Efficient fluoride-mediated synthesis of 5-amino-substituted isothiazoles

Article abstract of DOI:10.1055/s-0029-1216844

Fluoride-mediated nucleophilic substitution reactions of tert-butyl 4,5-dichloroisothiazole-3-carboxylate with various amines occur under mild conditions yielding 5-(alkylamino)isothiazoles in moderate to high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216844

PAPER
2361
Efficient Fluoride-Mediated Synthesis of 5-Amino-Substituted Isothiazoles
F
luoride-Mediated
u
Synthesis
o
r
5-Amin
i
o-Substituted
S
Isothiazoles . Zubenko, Vladimir I. Potkin*
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, 13 Surganova Str., 220072 Minsk, Belarus
Fax +375(17)2841679; E-mail: potkin@ifoch.bas-net.by
Received 13 March 2009; revised 18 March 2009
procedures to study chlorine substitution at C5 of the
isothiazole ring (Table 1).
Abstract: Fluoride-mediated nucleophilic substitution reactions of
tert-butyl 4,5-dichloroisothiazole-3-carboxylate with various
amines occur under mild conditions yielding 5-(alkylamino)isothi-
azoles in moderate to high yields.
Initially we explored reactions of ester 2 with secondary
cyclic amines. Piperidine and pyrrolidine reacted with 2 at
room temperature in dimethyl sulfoxide or N,N-dimethyl-
Key words: isothiazole, fluoride, substitution, amine
Table 1 Nucleophilic Substitution of the Chlorine Atom at C5 in the
Isothiazole Ring of 2a
Isothiazole chemistry has been of great interest over past
decades because of the large number of isothiazole com-
pounds synthesized that have antibacterial, antiviral, anti-
biotic, or anticancer activity.1–3
O
O
Cl
Cl
R1R2NH
Ot-Bu
Ot-Bu
R2R1N
N
N
Cl
S
S
Recently we have reported on the reaction of 4,5-dichlo-
ro-3-(trichloromethyl)isothiazole (1) with cyclic amines
in aprotic solvent.4 Substitution of the chlorine atom at C5
of the isothiazole with cyclic amines proceeded at ambient
temperature to give the corresponding 5-amino-4-chloro-
3-(trichloromethyl)isothiazoles; other amines did not re-
act under these conditions. Prolonged heating of substitut-
ed 4,5-dichloroisothiazole-3-carboxamides with an
excess of amine gave the corresponding 5-alkylamino de-
rivatives in low yields.5
2
3
Product
NR1R2
Method
Yieldb (%)
3a
piperidin-1-yl
pyrrolidin-1-yl
morpholin-4-yl
A
A
95
95
3b
3c
A
B
90
95
3d
3e
piperazin-1-yl
NHBn
A
B
90
95
Fluoride-mediated reactions are commonly used in SN2
and SNAr processes with O-, N-, and S-nucleophiles.6–8
However, the reaction of amines with isothiazole 1 in the
presence of alkali metal fluoride does not give the expect-
ed result in aprotic solvents, as we have already estab-
lished. At ambient temperature the reaction did not
proceed, whereas increasing the temperature up to 60–70
°C led to a mixture of products, probably due to decompo-
sition of the trichloromethyl group.
B
C
D
80
87
88
3f
NH(CH2)5Me
NHi-Pr
B
C
D
55
76
69
3g
3h
3i
B
C
D
55
70
75
We decided to transform the trichloromethyl group into a
tert-butyl carboxylate fragment, which is quite resistant to
nucleophiles. tert-Butyl 4,5-dichloroisothiazole-3-car-
boxylate (2) was prepared from 4,5-dichloro-3-(trichlo-
romethyl)isothiazole (1) according to literature
procedures (Scheme 1).9 We used different experimental
NHt-Bu
B
C
D
60
89
88
N(Me)Bn
N(Me)Bu
NBu2
B
C
D
35
74
70
O
1) HNO3 (concd)
2) SOCl2
3) t-BuOH, py
Cl
Cl
CCl3
3j
B
C
D
30
75
76
Ot-Bu
N
N
Cl
Cl
S
S
1
2
3k
B
C
D
15c
15c
30c
Scheme 1 Preparation of tert-butyl 4,5-dichloroisothiazole-3-car-
boxylate (2)
a Conditions: A: DMSO (or DMF), 25–80 °C; B: KF, DMSO, 80 °C;
C: CsF, DMSO, 60 °C; D: KF, NMP, 80 °C.
b Isolated yields.
