New 2,3-Disubstituted Thieno[3,4-b]pyrazines
1
2
,3-Dibromothieno[3,4-b]pyrazine (2). The reagents PBr
5
(10
122.9, 114.5, 113.4, 64.0, 14.4; IR (KBr) 2230 cm- (CtN str);
HRMS m/z 187.0080 [M + H]+ (calcd for C H N S 187.0073).
2,3-Dicyanothieno[3,4-b]pyrazine (9). CH CN (40 mL) was
added via syringe to a flask containing 2 (0.587 g, 2 mmol) and
KCN (0.651 g, 10 mmol), and the solution was stirred at room
temperature for 24 h. CH Cl was then added, and the mixture
2 4
O, dried with Na SO , concentrated,
and purified by silica chromatography (45% EtOAc/hexanes) to
mmol), Bu NBr (10 mmol), and Na CO (1.06 g, 10 mmol) were
4
2
3
8
3
4
added to 60 mL of xylenes in a 100 mL round-bottom flask
equipped with a condenser with an outlet submerged in 2.5 M KOH
aqueous solution. The reaction mixture was heated to reflux,
resulting in a color change from deep red to light yellow-orange.
Compound 5 (0.84 g, 5 mmol) was then added, and the solution
was heated at reflux overnight. Saturated aqueous NH
was added, and the mixture was extracted with CH
combined organic layers were then dried with Na SO , concentrated,
3
2
2
washed several times with H
2
4
Cl solution
2
2
Cl . The
give a yellow solid (15-20% yield). Mp 99 °C (dec); H NMR δ
1
13
2
4
8
.48 (s 2H); C NMR δ 140.2, 129.2, 123.4, 113.8; IR (KBr) 2230
and purified by silica chromatography (2% EtOAc/hexanes) to give
cm (CtN str); HRMS m/z 206.0384 [M + H]+ (calcd for
-1
1
a yellow solid (60-70% yield). Mp 139 °C (dec); H NMR δ 7.97
C
9
H
8
N
3
OS 206.0383).
1
3
(
s, 2H); C NMR δ 140.9, 140.2, 118.6.
2
,3-Bis(bromomethyl)thieno[3,4-b]pyrazine (4). 3,4-Diaminothio-
2
,3-Dichlorothieno[3,4-b]pyrazine (3). Compound 3 was pre-
pared as 2 above, substituting PCl and Me NCl for the reagents
PBr and Bu
phene (2.28 g, 20 mmol) was dissolved in absolute ethanol (40
mL) and added dropwise to a solution of 1,4-dibromo-2,3-
butanedione (4.88 g, 20 mmol) in 20 mL of ethanol at 0 °C. The
reaction mixture was stirred at 0 °C for 3 h. Water was added, and
Cl . The organic layer was dried
2 2
with Na SO , concentrated, and purified by silica chromatography
5
4
5
4
NBr, to give a yellow solid (∼5% yield). Mp
1 13
1
1
34.2-135.6 °C; H NMR δ 7.96 (s, 2H); C NMR δ 144.9, 140.2,
18.4.
General Synthesis of 2,3-Dialkoxythieno[3,4-b]pyrazines. The
the mixture was extracted with CH
2
4
appropriate alcohol (6 mmol) was syringed into a mixture of NaH
0.24 g, 6 mmol) in DMF (40 mL) and stirred at room temperature
for 5 min. Precursor 2 (0.60 g, 2 mmol) was then added and stirring
continued for 2 h. Aqueous NH Cl was added and the mixture
extracted with CH Cl . The organic layer was dried with Na SO
concentrated, and purified by silica chromatography.
,3-Dipentoxythieno[3,4-b]pyrazine (6a). Eluted with 2% EtOAc/
(
1
1
10% EtOAc/hexanes) to give a yellow solid (60-65% yield). Mp
(
1
13
07 °C (dec); H NMR δ 8.02 (s, 2H), 4.83 (s, 4H); C NMR δ
+
3
50.3, 144.6, 118.8, 31.3; HRMS m/z 467.7994 [M + AgCH CN]
4
(
calcd for C10
,3-Dihydrofuro[3,4-e]thieno[3,4-b]pyrazine (10). Compound
(0.64 g, 2 mmol) was dissolved in 40 mL of MeCN/H O (10:1)
9 2 3
H AgBr N S 467.7929).
