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Synlett 2012; 23(14): 2063-2068
DOI: 10.1055/s-0031-1290435
letter
© Georg Thieme Verlag Stuttgart · New York

Reaction of 2-Hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles with 1,3-N,N-Binucleophiles

Demyd S. Milokhov
a   Department of Chemistry, National Kyiv Taras Shevchenko University, 64 Volodymyrska st., Kyiv 01601, Ukraine, Fax: +380(44)2351273   Email: olgakh@univ.kiev.ua
,
Olga V. Khilya*
a   Department of Chemistry, National Kyiv Taras Shevchenko University, 64 Volodymyrska st., Kyiv 01601, Ukraine, Fax: +380(44)2351273   Email: olgakh@univ.kiev.ua
,
Yulian M. Volovenko
a   Department of Chemistry, National Kyiv Taras Shevchenko University, 64 Volodymyrska st., Kyiv 01601, Ukraine, Fax: +380(44)2351273   Email: olgakh@univ.kiev.ua
,
Gennady V. Palamarchuk
b   Division of Functional Materials Chemistry, SSI ‘Institute for Single Crystals’, National Academy of Sciences of Ukraine, 60 Lenina ave., Kharkiv 61001, Ukraine
,
Oleg V. Shishkin
b   Division of Functional Materials Chemistry, SSI ‘Institute for Single Crystals’, National Academy of Sciences of Ukraine, 60 Lenina ave., Kharkiv 61001, Ukraine
c   Department of Inorganic Chemistry, V. N. Karazin Kharkiv National University, 4 Svobody sq., Kharkiv 61202, Ukraine
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Further Information

Publication History

Received: 28 April 2012

Accepted after revision: 18 June 2012

Publication Date:
08 August 2012 (online)

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Abstract

The reactions of 2-hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles with 1,3-N,N-binucleophiles have been investigated. The mechanisms of the reactions have been discussed. Domino reactions of 2-hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles with amidines can provide an efficient access to 3-[2-substituted 6-amino-5-hetaryl-4-pyrimidinyl]-1-propanols.

Key words

Michael addition - 2-hetaryl-2-(tetrahydro-2-furanyliden)acetonitriles - binucleophiles - amidines - ring-transformation reactions - ω-hydroxyalkyl heterocycles - pyrimidines
 

