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Synlett 2005(1): 49-54  
DOI: 10.1055/s-2004-836034
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Facile and Efficient Synthesis of 3,5-Disubstituted Tetronic Acids in Aqueous Media Involving Acid-Catalyzed Intramolecular Oxa-Pyridylethylation

Xihe Bi, Qun Liu*, Shaoguang Sun, Jun Liu, Wei Pan, Lei Zhao, Dewen Dong*
Department of Chemistry, Northeast Normal University, Changchun, 130024, P. R. China
e-Mail: dongdw663@nenu.edu.cn;
Further Information

Publication History

Received 25 August 2004
Publication Date:
29 November 2004 (online)

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Abstract

A facile and efficient one-pot synthesis of 3-[bis(alkyl­thio/alkylamino)methylene]-5-(pyridyl/quinoylmethyl) furan-2,4(3H,5H)-diones 3 and 10, based on a sequential aldol condensation and lactonization reaction between α-oxo ketene-S,S-acetals 1 and pyridine/qinoline-carboxaldehydes 2 in aqueous media, has been developed. A mechanism involving an acid-catalyzed intramolecular oxa-pyridylethylation reaction is proposed for the ­formation of the lactone ring.

Key words

aqueous media - tetronic acid derivatives - α-oxo ketene-S,S-acetals - oxa-pyridylethylation - α-oxo ketene-N,N-acetals

