D.M. Gampe et al. / Tetrahedron 72 (2016) 3232e3239
3237
4
.2. Syntheses
precipitate was filtrated and washed with water. The crude product
was purified by hot filtration of an ethanol suspension to obtain 8 as
ꢁ
1
4.2.1. 7-Methylbenzo[c][1,2,5]thiadiazole-4-carbonitrile (9). To a so-
orange powder (170 mg, 0.7 mmol, 62%). Mp: 255 C; H NMR
(250 MHz, DMSO):
lution of 11 (2.6 g, 11.4 mmol) in NMP (20 mL) CuCN (1.2 g,
d
¼10.52 (s, 2H), 9.95 (s. 2H), 8.28 (s, 2H) ppm;
13
13.7 mmol, 1.2 equiv) was added portion wise under stirring at
C NMR (63 MHz, DMSO):
d
¼195.61, 150.15, 133.59, 130.61 ppm;
ꢁ
ꢁ
þ
þ
8
0 C. After heating the mixture to 150 C for 2 h, TLC (silica; tol-
MS (EI): m/z¼254 [M ], 221 [(MꢀHS) ]; EA calcd for C
8
H
6
N
4
S
3
: C,
uene) showed only a small amount of the desired product, and an
additional portion of CuCN (800 mg, 9 mmol, 0.8 equiv) was added.
The resulting dark reaction mixture was heated for additional 3 h at
37.78; H, 2.38; N, 22.03; found: C, 37.97; H, 2.26; N, 22.41.
4.2.5. Ethyl 2-(benzo[c][1,2,5]thiadiazol-4-yl)acetate (17). 3
g
ꢁ
ꢁ
1
50 C and stirred at 80 C overnight. After cooling to room tem-
perature aqueous NH (40 mL, 15%) was added and stirred for 1 h.
The resulting precipitate was filtrated. The filtrate was extracted
three times with CH Cl , while the precipitate was rinsed in-
tensively with CH Cl . The combined CH Cl phases were washed
with brine, dried over Na SO and evaporated to dryness. Purifi-
cation by column chromatography (silica; toluene) supplied the
nitrile (9; R z0.5; 1.5 g, 8.5 mmol, 74%) as white powder. Mp:
77 C; H NMR (250 MHz, CDCl ):
¼7.95 (d, J¼7.1 Hz, 1H), 7.45 (d,
J¼7.1 Hz, 1H), 2.83 (s, 3H) ppm; C NMR (63 MHz, CDCl
(15 mmol)of 18 were dissolved in 40 mL of ethanol and 1.3 mL
(17 mmol,1.1 equiv) of thionyl chloride were added drop wise. After
stirring under refluxing conditions over 3 h, as indicated by TLC
(silica; toluene:ethyl acetate/20:1), the reaction was quenched by
adding 5 mL of water. The reaction mixture was concentrated under
reduced pressure and diluted with water and diethyl ether. The
organic phase was separated and extracted with brine, dried over
3
2
2
2
2
2
2
2
4
f
4
MgSO and evaporated to dryness. The product (2.7 g, 12 mmol,
ꢁ
1
1
3
d
80%) was obtained as colorless oil after purification by column
13
1
3
):
¼154.89, 152.93, 138.61, 136.25, 127.51, 115.70, 103.46, 77.16,
chromatography (silica; toluene:ethyl acetate/20:1). H NMR
d
(250 MHz, Acetone):
d
¼7.95 (d, J¼8.6 Hz, 1H), 7.73e7.65 (m, 1H),
þ
þ
1
C
2
8.59 ppm; MS (EI): m/z¼175 [M ], 148 [(MꢀCN) ]; EA calcd for
7.61 (d, J¼6.7 Hz, 1H), 4.17 (s, 2H), 4.16e4.08 (m, 2H), 1.20 (t,
13
H
8 5
N
3
S: C, 54.84; H, 2.88; N, 23.98; found: C, 55.09; H, 2.79; N,
J¼7.1 Hz, 3H); C NMR (63 MHz, Acetone): ¼170.96, 155.76,
d
3.71.