SYNTHESIS 2009, No. 14, pp 2361–2364
x
x.
x
x
.
2
0
0
9
Advanced online publication: 25.05.2009
DOI: 10.1055/s-0029-1216844; Art ID: Z03909SS
© Georg Thieme Verlag Stuttgart · New York
c Determined by GC-MS analysis.

2362
Y. S. Zubenko, V. I. Potkin
PAPER
MS analysis were performed on a Hewlett Packard 5890/5972 spec-
trometer.
formamide to provide 5-(alkylamino) derivatives 3a,b in
greater than 90% yield. Whereas piperazine and morpho-
line reacted only when heated (Method A) to give 5-(alkyl-
amino) derivatives 3c,d; for other primary and secondary
amines (benzylamine, hexan-1-amine, isopropylamine,
tert-butylamine, N-methylbutan-1-amine, N-benzylmeth-
ylamine, and dibutylamine) the reaction mixture has to be
heated up to 80 °C in the presence of six equivalents of
solid alkali metal fluoride. When N,N-dimethylforma-
mide was used, the product was contaminated with the 5-
(dimethylamino) derivative formed from N,N-dimethyl-
formamide decomposition products. The substitution of
the chlorine atom with primary amines proceeded in the
presence of potassium fluoride at 80 °C to give 3e–h in
55–80% yields (Method B). However, N-methylalkyl-
amine and dialkylamine derivatives 3i–k were obtained in
low to moderate yields (15–35%). Replacing potassium
fluoride with the more soluble cesium fluoride led to an
increase in the product yield using both primary and sec-
ondary amines (Method C), but the temperature had to be
reduced to 60 °C because of blackening of the mixture.
With the aim of achieving higher product yields with po-
tassium fluoride than those available, we replaced dimeth-
yl sulfoxide with N-methylpyrrolidin-2-one (Method D).
This provided an increase in yields of compounds 3e–k up
to 70–80%; this is probably due to the improved solubility
of potassium fluoride in N-methylpyrrolidin-2-one com-
pare to dimethyl sulfoxide. In our experiments we used
three equivalents of the corresponding amine, but we used
six equivalents of isopropylamine to take account of its
volatility. Diisopropylamine did not reacted with ester 2
under any of the conditions utilized.
tert-Butyl 4,5-Dichloroisothiazole-3-carboxylate (2)
In a flask were placed anhyd t-BuOH (3.76 g, 50.8 mmol) and pyri-
dine (4.02 g, 50.8 mmol) in anhyd Et2O (30 mL). 4,5-Dichloro-
isothiazole-3-carbonyl chloride (10 g, 46 mmol) in anhyd Et2O (60
mL) was added dropwise to the stirred soln. When the addition was
complete, the mixture was stirred at r.t. for 4 h. The mixture was fil-
tered and the precipitate was washed with Et2O (3 × 25 mL). The
combined Et2O solns were washed with successive portions of 1 M
H2SO4 until free of pyridine, then with 1 M Na2CO3 (2 × 20 mL),
and dried (Na2CO3). After removal of the Et2O and distillation of
the residue at reduced pressure (95–98 °C/1.33 mbar) the product 2
(9.1 g, 77%) was obtained.
5-(Alkylamino)- and 5-(Dialkylamino)-Substituted tert-Butyl 4-
Chloroisothiazoles 3a–k; General Procedures
Method A: A soln of 2 (0.30 g, 1.18 mmol) and amine (3.54 mmol)
in DMSO (3 mL) was stirred at 80 °C for 24 h; excess H2O (~30
mL) was added. The precipitate was filtered and dried.
Method B: A soln of 2 (0.30 g, 1.18 mmol), amine (3.54 mmol), and
KF (0.40 g, 7.08 mmol) in DMSO (3 mL) was stirred at 80 °C for
12 h; excess H2O (~30 mL) was added. The aqueous layer was ex-
tracted with CH2Cl2 (3 × 30 mL) and the combined organic extracts
were washed with brine (30 mL), dried (MgSO4), and concentrated
in vacuo. The product was isolated by column chromatography (sil-
ica gel, hexane–EtOAc, 95:5).