2
2
2
4
,
1
4
2
2
mixture, and KOH (0.90 g, 16 mmol) was added to the solution.
After stirred for 3 h, the reaction mixture was quenched by water,
Cl . The combined
2 2
organic layers were dried with Na SO and concentrated by rotary
hexanes to give a white solid (75-80% yield). Mp 76.1-77.5 °C;
1
H NMR δ 7.37 (s, 2H), 4.41 (t, J ) 6.8 Hz, 4H), 1.86 (p, J ) 6.8
13
and the organic layer was extracted by CH
Hz, 4H), 1.43 (m, 8H), 0.94 (t, J ) 7.2 Hz, 6H); C NMR δ 150.3,
1
[
38.4, 112.5, 67.3, 28.4, 28.4, 22.6, 14.2; HRMS m/z 331.1445
2
4
+
evaporation. The crude product was purified by silica chromatog-
M + Na] (calcd for C16
24 2 2
H N NaO S 331.1451).
raphy (12% EtOAc in hexanes) to give a yellow solid (45-50%
2,3-Didecyloxythieno[3,4-b]pyrazine (6b). Eluted with 4% EtOAc/
1
13
yield). Mp 117 °C (dec); H NMR δ 7.90 (s, 2H), 5.07 (s, 4H);
C
hexanes to give a white solid (70-75% yield). Mp 69.7-71.3 °C;
1
NMR δ 156.4 142.4, 117.2, 70.6; HRMS m/z 179.0289 [M + H]
+
H NMR δ 7.37 (s, 2H), 4.41 (t, J ) 6.8 Hz, 4H), 1.85 (p, J ) 6.8
Hz, 4H), 1.46 (m, 4H), 1.37 (m, 4H), 1.27 (m, 20H), 0.88 (t, J )
(calcd for C OS 179.0274).
8 7 2
H N
1
3
6
2
+
.8 Hz, 6H); C NMR δ 150.3, 138.4, 112.5, 67.3, 32.1, 29.9,
General Synthesis of 2,3-Bis(alkoxymethyl)thieno[3,4-b]pyra-
zines. For the short chain systems, an alkoxide reagent was prepared
via the addition of NaH (0.24 g, 6 mmol) to 40 mL of the
appropriate alcohol and stirred for 5 min. For the preparation of
longer alkoxides, BuLi (8.0 mmol) was added to the alcohol (8
mmol) in 50 mL of THF. Precursor 4 (0.64 g, 2 mmol) was then
added to the alkoxide solution and stirred for 2 h. Aqueous NH Cl
was then added, and the mixture was extracted with CH Cl . The
2 4
organic layer was dried with Na SO , concentrated, and purified
by silica chromatography (12% EtOAc/hexanes) to give a yellow
oil.
9.8, 29.8, 29.6, 28.7, 26.2, 22.9, 14.3; HRMS m/z 471.2994 [M
+
Na] (calcd for C26
H
44
N
2
NaO
2
S 471.3016).
2,3-Bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)thieno[3,4-b]pyra-
zine (6c). Eluted with 35% EtOAc/hexanes to give a yellow oil
1
(
4
(
1
75-80% yield). H NMR δ 7.34 (s, 2H), 4.54 (t, J ) 5.2 Hz,
H), 3.88 (t, J ) 5.2 Hz, 4H), 3.71 (m, 4H), 3.64 (m, 4H), 3.61
m, 4H), 3.50 (m, 4H), 3.33 (s, 6H); 13C NMR δ 149.7, 138.1,
12.7, 72.0, 70.9, 70.8, 70.6, 69.0, 66.2, 59.1; HRMS m/z 483.1761
4
2
2
+
[
M + Na] (calcd for C20
,3-Di(N-decylamino)thieno[3,4-b]pyrazine (7). DMF (1 mL),
decylamine (1.6 mL, 8 mmol), and 2-isobutyrylcyclohexanone
0.067 g, 0.4 mmol) were added via syringe to a flask containing
32 2 8
H N NaO S 483.1772).
