ACS Combinatorial Science
RESEARCH ARTICLE
3-Bromo-N-propyl-1H-pyrazolo[3,4-d] pyrimidin-6-amine
(2a). To a mixture of 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-
d] pyrimidine 1 (0.49 g, 2.0 mmol) in THF (5.0 mL) was added
meta-chloroperoxybenzoic acid (0.52 g, 99%, 3.0 mmol) at room
temperature. The white mixture was stirred for 2.0 h and trans-
ferred into a THF (5.0 mL) solution of n-propylamine (0.82 mL,
10 mmol) at 0 °C. The resulting solution was heated at 40 °C for
2.0 h. After removal of the solvent under reduced pressure,
MeOH was added and the mixture was filtered. The white solid
was washed with MeOH (3ꢁ) and dried to provide the title
compound 2a (0.45 g, 88%). 1H NMR (400 MHz, DMSO-d6) δ
13.19 (bs, 1H), 8.63 (s, 1H), 7.69 (bs, 1H), 3.29ꢀ3.17 (m, 2H),
1.54 (qt, J = 14.4, 7.2 Hz, 2H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, DMSO-d6) δ 161.6, 157.0, 152.7, 120.1, 106.7, 42.7,
21.7, 11.5; HRMS (TOF, ESIþ) m/z: [M þ H]þ calculated for
C8H11BrN5, 256.0198; found 256.0195.
tert-Butyl 4-((3-(2-methoxyphenyl)-6-(propylamino)-1H-pyra-
zolo[3,4-d]pyrimidin-1-yl) methyl) piperidine-1-carboxylate
(4e) (Procedure C). A 10 mL microwave tube was charged with
2a (0.052 g, 0.20 mmol), K2CO3 (0.11 g, 0.80 mmol), DMF
(2.0 mL), and tert-butyl 4-(chloromethyl)piperidine-1-carboxy-
late (0.070 g, 0.30 mmol). The resulting mixture was heated at
150 °C for 10 min under microwave irradiation. After the
reaction was cooled to room temperature, 2-methoxyphenyl
boronic acid (0.046 g, 0.30 mmol), Pd(PPh3)4 (0.023 g, 0.020
mmol), and H2O (1.0 mL) were added sequentially. The mixture
was stirred at ambient temperature for 3.0 min and then heated at
150 °C for 15 min. After cooling to ambient temperature, the
mixture was partitioned in H2O and Et2O. The aqueous phase
was extracted with ether (3ꢁ). The combined organic extracts
were dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by an ISCO silica gel column to provide
the title compound 4e (0.079 g, 82%) as a white solid. 1H NMR
(400 MHz, CDCl3) δ 8.80 (s, 1H), 7.75 (dd, J = 7.6, 1.6 Hz, 1H),
7.41ꢀ7.34 (m, 1H), 7.08ꢀ6.99 (m, 2H), 5.55 (bs, 1H), 4.20 (d,
J = 7.1 Hz, 2H), 4.14ꢀ3.99 (m, 2H), 3.87 (s, 3H), 3.48ꢀ3.40 (m,
2H), 2.68 (t, J = 11.9 Hz, 2H), 2.28ꢀ2.16 (m, 1H), 1.72ꢀ1.57 (m,
4H), 1.43 (s, 9H), 1.34ꢀ1.22 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 159.2, 156.8, 156.1, 154.9, 153.8,
143.1, 130.6, 130.5, 121.8, 121.3, 111.4, 107.4, 79.5, 55.6, 51.5,
43.6, 36.7, 29.9, 28.6, 22.7, 11.7; HRMS (TOF, ESIþ) m/z:
[MþH]þ calculated for C26H37N6O3, 481.2927; found 481.2936.
1-Isopropyl-3-phenyl-N-propyl-1H-pyrazolo[3,4-d]pyri-
midin-6-amine (4j) (Procedure D). To a 0.15 M THF stock
solution of sulfone and sulfoxide (2.0 mL, 0.30 mmol) was added
propylamine (0.12 mL, 1.5 mmol) at ambient temperature. The
solution was then heated at 50 °C for 2.0 h. After evaporation of
the solvent, the residue was purified by an ISCO silica gel column
to provide the title compound 4j (0.068 g, 77%) as a white solid.
1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.92 (d, J = 7.1 Hz,
2H), 7.48 (t, J = 7.5 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 5.46 (s,
1H), 5.03 (septet, J = 6.7 Hz, 1H), 3.47 (dt, J = 13.2, 6.7 Hz, 2H),
1.69 (qt, J = 14.4, 7.3 Hz, 2H), 1.59 (d, J = 6.7 Hz, 6H), 1.02 (t,
J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.7, 155.3,
153.4, 143.7, 133.2, 129.0, 128.6, 127.0, 106.8, 48.5, 43.6, 22.9,
21.9, 11.7; HRMS (TOF, ESIþ) m/z: [M þ H]þ calculated for
C17H22N5, 296.1875; found 296.1870.
