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L. Zhang, Y. J. Zhang / Tetrahedron Letters 47 (2006) 775–778
Synthesis of 6-amino-5-bromo-1-methyluracil (8): To a
(m/z): C11H13N5O2 calcd 247.1; found [M+H]+ = 248.1.
1H NMR (400 MHz, DMSO-d6): d 10.48 (br s, 1H), 8.53
(d, J = 2.0 Hz, 1H), 8.41 (dd, J = 4.8, 2.4 Hz, 1H), 7.80
(dt, J = 7.6, 2.0 Hz, 1H), 7.28 (dd, 2.4, 2.0 Hz, 1H), 6.44
(s, 2H), 3.85(d, J = 6.0 Hz, 2H), 3.17 (s, 3H).
suspension of 6-amino-1-methyluracil (7.06 g, 50 mmol),
sodium bicarbonate (4.2 g, 50 mmol) in methanol (50 mL)
was added bromine (2.57 mL, 50 mmol) under vigorous
stirring at 0 ꢁC during 0.5 h. The mixture was stirred at
room temperature for 2 h. After it was stirred at room
temperature for 2 h, the solution was cooled to 4 ꢁC, and
the white precipitate was collected by filtration. The white
solid was stirred in water (100 mL) at 4 ꢁC, filtered,
washed with cold water, and dried under high vacuum
over calcium sulfate. The off-white solid (11.0 g, yield
Microwave Assisted synthesis of 8-mercapto-3-methyl-7-
alkylxanthine (7a–f): The mixture of corresponding 6-
amino-1-methyl-5-alkylaminouracil (9a–f, 0.2 mmol) and
potassium ethyl xanthate (256 mg, 1.6 mmol) in anhy-
drous DMF (2 mL) was capped and irradiated on CEM
Explorer microwave synthesizer. The reactions were held
at 120 ꢁC for 10 min to afford a yellow to brown solution.
After cooling to room temperature, the solvent was
evaporated under vacuum. The residue was stirred with
5 mL of water in an ice-water bath to give a clear solution
that was acidified with 2 N HCl solution to pH = 4–5. The
resulting precipitate was filtered, washed with cold water,
small amount of ethanol, and diethyl ether, and dried
under vacuum to give off-white or pink solid 7a–f. The
products were characterized by HPLC–MS and 1H NMR.
The conversion rate and purity were calculated by
analyzing UV spectra of final reaction mixtures and
isolated products by HPLC on an automated Gilson
system using a gradient of 0% MeCN to 100% MeCN in
1
100%) was characterized by HPLC/MS and H NMR as
pure product. MS (m/z): C5H6BrN3O2 calcd 219.0; found
[M+H]+ = 220.1, 222.1; [MÀH]À = 218.0, 219.9. 1H
NMR (DMSO-d6, d): 10.89 (s, 1H), 7.03 (s, 2H), 3.26 (s,
3H).
Microwave assisted synthesis of 6-amino-1-methyl-5-alkyl-
aminouracil (9a–f): An oven dried 10 mL microwave reac-
tion tube charged with 6-amino-5-bromo-1-methyluracil
8 (10 mg, 0.5 mmol) and corresponding amine (0.5 mL,
3–4 mmol), was capped and irradiated on CEM Explorer
microwave synthesizer. The reactions were held at 120 ꢁC
for 10 min to afford an orange to brown solution. After
cooling to room temperature, 8 mL of diethyl ether was
introduced to lead to solid precipitate that were filtered,
washed with small amount of ethyl acetate, diethyl ether,
and water, and dried under vacuum to give off-white solid
9a–f. The products were characterized by HPLC–MS,
TLC, and 1H NMR. The conversion rate is determined by
the disappearance of starting material 8 and purity was
H2O (0.1% FA) over 10 min on
a C18 column
(4.6 · 50 mm).
7-Butyl-8-mercapto-3-methyl-1H-purine-2,6(3H,7H)-dione
(7a) off-white solid, yield = 75.9%. MS (m/z): C10H14-
N4O2S calcd 254.1; found [M+H]+ = 255.1; [MÀH]À
=
253.1. Retention time: 5.12 min. 1H NMR (400 MHz,
DMSO-d6): d 11.29 (s, 1H), 4.17 (t, J = 7.4 Hz, 2H), 3.28
(s, 3H), 1.65 (m, J = 7.4 Hz, 2H), 1.27 (m, J = 7.4 Hz,
2H), 0.88 (t, J = 7.4 Hz, 3H).
1
calculated by analyzing TLC plate and H NMR spectra.
6-Amino-5-(butylamino)-1-methylpyrimidine-2,4(1H,3H)-
dione (9a) off-white solid, yield = 79.2%. MS (m/z):
C9H14N4O2 calcd 212.1; found [M+H]+ = 213.1. 1H
NMR (400 MHz, DMSO-d6): d 10.46 (s, 1H), 6.34
(s, 2H), 3.20 (s, 3H), 2.71 (br s, 1H), 2.59 (t, J =
7.2 Hz, 2H),1.39 (m, J = 7.2 Hz, 2H), 1.28 (m, J = 7.2
Hz, 2H), 0.86 (t, J = 7.2 Hz, 3H).
