1182 Journal of Natural Products, 2009, Vol. 72, No. 6
Wright et al.
completed the vessel was uncapped and another portion of iodomethane
was added to it followed by heating. This process was repeated once
to ensure full consumption of the starting amide. The reaction was
worked up following the standard protocol to afford 590 mg (100%)
of the desired tertiary amide as an off-white solid. The compound was
used without further purification. N-(4-Methoxyphenethyl)-N-methy-
(two carbons, minor), 118.6 (two carbons, minor), 118.3 (two carbons,
major), 79.3, 71.4, 52.2 (minor), 49.5 (major), 38.2, 37.1 (major), 33.8
(minor), 33.6 (minor), 32.6 (major), 30.2, 28.6 (three carbons), 22.1
(major), 21.3 (minor).
tert-Butyl-3-(2,6-dibromo-4-(2-(N-methylacetamido)ethyl)phenoxy)-
propylcarbamate (1.78 g, 3.50 mmol) was dissolved in 1,4-dioxane (40
mL), and the resulting solution was placed in an ice bath. Concentrated
HCl (500 µL, 37%) was added dropwise, and the bath was removed.
The reaction was completed in 1.5 h, as revealed by TLC. The pH of
the solution was adjusted to 7 by adding 1 M NaOH and extracted
with EtOAc (3 × 100 mL), dried (MgSO4), and concentrated in Vacuo
to yield 1.37 g (96%) of 9: 1H NMR (400 MHz, DMSO-d6) δ 8.40 (br
s, 2H), 7.63 (s, 2H, major), 7.53 (s, 2H, minor), 4.95 (br s, 1H), 3.98
(t, J ) 5.9 Hz, 2H), 3.44 (m, 2H), 3.01 (t, J ) 7.4 Hz, 2H), 2.93 (s,
3H, minor), 2.786 (s, 3H, major), 2.785 (m, 2H, minor), 2.69 (dd, J )
7.5, 7.5 Hz, 2H, major), 2.05 (m, 2H), 1.94 (s, 3H, minor), 1.86 (s,
3H, major); 13C NMR (100 MHz, DMSO-d6) δ 169.5 (minor), 169.3
(major), 150.6 (major), 150.4 (minor), 139.0 (minor), 138.6 (major),
133.3 (two carbons, major), 132.9 (two carbons, minor), 117.3 (two
carbons, major), 117.2 (two carbons, minor), 70.59 (major), 70.53
(minor), 51.0 (minor), 47.7 (major), 36.5, 35.7 (minor), 32.6 (major),
32.3 (minor), 31.4 (major), 28.4, 21.6 (minor), 20.9 (major).
Preparation of 3-Methyl-3H-purin-6(9H)-one (12). Sodium metal
(1.47 g, 64.0 mmol, 2 equiv) was dissolved in absolute EtOH (60.0
mL) to prepare 1.0 M sodium ethoxide in EtOH. Compound 10 (4.55
g, 32.0 mmol) was added to the solution at room temperature and stirred
until all material dissolved. A solution of thiourea 11 (2.88 g, 32.0
mmol) in 42 mL of 2-methoxyethanol was combined with the reaction
mixture, and the resulting mix was refluxed for 5.5 h. After cooling to
0 °C, 1.0 M HCl was added dropwise until a pH of 2 was obtained. A
blue-gray solid formed, which was filtered, washed with a small portion
of ice-cold H2O, and dried in an oven overnight to yield 5.10 g (86%)
of 6-amino-2-mercapto-1-methyl-5-nitrosopyrimidin-4(1H)-one. The
compound was used without purification.
1
lacetamide: H NMR (400 MHz, CDCl3) δ 7.13 (d, J ) 8.6 Hz, 2H,
minor), 7.06 (d, J ) 8.6 Hz, 2H, major), 6.85 (d, J ) 8.6 Hz, 2H,
major), 6.83 (d, J ) 8.6 Hz, 2H, minor), 3.788 (s, 3H, major), 3.786
(s, 3H, minor), 3.54 (dd, J ) 7.6, 7.6 Hz, 2H, minor), 3.46 (t, J ) 7.1
Hz, 2H, major), 2.93 (s, 3H, minor), 2.89 (s, 3H, major), 2.79 (t, J )
7.1 Hz, 2H, major), 2.78 (dd, J ) 7.6, 7.6 Hz, 2H, minor), 2.06 (s, 3H,
major), 1.85 (s, 3H, minor); 13C NMR (100 MHz, CDCl3) δ 170.7
(minor), 170.5 (major), 158.5 (major), 158.2 (minor), 131.3 (major),
130.3 (minor), 129.83 (two carbons, minor), 129.81 (two carbons,
major), 114.2 (two carbons, major), 114.0 (two carbons, minor), 55.35
(major), 55.32 (minor), 52.9 (major), 50.0 (minor), 37.0 (minor), 33.9
(major), 33.5 (minor), 32.9 (major), 22.1 (minor), 21.1 (major).
