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Wityak, J.; Barrish, J. C. J. Med. Chem. 2006, 49, 6819–6832; (b) Trevino, J. G.;
Summy, J. M.; Lesslie, D. P.; Parikh, N. U.; Hong, D. S.; Lee, F. Y.; Donato, N. J.;
Abbruzzese, J. L.; Baker, C. H.; Gallick, G. E. Am. J. Pathol. 2006, 168, 962–972.
5. Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1979, 18, 707–721.
6. Kamino, T.; Kuramochi, K.; Kobayashi, S. Tetrahedron Lett. 2003, 44, 7349–7351.
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6362.
14. Lee, J.-H.; Cho, C.-G. Tetrahedron Lett. 2003, 44, 65–67.
15. Typical procedure for synthesis of 21k: A sealed tube was charged with 200 mg
(0.486 mmol) of 6-[(2-chloro-6-methylphenyl)carbamoyl]-4-oxo-4H-pyran-3-
yl trifluoromethanesulfonate (13e), 45 mg (10 mol %) of Pd2dba3, 56 mg
(20 mol %) of xantphos, and 238 mg (0.729 mmol) of cesium carbonate. After
adding 4 mL of toluene, the mixture was degassed and backfilled with argon
where upon were added 205 mg (0.583 mmol) of 6-{4-[2-(tert-butyldi-
methylsilyloxy)ethyl]piperazin-1-yl}-2-methyl pyrimidin-4-ylamine (20).
After stirring for 90 min at 110 °C, the reaction mixture was cooled to room
temperature, diluted with dichloromethane, filtered through Celite, and
concentrated. The crude material was purified by using column
chromatography (dichloromethane/methanol 98/2) to give the product 14k
as a yellow solid in 30% yield.Mp 176–177 °C. 1H NMR (400 MHz, DMSO-d6): d
(ppm) 0.09 (s, 6H, 2CH3), 0.91 (s, 9H, 3CH3), 2.27 (s, 3H, CH3), 2.41 (s, 3H, CH3),
2.51–2.54 (m, 6H), 3.50–3.53 (m, 4H), 3.76 (t, 2H, J = 6.1 Hz), 6.55 (s, 1H), 7.10
(s, 1H, H3), 7.33–7.35 (m, 2H), 7.44–7.48 (m, 1H), 8.42 (s, 1H, NH), 9.78 (s, 1H,
H6), 10.65 (s, 1H, NHCO). 13C NMR (100 MHz, DMSO-d6): d (ppm) À5.1, 18.1,
18.3, 26.0, 26.2, 43.9, 53.1, 60.1, 61.1, 84.3, 112.1, 127.3, 128.9, 129.3, 131.8,
132.1, 132.6, 138.6, 141.6, 154.3, 157.6, 160.4, 162.7, 165.7, 172.3. IR (KBr):
3308, 2927, 1692, 1641, 1594, 1508, 1251, 1103, 836 cmÀ1. MS-ES+ (MeOH):
m/z 613.
9. Mp 206–207 °C. 1H NMR (400 MHz, DMSO-d6): d (ppm) 7.25 (s, 1H, H3), 9.26 (s,
1H, H6). 13C NMR (100 MHz, DMSO-d6): d (ppm) 117.4 (J = 319.0 Hz), 118.9,
141.6, 152.3, 154.9, 160.0, 170.8. IR (KBr): 3096, 2928, 1746, 1648, 1620, 1429,
1229, 1142 cmÀ1. MS-ES+ (MeOH): m/z 288.
10. Mp 56–57 °C. 1H NMR (400 MHz, DMSO-d6): d (ppm) 4.42 (d, 2H, CH2OH,
J = 5.9 Hz), 5.89 (t, 1H, CH2OH, J = 5.9 Hz), 6.63 (s, 1H, H5), 9.12 (s, 1H, H2). 13C
NMR (100 MHz, DMSO-d6): d (ppm) 59.3, 112.8, 118.2 (J = 319.0 Hz), 140.6,
151.6, 170.5, 170.9. IR (KBr): 3432, 3076, 2922, 1664, 1631, 1429, 1217, 1133,
844 cmÀ1. MS-ES+ (MeOH): m/z 274.
11. Typical procedure for synthesis of 13e: To a solution of 0.6 g (2.08 mmol) of 4-
oxo-5-{[(trifluoromethyl)sulfonyl]oxy}-4H-pyran-2-carboxylic
370 L (2.29 mmol) of phenyl dichlorophosphate, and 281 L (2.29 mmol) of
2-chloro-6-methylaniline in 30 mL of anhydrous dichloromethane at 0 °C are
added 870 L (6.24 mmol) of triethylamine dropwise. After being stirred for
acid
(12),
l
l
l
15 min under nitrogen atmosphere, the reaction mixture was hydrolyzed and
extracted with dichloromethane. The organic layer was dried over anhydrous
sodium sulfate, filtered, and concentrated to dryness by rotary evaporation.
Further purification by column chromatography on silica gel (dichloromethane/
methanol 99/1) furnished 13e as a yellow solid in 90% yield.
16. Czeskis, B. A. J. Labelled Compd. Radiopharm. 2004, 47, 699–704.
17. Sekiguchi, Y.; Kanuma, K.; Omodera, K.; Tran, T. A.; Semple, G.; Kramer, B. A.
Patent WO 2005/095357, 2005; Chem. Abstr. 2005, 143, 387051.
Mp 166–167 °C. 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.26 (s, 3H, CH3), 7.33–
7.35 (m, 2H, 2HPh), 7.34 (s, 1H, H5), 7.43–7.48 (m, 1H, HPh), 9.31 (s, 1H, H2),
10.74 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d (ppm) 18.3, 117.2, 118.2
(J = 319 Hz), 127.3, 129.1, 129.4, 132.0, 132.3, 138.6, 141.6, 152.0, 156.6, 156.7,
170.6. IR (KBr): 3257, 3091, 2978, 1692, 1670, 1427, 1220, 1137 cmÀ1. MS-ES+
(MeOH): m/z 411.
18. Mp 225–226 °C. 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.27 (s, 3H, CH3Ph),
2.41 (s, 3H, CH3), 2.43–2.54 (m, 6H), 3.53–3.58 (m, 6H), 4.48 (t, 1H, OH,
J = 5.3 Hz), 6.54 (s, 1H), 7.10 (s, 1H, H3), 7.32–7.35 (m, 2H), 7.42–7.48 (m, 1H),
8.42 (s, 1H, NH), 9.77 (s, 1H, H6), 10.65 (s, 1H, NHCO). 13C NMR (100 MHz,
DMSO-d6): d (ppm) 18.3, 26.2, 43.8, 52.9, 58.7, 61.4, 84.2, 112.1, 127.3, 128.9,
129.4, 131.8, 132.2, 132.6, 138.6, 141.7, 154.3, 157.7, 160.4, 162.7, 165.7, 172.3.
12. (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125–146; (b)
Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046–2067; (c) Ahman, J.;
IR (KBr): 3390, 3326, 2927, 1697, 1646, 1595, 1512, 1210 cmÀ1 MS-ES+
.
(MeOH): m/z 498.