One-pot synthesis of new 2,4,5-trisubstituted 1,3-thiazoles and 1,3-selenazoles

Article abstract of DOI:10.1016/j.tet.2009.01.104

In this work, we describe the synthesis of new 2,4,5-trisubstituted-1,3-thiazoles and 1,3-selenazole achieved by an easy one-pot four-step procedure. Expected compounds were obtained in good yield from dimethyl cyanodithioimidocarbonate, which was the com

Full text of DOI:10.1016/j.tet.2009.01.104

Tetrahedron 65 (2009) 2982–2988
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One-pot synthesis of new 2,4,5-trisubstituted 1,3-thiazoles and 1,3-selenazoles
a
a
a
a
b
´
David Thomae , Enrico Perspicace , Zhanjie Xu , Dorothee Henryon , Serge Schneider ,
a
a,
c
*
´
Stephanie Hesse , Gilbert Kirsch , Pierre Seck
a
´
´
Laboratoire d’Ingenierie Moleculaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843, 1 Boulevard Arago, 57070 Metz, France
b Laboratoire National de Sante´, Division de Toxicologie, Universite´ de Luxembourg, 162a, avenue de la Fa¨ıencerie, L-1511 Luxembourg, Grand-Duche´ de Luxembourg
c Laboratoire de Chimie, Faculte´ des Sciences, de la Technologie et de la Communication, Universite´ du Luxembourg, 162a, avenue de la Fa¨ıencerie,
L-1511 Luxembourg, Grand-Duche´ de Luxembourg
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work, we describe the synthesis of new 2,4,5-trisubstituted-1,3-thiazoles and 1,3-selenazole
achieved by an easy one-pot four-step procedure. Expected compounds were obtained in good yield from
dimethyl cyanodithioimidocarbonate, which was the common starting material for the preparation of all
1,3-thiazoles and 1,3-selenazoles. Chemical diversity was introduced on thiazole and selenazole rings by
varying the amines and the activated halides used.
Received 28 November 2008
Received in revised form 27 January 2009
Accepted 29 January 2009
Available online 5 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Substituted 4-amino-1,3-thiazoles
Substituted 4-amino-1,3-selenazoles
Dimethyl cyanodithioimidocarbonate
N
N
S
1. Introduction
R
n
NH2
CN
CN
Thiazole is an important scaffold in heterocyclic chemistry and
1,3-thiazole ring is present in many pharmacological active sub-
stances.1 For example thiazole-5-ylacetic acid derivatives have
strong anti-inflammatory activity.2 It has also been shown that
1,3-benzothiazoles derivatives are histamine H3 antagonists.3
Imidazo[2,1-b]thiazole moiety has versatile biological properties
NH2
N
N
N
R
MeS
SMe
S
N
S
N
N
R
R = MeS, 4-morpholinyl-, 1-pyrolidinyl-
R1
depending on the substituents. Substituted by
a 2,4,6-tri-
Scheme 1. Synthesis of thiazolopyridines and thiazolotriazines.
chlorophenyl group, this compound has herbicidal activity.4
Imidazo[2,1-b]thiazole guanylhydrazones showed antitumoral
activity.5 Recently, imidazo[2,1-b]thiazoles substituted by dihydro-
pyridines showed selective cardiodepressant activity.6
2. Results and discussion
There are many pathways to synthesize substituted 2-amino-
1,3-thiazoles. Thiourea is a convenient starting material to prepare
2-amino-1,3-thiazoles.9 For 1,3-thiazoles substituted by a primary
amine in position 2, Gewald et al. used cyanamide, an iso-
thiocyanate, and an activated halide.10 Another efficient strategy is
to choose amidino-thiourea as starting material.1a,11 1,3-Oxathio-
lium cation can afford 1,3-thiazoles substituted in position 2 by
a secondary amine but it is not the easiest way to obtain this class of
compounds.2b SNAr reactions with secondary amine on 2-(methyl-
sulfanyl)-1,3-thiazole derivatives are well described.3,12
One major field of investigation of our team is the synthesis
of heterocyclic compounds with potential biological activity.7
In a previous work, we described the synthesis of thiazolo-
pyridines and thiazolotriazines from substituted 4-amino-1,3-
thiazole-5-carbonitriles (Scheme 1).8 These useful starting
materials were prepared by a new sequential reaction from
dimethyl cyanodithioimidocarbonate. In this work, we extended
this method to five activated halides and we have optimized
the conditions to obtain new substituted 3-amino-1,3-thiazoles
and selenazoles.