To a solution of N-(4-Methoxyphenethyl)-N-methylacetamide (1.05
g, 5.07 mmol) in CH2Cl2 (50 mL) at 0 °C was added dropwise BBr3 (1
M, 25.33 mL, 25.33 mmol, 5.0 equiv). The reaction mixture was slowly
brought to room temperature, stirred for 2 h, and then was quenched
with H2O. The aqueous phase was extracted with EtOAc once. The
combined organic layers were extracted with 1 M NaOH. The aqueous
layer was neutralized with 1 M HCl and extracted with EtOAc, dried
(MgSO4), and concentrated in Vacuo to afford 870 mg (89%) of the
unprotected phenol 7 as an off-white solid: 1H NMR (400 MHz, CDCl3)
δ 8.10 (br s, 1H), 7.03 (d, J ) 8.5 Hz, 2H, minor), 6.94 (d, J ) 8.5
Hz, 2H, major), 6.740 (d, J ) 8.5 Hz, 2H, major), 6.736 (d, J ) 8.5
Hz, 2H, minor), 3.59 (dd, J ) 7.3, 7.3 Hz, 2H, minor), 3.48 (dd, J )
6.3, 6.3 Hz, 2H, major), 2.97 (s, 3H, major), 2.91 (s, 3H, minor), 2.755
(dd, J ) 6.3, 6.3 Hz, 2H, major), 2.752 (dd, J ) 7.3, 7.3 Hz, 2H,
minor), 2.03 (s, 3H, minor), 1.65 (s, 3H, major); 13C NMR (100 MHz,
CDCl3) δ 171.9 (major), 171.1 (minor), 155.9 (major), 155.1 (minor),
129.84 (major, two carbons), 129.75 (minor, two carbons; minor, one
carbon), 128.9 (major), 115.8 (major, two carbons), 115.4 (minor, two
carbons), 52.9 (major), 49.3 (minor), 36.4 (minor), 33.5 (major), 33.5
(major), 32.7 (minor), 21.7 (minor), 20.7 (major).
6-Amino-2-mercapto-1-methyl-5-nitrosopyrimidin-4(1H)-one (5.10
g, 27.4 mmol) was dissolved in 100 mL of 1.0 M NaOH, and sodium
dithionite (17.65 g, 101.4 mmol, 3.7 equiv) was added. After 1.5 h at
room temperature, the solids were filtered off and dried in an oven to
obtain 4.7 g of 5,6-diamino-2-mercapto-1-methylpyrimidin-4(1H)-one
in quantitative yield. These steps were repeated to provide sufficient
material for the last stage of the synthesis of 12.
Preparation of N-(3,5-Dibromo-4-hydroxyphenethyl)-N-meth-
ylacetamide (2). Phenol 7 (510.0 mg, 2.64 mmol) was dissolved in
glacial acetic acid (5.30 mL) and then treated with Br2 (340 µL, 6.62
mmol, 2.5 equiv) dropwise at room temperature. The reaction went to
completion within 3 h, as monitored by TLC, and was quenched with
10% aqueous Na2S2O3. The product 2 was extracted with EtOAc, dried
(MgSO4), and concentrated in Vacuo to provide 820 mg (88%) of tan-
colored material, which was used without further purification: 1H NMR
(400 MHz, CD3OD) δ 7.37 (s, 2H, minor), 7.36 (s, 2H, major), 3.54
(t, J ) 7.0 Hz, 2H, minor), 3.50 (dd, J ) 7.7, 7.7 Hz, 2H, major), 2.98
(s, 3H, major), 2.90 (s, 3H, minor), 2.78 (t, J ) 7.0 Hz, minor), 2.71
(dd, J ) 7.5, 7.5 Hz, 2H, major), 2.05 (s, 3H, major), 1.87 (s, 3H,
minor); 13C NMR (100 MHz, CD3OD) δ 173.3, 151.1 (major), 150.8
(minor), 134.6 (major), 134.1 (minor), 133.9 (two carbons, minor),
133.7 (two carbons, major), 112.3 (two carbons, minor), 112.2 (two
carbons, major), 53.3 (minor), 50.5 (major), 37.2 (major), 33.8 (minor),
33.7 (minor), 32.8 (major), 21.7 (major), 21.0 (minor).
