1328
V. Kavala et al. / Tetrahedron 68 (2012) 1321e1329
7.10e7.04 (m, 4H), 6.94 (dd, J¼4.8, 8.2 Hz, 1H), 4.25 (dd, J¼4.0,
10.9 Hz,1H), 3.17 (ddd, J¼2.5, 3.3,17.5 Hz,1H), 2.73 (ddd, J¼3.2,10.9,
6.13 (s, 2H), 6.11 (s, 2H), 4.84e4.77 (m, 1H), 3.98e3.95 (m, 1H), 3.83
(s, 12H), 3.76 (s, 6H), 3.07e3.01 (m, 1H), 2.84e2.78 (m, 1H). 13C NMR
(CDCl3, 100 MHz): 170.6, 169.6, 163.8, 161.4, 160.6, 159.0, 128.2,
111.8, 110.8, 109.5, 104.6, 102.6, 91.4, 91.0, 65.9, 56.0, 55.9, 55.8, 55.7,
55.6, 55.5, 55.3, 55.2, 46.6, 28.4. MS m/z (relative intensity) 515
(MþNa, 26), 510 (Mþ2, 25) 509 (MþH, 100), 314 (15), 196 (32);
HRMS calcd for chemical formula: C28H32N2O7 (MþH) 509.2288
found 539.2279.
17.5 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 169.4, 163.9 (d,
JCeF¼245 Hz), 163.62 (d, JCeF¼245 Hz), 161.9, 138.2 (d, JCeF¼3 Hz),
137.4 (d, JCeF¼3 Hz),132.7,128.7 (d, JCeF¼8 Hz),128.0 (d, JCeF¼8 Hz),
118.9, 118.1 (d, JCeF¼130 Hz), 115.9, 115.7, 115.5, 74.6, 54.9, 34.4. MS
(EI) m/z (%) 365 (Mþ1, 75), 364 (Mþ, 50), 230 (72), 154 (100), 136
(62), 122 (20). HRMS calcd for chemical formula: C22H19N2OF2 (Mþ)
365.1465 found 365.1466.
4.4.29. 2-(2,6-Bis(2,4,6-trimethoxyphenyl)-1,2,5,6-tetrahydropyr-
4.4.23. 2-(2,6-Bis(4-fluorophenyl)-1,2,5,6-tetrahydro pyrimidin-4-yl)
imidin-4-yl)-4-methoxyphenol (viii). Yellow solid mp: 168e170 ꢀC
phenol (iii0). Yellow solid; 1H NMR (400 MHz, CDCl3):
d
7.57 (d,
(decomposed),
d
7.25 (d, J¼8.2 Hz, 1H), 6.25 (s, 1H), 6.19e6.14 (m, 2H),
J¼8.0 Hz, 1H), 7.54e7.49 (m, 2H), 7.39e7.31 (m, 3H), 7.15e7.01 (m,
4H), 6.87 (t, J¼7.8 Hz, 1H), 4.05 (dd, J¼4.9, 9.2 Hz, 1H), 3.18 (dd,
J¼4.9, 17.8 Hz, 1H), 2.80 (ddd, J¼1.3, 9.2, 17.7 Hz, 1H); 13C NMR
6.11 (s, 2H), 6.09 (s, 2H), 4.79 (m, 1H), 4.07e4.01 (m, 1H), 3.7 (s, 21H),
3.08e3.01 (m, 1H), 2.82 (d, J¼15.3 Hz, 1H). 13C NMR (CDCl3,100 MHz):
d
170.6, 169.6, 163.8, 161.4, 160.6, 159.0, 128.2, 111.8, 110.8, 109.5, 104.6,
(100 MHz, CDCl3):
d
169.9, 163.8 (d, JCeF¼245 Hz), 163.7 (d,
102.6, 91.4, 91.0, 65.9, 56.0, 55.9, 55.8, 55.7, 55.6, 55.5, 55.3, 46.6, 28.4.
