G. Zhang, S. Li, F. Wang et al.
European Journal of Medicinal Chemistry 213 (2021) 113148
J ¼ 7.8, 4.8 Hz,1 H); HRMS (MM: ESI-APCI) calc’d for C7H7N2O2 [M þ
H]þ: 151.0502, found 151.0503.
NMR (300 MHz, DMSO‑d6): d 11.04 (s, 1 H), 8.81 (s, 1 H), 7.61-7.56
(m, 2 H), 7.41-7.29 (m, 3 H), 6.37 (dd, J ¼ 17.2, 10.2 Hz, 1 H), 5.86 (dd,
J ¼ 17.2,1.6 Hz,1 H), 5.65 (dd, J ¼ 10.2,1.6 Hz,1 H),1.82 (s,9 H). HRMS
(EIþ) m/z calc’d for C18H19N5O [M]þ: 321.1590, found 321.1598. The
13C NMR data with good quality could not be obtained due to poor
signal-to-noise as a result of a peak broadening presumed to be a
result of the dynamic process that was not investigated further due
to the high reactivity of 18.
E-1-nitro-3-(2-nitrovinyl)benzene (14). Prepared by the above
procedure (3-nitrobenzaldehyde, 0.389 g). Purified by flash chro-
matography (SiO2, 17% EtOAc in hexane), followed by recrystalli-
zation from ethanol to yield (14) (0.228 g, 46% yield) as pale yellow
powder: 1H NMR (300 MHz, CDCl3)
d
8.42 (t, J ¼ 1.8 Hz, 1 H), 8.35
(ddd, J ¼ 8.1, 1.8, 1.2 Hz, 1 H), 8.05 (d, J ¼ 13.5 Hz, 1 H), 7.87 (dt,
J ¼ 7.5, 1.2 Hz, 1 H), 7.68 (t, J ¼ 7.8 Hz, 1 H) 7.66 (d, J ¼ 13.8 Hz, 1 H).
E-pentafluoro(2-nitrovinyl)benzene (15). Prepared by the above
procedure (pentafluoro benzaldehyde, 0.538 g, 2.7 mmol). Purified
by filtration through a short plug (SiO2, 50% EtOAc in hexanes)
followed by flash chromatography (SiO2, 10% EtOAc in hexanes) to
yield (15) (0.142 g, 22% yield) as yellow oil: 1H NMR (300 MHz,
N-acryloyl-N-(1-(tert-butyl)-3-phenyl-1H-pyrazolo[3,4-d]pyr-
imidin-4-yl)acrylamide (19) as white solid (0.019 g, 0.051 mmol,
16.2% yield). 1H NMR (300 MHz, CDCl3):
d 8.94 (s, 1 H), 7.50-7.45 (m,
2 H), 7.40-7.35 (m, 3 H), 6.31 (dd, J ¼ 16.7, 2.3 Hz, 2 H), 6.22 (dd,
J ¼ 16.7, 9.3 Hz, 2 H), 5.63 (dd, J ¼ 9.3, 2.3 Hz, 2 H), 1.9 (s, 9 H). 13
C
NMR (75 MHz, CDCl3): d 167.2, 155.4, 154.0, 153.5, 142.7, 132.1, 131.0,
CDCl3)
(282 MHz, CDCl3)
159.7 (m, 2 F).
d
8.04 (d, J ¼ 13.8 Hz, 1 H), 7.82 (d, J ¼ 13.8 Hz, 1 H); 19F NMR
129.8, 129.1, 129.0, 128.9, 110.2, 61.4, 29.3. HRMS (EIþ) m/z calc’d for
d
135.8 (m, 2 F), 146.6 (tt, J ¼ 20.7, 4.6 Hz, 1 F),
C
21H21N5O2 [M]þ: 375.1695, found 375.1695.
E-2-bromo-1-fluoro-4-(2-nitrovinyl)benzene (16). Prepared by
the above procedure (3-bromo-4-fluorobenzaldehyde, 0.500 g,
2.5 mmol). Purified by filtration through a short plug (SiO2, 50%
EtOAc in hexanes) followed by recrystallization from ethanol to
yield (16) (0.311 g, 51% yield) as yellow microcrystals: 1H NMR
4.1.3.2. Synthesis of compound 20. Synthesis of compound 20 see
Scheme 4. To a THF (10 mL, 0.1 M) solution of phenyl pyr-
azolopyrimidine (17) (0.25 g, 0.94 mmol) was Et3N (0.17 mL,
1.2 mmol). Chloroacetic chloride (0.1 mL, 1.2 mmol) was added
dropwise. After 12 h at ambient temperature, the mixture was
quenched with H2O (10 mL) and extracted with CHCl3 (3x10 mL).