11

General Procedure for the Preparation of 3 (3a as example).
To a solution of α-acetyl-α-ethoxylcarbonyl ketene cyclic dithioacetal 1a (2.32 g, 10 mmol) and 4-pyridine carboxaldehyde 2a (1.28 g, 12 mmol) in 30 mL EtOH-H2O (2:1, v/v), NaOH (0.8 g, 20 mmol) was added. After stirring at r.t. for 0.5 h, the mixture was acidified with aq HCl (1 N) to adjust the pH value to 5 and was stirred for another 0.5 h. The resulting mixture was poured into cold sat. aq NaHCO3 and was stirred for 10 min. A yellowish solid was filtered and washed with H2O (3 × 30 mL). The crude product was purified by column chromatography over silica gel using acetone-Et2O (2:1, v/v) as eluent to give product 3a (2.80 g, 95%) as a white crystal.
3-(1,3-Dithiolan-2-ylidene)-5-(pyridin-4-ylmethyl)furan-2,4(3 H ,5 H )-dione ( 3a): white crystal; mp 195-197 °C. 1H NMR (400 MHz, CDCl3): δ = 3.04 (dd, J = 8.0, 16.0 Hz, 1 H), 3.29 (dd, J = 4.0, 16.0 Hz, 1 H), 3.57-3.65 (m, 4 H), 4.89 (dd, J = 4.0, 8.0 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 2 H), 8.50 (d, J = 4.0 Hz, 2 H). 13C NMR (125 MHz, CDCl3): δ = 192.5, 186.1, 168.0, 149.9 (2 C), 144.5, 124.9 (2 C), 106.3, 82.2, 38.7, 37.9, 36.8. IR (KBr): 1739, 1680, 1601, 1486, 1195, 1074, 828 cm-1. Anal. Calcd for C13H11NO3S2: C, 53.22; H, 3.78; N, 4.77; found: C, 53.46; H, 3.95; N, 4.98. Selected crystal data for 3a: colorless plate orthorhombic space group P2 (1)2(1)2(1), a = 4.9141 (3), b = 10.8597 (6), c = 24.4537 (15) Å, V = 1304.99 (13) Å3, β = 90°, Z = 4, D c = 1.493 g cm-3, µ (Cu-Kα) = 1.40 cm-1.
3-(1,3-Dithiolan-2-ylidene)-5-(pyridin-4-yl-mono-deuterated methyl) Furan-2,4(3 H ,5 H )-dione (3a-D): white solid; mp 194-196 °C. 1H NMR (500 MHz, CDCl3): δ = 3.03 (d, J = 7.0 Hz, 0.5 H), 3.27 (d, J = 3.5 Hz, 0.5 H), 3.57-3.66 (m, 4 H), 4.88 (dd, J = 3.5, 7.0 Hz, 1 H), 7.20 (d, J = 4.5 Hz, 2 H), 8.51 (d, J = 4.5 Hz, 2 H). 13C NMR (125 MHz, CDCl3): δ = 192.9, 186.0, 168.2, 150.1 (2 C), 144.8, 125.0 (2 C), 106.9, 82.4, 38.5, 38.1. IR (KBr): 1741, 1679, 1601, 1488, 1191, 1074, 1029, 791 cm-1. MS (ESI):
m/z (%) = 295 (100) [M + 1]+.
3-(1,3-Dithian-2-ylidene)-5-(pyridin-4-ylmethyl)furan-2,4(3 H ,5 H )-dione ( 3b): white solid; mp 199-201 °C. 1H NMR (300 MHz, CDCl3): δ = 2.32-2.36 (m, 2 H), 2.97 (dd, J = 7.2, 14.7 Hz, 1 H), 3.11-3.13 (m, 4 H), 3.24 (dd, J = 3.6, 14.7 Hz, 1 H), 4.75 (dd, J = 3.6, 7.2 Hz, 1 H), 7.18 (d, J = 5.7 Hz, 2 H), 8.49 (d, J = 5.7 Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ = 192.5, 184.0, 167.5, 149.8 (2 C), 144.3, 124.8 (2 C), 108.7, 81.0, 36.7, 30.9, 28.5, 28.4, 21.1. IR (KBr): 1733, 1669, 1433, 1173, 1074, 818 cm-1. Anal. Calcd for C14H13NO3S2: C, 54.70; H, 4.26; N, 4.56. Found: C, 54.48; H, 4.38; N, 4.75.
3-(1,3-Dithiolan-2-ylidene)-5-(pyridin-2-ylmethyl)furan-2,4(3 H ,5 H )-dione ( 3c): white solid; mp 182-184 ºC.
1H NMR (400 MHz, CDCl3): δ = 3.14 (dd, J = 8.0, 16.0 Hz, 1 H), 3.50 (dd, J = 4.0, 16.0 Hz, 1 H), 3.59-3.65 (m, 4 H), 5.20 (dd, J = 4.0, 8.0 Hz, 1 H), 7.14-7.17 (m, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 7.59-7.64 (m, 1 H), 8.52 (d, J = 4.4 Hz, 1 H). IR (KBr): 1736, 1678, 1591, 1492, 1436, 1196, 1071, 779 cm-1. MS (ESI): m/z (%) = 294 (100) [M + 1]+. Anal. Calcd for C13H11NO3S2: C, 53.22; H, 3.78; N, 4.77. Found: C, 53.41; H, 3.94; N, 4.96.