MS m/z (relative intensity) 561 (MþNa, 20), 540 (Mþ2, 32) 539 (MþH,
100), 344 (17), 196 (22); HRMS calcd for chemical formula:
C28H32N2O7 (MþH) 539.2393 found 539.2341.
JCeF¼245 Hz), 162.3, 138.0 (d, JCeF¼3 Hz), 137.1 (d, JCeF¼3 Hz), 132.9,
129.1 (d, JCeF¼8 Hz), 128.3 (d, JCeF¼8 Hz), 126.9, 119.2, 118.3 (d,
JCeF¼130 Hz), 115.9, 115.7, 115.6, 115.4, 70.8, 48.1, 32.3.
4.4.24. 2-(2,6-Bis(4-methoxyphenyl)-1,2,5,6-tetrahydropyrimidin-4-
Acknowledgements
yl)phenol (iv). Yellow solid mp: 168e170 ꢀC (decomposed), 1H NMR
(400 MHz, CDCl3):
d
7.25 (d, J¼8.2 Hz, 1H), 6.25 (s, 1H), 6.19e6.14
We wish to express our sincere gratitude to the National Science
Council of the Republic of China and National Taiwan Normal
University (99T3030-2 and 99-D) for providing financial support
for the pursuit of this work.
(m, 2H), 6.11 (s, 2H), 6.09 (s, 2H), 4.79 (m, 1H), 4.07e4.01 (m, 1H),
3.7 (s, 21H), 3.08e3.01 (m, 1H), 2.82 (d, J¼15.3 Hz, 1H). 13C NMR
(CDCl3, 100 MHz):
d 170.6, 169.6, 163.8, 161.4, 160.6, 159.0, 128.2,
111.8, 110.8, 109.5, 104.6, 102.6, 91.4, 91.0, 65.9, 56.0, 55.9, 55.8, 55.7,
55.6, 55.5, 55.3, 46.6, 28.4. MS m/z (relative intensity) 412
(MþNaþH, 20), 411 (MþNa, 95) 389 (MþH, 100), 254 (60); HRMS
calcd for chemical formula: C24H24N2O3 (MþH) 389.1865 found
389.1866.
References and notes
1. (a) Blicke, F. F. Org. React. 1942, 1, 303e341; (b) Kleinnmann, E. F. In Compre-
hensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York, NY, 1991; Vol.
2, Chapter 4.1; (c) Martin, S. F. Acc. Chem. Res. 2002, 35, 895e904; (d) Cordova,
ꢀ
A. Acc. Chem. Res. 2004, 37, 102e112.
2. Kabayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069e1094.
4.4.25. 4-Chloro-2-(2,6-diphenyl-1,2,5,6-tetrahydro pyrimidin-4-yl)
phenol (v). Yellow solid; mp: 157e159 ꢀC; 1H NMR (400 MHz,
3. (a) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37,
1044e1070; (b) Hudlicky, T. Chem. Rev. 1996, 96, 3e30.
4. (a) Misra, M.; Pandey, S. K.; Pandey, V. P.; Pandey, J.; Tripathi, R.; Tripathi, R. P.
Bioorg. Med. Chem. 2009, 17, 625e633; (b) Khan, A. T.; Parvin, T.; Choudhury, L.
H. J. Org. Chem. 2008, 73, 8398e8402; (c) Clarke, P. A.; Zaytzev, A. V.; Whitwood,
A. C. Tetrahedron Lett. 2007, 48, 5209e5212.
CDCl3),
d
7.53 (d, J¼6.9 Hz, 2H), 7.45e7.31 (m, 9H), 7.25e7.23 (m,
1H), 7.32e7.29 (d, J¼8.8 Hz, 1H), 4.09 (dd, J¼10.8, 4.0 Hz, 1H), 3.16
(ddd, J¼17.5, 3.3, 2.9 Hz, 1H), 2.74 (ddd, J¼17.5, 10.8, 3.2 Hz, 1H). 13C
NMR (100 MHz, CDCl3)
d 168.9, 160.9, 142.4, 141.4, 132.5, 129.2,
5. (a) Zhang, Z.-W.; Lu, G.; Chen, M.-M.; Lin, N.; Li, Y.-B.; Hayashi, T.; Chan, A. S. C.