  • References and Notes

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  • 10 General Procedure for the Preparation of 3-[2-(R)-6-Amino-5-(2-hetaryl)pyrimidin-4-yl]propan-1-ols 5a–k, Dihydropyrimidines 7a–c, and Fused Pyrimidines 8a,bTo a stirred solution of sodium (0.09 g, 4 mmol) in anhyd EtOH (5 mL) the corresponding amidine 4 (4 mmol) and 2-hetaryl-2-(tetrahydro-2-furanyliden)acetonitrile 3 (2 mmol) were added. The reaction mixture was refluxed for 0.5–1 h, and EtOH was then evaporated in vacuo. The residue was triturated with H2O, acidified with HCl to pH 7, filtered off, and recrystallized from the appropriate solvent.Compound 5aWhite microcrystals (from aq EtOH); mp 231–232 °C; yield 0.57 g (95%). IR (KBr): 3344, 3137, 1655, 1555, 1434, 1076 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.84 (m, 2 H, 2-CH2), 2.78 (t, J = 7.8 Hz, 2 H, 3-CH2), 3.46 (t, J = 6.4 Hz, 2 H, 1-CH2), 4.34 (s, 1 H, OH), 6.27 (s, 2 H, 2-NH2), 7.22 (br s, 2 H, 6-NH2), 7.36 (t, J = 7.8 Hz, 1 H, НHet), 7.46 (t, J = 7.8 Hz, 1 H, НHet), 7.96 (d, J = 7.8 Hz, 2 H, НHet). 13C NMR (100 MHz, DMSO-d 6): δ = 32.24, 33.18, 61.39, 100.18, 121.71, 122.59, 125.05, 126.41, 134.98, 152.67, 162.43, 162.78, 165.14, 169.22. Anal. Calcd for C14H15N5OS: C, 55.80; H, 5.02; N, 23.24; S, 10.64. Found: C, 55.38; H, 5.05; N, 23.76; S, 10.25.Compound 5bWhite microcrystals (from EtOH); mp 161–162 °C; yield 0.52 g (86%). IR (KBr): 3478, 3294, 3134, 1619, 1536, 1059 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.80 (m, 2 H, 2-CH2), 2.40 (s, 3 H, Me), 2.70 (t, J = 7.6 Hz, 2 H, 3-CH2), 3.39 (q, J = 6.0 Hz, 2 H, 3-CH2), 4.30 (t, J = 6.0 Hz, 1 H, OH), 7.14 (s, 2 H, NH2), 7.42 (t, J = 7.9 Hz, 1 Н, НHet), 7.50 (t, J = 7.9 Hz, 1 Н, НHet), 8.03 (d, J = 7.9 Hz, 2 Н, НHet). 13C NMR (100 MHz, DMSO-d 6): δ = 26.04, 32.20, 32.77, 61.30, 106.35, 122.13, 123.34, 125.75, 126.59, 135.79, 153.03, 161.81, 163.58, 167.04, 167.42. Anal. Calcd for C15H16N4OS: C, 59.98; H, 5.37; N, 18.65; S, 10.68. Found: C, 59.62; H, 5.39; N, 18.95; S, 10.93.Compound 5cWhite microcrystals (from EtOH); mp 124–125 °C; yield 0.46 g (70%). IR (KBr): 3540, 3317, 3142, 2959, 1618, 1534 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.26 (d, J = 7.0 Hz, 6 Н, i-Pr), 1.83 (m, 2 H, 2-CH2), 2.75 (t, J = 7.6 Hz, 2 H, 3-CH2), 2.87 (m, 1 H, i-Pr), 3.43 (q, J = 4.0 Hz, 2 H, 1-CH2), 4.32 (t, J = 4.0 Hz, 1 H, OH), 7.14 (s, 2 H, NH2), 7.42 (t, J = 7.6 Hz, 1 Н, НHet), 7.50 (t, J = 7.6 Hz, 1 Н, НHet), 8.03 (d, J = 7.6 Hz, 2 Н, НHet). 