3-(1,3-Dithian-2-ylidene)-5-(pyridin-2-ylmethyl)furan-2,4(3 H ,5 H )-dione ( 3d): white solid; mp 171-173 °C. 1H NMR (600 MHz, CHCl3): δ = 2.36-2.40 (m, 2 H), 3.09 (dd, J = 9.0, 14.4 Hz, 1 H), 3.13-3.16 (m, 4 H), 3.46 (dd, J = 3.6, 14.4 Hz, 1 H), 5.08 (dd, J = 3.6, 9.0 Hz, 1 H), 7.14-7.16 (m, 1 H), 7.23 (d, J = 7.8 Hz, 1 H), 7.60-7.63 (m, 1 H), 8.53 (d, J = 4.8 Hz, 1 H). IR (KBr): 1727, 1664, 1433, 1421, 1175, 1079 cm-1. Anal. Calcd for C14H13NO3S2: C, 54.70; H, 4.26; N, 4.56. Found: C, 54.85; H, 4.06; N, 4.78.
3-(1,3-Dithiolan-2-ylidene)-5-(quinolin-2-ylmethyl)fu-ran-2,4(3 H ,5 H )-dione ( 3e): white solid; mp 152-154 °C. 1H NMR (300 MHz, CDCl3): δ = 3.42 (dd, J = 7.8, 15.6 Hz, 1 H), 3.57-3.66 (m, 4 H), 3.68 (dd, J = 3.9, 15.6 Hz, 1 H), 5.28 (dd, J = 3.9, 7.8 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.45-7.50 (m, 1 H), 7.62-7.67 (m, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.90 (d, J = 8.4 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H). IR (KBr): 1740, 1675, 1501, 1428, 1197, 1074, 1008 cm-1. Anal. Calcd for C17H13NO3S2: C, 59.46; H, 3.82; N, 4.08. Found: C, 59.71; H, 4.08; N, 3.82.
3-(1,3-Dithian-2-ylidene)-5-(quinolin-2-ylmethyl)furan-2,4(3 H ,5 H )-dione ( 3f): white solid; mp 194-196 °C. 1H NMR (500 MHz, CDCl3): δ = 2.34-2.36 (m, 2 H), 3.10-3.13 (m, 4 H), 3.37 (dd, J = 8.0, 15.5 Hz, 1 H), 3.64 (dd, J = 4.0, 15.5 Hz, 1 H), 5.15 (dd, J = 4.0, 8.0 Hz, 1 H), 7.31-7.33 (m, 1 H), 7.46-7.49 (m, 1 H), 7.64-7.67 (m, 1 H), 7.76 (d, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H). IR (KBr): 1733, 1670, 1599, 1436, 1173, 1079 cm-1. Anal. Calcd for C18H15NO3S2: C, 60.48; H, 4.23; N, 3.92. Found: C, 60.69; H, 4.05; N, 4.08.
( E )-2-(1,3-Dithiolan-2-ylidene)-3-oxo-5-(pyridin-3-yl)-pent-4-enoic Acid ( 4g): yellowish solid; mp 186-188 °C. 1H NMR (500 MHz, DMSO): δ = 3.38-3.41 (m, 4 H), 7.42-7.45 (m, 1 H), 7.46 (d, J = 16.0 Hz, 1 H), 7.52 (d, J = 16.0 Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 8.56 (d, J = 4.5 Hz, 1 H), 8.83 (s, 1 H). IR (KBr): 3419, 1683, 1642, 1586, 1419, 1206, 733 cm-1. Anal. Calcd for C13H11NO3S2: C, 53.22; H, 3.78; N, 4.77. Found: C, 53.02; H, 3.91; N, 4.58.
( E )-2-(1,3-Dithiolan-2-ylidene)-5-(4-nitrophenyl)-3-oxo-pent-4-enoic Acid ( 4h): yellowish solid; mp 188-189 °C. 1H NMR (500 MHz, DMSO): δ = 3.44-3.60 (m, 4 H), 7.52 (d, J = 16.0 Hz, 1 H), 7.58 (d, J = 16.0 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 2 H), 8.25 (d, J = 8.0 Hz, 2 H). IR (KBr): 3445, 1634, 1599, 1510, 1416, 1343, 1205, 731 cm-1; known compound, see ref. [10]
( E )-2-(1,3-Dithiolan-2-ylidene)-5-(2-nitrophenyl)-3-oxo-pent-4-enoic Acid ( 4i): yellowish solid; mp 191-193 °C. 1H NMR (500 MHz, DMSO): δ = 3.39-3.45 (m, 4 H), 7.34 (d, J = 15.0 Hz, 1 H), 7.64-7.67 (m, 1 H), 7.74 (d, J = 15.0 Hz, 1 H), 7.77-7.86 (m, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1 H). IR (KBr): 2929, 1654, 1628, 1578, 1525, 1428, 1391, 1342, 1274, 1207, 727 cm-1. Anal. Calcd for C14H11NO5S2: C, 49.84; H, 3.29; N, 4.15. Found: C, 50.11; H, 3.34; N, 4.28.