Tetrahedron: Asymmetry 2010, 21, 1715e1721; (b) Aydin, J.; Kumar, K. S.;
Eriksson, L.; Szabo, K. J. Adv. Synth. Catal. 2007, 349, 2585e2594; (c) Benito-
Garagorri, D.; Bocokic, V.; Kirchner, K. Tetrahedron Lett. 2006, 47, 8641e8644;
(d) Lin, Y.-R.; Zhou, X.-T.; Dai, L.-X.; Sun, J. J. Org. Chem. 1997, 62, 1799e1803.
6. Kobayashi, S.; Furuta, T. T.; Sugita, K.; Okitsu, O.; Oyamada, H. Tetrahedron Lett.
1999, 40, 1341e1344.
128.9, 128.6, 128.3, 127.1, 126.8, 126.6, 122.8, 120.1, 119.8, 75.5, 55.6,
34.6. MS m/z (relative intensity) 363 (Mþ1, 55), 362 (Mþ, 42), 307
(33), 260 (19), 258 (47), 194 (100), 136 (57), 106 (23).
4.4.26. 2-(2,6-Diphenyl-1,2,5,6-tetrahydropyrimidin-4-yl)-4-
methoxyphenol (vi). Pale yellow solid; 1H NMR (400 MHz, CDCl3):
€
7. Siener, T.; Muller, U.; Jansen, M.; Holzgrabe, U. Pharmazie 1998, 53, 442e445.
8. (a) Ohta, Y.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2009, 11, 1979e1982; (b)
Suzuki, Y.; Ohta, Y.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74,
4246e4251; (c) Dotsenko, V. V.; Krivokolysko, S. G.; Rusanov, E. B.; Litvinov, V.
P. Russ. Chem. Bull. 2007, 56, 1437e1440; (d) Roth, H. J.; Troschutz, R. Arch.
Pharm. 1977, 310, 48e55.
9. (a) Zhou, Z.; Zhao, P.; Huang, W.; Yang, G. Adv. Synth. Catal. 2006, 348, 63e67;
(b) Paredes, A.; Alzuru, M.; Mendez, J.; Rodriguez-Ortega, M. Biol. Pharm. Bull.
2003, 26, 108e109; (c) Nussbaumer, P.; Lehr, P.; Billich, A. J. Med. Chem. 2002,
45, 4310e4320; (d) Khattab, A. M.; Grace, M. H.; El-Khrisy, E. A. Pharmazie 2001,
56, 661e662; (e) van Acker, F. A. A.; Hageman, J. A.; Haenen, G. R. M. M.; van der
Vijgh, W. J. F.; Bast, A.; Menge, W. M. P. B. J. Med. Chem. 2000, 43, 3752e3760; (f)
Horie, T.; Tominaga, H.; Kawamura, Y.; Hada, T.; Ueda, N.; Amano, Y.; Yama-
moto, S. J. Med. Chem. 1991, 34, 2169e2176.
d
7.55 (d, J¼7.0 Hz, 2H), 7.44 (d, J¼5.5 Hz, 1H), 7.41e7.30 (m, 8H),
6.43 (d, J¼2.4 Hz, 1H), 6.38 (dd, J¼8.8, 1.1 Hz, 1H), 4.30 (dd, J¼10.9,
4.0 Hz,1H), 3.82 (s, 3H), 3.15 (ddd, J¼17.4, 4.0, 2.5 Hz,1H), 2.81 (ddd,
€
J¼17.4, 10.9, 3.0 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 169.3, 165.6,
163.5, 142.7, 141.8, 128.9, 128.7, 128.1, 127.1, 126.6, 112.8, 106.0, 101.9,
74.9, 55.7, 48.6, 32.3; MS m/z (relative intensity) 359 (Mþ1, 62), 358
(Mþ, 37), 254 (65), 194 (100); HRMS calcd for chemical formula:
C23H23N2O2 (Mþ) 359.1760 found 359.1761.