The combined organic layers were dried with MgSO4, filtered, and
concentrated. The crude oil was purified by silica gel column
chromatography (1:1 hexanes/ethyl acetate) to provide 20 as white
(300 MHz, CDCl3)
1 H), 7.51 (d, J ¼ 13.8 Hz, 1 H), 7.49 (m, 1 H), 7.21 (t, J ¼ 8.4 Hz, 1 H);
13C NMR (125 MHz, CDCl3)
d
7.91 (d, J ¼ 13.5 Hz, 1 H), 7.77 (dd, J ¼ 6.6, 2.4 Hz,
d
161.1 (d, J ¼ 255 Hz), 137.7 (d,
J ¼ 2.9 Hz), 136.4, 134.2, 129.9 (d, J ¼ 10.6 Hz), 127.8 (d, J ¼ 3.4 Hz),
117.6 (d, J ¼ 22.9 Hz), 110.6 (d, J ¼ 21.9 Hz); 19F NMR (282 MHz,
solid (0.18 g, 56% yield). 1H NMR (300 MHz, CDCl3):
d 8.65 (br s, 2 H),
CDCl3)
d
100.3 (dd, J ¼ 11.8, 7.1 Hz, 1 F).
7.69 (br s, 2 H), 7.56-7.42 (m, 3 H), 4.37 (s, 2 H), 1.84 (s, 9 H). Many of
the peaks in the 13C NMR spectrum were broadened by a dynamic
process that was not investigated further. Poor signal-to-noise
prevented acquisition of good 13C NMR spectral data. HRMS
(FABþ) m/z calc’d for C17H19ON5Cl [M þ H]: 344.1273, found
344.1270.
4.1.3. Synthesis of pyrazolopyrimidine analogues
Pyrazolopyrimidines 17, 21, and 26 were synthesized from the
corresponding acid chloride [47,58] and Scheme 2 shows synthetic
Route of Pyrazolopyrimidine analogues.
4.1.3.1. Synthesis of compounds 18 and 19. Representative Procedure
for Acylation of Pyrazolopyrimidines see Scheme 3. To a solution of 4-
amino-1-t-butyl-3-phenylpyrazolo[3,4-d] pyrimidine (17) (0.103 g,
0.387 mmol) in CH2Cl2 (4 mL, 0.1 M) was added Et3N (0.043 mL,
0.31 mmol). The solution was cooled in an ice water bath, and
acryloyl chloride (0.027 mL, 0.314 mmol) was added dropwise.
After stirring for 30 min while warming to room temperature, the
solution was partially concentrated and purified directly by silica
gel column chromatography (10% ethyl acetate/hexanes). In addi-
tion to recovered starting material (0.0306 g, 0.1145 mmol, 29.6%
yield), three products were isolated:
4.1.3.3. Synthesis of compounds 22 and 23. Synthesis of compounds
22 and 23 see Scheme 5. 2-Naphthyl pyrazolopyrimidine (21)
(0.1134 g, 0.357 mmol) was acylated as described in the above
representative procedure using CH2Cl2 (3 mL), Et3N (0.1 mL,
0.72 mmol) and acryloyl chloride (0.05 mL, 0.547 mmol). Water
(10 mL) and NaHCO3 (10 mL, saturated aq.) were added and
extracted with CH2Cl2 (3 x 10 mL). The combined organic layers
were dried with Na2SO4, filtered, and concentrated under reduced
pressure. The crude yellow oil was purified by silica column chro-
matography (1:9->1:3->1:0 ethyl acetate/hexanes) to provide
three products in addition to recovered starting material (0.0184 g,
0.0466 mmol, 13% yield).
N-(1-(tert-butyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)
acrylamide (18) as white solid (0.015 g, 0.046 mmol,14.5% yield). 1H
N-(1-(tert-butyl)-3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyr-
imidin-4-yl)acrylamide (22) as white solid (0.026 g, 0.069 mmol,
19% Yield). 1H NMR (300 MHz, DMSO)
d 11.23 (br s, 1 H), 8.82 (s,
1 H), 8.20 (s, 1 H), 7.91 (m, 3 H), 7.82 (d, J ¼ 8 Hz, 1 H), 7.50 (m, 2 H),
6.32 (dd, J ¼ 10, 17 Hz, 1 H), 5.73(d, J ¼ 17 Hz, 1 H), 5.51 (d, J ¼ 10 Hz,
1 H), 1.86 (s, 9 H). Many of the peaks in the 13C NMR spectrum were
Scheme 2. Synthetic Route of Pyrazolopyrimidine analogues.
Scheme 3. Synthesis of compounds 18 and 19.
10