M. P. Zawistoski et al. / Tetrahedron Letters 50 (2009) 7286–7287
7287
Table 1
Table 3
Synthesis of isothiazoles 9a–d and 10a–d
Proposed mechanism for the formation of 14a and 14b
Et3N, EtOH
-78 C to r.t.;
Et3N, EtOH,
-78 °C to r.t.
R
°
F3C
H2N
NH2
X3C
CN
NHR
S
2 or 11
NIS
+
NC
S
CX3CN
CF3
NHR
N
or
S
3
X = F
Et3N, EtOH,
r.t. to 50 °C
N
5 X = Cl
8a-d
9a-d
X = F
12a R = CN
12b
10a-d X = Cl
R = CO2Et
R
Product
% Yield 9
Product
% Yield 10
R
R
F3C
NH
S
CH3
Benzyl
Cyclohexyl
Phenyl
9a
9b
9c
9d
44
36
46
65
10a
10b
10c
10d
25
36
49
56
+
F3C
H2N CF3
NH2S CF3
NH
NH
NH2
13a R = CN
14a R = CN
14b
13b
R = CO2Et
R = CO2Et
Table 2
Synthesis of isothiazoles 1d and 1f
Entry
Thioamide
% Yield 12
% Yield 14
4
5
2
11
35
6
4
68
O
X3C
OEt
NH2
S
O
+
CX3CN
H2N
OEt
N
S
3 X = F
11
5
X = Cl
pact on the observed reaction pathways. Reactions with CF3CN (3)
require an oxidant to mediate cyclization, while CCl3CN (5) func-
tions as both the reactant and oxidant. CF3CN (3) is more reactive
with ester intermediate 12b than with nitrile intermediate 12a,
thereby requiring oxidation at low temperature after a short time
period to obtain ester 1d.
1d X = F
1f X = Cl
Entry Nitrile Conditions
Product % Yield
1
1
3
(1) Et3N, À78 °C to room temperature; 1d
0
(2) H2O2
2
3
5
3
Et3N, À78 °C to room temperature
1f
1d
14
30
Acknowledgements
(1) Et3N, À78 °C, 1 h; (2) H2O2
We wish to thank Professor Andy Myers, Steven Wright and
Daniel Kung for helpful suggestions with this chemistry.
yields of the desired isothiazoles (Table 1). The highest yields were
obtained using the N-phenyl thioamide.
Supplementary data
Towards the synthesis of isothiazole ester 1d, we examined iso-
thiazole formation with ester 11 in place of nitrile 2. However, in
the reaction of 11 with CF3CN (3) using the conditions described
above (Et3N, À78 °C to room temperature; H2O2), none of the de-
sired isothiazole (1d) was formed (Table 2, entry 1). In contrast,
the reaction of 11 with CCl3CN (5) provided isothiazole 1f (Table 2,
entry 2), albeit in modest yield (14%).
To better understand the different outcomes upon reaction of
CF3CN (3) with nitrile 2 and ester 11, we sought to characterize
the intermediates prior to oxidation. The reaction of nitrile 2 with
CF3CN (3) gave two products (Table 3, entry 4). The major product
was the expected vinylogous thiourea 12a, (35% isolated yield after
purification), and the minor component was dinitrile 14a which
was likely formed by the mechanism shown in Table 3. When oxi-
dant was added to purified 12a, it proceeded to give the desired
isothiazole 1c.
In contrast, the reaction of ester 11 with CF3CN (3) provided the
desired intermediate 12b as the minor product, while nitrile side-
product 14b was the predominant product (Table 3, entry 5). Fur-
thermore, when the reaction was warmed or allowed to proceed
for several hours, only 14b was isolated. We therefore sought to
generate intermediate 12b and then oxidize it to 1d before it could
react with excess CF3CN (3);9 addition of H2O2 at À78 °C 1 h after
the addition of Et3N gave 1d (Table 2, entry 3) in 30% yield.
In conclusion, we have developed a novel synthesis of 4,5-
disubstituted-3-trihalomethylisothiazoles. This methodology is
tolerant of N-substituted thioamides, but appears to require aceto-
nitriles containing strongly electron-withdrawing groups. The
reactivity of the necessary trihaloacetonitriles has a significant im-
Supplementary data (experimental procedures and character-
ization of final products) associated with this article can be found,
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