26

General Procedure for the Preparation of 10 (10e as example). To a solution of 1a (2.32 g, 10 mmol) and 2a (1.28 g, 12 mmol) in 30 mL EtOH-H2O (2:1, v/v), NaOH (0.8 g, 20 mmol) was added. After stirring at r.t. for 0.5 h, the mixture was acidified with aq HCl (1 N) to adjust the pH value to 5 and was stirred for another 0.5 h till the lactonization reaction was completed (monitored by TLC). Then, aq NH4OH (6 mL, 27%) was added and the reaction mixture was heated to 80 ºC. After stirring for 3 h, the mixture was allowed to cool down to r.t. and poured into cold aq NH4Cl. A yellowish solid precipitated from the system, which was filtered and washed with H2O (3 × 30 mL). The crude product was purified by column chromatography over silica gel using acetone-Et2O (5:1, v/v) as eluent to give product 10e as a white solid (1.65 g, 71%).
3-(Imidazolidin-2-ylidene)-5-(pyridin-4-ylmethyl)furan-2,4(3 H ,5 H )-dione ( 10a): white solid; decomposition point 241-243 °C.1H NMR (400 MHz, DMSO): δ = 2.80 (dd, J = 8.0, 14.4 Hz, 1 H), 2.33 (dd, J = 4.0, 14.4 Hz, 1 H), 3.57 (br s, 4 H), 4.74 (dd, J = 4.0, 8.0 Hz, 1 H), 7.26 (d, J = 6.0 Hz, 2 H), 8.45 (d, J = 6.0 Hz, 2 H). IR (KBr): 3334, 1734, 1647, 1601, 1447, 1058, 1000 cm-1. Anal. Calcd for C13H13N3O3: C, 60.22; H, 5.05; N, 16.21. Found: C, 60.47; H, 4.82; N, 16.43.
5-(Pyridin-4-ylmethyl)-3-(tetrahydropyrimidin-2(1 H )-ylidene)furan-2,4(3 H ,5 H )-dione ( 10b): white solid; mp 112-113 °C. 1H NMR (400 MHz, CDCl3): δ = 2.01-2.07 (m, 2 H), 2.95 (dd, J = 8.0, 16.0 Hz, 1 H), 3.25 (dd, J = 4.0, 16.0 Hz, 1 H), 3.42 (br s, 4 H), 4.70 (dd, J = 4.0, 8.0 Hz, 1 H), 7.22 (d, J = 4.0 Hz, 2 H), 7.87 (br s, 1 H), 8.50 (d, J = 4.0 Hz, 2 H), 8.60 (br s, 1 H). 13C NMR (100 MHz, DMSO): δ = 192.8, 173.1, 154.7, 149.2 (2 C), 145.9, 124.7 (2 C), 79.7, 37.6 (2 C), 36.2, 19.0. IR (KBr): 3325, 3279, 1710, 1634, 1602, 1464, 1417, 1151, 1007 cm-1. Anal. Calcd for C14H13NO3S2: C, 54.70; H, 4.26; N, 4.56. Found: C, 54.77; H, 4.38; N, 4.55. MS (ESI): m/z (%) = 569 (100) [2 M + 23]+.
3-(1,3-Diazepan-2-ylidene)-5-(pyridin-4-ylmethyl)furan-2,4(3 H ,5 H )-dione ( 10c): white solid; mp 193-194 °C. 1H NMR (400 MHz, CDCl3): δ = 1.91 (br s, 4 H), 2.93 (dd, J = 7.2, 14.4 Hz, 1 H), 3.25 (dd, J = 3.6, 14.4 Hz, 1 H), 3.47 (br s, 4 H), 4.69 (dd, J = 3.6, 7.2 Hz, 1 H), 7.23 (d, J = 5.6 Hz, 2 H), 8.27 (br s, 1 H), 8.50 (d, J = 5.6 Hz, 2 H), 9.05 (br s, 1 H). 13C NMR (100 MHz, DMSO): δ = 193.9, 174.5, 163.1, 149.6 (2 C), 145.1, 124.8 (2 C), 82.2, 80.08, 44.4 (2 C), 36.6, 27.0 (2 C). IR (KBr): 3269, 1709, 1635, 1467, 1062, 993 cm-1. Anal. Calcd for C15H15NO3S2: C, 56.05; H, 4.70; N, 4.36. Found: C, 56.25; H, 4.81; N, 4.33. MS (ESI): m/z (%) = 596 (100) [2 M + 23]+.
3-[Bis(methylamino)methylene]-5-(pyridin-4-ylmethyl)furan-2,4-(3 H ,5 H )-dione ( 10d): white solid; mp 151-153 °C. 1H NMR (500 MHz, DMSO): δ = 2.79 (dd, J = 7.5, 14.0 Hz, 1 H), 3.12 (dd, J = 3.5, 14.0 Hz, 1 H), 3.00 (br s, 6 H), 4.70 (br s, 1 H), 7.25 (d, J = 6.0 Hz, 2 H), 8.26 (br s, 2 H), 8.44 (d, J = 6.0 Hz, 2 H). IR (KBr): 3252, 1713, 1641, 1601, 1465, 1070, 811, 787 cm-1. Anal. Calcd for C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C, 59.91; H, 5.98; N, 16.29.
