mmol) at -78 °C. The solution was allowed to warm to 20 °C within 12 h. To the solution was added an aq solution of NH₄Cl (100 mL, 1 M). The organic layer and the aqueous layer were separated and the latter was extracted with Et₂O (4 × 150 mL). The combined organic layers were dried (MgSO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel, pentane-Et₂O = 10:1 → 1:1) to give the 3-arylamino-2,5-dihydropyrrol-2-ones 3 as yellow to red crystals. Compound 3c: Starting with a THF solution (40 mL) of LDA (6.9 mmol, 2.3 equiv), 2-acetyltetralone (3.0 mmol, 0.57 g) and a THF solution (40 mL) of oxalic acid-bis(o-methoxyphenyl)imidoyl chloride (3.0 mmol, 1.01 g), 3c was isolated after chromatography (n-hexane-EtOAc = 25:1 → 20:1) as a yellow solid (1.15 g, 85%). ¹H NMR: δ = 2.89 (m, 2 H, CH₂), 2.96 (m, 2 H, CH₂), 3.90 (s, 3 H, OCH₃), 3.94 (s, 3 H, OCH₃), 6.91-6.94 (m, 1 H, Ar), 6.99-7.05 (m, 3 H, Ar), 7.17-7.26 (m, 2 H, Ar), 7.32-7.51 (m, 5 H, Ar), 7.69 (s, 1 H, 4-H), 7.87 (s, NH), 8.06-8.09 (dd, 1 H, Ar). ¹³C NMR: δ = 24.79 (CH₂), 28.79 (CH₂), 55.97 (CH₃), 56.21 (CH₃), 100.27 (CH), 109.00 (C), 110.59, 112.26, 116.59, 121.01, 121.52, 122.98, 123.99, 126.53, 127.08, 127.48, 128.25 (CH), 129.57 (C), 132.68 (CH), 134.16, 135.26, 139.36, 143.17, 148.90, 152.43, 152.65 (C), 161.69 (CO), 187.82 (CO). IR (KBr): 3369.6 (m), 3345.8 (m), 1701.5 (s), 1631.0 (s), 1596.6 (s), 1558.0 (s), 1536.0 (s), 1490.6 (s), 1461.5 (s), 1346-3 (s), 1296.7 (s), 1243.0 (s), 1210.1 (m), 1122.0 (s), 1027.3 (s), 927.68 (s), 738.4 (s) cm^-1. UV/Vis: λ_max (lg ε) = 248.9 (5.17), 271.6 (5.21), 433.2 (5.39). MS (EI, 70 eV): m/z (%) = 453.3 (27.4) [M⁺ + 1], 452.2 (100.0) [M⁺], 423.2 (46.1), 330.1 (15.8), 302.1 (74.4), 274.1 (5.0), 141.1 (31.8), 114.4 (36.2), 77.4 (24.9). The exact molecular mass m/z = 452.1736 ± 2 mD ([M]⁺) of C₂₈H₂₄O₄N₂ was confirmed by HRMS (EI, 70 eV). Anal. Calcd for C₂₈H₂₄O₄N₂: C, 74.30; 5.35. Found: C, 73.99; H, 5.02.

6

General Procedure for the Synthesis of Carbamoylpyran-4-ones ( 4): The 3-arylamino-2,5-dihydropyrrol-2-one (3) was dissolved in THF (25 mL) at 20 °C. To this solution, an aq solution of HCl (15 mL, 1 M) was added under vigorous stirring. After stirring for 24 h at 20 °C, the pale yellow solution was poured into H₂O (150 mL). The organic and the aqueous layer were separated and the latter was extracted with Et₂O (3 × 100 mL). The combined organic layers were dried (MgSO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (silica gel) to give 4 as colorless or yellow solids. Compound 4c: Starting with a THF solution (50 mL) of 3c (120 mg) and an aq solution of HCl (40 mL, 10%), 4c was isolated by chromatography (silica gel, n-hexane-EtOAc = 5:1 → 3:1) as a colorless solid (68 mg, 85%). ¹H NMR: δ = 2.87 (t, 2 H, CH₂), 2.97 (t, 2 H, CH₂), 4.03 (s, 3 H, CH₃), 6.96-7.06 (m, 1 H, Ar), 7.13-7.18 (m, 1 H, Ar), 7.24 (s, 1 H, CHCO), 7.31 (d, 1 H, Ar), 7.41-7.46 (m, 1 H, Ar), 7.44 (d, 2 H, Ar), 7.85 (d, 1 H, Ar), 8.51 (d, 1 H, Ar), 9.37 (s, 1 H, NH). ¹³C NMR: δ = 18.90 (CH₂), 26.94 (CH₂), 56.26 (CH₃O), 110.32 (CH), 115.63 (CH), 119.93 (CH), 121.69 (CH), 122.52 (C), 122.96 (CH), 125.23 (CH), 126.62 (C), 127.26 (CH), 127.57 (C, 128.85 (CH), 131.66 (CH), 139.39 (C), 148.31 (C), 154.14 (C), 156.44 (C), 157.18 (CO), 178.56 (CO). IR (KBr): 3407.8 (m), 2941.6 (w), 1765.1 (m), 1693.8 (s, 1651.0 (s), 1603.0 (s), 1536.0 (s), 1462.6 (s), 1417.0 (s), 1333.3 (m), 1252.9 (s), 1159.5 (m), 1121.8 (m), 1024.5 (m), 758.5 (m), 632.9 (m), 542.6 (w) cm^-1. UV/Vis: λ_max (lg ε) = 213.2 (5.4), 219.4 (5.39), 252.1 (5.14), 290.5 (5.18), 311.7 (5.24). MS (EI, 70 eV): m/z (%) = 348.7 (2.2) [M⁺ + 1], 347.6 (18.9) [M⁺], 346.7 (88.2), 345.7 (100.0), 196.8 (20.3), 170.8 (20.3), 140.9 (29.3), 114.3 (20.6), 91.9 (7.9), 28.0 (6.4). The exact molecular mass m/z = 347.1158±2 mD ([M]⁺) of C₂₁H₁₇O₄N was confirmed by HRMS (EI, 70 eV). Anal. Calcd for C₂₁H₁₇O₄N: C, 69.15; H, 4.94. Found: C, 69.50; H, 5.16.