Method C: A soln of 2 (0.30 g, 1.18 mmol), amine (3.54 mmol), and
CsF (1.07 g, 7.08 mmol) in DMSO (3 mL) was stirred at 60 °C for
12 h; excess H2O (~30 mL) added. The aqueous layer was extracted
with CH2Cl2 (3 × 30 mL) and the combined organic extracts were
washed with brine (30 mL), dried (MgSO4), and concentrated in
vacuo. The product was isolated by column chromatography (silica
gel, hexane–EtOAc, 95:5).
Method D: A soln of 2 (0.30 g, 1.18 mmol), amine (3.54 mmol), and
In conclusion, it was shown that amines substitute the KF (0.40 g, 7.08 mmol) in NMP (3 mL) was stirred at 80 °C for 12
h; excess H2O (~30 mL) was added. The aqueous layer was extract-
ed with CH2Cl2 (3 × 30 mL) and the combined organic extracts
chlorine atom at C5 in 4,5-dichloroisothiazole-3-carboxy-
late regioselectively, with no corresponding amide forma-
were washed with brine (30 mL), dried (MgSO4), and concentrated
tion. It was observed that the amine activity decreases as
shown in Scheme 2.
in vacuo. The product was isolated by column chromatography (sil-
ica gel, hexane–EtOAc, 95:5).
tert-Butyl 4-Chloro-5-(piperidin-1-yl)isothiazole-3-carboxylate
(3a)
Mp 77–79 °C.
NH
>
>
RNHMe
>
NH
>
RNH2
RNHR
X
n
n = 1, 2
X = O, NH
IR (KBr): 3007, 2972, 2937, 2850, 1725, 1519, 1410, 1367, 1245,
1158, 986, 855, 643 cm–1.
Scheme 2 Relative amine activity in nucleophilic aromatic substi-
tution
1H NMR: d = 1.56 (m, 11 H), 1.7 (m, 4 H), 3.26 (t, J = 4.8 Hz, 4 H).
13C NMR: d = 23.75, 25.25, 28.19, 52.21, 83.15, 107.94, 156.52,
159.98, 173.51.
Considering firstly the similar yields of products for pri-
mary alkylamines and the more basic N-methylalkyl-
amines and secondly the dramatically decrease in yield for
dibutylamine, we suggested that amine activity depends
on the availability of the nitrogen atom.
GC-MS (EI, 70 eV): m/z = 302 [M]+, 246, 229, 84, 57.
Anal. Calcd for C13H19ClN2O2S: C, 51.56; H, 6.32; Cl, 11.71; N,
9.25; S, 10.59. Found: C, 51.49; C, 6.41; Cl, 11.65; N, 9.20; S,
10.50.
tert-Butyl 4-Chloro-5-(pyrrolidin-1-yl)isothiazole-3-carboxy-
late (3b)
Mp 40–41 °C.
All amines were purchased from Aldrich and used without further
purification. DMF was dried by distillation over P2O5. DMSO and
NMP was dried by distillation over CaH2. Alkali metal fluorides
were heated at 200 °C in vacuo for 2 h prior to use. Melting points
were determined on Boetius heating table. IR spectra was recorded
on a Nicolet Protégé spectrophotometer, using KBr discs. NMR
spectra were recorded on a Bruker Avance-500 spectrometer in
CDCl3 at 500 MHz for 1H NMR and 125 MHz for 13C NMR. GC-
IR (KBr): 2977, 2931, 2881, 2849, 1719, 1548, 1429, 1246, 1159,
1004, 848, 638 cm–1.
1H NMR: d = 1.56 (s, 9 H), 1.96 (t, J = 6.6 Hz, 4 H), 3.51 (t, J = 6.6
Hz, 4 H).
Synthesis 2009, No. 14, 2361–2364 © Thieme Stuttgart · New York

PAPER
Fluoride-Mediated Synthesis of 5-Amino-Substituted Isothiazoles
2363
13C NMR: d = 25.71, 28.19, 51.66, 82.91, 101.2, 156.2, 160.25,
168.07.
