P. Raboisson et al. / European Journal of Medicinal Chemistry 43 (2008) 816e829
825
NMR (200 MHz, CDCl3) d3.28(d, J ¼ 5.1, 3H, CH3),4.11(s,2H,
CH2), 6.60 (br s, 1H, NH), 7.13e7.42(m, 5H, ArH), 7.83(s, 1H, 7-
H); m/z 308 (M þ H)þ. Anal. Found: C14H12F3N5 (C, H, N).
J ¼ 5.1, 3H, CH3), 4.25 (s, 2H, CH2), 6.47 (br s, 1H, NH),
7.43e7.82 (m, 7H, ArH), 7.86 (s, 1 H, 7-H); m/z 304
(M þ H)þ. Anal. Found: C18H17N5$0.3H2O (C, H, N).
6.1.27. 8-(2-Methoxybenzyl)-4-(N-methylamino)-2-n-
propylpyrazolo[1,5-a]-1,3,5-triazine (14d)
Prepared from 13d using the procedure described for 14a.
6.1.33. 2-Methyl-4-(N-methyl-N-phenylamino)-8-(prop-1-
ynyl)pyrazolo[1,5-a]-1,3,5-triazine (15a)
Methylacetylene (2 mL) was condensed in a sealed tube at
ꢀ78 ꢁC. Then, 11a [19] (157 mg, 0.43 mmol), CuI (12 mg,
0.063 mg), PdCl2 (7 mg, 0.039 mmol), triphenylphosphine
(23 mg, 0.088 mmol), triethylamine (2 mL, 14 mmol) and ace-
tonitrile (3 mL) were added. The reaction mixture was stirred
at room temperature for 24 h. After the solution was cooled to
ꢀ78 ꢁC, the sealed tube was opened and slowly heated at room
temperature. The solvent was evaporated under reduced pres-
sure and the crude reaction product was purified by column
chromatography on silica gel (EtOAc/hexane, 1:1) as a yellow
solid (73%): 1H NMR (200 MHz, CDCl3) d 2.07 (s, 3H, CH3),
2.64 (s, 3H, CH3), 3.78 (s, 3H, CH3), 7.14e7.20 (m, 2H, ArH),
7.36e7.48 (m, 3H, ArH), 7.74 (s, 1H, 7-H).
1
Compound 14d was obtained (76%) as colorless prisms: H
NMR (300 MHz, CDCl3) d 1.04 (t, J ¼ 7.4, 3H, CH3),
1.86e1.89 (m, 2H, CH2), 2.77 (t, J ¼ 7.7, 2H, CH2), 3.21 (d,
J ¼ 5.3, 3H, CH3), 3.87 (s, 3H, CH3), 4.04 (s, 2H, CH2),
6.41 (br s, 1H, NH), 6.85e6.90 (m, 2H, ArH), 7.18e7.22
(m, 2H, ArH), 7.58 (s, 1H, 7-H); m/z 312 (M þ H)þ. Anal.
Found: C17H21N5O$0.1H2O (C, H, N).
6.1.28. 2-Trifluoromethyl-8-(2-methoxybenzyl)-4-(N-
methylamino)pyrazolo[1,5-a]-1,3,5-triazine (14e)
Prepared from 13e using the procedure described for 14a.
1
Compound 14e was obtained (76%) as colorless prisms: H
NMR (300 MHz, CDCl3) d 3.30 (d, J ¼ 4.9, 3H, CH3), 3.87
(s, 3H, CH3), 4.09 (s, 2H, CH2), 6.72 (br s, 1H, NH), 6.87e
6.92 (m, 2H, ArH), 7.19e7.28 (m, 2H, ArH), 7.89 (s, 1H, 7-
H); m/z 338 (M þ H)þ. Anal. Found: C15H14F3N5O (C, H, N).
6.1.34. 2-Methyl-4-(N-methyl-N-phenylamino)-8-(pent-1-
ynyl)pyrazolo[1,5-a]-1,3,5-triazine (15b)
A solution of 11a [19] (200 mg, 0.55 mmol), 1-pentyne
(980 mL, 10 mmol), CuI (12 mg, 0.063 mmol), PdCl2 (7 mg,
0.039 mmol), triphenylphosphine (23 mg, 0.088 mmol), trie-
thylamine (2 mL, 14 mmol) and acetonitrile (3 mL) was
stirred under nitrogen at 25 ꢁC for 24 h. The solvent was evap-
orated under reduced pressure and the crude reaction product
was purified by column chromatography on silica gel (EtOAc/
hexane, 1:1). Recrystallization from dichloromethane and hex-
anes yielded compound 15b (119 mg, 71%) as colorless solid:
1H NMR (200 MHz, CDCl3) d 1.07 (t, J ¼ 7.3, 3H, CH3),
1.65e1.69 (m, 2H, CH2), 2.47 (t, J ¼ 7.3, 2H, CH2), 2.63 (s,
3H, CH3), 3.76 (s, 3H, CH3), 7.15e7.20 (m, 2H, ArH),
7.35e7.45 (m, 3H, ArH), 7.76 (s, 1H, 7-H); 13C NMR
(CDCl3, 75 MHz) d 14.07, 22.32, 22.68, 26.21, 42.54, 70.03,
92.42, 94.24, 126.35, 127.49, 129.40, 144.96, 147.19,
149.54, 152.02, 164.12; m/z 306 (M þ H)þ.
