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

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.

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

References

1a Haynes LJ. Plimmer JRQ. Rev. Chem. Soc.  1960,  14:  292 

1b Pilli RA. Ferreira de Oliveira MC. Nat. Prod. Rep.  2000,  17:  117 

2a Ishida K. Teruya T. Simizu S. Osada H. J. Antibiot.  2004,  57:  136 

2b Liu Y. Hong J. Lee C. Im K. Kim N. Choi J. Jung J. J. Nat. Prod.  2002,  65:  1307 

2c Sodeoka M. Sampe R. Kojima S. Baba Y. Usui T. Ueda K. Osada H. J. Med. Chem.  2001,  44:  3216 

2d Usui T. Kojima S. Kidokoro S. Ueda K. Osada H. Sodeoka M. Chem. Biol.  2001,  8:  1209 

2e Buhler H. Bayer A. Effenberger F. Chem.-Eur. J.  2000,  6:  2564 

2f Hegde VR. Patel MG. Das PR. Pramanik B. Puar MS. J. Antibiot.  1997,  50:  126 

2g Roggo BE. Petersen F. Delmendo R. Jenny HB. Peter HH. Roesel J. J. Antibiot.  1994,  47:  136 

3a Schobert R. Gordon GJ. Mullen G. Stehle R. Tetrahedron Lett.  2004,  45:  1121 

3b Kemmler M. Bach T. Angew. Chem. Int. Ed.  2003,  42:  4824 

3c Paintner FF. Allmendinger L. Bauschke G. Synlett  2003,  83 

3d Paintner FF. Allmendinger L. Bauschke G. Polborn K. Synlett  2002,  1308 

3e Velázquez F. Olivo HF. Org. Lett.  2002,  4:  3175 

4a Schobert R. Jagusch C. Tetrahedron Lett.  2003,  44:  6449 

4b Pévet I. Meyer C. Cossy J. Tetrahedron Lett.  2001,  42:  5215 

4c Langer P. Eckardt T. Schneider T. Göbel C. Herbst-Irmer R. J. Org. Chem.  2001,  66:  2222 

4d Schobert R. Siegfried S. Gordon G. Mulholland D. Nieuwenhuyzen M. Tetrahedron Lett.  2001,  42:  4561 

4e Langer P. Eckardt T. Synlett  2000,  844 

4f Paleta O. Volkov A. Hetflejs J. J. Fluorine Chem.  2000,  102:  147 

4g Mitsos CA. Zografos AL. Igglessi-Markopoulou O. J. Org. Chem.  2000,  65:  5852 

4h Effenberger F. Syed J. Tetrahedron: Asymmetry  1998,  9:  817 ; and references therein

For reviews, see:

5a Dieter RK. Tetrahedron  1986,  42:  3029 

5b Junjappa H. Ila H. Asokan CV. Tetrahedron  1990,  46:  5423 

5c Kolb M. Synthesis  1990,  171 

5d Ila H. Junjappa H. Barun O. J. Organomet. Chem.  2001,  624:  34 

6 Ila H. Junjappa H. Mohanta PK. In Progress in Heterocyclic Chemistry   Vol. 13:  Gribble GH. Gilchrist LT. Pergamon Press; Oxford: 2001.  Chap. 1. p.1-24  

7a Kocienski PJ. Alessandro P. Liu Q. J. Chem. Soc., Perkin Trans. 1  2001,  2356 

7b Gill S. Kocienski P. Kohler A. Pontiroli A. Liu Q. Chem. Commun.  1996,  1743 

7c Barun O. Nandi S. Panda K. Ila H. Junjappa H. J. Org. Chem.  2002,  67:  5398 

7d Nandi S. Syam Kumar UK. Ila H. Junjappa H. J. Org. Chem.  2002,  67:  14 

7e Joseph BK. Verghese B. Sudarsanakumar C. Deepa S. Viswam D. Chandran P. Asokan CV. Chem. Commun.  2002,  736 

8 Choi EB. Youn IK. Pak CS. Synthesis  1991,  15 

9 Zhao Y. Liu Q. Sun R. Zhang Q. Xu X. Synth. Commun.  2004,  34:  463 

10 Wang M. Xu X. Liu Q. Xiong L. Yang B. Gao L. Synth. Commun.  2002,  32:  3437 

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) ų, β = 90°, Z = 4, D _c = 1.493 g cm^-3, µ (Cu-K_α) = 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.

12 Perlmutter P. Conjugate Addition Reaction in Organic Synthesis   Pergamon Press; Oxford: 1992. 

13 Doering WE. Weil RAN. J. Am. Chem. Soc.  1947,  69:  2461 

14 For a review see: Friedman M. J. Protein Chem.  2001,  20:  431 

15a Shapiro S. Rose I. Freedman L. J. Am. Chem. Soc.  1957,  79:  2811 

15b Safak C. Erdojjan H. Palaska E. Sunal R. Durd S. J. Med. Chem.  1992,  35:  1296 

15c Babaev EV. Tsisevich AA. J. Chem. Soc., Perkin Trans. 1  1999,  399 

15d Kuzmich D. Mulrooney C. Synthesis  2003,  1671 

15e Cliffe IA. Ifill AD. Mansell HL. Todd RS. White AC. Tetrahedron Lett.  1991,  32:  6789 ; and references therein

16a Levine R. Wilt MH. J. Am. Chem. Soc.  1952,  74:  342 

16b Wilt MH. Levine R. J. Am. Chem. Soc.  1953,  75:  1368 

16c Houpis IN. Lee J. Dorziotis I. Molina A. Reamer B. Volante RP. Reider PJ. Tetrahedron  1998,  54:  1185 

17 Hersman MF. Audrieth LF. J. Org. Chem.  1958,  23:  1889 

18 Holler M. Sin HS. James A. Burger A. Trisch D. Biellmann JF. Chem.-Eur. J.  2000,  6:  2053 

19 Nozakura S. Bull. Chem. Soc. Jpn.  1956,  29:  784 

20a Paquette LA. J. Org. Chem.  1962,  27:  2780 

20b Bissot TC. Parry RW. Campbell DH. J. Am. Chem. Soc.  1957,  79:  796 

21 Salamone JC. Snider B. Fitch WL. Macromolecules  1970,  3:  707 

22 Teller F. Audouin M. Sauvetre R. J. Fluorine Chem.  2002,  113:  167 

23 For a related report ‘protonated pyridylazo moiety activated the phenyl ring to nucleophilic attack in aqueous sulfuric acid’, see: Miura Y. Momoki M. J. Chem. Soc., Perkin Trans. 2  1998,  1185 

24a Choi EB. Youn IK. Pak CS. Synthesis  1988,  792 

24b Mellor JM. Schofield RS. Korn SR. Tetrahedron  1997,  53:  17151 

24c Hu Y. Liu Q. Dong D. Chin. Chem. Lett.  1992,  3:  417 

25 For a review, see: Huang Z. Wang M. Heterocycles  1994,  37:  1233 

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) ų, β = 95.853 (3)°, Z = 4, D _c = 1.435 g cm^-3, µ (Cu-K_α) = 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.