The Journal of Organic Chemistry
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temperature, diluted with water (50 mL), and extracted methylene
chloride (3 × 100 mL). Column chromatography on silica gel eluted
with a gradient of 2−6% methanol in CH Cl gave 18c as an orange
an ice bath. To this orange biphasic mixture was added dropwise an
ice-cold solution of p-toluenesulfonyl chloride (455 mg, 3 equiv) in
tetrahydrofuran (1.5 mL). The resulting mixture was stirred vigorously
in an ice bath for 1.5 h. During this time the mixture turned yellow.
The mixture was then poured into an ice−water slurry (100 mL) and
stirred for 30 min to give a yellow precipitate. The solid was collected
by vacuum filtration, then washed with water and diethyl ether, and
2
2
1
solid (16 mg, 30%): H NMR (500 MHz, DMSO-d ) δ 8.01 (d, J =
6
9
.8, Hz, 1H), 7.81 (bs 2H), 7.27 (dd, J = 9.8, 2.7 Hz, 1H), 7.05 (d, J =
13
2.7 Hz, 1H), 3.96 (t, J = 6.7 Hz, 4H), 3.85 (t J = 6.7 Hz, 4H);
C
NMR (125 MHz, DMSO-d ) δ 152.3, 151.5, 139.7, 123.4, 123.0,
6
1
15.8, 92.2; HRMS (ESI) m/z calculated for C H Cl N O (M +
dried in a desiccator to give 21 (356 mg, 61% overall yield over two
11
14
2
5
2
+
1
H ) 318.0519, found 318.0519.
steps): H NMR (500 MHz, DMSO-d ) δ 8.87 (s, 1H), 7.96 (d, J =
6
Synthesis of 3-Amino-5-tosyl-6-(bis(2-hydroxyethyl)amino)-
9.2 Hz, 1H), 7.57 (d, J = 8.3 Hz, 4H), 7.19 (d, J = 8.0, 4H), 7.14 (dd, J
= 9.8, 2.6 Hz, 1H), 6.64 (d, J = 2.7 Hz, 1H), 4.18 (t, J = 5.1 Hz, 4H),
3.71 (t, J = 5.1 Hz, 4H), 2.20 (s, 6H); 13C NMR (500 MHz, DMSO-
d6) δ 154.8, 152.1, 149.2, 145.2, 131.9, 130.2, 127.8, 127.4, 120.7,
120.3, 103.7, 67.6, 49.3, 21.2. HRMS (ESI) m/z calculated for
1
,2,4-benzotriazine 1-Oxide (19). Compound 15 (52 mg, 0.18
mmol) was suspended in a stirred solution of pyridine in an ice bath,
and tosyl chloride (172 mg, 5 equiv) was added. The mixture was
stirred in an ice bath for 12 h, poured into ice-cold water (20 mL), and
extracted with methylene chloride (5 × 25 mL). The combined
organic fractions were washed with brine and dried over Na SO , and
+
C H N O S (M + H ) 559.1316, found 559.1320. Compound 25
25
27
4
7 2
2
4
was prepared in from 24 by heating for 4 days using the same
1
solvent was removed by rotary evaporation. Column chromatography
conditions (390 mg, 57% overall yield over two steps): H NMR (500
on silica gel eluted with 1% methanol in methylene chloride 19 as an
MHz, DMSO-d ) δ 8.89 (s, 1H), 7.73 (d, J = 9.4 Hz, 1H), 7.56 (d, J =
6
1
orange solid (6 mg, 10%): H NMR (500 MHz, DMSO-d ) δ 7.85 (d,
8.2 Hz, 4H), 7.44 (dd, J = 9.5, 2.8, 1H), 7.16 (d, J = 8.1 Hz, 4H), 6.86
(d, J = 2.8 Hz, 1H), 4.19 (t, J = 5.0 Hz, 4H), 3.69 (t, J = 5.0 Hz, 4H),
6
J = 9.8 Hz, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.739 (d, J = 8.2 Hz, 2H),
2.17 (s, 6H); 13C NMR (125 MHz, DMSO-d ) δ 150.2, 148.6, 145.2,
7
3
1
.19 (d, J = 9.8 Hz, 1H), 6.94 (bs 2H), 4.65 (t, J = 5.1 Hz, 2H), 3.47−
6
.40 (m, 8H); 13C NMR (125 MHz, DMSO-d ) δ 160.1, 148.2, 145.9,
6
140.7, 135.8, 132.0, 130.1, 129.5, 127.7, 125.0, 94.8, 67.5, 49.1, 21.2.