3-(Diaminomethylene)-5-(pyridin-4-ylmethyl)furan-2,4-(3 H ,5 H )-dione ( 10e): white solid; mp 196-198 °C. 1H NMR (500 MHz, DMSO): δ = 2.74 (dd, J = 3.5, 14.5 Hz, 1 H), 3.10 (dd, J = 7.5, 14.5 Hz, 1 H), 4.43 (dd, J = 3.5, 7.5 Hz, 1 H), 7.08 (br s, 1 H), 7.17 (br s, 1 H), 7.27 (d, J = 5.5 Hz, 2 H), 7.90 (d, J = 5.0 Hz, 1 H), 8.45 (d, J = 5.5 Hz, 2 H), 9.66 (d, J = 5.0 Hz, 1 H). 13C NMR (100 MHz, DMSO): 192.3, 189.7, 173.4, 149.0 (2 C), 146.9, 124.8 (2 C), 93.6, 77.5, 37.0. IR (KBr): 3268, 3132, 1700, 1592, 1463, 1049, 834 cm-1. Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C, 56.42; H, 4.90; N, 18.23.
3-[Bis(2-hydroxyethylamino)methylene]-5-(pyridin-4-ylmethyl)furan-2,4(3 H ,5 H )-dione ( 10f): white solid; mp 157-158 °C. 1H NMR (500 MHz, DMSO): δ = 2.78 (dd, J = 8.5, 14.5 Hz, 1 H), 3.14 (dd, J = 2.5, 14.5 Hz, 1 H), 3.54-3.56 (m, 8 H), 4.75 (dd, J = 2.5, 8.5 Hz, 1 H), 5.07 (br s, 2 H), 7.26 (d, J = 5.0 Hz, 2 H), 8.45 (d, J = 5.0 Hz, 2 H), 8.55 (br s, 2 H). IR (KBr): 3334, 1709, 1648, 1560, 1466, 1210, 1009 cm-1. Anal. Calcd for C15H19N3O5: C, 56.07; H, 5.96; N, 13.08. Found: C, 56.17; H, 6.01; N, 13.05.
3-(Imidazolidin-2-ylidene)-5-(pyridin-2-ylmethyl)furan-2,4(3 H ,5 H )-dione ( 10g): white solid; decomposition point 240-241 °C. 1H NMR (400 MHz, DMSO): δ = 2.85 (dd, J = 9.6, 14.4 Hz, 1 H), 3.25 (dd, J = 3.2, 14.4 Hz, 1 H), 3.59 (br s, 4 H), 4.85 (dd, J = 3.2, 9.6 Hz, 1 H), 7.26-7.29 (m, 1 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.73-7.78 (m, 1 H), 8.29 (br s, 2 H), 8.52 (d, J = 4.4 Hz, 1 H). IR (KBr): 3316, 1716, 1646, 1615, 1448, 1061, 785, 630 cm-1. Anal. Calcd for C13H13N3O3: C, 60.22; H, 5.05; N, 16.21. Found: C, 60.55; H, 4.79; N, 16.34. Selected crystal data: monoclinic, P2
(1)/c, a = 5.1342 (2), b = 25.5679 (14), c = 11.3206 (9) Å, V = 1478.32 (15) Å3, β = 95.853 (3)°, Z = 4, D c = 1.435 g cm-3, µ (Cu-Kα) = 1.40 cm-1.
3-(Diaminomethylene)-5-(pyridin-2-ylmethyl)furan-2,4-(3 H ,5 H )-dione ( 10h): white solid; mp 198-200 °C. 1H NMR (400 MHz, DMSO): δ = 2.84 (dd, J = 9.6, 14.8 Hz, 1 H), 3.24 (dd, J = 3.2, 14.8 Hz, 1 H), 4.86 (dd, J = 3.2, 9.6 Hz, 1 H), 7.22-7.25 (m, 1 H), 7.30 (d, J = 7.6 Hz, 1 H), 7.60 (s, 2 H), 7.71-7.73 (m, 1 H), 7.74 (br s, 2 H), 8.50 (d, J = 4.4 Hz, 1 H). 13C NMR (100 MHz, DMSO): δ = 193.1, 189.6, 174.0, 157.8, 148.7, 136.6, 123.7, 93.3, 78.1, 40.5. IR (KBr): 3282, 3140, 1699, 1631, 1596, 1456, 1061, 1012, 759 cm-1. MS (ESI): m/z (%) = 234 (100) [M + 1]+. Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C, 56.39; H, 4.89; N, 18.25.
3-[Bis(2-hydroxyethylamino)methylene]-5-(pyridin-2-ylmethyl)furan-2,4(3 H ,5 H )-dione ( 10i): white solid; mp 158-159 °C. 1H NMR (400 MHz, DMSO): δ = 2.82 (dd, J = 10.0, 14.8 Hz, 1 H), 3.25 (dd, J = 2.4, 14.8 Hz, 1 H), 3.57 (br s, 8 H), 4.86 (dd, J = 2.4, 10.0 Hz, 1 H), 5.07 (br s, 2 H), 7.23-7.26 (m, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.70-7.74 (m, 1 H), 8.51 (d, J = 4.0 Hz, 1 H), 8.62 (br s, 2 H). IR (KBr): 3340, 1710, 1655, 1559, 1465, 1196, 1070 cm-1. MS (ESI): m/z (%) = 322 (100) [M + 1]+. Anal. Calcd for C15H19N3O5: C, 56.07; H, 5.96; N, 13.08. Found: C, 56.20; H, 6.07; N, 13.13.