2
2
,3-Bis(ethoxymethyl)thieno[3,4-b]pyrazine (11a). Yield 85-
(
2
0
1
9
4
7
0%; H NMR δ 7.96 (s, 2H), 4.82 (s, 4H), 3.65 (q, J ) 7.2 Hz,
(0.587 g, 2 mmol), Cs
.1 mmol). The suspension was heated at 90 °C for 1 h and then
cooled to room temperature. Ethyl acetate (20 mL) was added, and
the suspension was filtered to remove inorganic salts and then
purified via silica chromatagraphy (7% EtOAc/hexanes) to give a
2
CO
3
(1.30 g, 4 mmol), and CuI (0.019 g,
13
H), 1.27 (t, J ) 6.8 Hz, 6H); C NMR δ 151.9, 141.7, 117.9,
2.5, 66.9, 15.4; HRMS m/z 275.0834 [M + Na]+ (calcd for
12 16 2 2
C H N NaO S 275.0825).
2
,3-Bis(butoxymethyl)thieno[3,4-b]pyrazine (11b). Yield 85-
1
9
0%; H NMR δ 7.96 (s, 2H), 4.81 (s, 4H), 3.57 (t, J ) 5.6 Hz,
1
white solid (84% yield). Mp 75.1-76.1 °C; H NMR δ 7.18 (s,
13
4
H), 1.62 (m, 4H), 1.37 (m, 4H), 0.91 (t, J ) 7.2 Hz, 6H);
C
2
H), 4.81 (br t, J ) 5.6 Hz, 2H), 3.43 (dd, J ) 5.6, 7.2 Hz, 4 H),
.60 (p, J ) 7.2 Hz, 4H), 1.34 (m, 28 H), 0.88 (t, J ) 6.8 Hz, 6H);
C NMR δ 145.1, 139.0, 109.8, 42.1, 32.1, 29.8, 29.6, 29.5, 29.3,
NMR δ 152.1, 141.7, 117.9, 72.9, 71.4, 32.0, 19.5, 14.1; HRMS
m/z 331.1448 [M + Na]+ (calcd for C16
NaO S 331.1451).
,3-Bis(pentoxymethyl)thieno[3,4-b]pyrazine (11c). Yield 55-
1
H
24
N
2
2
1
3
2
-
1
2
4
7.4, 22.9, 14.3; IR (KBr) 3370 cm (N-H str); HRMS m/z
1
6
0%; H NMR δ 7.96 (s, 2H), 4.81 (s, 4H), 3.56 (t, J ) 6.8 Hz,
H), 1.64 (m, 4H), 1.33 (m, 8H), 0.88 (t, J ) 6.8 Hz, 6H);
+
47.3521 [M + H] (calcd for C26
47 4
H N S 447.3516).
13
4
C
2-Cyano-3-ethoxythieno[3,4-b]pyrazine (8). Ethanol (100%, 25
NMR δ 152.1, 141.7, 117.9, 72.8, 71.7, 29.6, 28.5, 22.7, 14.2;
HRMS m/z 359.1775 [M + Na]+ (calcd for C18
NaO
59.1764).
2,3-Bis(2-(2-(2-methoxyethoxy)ethoxy)ethoxymethyl)thie-
mL) was added via syringe to a flask containing 2 (0.357 g, 1.2
mmol) and NaCN (0.15 g, 3.0 mmol). The solution was heated at
reflux for 30 min, cooled to room temperature, diluted with 100
mL H
were dried with Na
chromatography (3% EtOAc/hexanes) to give a yellow solid
H
28
N
2
2
S
3
2
O, and extracted with CH
2 2
Cl . The combined organic layers
1
2
SO , concentrated, and purified by silica
4
no[3,4-b]pyrazine (11d). Yield 55-60%; H NMR δ 7.97 (s, 2H),
4.87 (s, 4H), 3.73 (m, 4H), 3.67 (m, 4H), 3.62 (m, 12H), 3.52 (m,
1
13
(
3
1
80-85% yield). Mp 114.8-115.5 °C; H NMR δ 8.16 (d, J )
4H), 3.34 (s, 6H); C NMR δ 151.7, 141.4.1, 117.9, 72.96, 72.0+,
.6 Hz, 1H), 7.58 (d, J ) 3.6 Hz, 1H), 4.55 (q, J ) 6.8 Hz, 2H),
70.6(4), 70.6(0), 70.5, 70.4, 59.2; HRMS m/z 511.2071 [M + Na]
1
3
.51 (t, J ) 6.8 Hz, 3H); C NMR δ 154.7, 139.8, 139.5, 124.6,
42 2 8
(calcd for C22H N NaO S 511.2085).
J. Org. Chem. Vol. 73, No. 21, 2008 8535