T. Semeraro et al. / Tetrahedron 64 (2008) 11249–11255
11253
temperature under N2 for 1 h and the appropriate amine
(0.023 mmol) and DIPEA (50 L, 0.285 mmol) were then added. The
CD3OD-d4): d 8.13 (s, 1H), 7.64 (s, 1H), 6.76 (m, 3H), 5.88 (s, 2H), 5.81
m
(s, 2H), 4.18 (m, 4H), 1.25 (t, J¼7.0 Hz, 3H); MS m/z 398 (MþH)þ; IR
reaction mixture was stirred at room temperature for 2–6 h, then
the solvent was removed in vacuo, the residue was dissolved in
EtOAc and the organic layer was washed with H2O, aqueous HCl,
aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to
dryness. The crude residue was purified by column chromatogra-
phy to give 8 as pure compounds.
(Nujol): n
3423, 3322, 3222, 1726, 1641, 923 cmꢂ1. Anal. Calcd for
C19H19N5O5: C, 57.43; H, 4.82; N, 17.62. Found: C, 57.28; H, 4.85; N,
17.75.
4.1.6.8. 4-Amino-6-(2-bromo-3,4,5-trimethoxybenzyl)-N-allyl-6H-pyr-
rolo[3,4-d]pyrimidine-7-carboxamide (8h). Eluent: DCM/MeOH, 9:1.
Pale yellow solid (74% yield); mp 174–175 ꢁC (EtOAc); 1H NMR
4.1.6.1. 4-Amino-6-(4-methoxybenzyl)-N-propyl-6H-pyrrolo[3,4-d]-
pyrimidine-7-carboxamide (8a). Eluent: DCM/MeOH, 9:1. White
solid (28% yield); mp 178–179 ꢁC (DCM); 1H NMR (200 MHz,
(200 MHz, CDCl3): d 9.23 (br s, 1H), 8.21 (s, 1H), 7.30 (s, 1H), 6.52 (s,
1H), 6.37 (br s, 2H), 6.00 (s, 2H), 5.96–5.82 (m, 1H), 5.16 (dd,
J1¼10.1 Hz, J2¼1.6 Hz, 2H), 4.06 (br s, 2H), 3.81 (s, 3H), 3.78 (s, 3H),
CD3OD-d4):
d
8.12 (s, 1H), 7.59 (s, 1H), 7.20 (d, J¼8.4 Hz, 2H), 6.86 (d,
3.61 (s, 3H); MS m/z 478 (MþH)þ; IR (CHCl3):
n 3406, 3291, 3106,
J¼8.4 Hz, 2H), 5.87 (s, 2H), 3.74 (s, 3H), 3.36 (t, J¼6.9 Hz, 2H), 1.67
1667, 925 cmꢂ1. Anal. Calcd for C20H22BrN5O4: C, 50.43; H, 4.66; N,
14.70. Found: C, 50.56; H, 4.63; N, 14.61.
(m, 2H), 0.99 (t, J¼7.0 Hz, 3H); MS m/z 340 (MþH)þ; IR (Nujol):
n
3304, 2968, 1672, 1609 cmꢂ1. Anal. Calcd for C18H21N5O2: C, 63.70;
H, 6.24; N, 20.64. Found: C, 63.90; H, 6.20; N, 20.49.
4.1.6.9. 4-Amino-6-(2-bromo-3,4,5-trimethoxybenzyl)-N-propyl-6H-
pyrrolo[3,4-d]pyrimidine-7-carboxamide (8i). Eluent: DCM/MeOH,
92:8. Yellow solid (68% yield); mp 204–205 ꢁC (EtOAc/n-hexane);
4.1.6.2. 4-Amino-6-(4-methoxybenzyl)-N-allyl-6H-pyrrolo[3,4-d]py-
rimidine-7-carboxamide (8b). Eluent: DCM/MeOH, 11:1. Pale yellow
solid (20% yield); mp 206–207 ꢁC (EtOAc); 1H NMR (200 MHz,
1H NMR (200 MHz, CDCl3):
(s, 1H), 6.57 (s, 1H), 6.15 (br s, 2H), 6.05 (s, 2H), 3.84 (s, 3H), 3.81 (s,
d
9.14 (t, J¼5.6 Hz, 1H), 8.25 (s, 1H), 7.27
CD3OD-d4):
d
8.11 (s, 1H), 7.60 (s, 1H), 7.20 (d, J¼8.6 Hz, 2H), 6.85 (d,
3H), 3.63 (s, 3H), 3.41 (q, J¼6.5 Hz, 2H), 1.64 (m, 2H), 0.97 (t,
J¼8.6 Hz, 2H), 6.01 (m,1H), 5.86 (s, 2H), 5.26 (dd, J1¼5.0 Hz, J2¼1.7 Hz,
J¼7.3 Hz, 3H); MS m/z 479.9(MþH)þ; IR (CHCl3):
n 3412, 3293, 3004,
2H), 4.02 (d, J¼5.0 Hz, 2H), 3.74 (s, 3H); MS m/z 338 (MþH)þ; IR
1624, 1169, 1006 cmꢂ1. Anal. Calcd for C20H24BrN5O4: C, 50.22; H,
5.06; N, 16.70. Found: C, 50.07; H, 5.07; N, 16.81.