130.64, 130.37, 129.24, 121.04, 61.29, 37.67, 29.84, 14.47; MS (EI): m/
þ
þ
z¼222 [M ], 149 [(MꢀHCO
2 10 2 2
Et) ]; EA calcd for C10H N O S: C,
4.2.2. Benzo[c][1,2,5]thiadiazole-4,7-dicarbonitrile (10). A mixture
54.04; H, 4.53; N, 12.60; found: C, 53.71; H, 4.61; N, 12.74.
of 12 (1 g, 3.4 mmol), 0.55 mL of pyridine (6.9 mmol, 2 equiv) and
sodium iodide (0.03 mmol, 0.01 equiv) in 10 mL of DMF was
4.2.6. Ethyl 2-(benzo[c][1,2,5]thiadiazol-4-yl)-2-bromoacetate
(16). To a mixture of 2.7 g (12 mmol) of 17 and 2.27 g of N-bro-
mosuccinimide (13 mmol, 1.05 equiv) in 150 mL tetrachloroethylen,
3 droplets of hydrobromic acid (62%) were added and the resulting
suspension was stirred over 12 h under reflux. As indicated by TLC
(silica; toluene) the reaction turnover stops at about 50%, so the
degassed with nitrogen over 15 min. Under N
3.7 mmol, 4 equiv) was added and the suspension was heated to
reflux for 20 h, as indicated by TLC (silica; CH Cl ). The mixture was
allowed to cool to room temperature and cold aqueous NH (20 mL,
5%) was added. The resulting dark suspension was stirred for an
additional hour and the precipitate was filtrated and rinsed in-
tensively with CH Cl . The resulting organic layer was washed with
water, dried over MgSO and evaporated to dryness to obtain the
crude product. Purification by column chromatography (silica;
2
, CuCN (1.2 g,
1
2
2
3
1
reaction was quenched by adding a saturated Na
organic phase was separated and extracted twice with Na
solution and water. After drying over MgSO , the mixture was
2
2
S O
3
-solution. The
2
2
2 3
CO -
4
4
evaporated and a yellow oil was obtained. The product/educt (1/
CH
2
Cl
2
) supplied 10 (R
f
z0.8, 350 mg, 1.9 mmol, 56%) as pale yellow
0.7) mixture was used as obtained for further reaction steps (2.5 g
ꢁ
1
1
powder. Mp: 183 C; H NMR (300 MHz, CDCl
ppm;
3
):
¼152.41, 134.42, 113.82,
S: C, 51.61;
d¼8.13 (s, 2H)
mixture: 1.5 g, 5 mmol, 42%). H NMR (250 MHz, Acetone):
d
¼8.09
1
3
C NMR (63 MHz, CDCl
3
):
d
(dd, J¼8.8, 0.9 Hz, 1H), 8.02 (d, J¼6.9 Hz, 1H), 7.79 (dd, J¼8.8, 7.0 Hz,
þ
1
10.67 ppm; MS (EI): m/z¼186 [M ]; EA calcd for C
8 2 4
H N
1H), 6.39 (s, 1H), 4.25 (q, J¼7.1 Hz, 2H), 1.21 (t, J¼5.6 Hz, 3H) ppm;
þ
þ
þ
H, 1.08; N, 30.09; found: C, 51.92; H, 1.10; N, 29.91.
MS (EI): m/z¼300 [M ], 302 [(Mþ2) ], 221 [(MꢀBr) ].