+
45.5, 132.6, 129.5, 128.8, 126.6, 123.6, 118.8, 118.7, 58.4, 54.3, 21.3;
HRMS (ESI) m/z calculated for C H N O S (M + H ) 559.1316,
25
27
4
7 2
+
HRMS (ESI) m/z calculated for C H N O S (M + H ) 436.1285,
found 559.1317.
18
22
5
6
found 436.1293. Crystals suitable for X-ray crystallography were
prepared by vapor diffusion with ethyl acetate and hexane. The crystal
structure and crystallographic data for 19 are shown in Supplementary
Figure S1 and Table S1, respectively.
Preparation of 6-(Bis(2-(tosyloxy)ethyl)amino))-1,2,4-benzo-
triazine 1,4-Dioxide (22). Compound 21 (20 mg, 0.04 mmol) and
NaHCO (30 mg, 10 equiv) were suspended in methanol (6.25 mL).
3
Oxone (110 mg, 5 equiv) was added, followed by water (2.5 mL), and
the mixture was stirred at 50 °C under an atmosphere of nitrogen gas
for 16 h. The reaction was cooled to room temperature and extracted
with methylene chloride (5 × 10 mL). The organic layers were
combined, washed with brine, and dried over anhydrous sodium
sulfate. Column chromatography on silica gel eluted with 1% MeOH
in CH Cl gave compound 22 as an red-orange solid (2 mg, 10%) with
Synthesis of Desamino-tirapazamine Derivatives 6-Fluoro-
1
,2,4-benzotriazine 1-Oxide (20) and 7-Fluoro-1,2,4-benzo-
triazine 1-Oxide (24). Following the general procedure of Boyd et
9
3
al.
23 (930 mg, 5 mmol) was dissolved in anhydrous
dimethylformamide (50 mL), and the mixture was degassed by
bubbling argon through the solution for 30 min. To this mixture was
added tert-butyl nitrite (3.5 mL, 5 equiv, 90%) by syringe, and the
mixture was heated in a 60 °C oil bath for 2 h under an atmosphere of
argon gas. The reaction was cooled, and the solvent was removed
under vacuum. The resulting dark residue was taken up in ethyl acetate
2
2
1
50% recovery of starting materials: H NMR (500 MHz, DMSO-d ) δ
6
9.15 (s, 1H), 7.96 (d, J = 9.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 4H), 7.25−
7.18 (m, 5H), 6.84 (d, J = 2.8 Hz, 1H), 4.21 (t, J = 5.0 Hz, 4H), 3.70
(t, J = 4.9 Hz, 4H), 2.25 (s, 6H); 13C NMR (125 MHz, DMSO-d ) δ
6
(
300 mL), mixed with brine (150 mL), and stirred vigorously. The
152.0, 145.3, 142.5, 140.7, 132.0, 130.2, 127.8, 127.3, 122.4, 120.9,
phases were allowed to separate, the organic layer was washed with
brine (2 × 150 mL) and dried over anhydrous sodium sulfate, and the
solvent was removed by rotary evaporation. Column chromatography
on silica gel eluted with a gradient of 0−10% ethyl acetate in CH Cl
84.6, 67.4, 49.1, 21.2. HRMS (ESI) m/z calculated for C H N O S
(M + H ) 575.1265, found 575.1263.