In a previous work,8 we took advantage of the good leaving
group property of the methylsulfanyl group of 4-amino-2-(methyl-
sulfanyl)-1,3-thiazole-5-carbonitrile 2. Our synthesis began with
the preparation of dimethyl cyanodithioimidocarbonate 1 from
cyanamide as described in the literature.13 Compound 1 was
* Corresponding author. Tel.: þ33 3 87 31 52 95; fax: þ33 3 87 31 58 01.
E-mail address: kirsch@univ-metz.fr (G. Kirsch).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.104

D. Thomae et al. / Tetrahedron 65 (2009) 2982–2988
Method B
2983
engaged in a one-pot three-step procedure and was reacted suc-
cessively with sodium sulfide, chloroacetonitrile, and potassium
carbonate. Finally, SNAr on thiazole 2 with secondary amines
allowed the formation of thiazoles 3–5 in good yields (Scheme 2).
1) HNR1R2
DMF
2) Na2S.9H2O
3) BrCH2CO2Et (2 eq.)
4) K2CO3
NH2
CO2Et
CN
N
N
R1
N
R2
S
SMe
MeS
NH2
CN
S
6-8
i, ii, iii
N
iv, v, vi
N
1
NH2CN
S
CN
S
S
Method C
1
71%
2
85%
NH2
CO2Et
1) HNR1R2
CN
N
vii
N
MeS
1
DMF
R1
N
S
2) HSCH2CO2Et (1eq.)
R2
K2CO3
SMe
3
4
5
90% R1-R2 = 4-morpholinyl-
95% R1-R2 = 1-pyrolidinyl-
74%R1-R2= 1-piperidinyl-
NH2
CN
6-8
N
S
R1
N
R2
Scheme 4. Synthesis of ethyl 4-amino-1,3-thiazole-5-carboxylates.
Scheme 2. Synthesis of thiazoles 3–5 via SNAr reaction on thiazole 2 (Method A).
Reagents and conditions: (i) KOH; (ii) CS2; (iii) MeI; (iv) Na2S$9H2O, DMF; (v) ClCH2CN;
(vi) K2CO3; (vii) R1R2NH.
Here, we completed our study on this one-pot four-step pro-
cedure in order to optimize it and extend it to other activated ha-
lides. Indeed, we performed this reaction with 1, 2 or 3 equiv of
chloroacetonitrile (Table 1). When 1 equiv of chloroacetonitrile was
added, no reaction was observed by TLC with the sodium salt of
cyanoimidothiocarbamate. So we repeated the reaction adding
2 equiv of chloroacetonitrile and expected products 3–5 were
obtained in good yields (49–67%, Table 1). Using 3 equiv of chloro-
acetonitrile, the yields were improved (69–78%, Table 1).
In the same work, we have also used a one-pot four-step pro-
cedure to synthesize thiazoles 3–5 starting from 1. Dimethyl cya-
nodithioimidocarbonate was dissolved in DMF, then the secondary
amine was added and heated at 70 ꢀC for 1 h. After this time, so-
dium sulfide was added to form the thiolate that reacted with
chloroacetonitrile and finally, potassium carbonate was added to
complete the cyclization (Scheme 3).
CN
Table 2
CN
N
CN
N
+
Synthesis of ethyl 4-amino-1,3-thiazole-5-carboxylates
N
HNR1R2
Na2S.9H2O
90 min
R1
R1
N
R2
Na
S
MeSH
N
R2
SMe
Compound
Compound no.
Yield (%)
DMF
1h, 70 °C
+
SMe
MeS
Method B
Method C
50
70 °C
MeSH
MeS
Na
1
NH2
CO2Et
N
ClCH2CN
2 or 3 eq.