4
.2.3. 7-Methylbenzo[c][1,2,5]thiadiazole-4-carbothioamide (7). A
4.2.7. 2-(7-Methylbenzo[c][1,2,5]thiadiazol-4-yl)-5-phenylthiazol-4-
ol (4). A suspension of 7 (720 mg, 3.5 mmol), 0.78 mL of ethyl-2-
bromo-2-phenylacetate (21; 4.5 mmol, 1.3 equiv) and sodium ac-
etate (710 mg, 8.6 mmol, 2.5 equiv) in 10 mL of ethanol was heated
to reflux. After 6 h the red reaction mixture was allowed to cool to
room temperature and water was added. The red precipitate was
0
mixture of 9 (1.5 g, 8.6 mmol), O,O -diethyldithiophosphate
ꢁ
(
1.55 mL, 9.7 mmol, 1.1 equiv) and 1 mL of THF was heated to 80 C
for 6 h. The reaction was quenched by diluting the mixture with
0 mL of saturated NaHCO -solution and stirred for an additional
4
3
hour. The resulting yellow precipitate was filtrated and washed
with water and small amount of ethanol. The orange, crystalline
filtrated and rinsed with water, ethanol, CHCl
3
and pentane. After
product (7; 1.5 g, 7.2 mmol, 84%) was obtained after re-
drying under reduce pressure the product was obtained as red
ꢁ
ꢁ
1
crystallization from cyclohexane/CHCl
3
(1:1). Mp: 191e193
C
powder (590 mg, 1.8 mmol, 53%). Mp: 325 C (dec); H NMR
(400 MHz, DMSO):
¼11.28 (s, 1H), 8.37 (d, J¼7.4 Hz, 1H), 7.81 (d,
1
(
dec); H NMR (400 MHz, CDCl
H), 8.16 (s, 1H), 7.51 (d, J¼7.4 Hz, 1H), 2.79 (s, 3H) ppm; C NMR
101 MHz, CDCl ):
¼196.33, 155.77, 151.22, 138.70, 137.28, 128.53,
3
):
d
¼10.47 (s, 1H), 9.03 (d, J¼7.4 Hz,
d
13
1
J¼7.5 Hz, 2H), 7.67 (d, J¼7.3 Hz, 1H), 7.42 (t, J¼7.8 Hz, 2H), 7.25 (t,
13
(
3
d
J¼7.4 Hz,1H), 2.76 (s, 3H) ppm; C NMR could not be measured due
þ
þ
þ
125.25, 18.37 ppm; MS (EI): m/z¼209 [M ], 176 [(MꢀHS) ]; EA
to bad solubility; MS (EI): m/z¼325 [M ]; EA calcd for C16
11 3 2
H N OS :
calcd for C
8
H
7
N
3
S
2
: C, 45.91; H, 3.37; N, 20.08; found: C, 46.23; H,
C, 59.06; H, 3.41; N, 12.91; found: C, 59.45; H, 3.35; N, 12.72.
3
.24; N, 20.36.
4
.2.8. 4-(4-(Hexyloxy)-5-phenylthiazol-2-yl)-7-methylbenzo[c]
4
.2.4. Benzo[c][1,2,5]thiadiazole-4,7-bis(carbothioamide)
(8). To
[1,2,5]thiadiazole (1). To a stirred suspension of 4 (580 mg,
1.8 mmol) and 250 mg potassium carbonate (1.8 mmol) in acetone
(20 mL), 1-iodohexane (0.34 mL, 2.3 mmol, 1.3 equiv) was added
and the resulting mixture was heated to reflux. After 7 h the mix-
ture was allowed to cool down and water was added, while an
orange precipitate was formed. The mixture was filtrated and the
crude product was rinsed with water. Purification was done by
recrystallization from ethanol to afford compound 1 (495 mg,
phosphorus pentasulfide (600 mg, 2.7 mmol, 2.5 equiv) ethanol
was added very carefully under vigorous stirring, until a clear so-
lution accrued. To this freshly prepared O,O -dieth-
yldithiophosphate, compound 10 (200 mg, 1.1 mmol) was added in
small portions. The reaction was heated to reflux. After 4 h the
mixture was allowed to cool down and diluted with saturated
0
3
NaHCO -solution (20 mL) and stirred for an additional hour. The