3290
V. Majce et al. / Tetrahedron Letters 52 (2011) 3287–3290
13. Di Stefano, A.; Sozio, P.; Iannitelli, A.; Marianecci, C.; Santucci, E.; Carafa, M. J.
Drug Targeting 2006, 14, 652–661.
14. Kleiner, R. E.; Dumelin, C. E.; Tiu, G. C.; Sakurai, K.; Liu, D. R. J. Am. Chem. Soc.
2010, 132, 11779–11791.
15. Breuning, A.; Degel, B.; Schulz, F.; Buchold, C.; Stempka, M.; Machon, U.;
Heppner, S.; Gelhaus, C.; Leippe, M.; Leyh, M.; Kisker, C.; Rath, J.; Stich, A.; Gut,
J.; Rosenthal, P. J.; Schmuck, C.; Schirmeister, T. J. Med. Chem. 2010, 53, 1951–
1963.
16. Machon, U.; Buchold, C.; Stempka, M.; Schirmeister, T.; Gelhaus, C.; Leippe, M.;
Gut, J.; Rosenthal, P. J.; Kisker, C.; Leyh, M.; Schmuck, C. J. Med. Chem. 2009, 52,
5662–5672.
overnight (16 h). The reaction mixture was washed with water (3 ꢂ 15 mL),
dried over Na2SO4, and the solvent evaporated, giving 0.838 g (97%) of the
crude product, which was purified by triturating with 10 mL of Et2O, and
filtering the resulting yellow powder, which required no further purification.
Analysis: pale yellow powder, yield 0.838 g (97%), mp 114–116.5 °C (Et2O); IR
(KBr)
m ;
3282, 2803, 1606, 1562, 1511, 1255, 841 cmꢁ1 1H NMR (300 MHz,
DMSO-d6) d (ppm) 2.26 (s, 3H); 4.38 (d, J = 5.7 Hz, 2H), 6.30 (s, 2H), 7.12 and
7.50 (AA0XX0, J = 8.3 Hz, 4H), 7.28 (m, 5H), 9.16 (t, J = 5.7 Hz, 1H); 11.08 (s, 1H);
13C NMR (75.5 MHz, DMSO-d6) d (ppm) 21.4, 43.2, 120.2, 127.8, 128.3, 129.2,
130.0, 131.8, 133.4, 133.8, 137.2, 139.6, 163.8, 165.8; MS-ES m/z 293 ([MꢁH]ꢁ,
53%). Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.20; H,
6.17; N, 9.39.
17. Smaill, J. B.; Hollis Showalter, H. D.; Zhou, H.; Bridges, A. J.; McNamara, D. J.;
Fry, D. W.; Nelson, J. M.; Sherwood, V.; Vincent, P. W.; Roberts, B. J.; Elliott, W.
L.; Denny, W. A. J. Med. Chem. 2001, 44, 429–440.
21. For the equipment applied here and the methodology in general, see, for
ˇ
example: (a) Maraš, N.; Polanc, S.; Kocevar, M. Tetrahedron 2008, 64, 11618–
ˇ ˇ ˇ
11624; (b) Hren, J.; Pozgan, F.; Bunic, A.; Parvulescu, V. I.; Polanc, S.; Kocevar,
18. Pinto, I. L.; Jarvest, R. L.; Clarke, B.; Dabrowski, C. E.; Fenwick, A.; Gorczyca, M.
M.; Jennings, L. J.; Lavery, P.; Sternberg, E. J.; Tew, D. G.; West, A. Bioorg. Med.
Chem. Lett. 1999, 9, 449–452.
ˇ
M. Tetrahedron 2009, 65, 8216–8221; (c) Kranjc, K.; Kocevar, M. Curr. Org. Chem.
2010, 14, 1050–1074.
19. Preparation of 1b: p-Toluidine (3.30 mL, 30 mmol) was added to a stirred
solution of maleic anhydride (2.94 g, 30 mmol) in Et2O (180 mL). The reaction
mixture was stirred for 2 h at rt, and the resulting precipitate was filtered and
washed with Et2O. Analysis: Yellow powder, yield 6.00 g (98%), mp 183–185 °C
22. Typical procedure: To a thick-wall borosilicate glass vial (10 mL) were added 2b
(147 mg, 0.5 mmol), piperidine (4.0 lL, 0.04 mmol), CH3CN (0.5 mL), and a
magnetic stir bar. The vial was sealed, the reaction mixture pre-stirred for
1 min and then irradiated in a CEMÒ Discover focused microwave reactor for
10 min at 120 °C at 200 W. The reaction mixture was allowed to cool to room
temperature, and the resulting precipitate was filtered, washed with a small
amount of CH3CN, and dried to give 3b. Analysis: white powder, yield 0.116 g
(Et2O); IR (KBr)
m ;
3286, 3096, 1703, 1634, 1536, 1404, 850 cm–1 1H NMR
(300 MHz, DMSO-d6) d (ppm) 2.26 (s, 3H), 6.29 (d, J = 12.1 Hz, 1H), 6.46 (d,
J = 12.1 Hz, 1H), 7.14 and 7.50 (AA0XX0, J = 8.3 Hz, 4H), 10.36 (s, 1H), 13.26 (s,
1H); 13C NMR (75.5 MHz, DMSO-d6) d (ppm) 20.5, 119.7, 129.2, 130.8, 131.7,
133.1, 135.9, 163.1, 166.7; MS–ES m/z 204 ([MꢁH]ꢁ, 48%). Anal. Calcd for
(79%), mp 287–288 °C (EtOAc/Et2O); IR (KBr)
m 3289, 1638, 1557, 1536, 1337,
993, 696 cmꢁ1 1H NMR (300 MHz, DMSO-d6) d (ppm) 2.26 (s, 3H), 4.40 (d,
;
C11H11NO3: C, 64.38; H, 5.40; N, 6.83. Found: C, 64.41; H, 5.14; N, 6.79.
J = 5.8 Hz, 2H), 7.01 (d, J = 15.1 Hz, 1H), 7.08 (d, J = 15.1 Hz, 1H), 7.13 and 7.56
(AA0XX0, J = 8.4 Hz, 4H), 7.30 (m, 5H), 8.95 (t, J = 5.8 Hz, 1H), 10.34 (s, 1H); 13C
NMR (75.5 MHz, DMSO-d6) d (ppm) 21.4, 43.3, 120.2, 127.8, 128.2, 129.3,
130.1, 133.7, 134.2, 134.3, 137.2, 139.8, 162.9, 164.5; MS-ES m/z 293 ([M–H]–,
62%). Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.34; H,
5.98; N, 9.51.
20. Preparation of 2b: N-Methylmorpholine (0.679 mL, 6.17 mmol) was added to a
stirred suspension of 1b (0.604 g, 2.94 mmol) in CH2Cl2 (30 mL). The resulting
solution was cooled to 0 °C on an ice bath and then EDCꢀHCl (0.620 g,
3.2 mmol) was added. After 10 min, benzylamine (0.321 mL, 2.94 mmol) was
added and the reaction mixture was left to warm slowly to rt and stirred