2h, 50 °C
6
7
77
71
N
S
O
NH2
CO2Et
NH2
CN
CN
N
N
N
65
49
K2CO3
1h, 50 °C
R1
R1
N
N
R2
S
CN
S
N
R2
S
NH2
CO2Et
3-5
N
Scheme 3. Method B: one-pot four-step sequential procedure.
8
74
N
S
Table 1
Synthesis of substituted 4-amino-5-cyano-1,3-thiazoles, comparison of Methods A and B
Compound
Compound no.
Method A
Method B
Yield SNAr (%)
Overall yield
Yield (%)
Yield (%)
from 1 (%)
(2 equiv ClCH2CN)
(3 equiv ClCH2CN)
NH2
CN
NH2
N
3
90
77
57
78
N
S
O
N
4
5
95
74
81
63
67
49
76
69
CN
N
S
NH2
N
CN
N
S

2984
Method B
D. Thomae et al. / Tetrahedron 65 (2009) 2982–2988
CN
Se
CN
N
CN
N
+
CN
S
N
HNR1R2
Na2Se
R1
CN
N
R1
N
R2
Na
CN
N
+
N
R2
SMe
+
DMF
1h, 70 °C
N
20 min
70 °C
Na2S.9H2O
90 min
HNR1R2
DMF
1h, 70 °C
R1
MeS
SMe
R1
MeSH
N
Na
N
R2
SMe
+
MeSH
MeS
SMe
R2
MeS
Na
MeSH
1
70 °C
MeSH
MeS
Na
1
X-CH2-EWG
2-3 eq.
2h, 70 °C
X-CH2-EWG
2 eq.
2h, 50 °C
NH2
CN
N
N
K2CO3
1h, 70 °C
NH2
CN
R1
R1
N
EWG
N
R2
Se EWG
N
R2
N
K2CO3
Se
21-28
R1
R1
EWG
N
R2
S
EWG
N
R2
1h, 50 °C
S
X =Cl, Br
EWG = CN, CO2Et, Ac-, -NO2, Bz-, 4-Cl-Ph-CO-
9-20
X =Cl, Br
EWG = Ac-, -NO2, Bz-, 4-Cl-Ph-CO-
Scheme 6. Synthesis of substituted ethyl 2,4,5-trisubstituted-1,3-selenazoles: one-pot
four-step sequential procedure.
Scheme 5. Synthesis of substituted ethyl 2,4,5-trisubstituted-1,3-thiazoles: one-pot
four-step sequential procedure.
As we presumed, the one-pot four-step sequential procedure
could be applied to different activated halides and allowed the
access to new 2,4,5-trisubstituted 1,3-thiazoles (Scheme 5). In all
cases, the best results were obtained adding 2 equiv of reagent
(Table 3). When 1 equiv of activated halide was added, no reaction
was observed by TLC with the sodium salt of cyanoimidothio-
carbamate. When 3 equiv were used, a mixture of the 1,3-thiazole
and a viscous material was obtained after the work-up. The re-
crystallization was more difficult to realize and the isolated yields
were lower. These experiments showed that methylthiolate is more
nucleophilic than the intermediate sodium salt of cyanoimido-
thiocarbamate and reacts faster with all these activated halides.
In comparison with the literature, this one-pot four-step pro-
cedure presents some improvements and advantages. The yields
that we obtained are very good and our method is one step shorter
than the SNAr way. Moreover, there is only one example of solid
phase synthesis to access 2,4,5-trisubstituted 1,3-thiazoles in a one-
pot four-step reaction.15 Here we obtained better yields and sodium
sulfide allowed the use of various activated halides and the access
to 4-amino-1,3-thiazoles substituted in position 5 with interesting
These experiments showed that chloroacetonitrile reacted first
with sodium methylthiolate, which is more nucleophilic than the
intermediate.