13C NMR (100 MHz, DMSO-d 6): δ = 22.02, 32.02, 32.88, 37.42, 61.32, 106.53, 122.11, 123.35, 125.73, 126.59, 135.76, 153.01, 161.96, 163.75, 167.38, 174.15. Anal. Calcd for C17H20N4OS: C, 62.17; H, 6.14; N, 17.06; S, 9.76. Found: C, 62.32; H, 6.09; N, 17.15; S, 9.86.Compound 5dWhite microcrystals (from EtOH); mp 159–160 °C; yield 0.70 g (97%). IR (KBr): 3396, 3260, 2930, 1528, 1429, 946 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.97 (m, 2 H, 2-CH2), 2.89 (t, J = 7.6 Hz, 2 H, 3-CH2), 3.51 (q, J = 5.5 Hz, 2 H, 1-CH2), 4.32 (t, J = 5.5 Hz, 1 H, OH), 7.40 (s, 2 H, NH2), 7.46 (m, 4 H, 3,5-HPh and HHet), 7.54 (t, J = 7.8 Hz, 1 Н, НHet), 8.06 (d, J = 7.8 Hz, 1 Н, НHet), 8.07 (d, J = 7.8 Hz, 1 Н, НHet), 8.40 (m, 2 H, 2,6-HPh). 13C NMR (100 MHz, DMSO-d 6): δ = 31.99, 32.96, 61.28, 107.27, 122.13, 123.38, 125.81, 126.66, 128.51, 128.67, 130.79, 135.74, 138.18, 152.97, 162.12, 162.74, 163.53, 167.77. Anal. Calcd for C20H18N4OS: C, 66.28; H, 5.01; N, 15.46; S, 8.85. Found: C, 66.25; H, 5.31; N, 15.21; S, 8.58.Compound 5eWhite microcrystals (from EtOH); mp 154–155 °C; yield 0.72 g (89%). IR (KBr): 3411, 3348, 2948, 1605, 1534, 1402 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.29 (d, J = 7.0 Hz, 6 Н, i-Pr), 1.95 (m, 2 H, 2-CH2), 2.89 (t, J = 7.6 Hz, 2 H, 3-CH2), 2.97 (m, 1 H, i-Pr), 3.49 (q, J = 6.1 Hz, 2 H, 1-CH2), 4.33 (t, J = 6.1 Hz, 1 H, OH), 7.29 (d, J = 7.3 Hz, 2 Н, 3,5-HPh), 7.38 (s, 2 H, NH2), 7.45 (t, J = 7.6 Hz, 1 Н, НHet), 7.53 (t, J = 7.6 Hz, 1 Н, НHet), 8.07 (d, J = 7.6 Hz, 2 Н, НHet), 8.30 (d, J = 7.3 Hz, 2 Н, 2,6-HPh). 13C NMR (100 MHz, DMSO-d 6): δ = 24.38, 31.95, 33.02, 34.22, 61.29, 107.04, 122.09, 123.32, 125.76, 126.49, 126.63, 128.79, 135.68, 135.96, 151.35, 152.93, 162.06, 162.83, 163.70, 167.66. Anal. Calcd for C23H24N4OS: C, 68.29; H, 5.98; N, 13.85; S, 7.93. Found: C, 68.08; H, 6.18; N, 14.15; S, 7.51.Compound 5fWhite microcrystals (from EtOH); mp 162–163 °C; yield 0.59 g (80%). IR (KBr): 3393, 3258, 1610, 1527, 1428, 946 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.95 (m, 2 H, 2-CH2), 2.86 (t, J = 7.6 Hz, 2 H, 3-CH2), 3.49 (q, J = 6.0 Hz, 2 H, 1-CH2), 4.31 (t, J = 6.0 Hz, 1 H, OH), 7.29 (dd, J = 3.7, 4.9 Hz, 1 Н, 4-Hthienyl), 7.46 (m, 3 H, NH2 and HHet), 7.52 (t, J = 7.6 Hz, 1 Н, НHet), 7.56 (dd, J = 4.9, 0.9 Hz, 1 Н, 3-Hthienyl), 7.90 (dd, J = 3.7, 0.9 Hz, 1 Н, 5-Hthienyl), 8.06 (d, J = 7.6 Hz, 1 Н, НHet), 8.07 (d, J = 7.6 Hz, 1 Н, НHet). 