N-(4-(3-Aminopropyloxy)-3,5-dibromophenethyl)-N-methylaceta-
mide (9). Phenol 2 (1.54 g, 4.39 mmol) was dissolved in CH3CN (22
mL) and treated with K2CO3 (910 mg, 6.58 mmol, 1.5 equiv) at room
temperature. The resulting suspension was heated to 50 °C, and alkyl
bromide 8 (1.04 g, 4.37 mmol, 1 equiv) in CH3CN (22 mL) was added
to it. The reaction was allowed to proceed overnight, then cooled to
room temperature and worked up following the standard protocol to
give 1.78 g (80%) of the desired alkylated phenol as an off-white solid.
In addition, the aqueous phase was neutralized with 1 M HCl and further
extracted with EtOAc (3 × 50 mL), dried (MgSO4), and concentrated
in Vacuo to yield 120 mg of the unreacted starting material (8%
recovery). The product was used without further purification: 1H NMR
(400 MHz, CDCl3) δ 7.36 (s, 2H, major), 7.32 (s, 2H, minor), 4.04 (t,
J ) 5.8 Hz, 2H, minor), 4.03 (t, J ) 5.8 Hz, 2H, major), 3.53 - 3.42
(m, 4H), 2.94 (s, 3H, minor), 2.93 (s, 3H, major), 2.77 (t, J ) 7.7 Hz,
2H, minor), 2.75 (dd, J ) 7.7, 7.7 Hz, 2H, major), 2.08 (s, 3H, major),
2.04 (m, 2H), 1.99 (s, 3H, minor), 1.44 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 170.7 (major), 170.4 (minor), 156.2, 152.1 (minor), 151.6
(major), 138.1 (major), 137.0 (minor), 133.1 (two carbons, major), 132.9
5,6-Diamino-2-mercapto-1-methylpyrimidin-4(1H)-one (7.74 g, 44.95
mmol) was dissolved in DMF (10 mL) and trimethyl orthoformate
(73.76 mL, 674.18 mmol, 15.0 equiv). The mixture was heated at reflux
for 5 days. After full conversion of the starting material was achieved
(LC-MS analysis) the reaction mixture was concentrated and the residual
material was recrystallized from water to obtain 8.19 g (100%) of
1
compound 12: H NMR (400 MHz, DMSO-d6) δ 13.84 (br s, 1H),
12.47 (br s, 1H), 8.17 (s, 1H), 3.78 (s, 3H).
3-Methyl-3H-purin-6(9H)-one (13). Raney nickel (16.0 g) was
washed three times with 2-methoxyethanol and then suspended in
minimal H2O. A solution of purinone 12 (8.20 g, 45.0 mmol) in 1.0 M
NaOH (55.0 mL) was added to the Raney nickel slurry. The reaction
mixture was heated to 80 °C for 3 h until all starting material was
consumed as determined by TLC. The room-temperature mixture was
filtered through a pad of Celite, which was washed with H2O and
2-methoxyethanol. The filtrate was concentrated in Vacuo. A total of
6.76 g of 13 was obtained and was used without purification: 1H NMR
(400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.32 (s, 1H), 3.66 (s, 3H).
6-Chloro-3-methyl-9H-purin-3-um chloride (14). To purinone 13
(100 mg, 666 µmol) was added pyridine (5.45 mL) and phosphorus
pentasulfide (454.5 mg, 2.04 mmol, 3.1 equiv), and the reaction was
refluxed for 4 h and then concentrated in Vacuo. To the resulting brown
solid was added boiling water. A suspension formed, which was allowed
to cool to room temperature. The solids were filtered off and dried in
an oven overnight to deliver 56 mg (51%) of the corresponding purine-
6(9H)-thione: 1H NMR (400 MHz, DMSO-d6) δ 13.65 (br s, 1H), 8.42
(s, 1H), 8.36 (s, 1H), 3.86 (s, 3H).
3-Methyl-3H-purine-6(9H)-thione (5.34 g, 32.13 mmol) was com-
bined with 2.5% aqueous NaOH (66.74 mL, 1.3 equiv) and iodomethane
(4.00 mL, 64.26 mmol, 2.0 equiv) at room temperature. The resulting
mixture was stirred for 2 h at room temperature, during which time a
white solid precipitated. The precipitate was filtered off and dried to
1
deliver 3.56 g (61%) of the methylthio product: H NMR (400 MHz,
DMSO-d6) δ 8.84 (s, 1H), 8.15 (s, 1H), 4.11 (s, 3H), 2.74 (s, 3H).