We extended this method to ethyl bromoacetate. The mecha-
nism of the reaction (Method B, Scheme 4) is similar to the previous
one shown in Scheme 3. The best results were obtained adding
2 equiv of ethyl bromoacetate. The expected compounds 6–8 were
obtained in good yields (71–77%, Table 2). An alternative to the
combination of sodium sulfide/activated halide was to use ethyl
thioglycolate (Method C, Scheme 4). Dimethyl cyanodithioimido-
carbonate 1 was heated for 1 h with secondary amine and then
ethyl thioglycolate and potassium carbonate were added and
heated for 3 h. The expected compounds 6–8 were obtained with
good yields (49–65%, Table 2). However the best yields were
obtained using sodium sulfide. Moreover, we extended this
reaction using other activated halides like chloroacetone, bromo-
nitromethane,14 chloroacetophenone, and
phenone (Scheme 5).
u-bromo-p-chloroaceto-
Table 3
Synthesis of 2,4,5-trisubstituted-1,3-thiazoles
Compound
–NR1R2
Activated halide used
Compound no.
Yield (%)
NH2
4-Morpholinyl-
1-Pyrolidinyl-
1-Piperidinyl-
9
10
11
51
75
85
N
R1
Chloroacetone (2 equiv)
N
S
O
R2
NH2
4-Morpholinyl-
1-Pyrolidinyl-
1-Piperidinyl-
12
13
14
65
72
70
N
R1
Bromonitromethane (2 equiv)
Chloroacetophenone (2 equiv)
NO2
N
S
R2
NH2
O
4-Morpholinyl-
1-Pyrolidinyl-
1-Piperidinyl-
15
16
17
76
82
87
N
Ph
R1
N
S
R2
4-Morpholinyl-
1-Pyrolidinyl-
1-Piperidinyl-
18
19
20
48
65
76
Cl
NH2
N
u
-Bromo-p-chloroacetophenone (2 equiv)
R1
N
R2
S
O

D. Thomae et al. / Tetrahedron 65 (2009) 2982–2988
2985
Table 4
Synthesis of 2,4,5-trisubstituted-1,3-selenazoles
Compound
EWG
Halide used
Compound no.
Yield (%)
NH2
EWG
-CN
-Ac
-Ac
Chloroacetonitrile (3 equiv)
Chloroacetone (2 equiv)
Chloroacetone (3 equiv)
21
22
22
23
55
28
36
32
N
N
Se
NH2
EWG
O
-NO2
Bromonitromethane (2 equiv)
N
-CN
-CO2Et
Chloroacetonitrile (3 equiv)
Ethyl bromoacetate (2 equiv)
24
25
70
52
N
Se
-CN
-Bz
Chloroacetonitrile (3 equiv)
Chloroacetophenone (2 equiv)
u-Bromo-p-chloroacetophenone (2 equiv)
26
27
28
67
41
50
NH2
EWG
N
-4-chlorobenzoyl
N
Se
functional groups such as cyano, ester, acetyl, nitro, and benzoyl
group. We then extended this method to the preparation of 2,4,5-
trisubstituted-1,3-selenazoles.
operated in EI mode at 70 eV and MS spectra were recorded from
m/z 50 to 650. HMRS were collected on a Bruker MICROTOF-Q ESI/
QqTOF spectrometer.
In the literature, 2-amino-1,3-selenazoles were synthesized
from selenourea and
Syntheses of compounds 1–5 are described in Ref. 8.
a
-chloroketones.16 Ketones like cyclohexa-
none or deoxybenzoin were reacted in presence of selenourea and
iodine and afforded 4,5-disubstituted 2-amino-1,3-selenazoles.17
From dimethyl dicyanothioimidocarbonate 1, we obtained in one-
pot new 2,4,5-trisubtituted-1,3-selenazoles (Scheme 6).
4.2. Synthesis of 2,4,5-trisubstituted-1,3-thiazoles
4.2.1. General method
Method B: Dimethyl cyanodithioimidocarbonate 1 (0.01 mol)
was dissolved in DMF (15 mL). The secondary amine (0.01 mol) was
added and the mixture was heated at 70 ꢀC for 1 h. Then,
Na2S$9H2O (0.01 mol) was added and heated for 90 min at 70 ꢀC.