6-Amino-5-(benzylamino)-1-methylpyrimidine-2,4(1H,3H)-
dione (9b) off-white solid, yield = 75%. MS (m/z): C12H14-
N4O2 calcd 246.1; found [M+H]+ = 247.1. 1H NMR
(400 MHz, DMSO-d6): d 10.49 (br s, 1H), 7.39 (d, J =
7.2 Hz, 2H), 7.28 (t, J = 7.2 Hz, 2H), 7.20 (t, J = 7.2 Hz,
1H), 6.39 (s, 2H), 3.80 (d, J = 6.4 Hz, 2H), 3.18 (s, 3H),
3.12 (t, J = 6.4 Hz, 1H).
7-Benzyl-8-mercapto-3-methyl-1H-purine-2,6(3H,7H)-dione
(7b) off-white solid, yield = 72.9%. MS (m/z): C13H12N4O2S
calcd 288.1; found [M+H]+ = 289.1; [MÀH]À = 287.1.
Retention time: 5.48 min. 1H NMR (400 MHz, DMSO-
d6): d 11.29 (s, 1H), 7.39 (d, J = 7.2 Hz, 2H), 7.32–7.22 (m,
3H), 5.40 (s, 2H), 3.29 (s, 3H).
8-Mercapto-3-methyl-7-phenethyl-1H-purine-2,6(3H,7H)-
dione (7c) off-white solid, yield = 87.8%. MS (m/z):
C14H14N4O2S calcd 302.1; found [M+H]+ = 303.1;
[MÀH]À = 301.1. Retention time: 5.77 min. 1H NMR
(400 MHz, DMSO-d6): d 11.35 (s, 1H), 7.33–7.20 (m, 5H),
4.37 (m, 2H), 3.30 (s, 3H), 2.95 (m, 2H).
6-Amino-1-methyl-5-(phenethylamino)pyrimidine-2,4(1H,
3H)-dione (9c) off-white solid, yield = 80.8%. MS (m/z):
C13H16N4O2 calcd 260.1; found [M+H]+ = 261.1. 1H
NMR (400 MHz, DMSO-d6): d 7.28–7.14 (m, 6H), 6.27
(s, 2H), 3.18 (s, 3H), 2.84 (m, 3H), 2.72 (t, J = 7.2 Hz, 2H).
6-Amino-5-(4-fluorophenethylamino)-1-methylpyrimidine-
2,4(1H,3H)-dione (9d) off-white solid, yield = 78.4%. MS
(m/z): C13H15FN4O2 calcd 278.1; found [M+H]+ = 279.1.
1H NMR (400 MHz, DMSO-d6): d 10.45 (br, 1H), 7.28–
7.05 (m, 4H), 6.25 (s, 2H), 3.17 (s, 3H), 2.99 (t, J = 7.2 Hz,
1H), 2.82 (m, 2H), 2.70 (t, J = 7.2 Hz, 2H).
6-Amino-1-methyl-5-(pyridine-2-ylmethylamino)pyrimidine-
2,4(1H,3H)- dione (9e) yellow solid, yield = 70.7%. MS
(m/z): C11H13N5O2 calcd 247.1; found [M+H]+ = 248.1.
1H NMR (400 MHz, DMSO-d6): d 10.50 (s, 1H), 8.49 (d,
J = 4.8 Hz, 1H), 7.72 (dt, J = 7.2, 2.0 Hz, 1H), 7.46 (d,
J = 7.6 Hz, 1H), 7.23 (dd, 7.2, 2.0 Hz, 1H), 6.60 (s, 2H),
3.90 (d, J = 6.0 Hz, 2H), 3.48 (br s, 1H), 3.19 (s, 3H).
6-Amino-1-methyl-5-(pyridine-3-ylmethylamino)pyrimidine-
2,4(1H,3H)-dione (9f) off-white solid, yield = 75.2%. MS
7-(4-Fluorophenethyl)-8-mercapto-3-methyl-1H-purine-
2,6(3H,7H)-dione (7d) off-white solid, yield = 96.8%.
MS (m/z): C14H13FN4O2S calcd 320.1; found [M+H]+
= 321.1; [MÀH]À = 319.2. Retention time: 6.01 min. 1H
NMR (400 MHz, DMSO-d6): d 11.34 (s, 1H), 7.26 (m, 2H),
7.12 (m, 2H), 4.36 (m, 2H), 3.29 (s, 3H), 2.95 (m, 2H).
8-Mercapto-3-methyl-7-(pyridine-2-ylmethyl)-1H-purine-
2,6(3H,7H)-dione (7e) pink solid, yield = 89.7%. MS (m/z):
C12H11N5O2S calcd 289.1; found [M+H]+ = 290.1;
[MÀH]À = 288.0. Retention time: 4.27 min. 1H NMR
(400 MHz, DMSO-d6): d 11.29 (s, 1H), 8.47 (m, 1H), 7.72
(dt, J = 7.6, 2.0 Hz, 1H), 7.25 (m, 1H), 7.06 (d, 7.6 Hz, 1H),
5.50 (s, 2H), 3.37 (s, 3H, overlapped with H2O signal).
8-Mercapto-3-methyl-7-(pyridine-3-ylmethyl)-1H-purine-
2,6(3H,7H)-dione (7f) off-white solid, yield = 73.4%. MS
(m/z): C12H11N5O2S calcd 289.1; found [M+H]+ = 290.1;
[MÀH]À = 288.0. Retention time: 3.49 min. 1H NMR
(400 MHz, DMSO-d6): d 10.34 (s, 1H), 8.63 (d, J = 1.6 Hz,
1H), 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 7.80 (dt, J = 8.0, 2.0 Hz,
1H),7.35(ddd,8.0,4.8,0.8 Hz,1H),5.43(s,2H),3.29(s,3H).