(Nujol): n
3432, 3208, 2360,1632 cmꢂ1. Anal. Calcd for C18H19N5O2: C,
64.08; H, 5.68; N, 20.76. Found: C, 63.90; H, 5.70; N, 20.87.
4.1.6.10. 4-Amino-6-((6-chlorobenzo[d][1,3]dioxol-5-yl)methyl)-N-p-
ropyl-6H-pyrrolo[3,4-d]pyrimidine-7-carboxamide (8j). Brown solid
(82% yield); mp 218.5–219 ꢁC (EtOAc/n-hexane); 1H NMR
4.1.6.3. 4-Amino-6-(4-methoxybenzyl)-N-(2-propynyl)-6H-pyrrolo-
[3,4-d]pyrimidine-7-carboxamide (8c). Eluent: DCM/MeOH, 9:1.
Pale yellow solid (16%); mp 213–215 ꢁC (EtOAc); 1H NMR (200 MHz,
(200 MHz, CDCl3):
d
9.11 (t, J¼5.4 Hz, 1H), 8.28 (s, 1H), 7.21 (s, 1H),
Me2SO-d6):
d
8.17 (s, 1H), 7.69 (s, 1H), 7.60 (br s, 2H), 7.18 (d,
6.78 (s, 1H), 6.56 (s, 1H), 6.00 (s, 2H), 5.88 (s, 2H), 3.42 (q, J¼6.6 Hz,
J¼8.7 Hz, 2H), 6.87 (d, J¼8.7 Hz, 2H), 5.85 (s, 2H), 4.13 (m, 2H), 3.69
2H), 1.66 (m, 2H), 0.99 (t, J¼7.4 Hz, 3H); MS m/z 389 (MþH)þ; IR
(s, 1H), 2.49 (m, 1H); MS m/z 336 (MþH)þ; IR (Nujol):
n
3402, 3298,
(CHCl3): n
3412, 3001, 2964, 1636, 1249, 1120, 1040 cmꢂ1. Anal.
1668, 956 cmꢂ1. Anal. Calcd for C18H17N5O2: C, 64.47; H, 5.11; N,
20.88. Found: C, 64.18; H, 5.13; N, 20.97.
Calcd for C18H18ClN5O3: C, 55.75; H, 4.68; N, 18.06. Found: C, 55.89;
H, 4.67; N, 17.98.
4.1.6.4. 4-Amino-6-((benzo[d][1,3]dioxol-5-yl)methyl)-N-propyl-6H-
4.1.7. General procedure for the synthesis of 9a–d
pyrrolo[3,4-d]pyrimidine-7-carboxamide (8d). Yellow solid (98%
A suspension of 7 (0.23 mmol) in 6 M HCl (10 mL) was heated at
reflux for 1–4 h (until the suspension became a solution). After
cooling to room temperature, the solution was neutralized using
Na2CO3 and the resulting precipitate was extracted with EtOAc. The
organic layer was dried over Na2SO4 and the solvent was removed
under reduced pressure. The residue was purified by flash chro-
matography or recrystallized to give the desired compounds in
a pure form.
yield); mp 196–197 ꢁC (EtOAc); 1H NMR (200 MHz, CDCl3):
d 9.11 (t,
J¼5.0 Hz, 1H), 8.24 (s, 1H), 7.18 (s, 1H), 6.63 (m, 3H), 5.82 (s, 2H),
5.79 (s, 2H), 3.41(m, 2H), 1.63 (m, 2H), 0.96 (t, J¼7.0 Hz, 3H); MS m/z
354 (MþH)þ; IR (Nujol):
n
3448, 3202, 1657, 930 cmꢂ1. Anal. Calcd
for C18H19N5O32: C, 61.18; H, 5.42; N, 19.82. Found: C, 61.33; H, 5.40;
N, 19.73.