Activated halide (0.02–0.03 mol) was added dropwise at 50 ꢀC (0 ꢀC
for bromonitromethane). The mixture was heated at 50 ꢀC for 2 h
and potassium carbonate was added (0.01 mol). The reaction was
stirred at 50 ꢀC for 1 h more. The mixture was poured onto water
(100 mL) with good stirring. When a precipitate appeared, it was
filtered, washed with water, and dried at room temperature until
constant weight. When a viscous mixture appeared, 25 mL of ether
was added and the precipitate was filtered, washed with water, and
dried at room temperature until constant weight. The isolated solid
was purified by recrystallization in ethanol or acetonitrile.
Method C: Dimethyl cyanodithioimidocarbonate 1 (0.01 mol)
was dissolved in DMF (15 mL). The secondary amine (0.01 mol) was
added and the mixture was heated at 70 ꢀC for 1 h. Then ethyl
thioglycolate (0.01 mol) and potassium carbonate (0.01 mol) were
added and heated for 3 h at 70 ꢀC. The mixture was poured onto
water (100 mL) with good stirring. The precipitated was filtered,
washed with water and dried at room temperature until constant
weight, and purified by recrystallization in ethanol.
Compound 1 was heated at 70 ꢀC for 1 h with a secondary amine
to form the first intermediate (Scheme 6). Sodium selenide was
prepared freshly, filtered under argon atmosphere and was added
to the reaction mixture at 70 ꢀC to form the intermediate seleno-
late. After 20 min, activated halide (2–3 equiv) was added dropwise
and stirred for 2 h more. Cyclization was performed by addition of
potassium carbonate. Pouring the reaction mixture in water gave
the compounds 21–28 as solids in moderate to good yields (Table
4). As for the preparation of 1,3-thiazoles 3–20, we had to use at
least 2 equiv of activated halide to isolate 2,4,5-trisubtituted-1,3-
selenazoles 21–28.
3. Conclusion
Here we demonstrated that our sequential procedure is very
convenient for the synthesis of 2,4,5-trisubstituted-1,3-thiazoles
and 1,3-selenazoles. We determined the conditions to obtain
expected compounds in good yields. This method is shorter than
the SNAr pathway. Another advantage is that dimethyl dicyano-
thioimidocarbonate 1 was obtained easily and in good yield from
cyanamide and was the same starting material for the preparation
of all thiazoles and selenazoles. If we use this reaction on ketene
dithioacetals, we will have access to tetra-substituted thiophenes
and selenophenes, this work will be reported in due course.
4.2.2. Ethyl 4-amino-2-(4-morpholinyl)-1,3-thiazole-5-
carboxylate (6)
Yield: 77% (Method B); 50% (Method C). Colorless solid; mp
4. Experimental section
4.1. General
132 ꢀC. IR: 3419, 3309, 3205, 1658, 1626, 1514 cmꢁ1 1H NMR
.
(250 MHz, DMSO-d6):
2ꢂCH2), 3.66 (m, 4H, 2ꢂCH2), 4.08 (q, 2H, CH2, J¼7.1 Hz), 6.80 (br s,
2H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
14.58, 47.20, 58.70,
d
1.18 (t, 3H, CH3, J¼7.1 Hz), 3.43 (m, 4H,
d
Melting points were determined on a Stuart SMP3 apparatus
and are uncorrected. IR spectra were performed on a Perkin–Elmer
FT-IR Baragon 1000PC equipped with a Graseby-Specac golden gate
and treated with the Spectrum (Perkin–Elmer) software version
65.22, 163.14, 163.29, 169.42, 170.46. GC–MS (EI, 70 eV): m/z (%):
257 (100), 229 (14), 212 (20), 185 (30), 113 (26), 69 (12). HRMS calcd
for C10H16N3O3S [MþH]þ 258.0907, found 258.0909.