6.1.29. 8-(Furfuryl)-2-methyl-4-(N-
methylamino)pyrazolo[1,5-a]-1,3,5-triazine (14f)
Prepared from 13f using the procedure described for 14a.
1
Compound 14f was obtained (62%) as colorless prisms: H
NMR (200 MHz, CDCl3) d 2.57 (s, 3H, CH3), 3.21 (d,
J ¼ 4.9, 3H, CH3), 4.06 (s, 2H, CH2), 6.01e6.04 (m, 1H,
ArH), 6.27e6.30 (m, 1H, ArH), 6.45 (br s, 1H, NH), 7.25e
7.34 (m, 1H, ArH), 7.84 (s, 1H, 7-H); m/z 244 (M þ H)þ.
Anal. Found: C12H13N5O (C, H, N).
6.1.30. 8-[(3-Furyl)methyl]-2-methyl-4-(N-
methylamino)pyrazolo[1,5-a]-1,3,5-triazine (14g)
Prepared from 13g using the procedure described for 14a.
1
Compound 14g was obtained (64%) as colorless prisms: H
NMR (200 MHz, CDCl3) d 2.57 (s, 3H, CH3), 3.22 (d, J ¼ 4.9,
3H, CH3), 3.84 (s, 2H, CH2), 6.30e6.34 (m, 1H, ArH), 6.48
(br s, 1H, NH), 7.25e7.37 (m, 2H, ArH), 7.56 (s, 1H, 7-H); m/
z 244 (M þ H)þ. Anal. Found: C12H13N5O (C, H, N).
6.1.35. 2-Methyl-4-(N-methylamino)-8-(prop-1-
ynyl)pyrazolo[1,5-a]-1,3,5-triazine hydrochloride (16a)
Prepared from 15a using the procedure described for 14a.
Compound 16a was obtained (62%) as a white solid: 1H
NMR (200 MHz, CDCl3) d 2.05 (s, 3H, CH3), 2.75 (s, 3H,
CH3), 3.20 (d, J ¼ 4.2, 3H, CH3), 7.91 (s, 1H, 7-H), 9.50 (br
s, 1H, NH); m/z 202 (M þ H)þ. Anal. Found:
C10H11N5$HCl$0.2H2O (C, H, N).
6.1.31. 2-Methyl-4-(N-methylamino)-8-[(2-
thienyl)methyl]pyrazolo[1,5-a]-1,3,5-triazine (14h)
Prepared from 13h using the procedure described for 14a.
1
Compound 14h was obtained (87%) as colorless prisms: H
NMR (200 MHz, CDCl3) d 2.57 (s, 3H, CH3), 3.22 (d, J ¼ 4.9,
3H, CH3), 4.25 (s, 2H, CH2), 6.45 (br s, 1H, NH), 7.86e7.94
(m, 2H, ArH), 7.11e7.25 (m, 1H, ArH), 7.81 (s, 1H, 7-H); m/z
260 (M þ H)þ. Anal. Found: C12H13N5S (C, H, N).
6.1.36. 2-Methyl-4-(N-methylamino)-8-(pent-1-
ynyl)pyrazolo[1,5-a]-1,3,5-triazine (16b)
Prepared from 15b using the procedure described for 14a.
1
Compound 16b was obtained (77%) as colorless prisms: H
6.1.32. 2-Methyl-4-(N-methylamino)-8-[(2-
NMR (300 MHz, CDCl3) d 1.06 (t, J ¼ 7.3, 3H, CH3),
1.62e1.72 (m, 2H, CH2), 2.46 (t, J ¼ 7.2, 2H, CH2), 2.60 (s,
3H, CH3), 3.23 (d, J ¼ 4.9, 3H, CH3), 6.49 (br s, 1H, NH),
7.9 (s, 1H, 7-H); 13C NMR (CDCl3, 75 MHz) d 14.07,
22.28, 22.65, 26.47, 27.67, 69.84, 85.81, 93.56, 94.18,
naphthyl)methyl]pyrazolo[1,5-a]-1,3,5-triazine (14i)
Prepared from 13i using the procedure described for 14a.
1
Compound 14i was obtained (86%) as colorless prisms: H
NMR (200 MHz, CDCl3) d 2.63 (s, 3H, CH3), 3.26 (d,