13C NMR (100 MHz, DMSO-d 6): δ = 31.88, 32.84, 61.24, 106.87, 122.08, 123.33, 125.78, 126.64, 128.30, 129.14, 130.28, 135.66, 144.34, 152.90, 159.79, 161.90, 163.45, 167.75. Anal. Calcd for C18H16N4OS2: C, 58.67; H, 4.38; N, 15.20; S, 17.40. Found: C, 58.32; H, 4.43; N, 15.16; S, 17.20.Compound 5gWhite microcrystals (from EtOH); mp 153–154 °C; yield 0.38 g (72%). IR (KBr): 3428, 3305, 3109, 1667, 1569, 1446 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.82 (m, 2 H, 2-CH2), 2.43 (s, 3 Н, Me), 2.68 (t, J = 7.6 Hz, 2 H, 3-CH2), 3.44 (t, J = 6.3 Hz, 2 H, 1-CH2), 4.43 (br s, 1 H, OH), 5.93 (s, 2 H, 2-NH2), 6.93 (br s, 2 H, 6-NH2), 7.09 (s, 1 Н, HHet). 13C NMR (100 MHz, DMSO-d 6): δ = 17.29, 32.03, 32.67, 61.13, 100.12, 114.46, 151.54, 162.10, 162.52, 163.17, 168.11. Anal. Calcd for C11H15N5OS: C, 49.79; H, 5.70; N, 26.39; S, 12.09. Found: C, 49.88; H, 5.33; N, 26.79; S, 12.08.Compound 5hWhite microcrystals (from EtOH); mp 156–158 °C; yield 0.37 g (70%). IR (KBr): 3411, 3277, 3092, 2946, 1639, 1538 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.81 (m, 2 H, 2-CH2), 2.37 (s, 3 H, Me), 2.49 (s, 3 H, Me), 2.73 (t, J = 7.5 Hz, 2 H, 3-CH2), 3.44 (t, J = 6 Hz, 2 H, 1-CH2), 4.36 (s, 1 H, OH), 7.18 (s, 2 H, NH2), 7.27 (s, 1 Н, HHet). 13C NMR (100 MHz, DMSO-d 6): δ = 17.20, 25.70, 31.85, 32.49, 61.03, 106.08, 115.54, 151.99, 161.45, 161.52, 165.83, 166.29. Anal. Calcd for C12H16N4OS: C, 54.52; H, 6.10; N, 21.19; S, 12.13. Found: C, 54.67; H, 6.09; N, 21.50; S, 12.14.Compound 5iWhite microcrystals (from EtOH); mp 127–128 °C; yield 0.49 g (75%). IR (KBr): 3400, 3204, 2952, 1597, 1535, 1434 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.98 (m, 2 H, 2-CH2), 2.48 (s, 3 Н, Me), 2.90 (t, J = 7.5 Hz, 2 H, 3-CH2), 3.52 (t, J = 6 Hz, 2 H, 1-CH2), 4.32 (t, J = 6 Hz, 1 H, OH), 7.33 (s, 1 Н, HHet), 7.43 (m, 5 H, NH2 and 3,4,5-HPh), 8.37 (m, 2 H, 2,6-HPh). 13C NMR (100 MHz, DMSO-d 6): δ = 17.50, 31.80, 33.15, 61.37, 107.30, 115.53, 128.58, 128.43, 130.54, 138.38, 152.13, 161.86, 161.92, 165.97, 166.74. Anal. Calcd for C17H18N4OS: C, 62.55; H, 5.56; N, 17.16; S, 9.82. Found: C, 62.48; H, 5.59; N, 17.10; S, 9.64.Compound 5jWhite microcrystals (from EtOH); mp 212–213 °C; yield 0.29 g (52%). IR (KBr): 3243, 2941, 1613, 1555, 1471, 1191 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.76 (m, 2 H, 2-CH2), 2.47 (s, 3 Н, Me), 2.72 (t, J = 7.8 Hz, 2 H, 3-CH2), 3.44 (t, J = 6.1 Hz, 2 H, 1-CH2), 4.42 (br s, 1 H, OH), 7.30 (s, 1 Н, HHet), 7.96 (s, 1H, NH), 8.24 (s, 1 H, NH), 12.25 (s, 1 H, SH). 