Anal. Calcd for C14H23ClN2O2S: C, 52.73; H, 7.27; Cl, 11.12; N,
8.79; S, 10.06. Found: C, 52.63; C , 7.38; Cl, 11.06; N, 8.75; S, 9.93.
GC-MS (EI, 70 eV): m/z = 288 [M]+, 232, 215, 70, 57.
tert-Butyl 4-Chloro-5-(isopropylamino)isothiazole-3-carboxy-
late (3g)
Mp 102–104 °C.
Anal. Calcd for C12H17ClN2O2S: C, 49.91; H, 5.93; Cl, 12.28; N,
9.70; S, 11.10. Found: C, 49.85; C, 6.23; Cl, 12.11; N, 9.67; S,
11.06.
IR (KBr): 3288, 2975, 2932, 2870, 1720, 1553, 1423, 1397, 1368,
1255, 1158, 1013, 860, 841 cm–1.
tert-Butyl 4-Chloro-5-(morpholin-4-yl)isothiazole-3-carboxy-
late (3c)
Mp 78–90 °C.
1H NMR: d = 1.27 (d, J = 6.3 Hz, 6 H), 1.56 (s, 9 H), 3.39 (oct,
J = 6.5 Hz, 1 H), 4.73 (d, J = 7.4 Hz, 1 H).
IR (KBr): 2991, 2972, 2937, 2858, 2828, 1716, 1508, 1411, 1366,
1274, 1237, 1156, 1116, 1050, 946, 888, 855, 647, 553 cm–1.
13C NMR: d = 22.61, 28.2, 49.98, 83.01, 84.16, 102.87, 146.62,
154.16, 159.57, 167.65.
1H NMR: d = 1.6 (s, 9 H), 3.31 (t, J = 4.7 Hz, 4 H), 3.85 (t, J = 4.7
Hz, 4 H).
GC-MS (EI, 70 eV): m/z = 276 [M]+, 220, 205, 178, 57, 43.
Anal. Calcd for C11H17ClN2O2S: C, 47.73; H, 6.19; Cl, 12.81; N,
10.12; S, 11.58. Found: C, 47.61; C, 6.25; Cl, 12.75; N, 10.09; S,
11.55.
13C NMR: d = 28.2, 50.92, 66.19, 83.45, 156.74, 159.71, 172.86.
GC-MS (EI, 70 eV): m/z = 304 [M]+, 248, 231, 190, 57.
Anal. Calcd for C12H17ClN2O3S: C, 47.29; H, 5.62; Cl, 11.63; N,
9.19; S, 10.52. Found: C, 47.15; C, 5.79; Cl, 11.58; N, 9.15; S,
10.47.
tert-Butyl 5-(tert-Butylamino)-4-chloroisothiazole-3-carboxy-
late (3h)
Mp 119–120 °C.
IR (KBr): 3288, 2974, 2927, 1723, 1539, 1417, 1367, 1254, 1222,
1157, 1012, 846, 644 cm–1.
tert-Butyl 4-Chloro-5-(piperazin-1-yl)isothiazole-3-carboxylate
(3d)
Mp 76–77 °C.
1H NMR: d = 1.36 (s, 9 H), 1.58 (s, 9 H), 4.85 (br s, 1 H).
IR (KBr): 3343, 2972, 2820, 2749, 1732, 1526, 1434, 1366, 1242,
1155, 1058, 989, 842, 807, 645 cm–1.
13C NMR: d = 28.20, 28.69, 53.27, 83.06, 104.86, 153.17, 159.67,
165.10.
1H NMR: d = 1.59 (s, 9 H), 1.84 (br s, 1 H), 3.96 (t, J = 4.9 Hz, 4
H), 3.28 (t, J = 4.9 Hz, 4 H).
GC-MS (EI, 70 eV): m/z = 290 [M]+, 234, 178, 57.
Anal. Calcd for C12H19ClN2O2S: C, 49.56; H, 6.59; Cl, 12.19; N,
9.63; S, 11.03. Found: C, 49.41; C, 6.70; Cl, 12.01; N, 9.59; S,
10.93.
13C NMR: d = 28.2, 45.42, 51.93, 83.32, 108.53, 156.67, 159.86,
173.21.