4.4.27. 2-(2,6-Diphenyl-1,2,5,6-tetrahydropyrimidin-4-yl)-4-
10. (a) Maiti, A.; Cuendet, M.; Croy, V. L.; Endringer, D. C.; Pezzuto, J. M.; Cushman,
methoxyphenol (vi0). Pale yellow solid; 1H NMR (400 MHz, CDCl3):
M. J. Med. Chem. 2007, 50, 2799e2806; (b) Roelens, F.; Heldring, N.; Dhooge, W.;
Bengtsson, M.; Comhaire, F.; Gustafsson, J.-A; Treuter, E.; Keukeleire, D. D. J.
ꢁ
d
7.53 (d, J¼7.4 Hz, 2H), 7.46 (d, J¼6.0 Hz, 1H), 7.45e7.34 (m, 7H),
Med. Chem. 2006, 49, 7357e7365; (c) Ferrali, M.; Donati, D.; Bambagioni, S.;
Fontani, M.; Giorgi, G.; Pietrangelo, A. Bioorg. Med. Chem. 2001, 9, 3041e3047;
(d) Lipinski, C. A.; Aldinger, C. E.; Beyer, T. A.; Bordner, J.; Burdi, D. F.; Bussolotti,
D. L.; Inskeep, P. B.; Siegel, T. W. J. Med. Chem. 1992, 35, 2169e2177; (e) Ank-
hiwala, M. D. J. Indian Chem. Soc. 1990, 67, pp 913e915; (f) Pouget, C.; Fagnere,
C.; Basly, J.-P.; Habrioux, G.; Chulia, A.-J. Bioorg. Med. Chem. Lett. 2002, 12,
1059e1061; (g) Hsieh, H. K.; Lee, T. H.; Wang, J. P.; Wang, J. J.; Lin, C. N. Pharm.
Res. 1998, 15, 39e46.
7.32e7.29 (m, 2H), 6.50 (d, J¼2.4 Hz, 1H), 6.42 (dd, J¼8.8, 2.5 Hz,
1H), 4.09 (dd, J¼9.3, 4.8 Hz, 1H), 3.84 (s, 3H), 3.16 (dd, J¼17.7, 4.8 Hz,
1H), 2.81 (ddd, J¼17.7, 9.4, 1.5 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d
169.3, 165.6, 163.5, 142.7, 141.4, 129.1, 128.5, 128.2, 127.3, 126.6,
112.8, 106.0, 101.9, 70.9, 55.5, 48.6, 32.3.
11. Li, W.-D. Z.; Ma, B.-C. Org. Lett. 2005, 7, 271e274.
4 . 4 . 2 8 . 2 - ( 2 , 6 - B i s ( 2 , 4 , 6 - t r i m e t h o x y p h e n yl ) - 1, 2 , 5 , 6 -
12. (a) Monserrat, J.-P.; Chabot, G. G.; Hamon, L.; Quentin, L.; Scherman, D.; Jaouen,
G.; Hillard, E. A. Chem. Commun. 2010, 5145e5147; (b) Kumar, D.; Patel, G.;
Mishra, B. G.; Varma, R. S. Tetrahedron Lett. 2008, 49, 6974e6976; (c) Kagawa,
H.; Shigematsu, A.; Ohta, S.; Harigaya, Y. Chem. Pharm. Bull. 2005, 53, 547e554;
tetrahydropyrimidin-4-yl)phenol (vii). Yellow solid mp: 126e128 ꢀC
(decomposed),
d
7.42 (dd, J¼7.9, 1.4 Hz, 1H), 7.25e7.21 (m, 1H), 6.85
(dd, J¼8.3, 1.0 Hz, 1H), 6.74e6.70 (m, 1H), 6.20 ( d, J¼11.9 Hz, 1H),