13C NMR (100 MHz, DMSO-d6 ): δ = 17.6, 27.73, 32.07, 60.54, 101.16, 115.85, 152.20, 156.86, 159.06, 160.14, 179.16. Anal. Calcd for C11H14N4OS2: C, 46.79; H, 5.00; N, 19.84; S, 22.71. Found: C, 46.66; H, 4.88; N, 19.64; S, 22.68.Compound 5kWhite microcrystals (from EtOH); mp 252–253 °C; yield 0.54 g (91%). IR (KBr): 3411, 3333, 3215, 1641, 1580, 1555 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.68 (m, 1 H, 2a-CH2), 1.74 (m, 1 H, 2b-CH2), 2.22 (m, 1 H, 3a-CH2), 2.25 (m, 1 H, 3b-CH2), 3.30 (t, J = 6.0 Hz, 2 H, 1-CH2), 3.65 (s, 3 Н, NMe), 4.80 (br s, 1 H, OH), 6.04 (s, 2 H, 2-NH2), 6.10 (br s, 2 H, 6-NH2), 7.19 (t, J = 7.8 Hz, 1 Н, НHet), 7.23 (t, J = 7.8 Hz, 1 Н, НHet), 7.48 (d, J = 7.8 Hz, 1 Н, НHet), 7.62 (d, J = 7.8 Hz, 1 Н, НHet). 13C NMR (100 MHz, DMSO-d 6): δ = 30.76, 31.69, 31.79, 60.60, 96.09, 110.77, 119.30, 121.93, 122.36, 136.44, 143.37, 150.75, 163.26, 163.57, 169.58. Anal. Calcd for C15H18N6O: C, 60.39; H, 6.08; N, 28.17. Found: C, 60.61; H, 6.13; N, 28.20.Compound 7aWhite microcrystals (from EtOH); mp 212–213 °C; yield 0.47 g (74%). IR (KBr): 3338, 3120, 2980, 1672, 1602, 1560 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.75 (m, 2 H, 2-CH2), 2.41 (m, 2 H, 3-CH2), 3.38 (m, 5 H, NMe and 1-CH2), 4.31 (s, 1 H, OH), 7.01 (s, 1 H, NH), 7.11 (s, 2 H, NH2), 7.38 (t, J = 7.8 Hz, 1 H, НHet), 7.47 (t, J = 7.8 Hz, 1 H, НHet), 7.97 (d, J = 7.8 Hz, 2 H, НHet). 13C NMR (100 MHz, DMSO-d6 ): δ = 30.57, 32.21, 32.91, 61.35, 103.93, 122.42, 123.03, 125.58, 126.70, 135.73, 153.23, 155.71, 157.16, 162.62, 164.95. Anal. Calcd for C15H17N5OS: C, 57.12; H, 5.43; N, 22.21; S, 10.17. Found: C, 57.14; H, 5.41; N, 22.44; S, 10.08.Compound 7bWhite microcrystals (from EtOH); mp 208–209 °C; yield 0.34 g (61%). IR (KBr): 3428, 3249, 3103, 1681, 1591, 1384 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.70 (m, 2 H, 2-CH2), 2.26 (m, 2 H, 3-CH2), 2.43 (s, 3 Н, Me), 3.35 (m, 5 H, NMe and 1-CH2), 4.38 (s, 1 H, OH), 6.63 (br s, 1 H, NH), 6.92 (s, 2 H, NH2), 7.16 (s, 1 Н, HHet). 13C NMR (100 MHz, DMSO-d 6): δ = 17.28, 30.65, 31.76, 32.26, 60.92, 103.45, 115.67, 152.14, 154.99, 157.64, 161.60, 162.34. Anal. Calcd for C12H17N5OS: C, 51.59; H, 6.13; N, 25.07; S, 11.48. Found: C, 51.42; H, 6.29; N, 25.85; S, 11.35.Compound 7cWhite microcrystals (from EtOH); mp 234–235 °C; yield 0.46 g (74%). IR (KBr): 3366, 3098, 1681, 1605, 1538, 1037 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.63 (m, 1 H, 2a-CH2), 1.73 (m, 1 H, 2b-CH2), 2.02 (m, 1 H, 3a-CH2), 2.10 (m, 1 H, 3b-CH2), 3.32 (t, J = 6 Hz, 2 H, 1-CH2), 3.40 (s, 3 H, NMe), 3.62 (s, 3 Н, NMeHet), 4.77 (s, 1 H, OH), 5.63 (br s, 1 H, NH), 7.02 (s, 2 H, NH2), 7.19 (t, J = 7.6 Hz, 1 Н, НHet), 7.24 (t, J = 7.6 Hz, 1 Н, НHet), 7.48 (d, J = 7.6 Hz, 1 Н, НHet), 7.62 (d, J = 7.6 Hz, 1 Н, НHet). 