4.1.6.5. 4-Amino-6-((benzo[d][1,3]dioxol-5-yl)methyl)-N-(cycloprop-
ylmethyl)-6H-pyrrolo[3,4-d]pyrimidine-7-carboxamide (8e). Eluent:
DCM/MeOH, 98:2. Pale yellow solid (72% yield); mp 171–173 ꢁC
4.1.7.1. 6-((6-Chlorobenzo[d][1,3]dioxol-5-yl)methyl)-6H-pyrrolo[3,4-d]
pyrimidin-4-amine (9a). Pale yellow solid (80% yield); mp 237–
(cyclohexane); 1H NMR (200 MHz, CDCl3):
d
9.16 (t, J¼5.0 Hz, 1H),
238 ꢁC (EtOAc); 1H NMR (200 MHz, CD3OD-d4):
d 7.93 (s, 1H), 7.46
8.24 (s,1H), 7.23 (s,1H), 6.62 (s,1H), 6.58 (s, 2H), 5.79 (s, 2H), 5.75 (s,
(s, 1H), 7.15 (s, 1H), 6.93 (s, 1H), 6.73 (s, 1H), 5.97 (s, 2H), 5.38 (s, 2H);
2H), 3.30 (t, J¼6.1 Hz, 2H), 1.07 (m, 1H), 0.49 (m, 2H), 0.24 (m, 2H);
MS m/z 305 (MþH)þ; IR (Nujol):
n
3322, 927, 874 cmꢂ1. Anal. Calcd
for C14H11ClN4O2: C, 55.55; H, 3.66; N, 18.51. Found: C, 55.72; H,
3.67; N, 18.33.
MS m/z 366 (MþH)þ; IR (neat):
n
3207, 1629, 1530, 1248, 1038 cmꢂ1
.
Anal. Calcd for C19H19N5O3: C, 62.46; H, 5.24; N, 19.17. Found: C,
62.59; H, 5.22; N, 19.04.
4.1.7.2. 6-((Benzo[d][1,3]dioxol-5-yl)methyl)-6H-pyrrolo[3,4-d]pyr-
imidin-4-amine (9b). Eluent: DCM/MeOH, 88:12. Pale brown solid
(36% yield); mp 233–234 ꢁC (dec, MeOH); 1H NMR (400 MHz,
4.1.6.6. 4-Amino-6-((benzo[d][1,3]dioxol-5-yl)methyl)-N-isobutyl-6H-
pyrrolo[3,4-d]pyrimidine-7-carboxamide(8f). White solid (98% yield);
mp 163–165 ꢁC (toluene); 1H NMR (200 MHz, CDCl3):
d
9.17 (br s, 1H),
CD3OD-d4): d 7.93 (s, 1H), 7.44 (s, 1H), 7.14 (s, 1H), 6.78 (s, 2H), 6.75
8.31 (s,1H), 7.10 (s,1H), 6.76 (m, 3H), 5.91 (s, 4H), 3.31 (t, J¼6.3 Hz, 2H),
(s, 1H), 5.91 (s, 2H), 5.24 (s, 2H); MS m/z 269 (MþH)þ; IR (Nujol):
n
1.94 (m, 1H), 1.00 (d, J¼6.9 Hz, 6H); MS m/z 368 (MþH)þ; IR (neat):
n
3316, 920, 826 cmꢂ1. Anal. Calcd for C14H12N4O2: C, 62.68; H, 4.51;
N, 20.88. Found: C, 62.46; H, 4.54; N, 20.97.
3389,1631,1248,1156,1039 cmꢂ1. Anal. Calcd for C19H21N5O3: C, 62.11;
H, 5.76; N, 19.06. Found: C, 62.31; H, 5.73; N, 18.98.
4.1.7.3. 6-(3,5-Dimethoxybenzyl)-6H-pyrrolo[3,4-d]pyrimidin-4-am-
4.1.6.7. Ethyl 2-(4-amino-6-((benzo[d][1,3]dioxol-5-yl)methyl)-6H-
pyrrolo[3,4-d]pyrimidine-7-carboxamido)acetate (8g). Pale yellow
solid (98% yield); mp 218–220 ꢁC (EtOAc); 1H NMR (200 MHz,
ine (9c). Eluent: DCM/MeOH, 85:15. White solid (42% yield); mp
191–192 ꢁC (EtOAc); 1H NMR (200 MHz, Me2SO-d6):
d
7.88 (s, 1H),
7.38 (s, 1H), 7.20 (s, 1H), 7.09 (br s, 2H), 6.42 (m, 3H), 5.25 (s, 2H),