2
5
27
4
8 2
+
Synthesis of 7-(Bis(2-(tosyloxy)ethyl)amino)-1,2,4-benzo-
triazine 1,4-Dioxide (26). Using a procedure adapted from Pchalek
2
2
1
94
gave 24 as a pale white solid (438 mg, 50%): mp 127−129 °C; H
and Hay, trifluoroacetic anhydride (300 μL) and methylene chloride
NMR (500 MHz, DMSO-d ) δ 9.20 (s, 1H), 8.24 (dd, J = 9.3, 5.3 Hz,
(1.5 mL) were mixed with stirring in an ice bath, and 70% H O (105
6
2
2
13
1
H), 8.20 (dd, J = 8.4, 2.8 Hz, 1H), 8.08 (m, 1H); C NMR (125
μL) was added dropwise. The mixture was stirred for 10 min and then
allowed to warm to room temperature. This solution was cooled in an
ice bath and slowly added to an ice-cold solution of 25 (110 mg, 0.2
mmol) in methylene chloride (10 mL). The reaction was stirred in an
ice bath for 30 min before being diluted with methylene chloride (100
MHz, DMSO-d ) δ 162.6 (d, J = 253.9), 154.0 (d, J = 2.6 Hz), 144.9,
6
1
36.0, 132.5 (d, J = 9.4 Hz), 126.7 (d, J = 25.9 Hz), 105.2 (d, J = 29.3
+
Hz); HRMS (ESI) m/z calculated for C H FN O (M + H ) 166.0411,
7
5
3
found 166.0419. Compound 20 was prepared from 13 (980 mg) by
1
the same method (447 mg, 50%): mp 160−162 °C; H NMR (500
mL) and washed with cold water, cold NaHCO (saturated), and then
3
MHz, DMSO-d ) δ 9.19 (s, 1H), 8.50 (dd, J = 9.6, 5.5 Hz, 1H), 7.99
brine. The organic layer was dried over anhydrous sodium sulfate, and
6
13
(
dd, J = 9.1, 2.7 Hz, 1H), 7.82 (m, 1H); C NMR (125 MHz, DMSO-
column chromatography on silica gel eluted with 0.5% MeOH in
1
d6) δ 166.1 (d, J = 256.7), 155.5, 149.3 (d, J = 15.1 Hz), 133.1, 123.8
CH
DMSO-d
2
Cl
2
gave 26 as a red solid (1 mg, 1%): H NMR (500 MHz,
6
(
(
1
d, J = 11.2 Hz), 121.8 (d, J = 26.6 Hz), 113.3 (d, J = 22.7 Hz); HRMS
) δ 9.06 (s, 1H), 7.96 (d, J = 9.7 Hz, 1H), 7.57 (d, J = 8.3
+
ESI) m/z calculated for C H FN O (M + H ) 166.0411, found
Hz, 4H), 7.41 (dd, J = 9.7, 2.7, 1H), 7.22 (d, J = 8.0 Hz, 4H), 6.85 (d, J
7
5
3
66.0417.
= 2.6 Hz, 1H), 4.19 (t, J = 5.0 Hz, 4H), 3.67 (t, J = 4.9 Hz, 4H), 2.25
(s, 6H); 13C NMR (125 MHz, DMSO-d
) δ 149.3, 144.9, 138.8, 135.6,
6
Synthesis of 6-(Bis(2-(tosyloxy)ethyl)amino))-1,2,4-benzo-
triazine 1-Oxide (21) and 7-(Bis(2-(tosyloxy)ethyl)amino)-
benzo[e][1,2,4]triazine 1-Oxide (25). Compound 20 (361 mg,
131.8, 131.7, 129.9, 127.4, 123.2, 119.5, 96.1, 67.1, 48.6, 20.9. HRMS
+
(ESI) m/z calculated for C H N O S (M + H ) 575.1265, found
25
27
4
8 2
2.2 mmol) and diethanolamine (500 mg, 2.5 equiv) were dissolved in
575.1275.
acetonitrile (7 mL), and the mixture was heated in an 80 °C oil bath
overnight. The reaction mixture was cooled, and solvent was removed
under reduced pressure by rotary evaporation. The resulting solid was
suspended in ethanol (10 mL), briefly heated to 80 °C with stirring,
and then cooled to 0 °C, and the resulting precipitate was collected by
vacuum filtration. The orange solid was washed with cold ethanol and
diethyl ether and dried in an oven overnight at 70 °C. The resulting
solid (200 mg) was dissolved in a biphasic mixture of tetrahydrofuran
Synthesis of 3-Amino-6-N-morpholino-1,2,4-benzotriazine
1-Oxide (27). Compound 13 (503 mg, 2.8 mmol) and morpholine
(0.72 mL, 3 equiv) were suspended in 1-methyl-2-pyrrolidinone (4
mL) and heated to 100 °C overnight. The resulting orange suspension
was cooled to room temperature, diluted with water (40 mL), and
filtered. The precipitate was washed with water and diethyl ether and
then dried in an oven overnight at 70 °C. The orange-yellow powder
was collected by vacuum filtration to give 27 (650 mg, 94%): mp 245−
1
(
9 mL) and NaOH (2.4 mL of a 4 M solution in water) and cooled in
250 °C dec; H NMR (500 MHz, DMSO-d ) δ 7.94 (d, J = 9.6 Hz,
6
7
528
dx.doi.org/10.1021/jo501252p | J. Org. Chem. 2014, 79, 7520−7531