GC-MS (EI, 70 eV): m/z = 303 [M]+, 205, 168, 56.
tert-Butyl 5-[Benzyl(methyl)amino]-4-chloroisothiazole-3-car-
boxylate (3i)
IR (film): 3029, 2979, 2931, 1727, 1537, 1453, 1410, 1393, 1368,
1247, 1158, 997, 851, 732, 698 cm–1.
Anal. Calcd for C12H18ClN3O2S: C, 47.44; H, 5.97; Cl, 11.67; N,
13.83; S, 10.55. Found: C, 47.15; C, 6.13; Cl, 11.52; N, 13.88; S,
10.41.
1H NMR: d = 1.59 (s, 9 H), 2.9 (s, 3 H), 4.6 (s, 2 H), 7.24–7.31 (m,
5 H).
tert-Butyl 5-(Benzylamino)-4-chloroisothiazole-3-carboxylate
(3C)
Mp 117–118 °C.
13C NMR: d = 28.24, 41.02, 58.02, 83.15, 105.26, 128.04, 128.85,
136.12, 156.74, 160.08, 172.02.
IR (KBr): 3199, 2973, 2930, 1725, 1555, 1422, 1351, 1243, 1158,
1092, 1064, 1007, 851, 743, 697 cm–1.
GC-MS (EI, 70 eV): dec.
1H NMR: d = 1.59 (s, 9 H), 4.39 (d, J = 5.5 Hz, 2 H), 5.45 (br s, 1
H), 7.34 (m, 5 H).
Anal. Calcd for C16H19ClN2O2S: C, 56.71; H, 5.65; Cl, 10.46; N,
8.27; S, 9.46. Found: C, 56.20; H, 5.74; Cl, 10.38; N, 8.25; S, 9.40.
13C NMR: d = 28.22, 41.03, 51.47, 83.2, 103.54, 127.88, 128.5,
129.10, 135.93, 154.09, 159.62, 168.56.
tert-Butyl 5-[Butyl(methyl)amino]-4-chloroisothiazole-3-car-
boxylate (3j)
GC-MS (EI, 70 eV): dec.
IR (film): 2960, 2932, 2872, 1728, 1540, 1456, 1412, 1393, 1368,
1319, 1246, 1159, 1080, 1001, 990, 851, 771, 732 cm–1.
Anal. Calcd for C15H17ClN2O2S: C, 55.46; H, 5.28; Cl, 10.91; N,
8.62; S, 9.87. Found: C, 55.32; C, 5.68; Cl, 10.81; N, 8.64; S, 9.71.
1H NMR: d = 0.81 (s, 3 H), 1.22 (m, 2 H), 1.49 (m, 11 H), 2.94 (s,
3 H), 3.35 (m, 2 H).
tert-Butyl 4-Chloro-5-(hexylamino)isothiazole-3-carboxylate
(3f)
Mp 48–50 °C.
13C NMR: d = 13.88, 19.86, 28.01, 29.38, 41.39, 54.71, 82.96,
103.25, 156.78, 160.18, 171.35.
GC-MS (EI, 70 eV): m/z = 304 [M]+, 248, 231, 205, 57, 44.
IR (KBr): 3279, 2978, 2950, 2928, 2855, 1719, 1560, 1420, 1369,
1235, 1157, 848 cm–1.
Anal. Calcd for C13H21ClN2O2S: C, 51.22; H, 6.94; Cl, 11.63; N,
9.19; S, 10.52. Found: C, 51.01; H, 7.05; Cl, 11.59; N, 9.17; S,
10.48.
1H NMR: d = 0.85 (t, J = 6.8 Hz, 3 H), 1.25–1.37 (m, 6 H), 1.56 (s,
9 H), 1.64 (q, J = 7.3 Hz, 2 H), 3.15 (m, 2 H), 4.9 (t, J = 5.3 Hz, 1
H).
13C NMR: d = 14.06, 22.59, 26.51, 28.18, 29.11, 31.44, 82.99,
102.68, 154.29, 159.60, 169.02.
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GC-MS (EI, 70 eV): m/z = 318 [M]+, 262, 191, 57.
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Y. S. Zubenko, V. I. Potkin
PAPER
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Synthesis 2009, No. 14, 2361–2364 © Thieme Stuttgart · New York