5.3.1. 1H and 13C NMR spectra (
d
in ppm) were recorded on an AC
4.2.3. Ethyl 4-amino-2-(1-pyrrolidinyl)-1,3-thiazole-5-
carboxylate (7)
Bruker 250 MHz spectrometer in CDCl3 or DMSO-d6. MS spectra
were recorded on an Agilent Technologies GC–MS instrument
equipped with a 7683 injector, 6890N gas chromatograph and
a 5973 mass selective detector. The mass spectrometer was
Yield: 71% (Method B); 65% (Method C). Colorless solid; mp
200 ꢀC. IR: 3415, 3278, 3168, 3112, 1642, 1614, 1559 cmꢁ1. 1H NMR
(250 MHz, DMSO-d6):
d
1.17 (t, 3H, CH3, J¼7.1 Hz), 1.96 (m, 4H,

2986
D. Thomae et al. / Tetrahedron 65 (2009) 2982–2988
2ꢂCH2), 3.34 (m, 4H, 2ꢂCH2), 4.08 (q, 2H, CH2, J¼7.1 Hz), 6.81 (br s,
2H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
14.61, 25.01, 48.88,
58.51, 79.03, 121.43, 163.65, 166.73. GC–MS (EI, 70 eV): m/z (%): 241
(100), 213 (20), 196 (23), 185 (11), 169 (37), 97 (38), 72 (10), 23 (23).
HRMS calcd for C10H16N3O2S [MþH]þ 242.0958, found 242.0966.
NH2). 13C NMR (62.9 MHz, DMSO-d6):
d 21.32, 22.84, 24.87, 109.65,
160.56, 167.20. GC–MS (EI, 70 eV): m/z (%): 194 (100), 165 (55), 139
(26), 83 (39), 69 (19), 55 (37). HRMS calcd for C8H13N4O2S [MþH]þ
229.0754, found 229.0735.
d
4.2.11. 4-Amino-5-benzoyl-2-(4-morpholinyl)-1,3-thiazole (15)
Yield: 76% (Method B). Colorless solid; mp 181 ꢀC; lit. mp: 179–
181 ꢀC.2b IR: 3370, 3230, 3134, 1599, 1534 cmꢁ1. 1H NMR (250 MHz,
4.2.4. Ethyl 4-amino-2-(1-piperidinyl)-1,3-thiazole-5-
carboxylate (8)
Yield: 74% (Method B); 49% (Method C). Colorless solid; mp
DMSO-d6):
d
3.48 (m, 4H, 2ꢂCH2), 3.66 (m, 4H, 2ꢂCH2), 7.45 (m, 3H,
145 ꢀC. IR: 3418, 3299, 3195, 1638, 1612 cmꢁ1
.
1H NMR (250 MHz,
3ꢂCH), 7.61 (m, 2H, 2ꢂCH), 8.07 (br s, 2H, NH2). 13C NMR
DMSO-d6):
d
1.19 (t, 3H, CH3, J¼7.1 Hz),1.56 (m, 6H, 3ꢂCH2), 3.43 (br
(62.9 MHz, DMSO-d6): d 47.43, 65.25, 92.95, 126.60, 128.30, 130.71,
s, 4H, 2ꢂCH2), 4.05 (q, 2H, CH2, J¼7.1 Hz), 6.75 (br s, 2H, NH2). 13
C
141.87, 166.06, 171.79, 182.15. GC–MS (EI, 70 eV): m/z (%): 289 (100),
230 (15), 203 (15), 105 (20), 77 (24). HRMS calcd for C14H16N3O2S
[MþH]þ 290.0958, found 290.0955.
NMR (62.9 MHz, DMSO-d6):
d 14.61, 23.34, 24.68, 48.24, 58.54,
79.23, 163.34, 163.73, 169.86. GC–MS (EI, 70 eV): m/z (%): 255 (100),
183 (37), 111 (30). HRMS calcd for C11H18N3O2S [MþH]þ 256.1114,
found 256.1093.
4.2.12. 4-Amino-5-benzoyl-2-(1-pyrrolidinyl)-1,3-thiazole (16)
Yield: 82% (Method B). Yellow solid; mp 181 ꢀC. IR: 3289, 3135,
4.2.5. 5-Acetyl-4-amino-2-(4-morpholinyl)-1,3-thiazole (9)
1604, 1537 cmꢁ1 1H NMR (250 MHz, DMSO-d6):
. d 1.94 (m, 4H,
Yield: 51% (Method B). Yellow solid; mp: 174 ꢀC. IR: 3370, 3262,
2ꢂCH2), 3.45 (m, 4H, 2ꢂCH2), 7.45 (m, 3H, 3ꢂCH), 7.61 (m, 2H,
3160, 1606 cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
2.05 (s, 3H, CH3),
2ꢂCH), 8.25 (br s, 2H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
d 24.96,
3.46 (m, 4H, 2ꢂCH2), 3.67 (m, 4H, 2ꢂCH2), 7.60 (br s, 2H, NH2). 13
C
49.08, 93.11, 126.58, 128.66, 130.00, 142.01, 166.54, 168.18, 181.53.