13C NMR (100 MHz, DMSO-d 6): δ = 29.98, 30.40, 31.04, 31.65, 60.33, 100.39, 110.56, 119.12, 121.83, 122.36, 135.80, 142.95, 150.40, 155.89, 158.02, 161.77. Anal. Calcd for C16H20N6O: C, 61.52; H, 6.45; N, 26.90. Found: C, 61.78; H, 6.05; N, 26.53.1-Amino-3-(3-hydroxypropyl)pyrimido[1,6-a]benzimidazole-4-carbonitrile (8a)Pale yellow microcrystals (from DMF); mp 337 °C; yield 0.45 g (84%). IR (KBr): 3484, 3103, 2229, 1555, 1457, 769 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.91 (m, 2 H, 2-CH2), 2.85 (t, J = 7.8 Hz, 2 H, 1-CH2), 3.53 (t, J = 6.3 Hz, 2 H, 3-CH2), 4.42 (s, 1 H, OH), 7.33 (dd, J = 8.3, 7.5 Hz, 1 H, НHet), 7.48 (dd, J = 8.1, 7.5 Hz, 1 H, НHet), 7.72 (d, J = 8.1 Hz, 1 H, НHet), 8.38 (d, J = 8.3 Hz, 1 H, НHet), 8.42 (br s, 2 H, NH2). 13C NMR (100 MHz, DMSO-d 6): δ = 32.09, 33.65, 60.94, 83.16, 114.74, 116.66, 119.14, 122.30, 126.77, 127.46, 145.09, 149.51, 150.91, 168.43. Anal. Calcd for C14H13N5O: C, 62.91; H, 4.90; N, 26.20. Found: C, 62.61; H, 5.00; N, 25.93.5-Amino-7-(3-hydroxypropyl)imidazo[1,2-c]pyrimidine-8-carbonitrile (8b)Pale yellow microcrystals (from EtOAc); mp 241–242 °C; yield 0.31 g (71%). IR (KBr): 3440, 3185, 2224, 1656, 1542, 713 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.33 (m, 2 H, 2-CH2), 2.27 (t, J = 7.6 Hz, 2 H, 1-CH2), 2.95 (m, 2 H, 3-CH2), 4.06 (t, J = 5.1 Hz,1 H, OH), 7.01 (s, 1 H, НHet), 7.44 (s, 1 H, НHet), 7.97 (br s, 2 H, NH2). 13C NMR (100 MHz, DMSO-d 6): δ = 32.33, 33.31, 60.91, 84.04, 110.37, 116.68, 134.13, 145.22, 148.82, 164.15. Anal. Calcd for C10H11N5O: C, 55.29; H, 5.10; N, 32.24. Found: C, 55.17; H, 5.19; N, 32.08.2-(1H-Benzimidazol-2-yl)-2-(tetrahydro-2-furanyliden)acetonitrile (3e)Compound 3e was obtained according to the procedure published earlier.[7] White microcrystals (from EtOAc); mp 149–150 °C; yield 0.69 g (77%). IR (KBr): 3300, 2224, 1638, 1532, 1214, 772 cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 2.23 (m, 2 H, 4-CH2), 3.09 (t, J = 7.8 Hz, 2 H, 3-CH2), 4.60 (t, J = 6.8 Hz, 2 H, 5-CH2), 6.90 (s, 2 Н, НHet), 11.42 (br s, 1 H, NHHet). 13C NMR (100 MHz, DMSO-d 6): δ = 23.47, 31.77, 76.22, 79.41, 117.65, 122.39, 122.72, 139.29, 172.34. Anal. Calcd for C9H11N3O: C, 61.00; H, 6.26; N, 23.71. Found: C, 59.87; H, 6.35; N, 23.63.
  • 11 X-ray crystallographic data for the structures 5a, 5k, and 8a will be available in the Cambridge Crystallographic Data Centre under deposit numbers CCDC 852937–852939, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: +44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
  • 12 Zefirov YV, Zorkiy PM. Usp. Khim. 1989; 58: 713
  • 13 Sheldrick G. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008; 64: 112
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