1-Isopropyl-6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]-
pyrimidine (3a) (Procedure A). A 10 mL microwave tube was
charged with 2a (0.052 g, 0.20 mmol), K2CO3 (0.14 g, 1.0 mmol),
DMF (2.0 mL), and isopropyl chloride (0.047 g, 0.60 mmol). The
resulting mixture was heated at 200 °C for10 min undermicrowave
irradiation. After the reaction was cooled to room temperature,
phenylboronic acid (0.037 g, 0.30 mmol), Pd(PPh3)4 (0.023 g,
0.020 mmol), and H2O (1.0 mL) were added sequentially. The
mixture was stirred at ambient temperature for 3.0 min and then
heated at 150 °C for 15 min. After cooling to ambient temperature,
the mixture was partitioned in H2O and Et2O. The aqueous phase
was extracted with diethyl ether (3ꢁ). The combined organic
extracts were dried (Na2SO4) and concentrated under reduced
pressure. The residue was purified by an ISCO silica gel column to
provide the title compound 3a (0.047 g, 82%) as a white solid. 1H
NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 7.95 (d, J = 7.2 Hz, 2H),
7.50 (t, J = 7.5 Hz, 2H), 7.42 (tt, J = 7.6, 2.0 Hz, 1H), 5.19 (septet,
J = 6.7 Hz, 1H), 2.66 (s, 3H), 1.63 (d, J = 6.7 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 169.4, 153.6, 152.2, 143.7, 132.5, 129.1,
129.0, 127.1, 109.8, 49.3, 22.0, 14.4; HRMS (TOF, ESIþ) m/z:
[M þ H]þ calcd 285.1174 for C15H17N4S; found 285.1179.
1-Cyclohexyl-3-phenyl-N-propyl-1H-pyrazolo[3,4-d]pyri-
midin-6-amine (4a) (Procedure B). A 10 mL microwave tube
was charged with 2a (0.052 g, 0.20 mmol), K2CO3 (0.14 g,
1.0 mmol), DMF (2.0 mL), and cyclohexyl chloride (0.072 g, 0.60
mmol). The resulting mixture was heated at 200 °C for 30 min
under microwave irradiation. After the reaction was cooled to
room temperature, phenylboronic acid (0.037 g, 0.30 mmol),
Pd(PPh3)4 (0.023 g, 0.020 mmol), and H2O (1.0 mL) were added
sequentially. The mixture was stirred at ambient temperature for
3.0 min and then heated at 150 °C for 15 min. After cooling to
ambient temperature, the mixture was partitioned in H2O and
Et2O. The aqueous phase was extracted with Et2O (3ꢁ). The
combined organic layers were dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by an ISCO
silica gel column to provide the title compound 4a (0.045 g, 67%)
as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.90
(d, J= 8.0 Hz, 2H), 7.48 (t, J= 6.0 Hz, 2H), 7.38(t, J =6.0 Hz, 1H),
5.42 (bs, 1H), 4.60 (tt, J = 11.6, 4.1 Hz, 1H), 3.48 (dt, J = 13.1,
6.8 Hz, 2H), 2.13 (ddd, J = 24.6, 12.5, 3.4 Hz, 2H), 2.04ꢀ2.00 (m,
2H), 1.95ꢀ1.92 (m, 2H), 1.77ꢀ1.74 (m, 1H), 1.69 (qt, J = 14.6,
7.4 Hz, 2H), 1.50 (qt, J = 13.06, 3.12 Hz, 2H), 1.35 (tt, J = 12.8, 6.3
Hz, 1H), 1.03 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
160.7, 155.4, 153.5, 143.7, 133.3, 129.1, 128.6, 127.1, 106.9, 56.1,
43.7, 32.2, 25.9, 25.6, 23.0, 11.8; HRMS (TOF, ESIþ) m/z: [M þ
H]þ calculated for C20H26N5, 336.2188; found 336.2180.
1-Isopropyl-N,3-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-6-
amine (4n) (Procedure E). To a 0.15 M DMSO stock solution of
sulfone and sulfoxide (2.0 mL, 0.30 mmol) was added aniline
(0.093 g, 1.0 mmol) at ambient temperature. The solution was
then heated at 150 °C for 12 h. After cooling to ambient
temperature, the reaction was diluted with CH2Cl2 and washed
with H2O. The aqueous layer was extracted with CH2Cl2 (3ꢁ).
The organic extracts were combined and dried (Na2SO4). After
evaporation of the solvent, the residue was purified by an ISCO
silica gel column to provide the title compound 4n (0.048 g,
1
73%) as a white solid. H NMR (400 MHz, CDCl3) δ 9.07
(s, 1H), 7.95 (d, J = 7.2 Hz, 2H), 7.77 (d, J = 7.8 Hz, 2H), 7.51
(t, 2H), 7.46ꢀ7.34 (m, 4H), 7.08 (t, J = 7.4 Hz, 1H), 5.12 (septet,
J = 6.7 Hz, 1H), 1.65 (d, J = 6.7 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 157.6, 154.4, 153.7, 143.9, 139.7, 132.9, 129.1, 129.1,
128.8, 127.1, 122.7, 119.1, 108.0, 49.1, 22.0.
6-(3-Chloropropoxy)-1-isopropyl-3-phenyl-1H-pyrazolo-
[3,4-d]pyrimidine (4q) (Procedure F). To a suspension of NaH
(0.020 g, 60% in mineral oil, 0.50 mmol) in THF (2.0 mL) was
added 3-chloro-1-propanol (0.057 g, 0.60 mmol) at 0 °C. The
mixture was allowed to warm to ambient temperature over 1.0 h.
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dx.doi.org/10.1021/co200039k |ACS Comb. Sci. 2011, 13, 414–420