GC–MS (EI, 70 eV): m/z (%): 273 (100), 196 (14), 97 (20), 77 (24).
HRMS calcd for C14H16N3OS [MþH]þ 274.1009, found 274.1069.
NMR (62.9 MHz, DMSO-d6):
d 28.66, 47.35, 65.24, 93.70, 163.68,
170.24, 184.58. GC–MS (EI, 70 eV): m/z (%): 227 (100), 212 (67), 184
(13),154 (16), 113 (24), 69 (12). HRMS calcd for C9H14N3O2S [MþH]þ
228.0801, found 228.0787.
4.2.13. 4-Amino-5-benzoyl-2-(1-piperidinyl)-1,3-thiazole (17)
Yield: 87% (Method B). Yellow solid; mp 160 ꢀC; lit. mp: 159–
160 ꢀC.2b IR: 3354, 3225, 3138, 1599, 1529 cmꢁ1. 1H NMR (250 MHz,
4.2.6. 5-Acetyl-4-amino-2-(1-pyrrolidinyl)-1,3-thiazole (10)
Yield: 75% (Method B). Yellow solid; mp 181 ꢀC. IR: 3315, 3171,
DMSO-d6):
d
1.60 (m, 6H, 3ꢂCH2), 3.48 (m, 4H, 2ꢂCH2), 7.44 (m, 3H,
1643, 1528 cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
1.93 (m, 4H,
2ꢂCH2), 1.98 (s, 3H, CH3), 3.38 (m, 4H, 2ꢂCH2), 7.65 (br s, 2H, NH2).
13C NMR (62.9 MHz, DMSO-d6):
24.99, 28.68, 49.04, 93.73, 164.22,
3ꢂCH), 7.61 (m, 2H, 2ꢂCH), 8.25 (br s, 2H, NH2). 13C NMR
(62.9 MHz, DMSO-d6):
d 23.31, 24.80, 48.54, 92.81, 126.92, 128.42,
d
130.02, 142.02, 166.52, 171.11, 181.71. GC–MS (EI, 70 eV): m/z (%):
287 (100), 105 (18), 77 (21). HRMS calcd for C15H18N3OS [MþH]þ
288.1165, found 288.1166.
166.59, 183.93. GC–MS (EI, 70 eV): m/z (%): 211 (100), 196 (87), 168
(23), 97 (36), 55 (23). HRMS calcd for C9H14N3OS [MþH]þ 212.0852,
found 212.0861.
4.2.14. 4-Amino-5-(4-chlorobenzoyl)-2-(4-morpholinyl)-1,3-
thiazole (18)
4.2.7. 5-Acetyl-4-amino-2-(1-piperidinyl)-1,3-thiazole (11)
Yield: 85% (Method B). Yellow solid; mp 173 ꢀC. IR: 3327, 3238,
Yield: 48% (Method B). Yellow solid; mp 135 ꢀC; lit. mp: 151–
3129, 1611, 1544 cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
1.58 (m, 6H,
3ꢂCH2), 2.02 (s, 3H, CH3), 3.47 (m, 4H, 2ꢂCH2), 7.60 (br s, 2H, NH2).
13C NMR (62.9 MHz, DMSO-d6):
23.34, 24.75, 28.64, 48.46, 93.49,
152 ꢀC.2b IR: 3366, 3272, 1614, 1535 cmꢁ1 1H NMR (250 MHz,
.
DMSO-d6):
d
3.45 (m, 4H, 2ꢂCH2), 4.37 (m, 4H, 2ꢂCH2), 7.52 (m, 2H,
d
2ꢂCH), 7.62 (m, 2H, 2ꢂCH), 8.15 (br s, 2H, NH2). 13C NMR (62.9 MHz,
164.10, 169.59, 184.10. GC–MS (EI, 70 eV): m/z (%): 225 (100), 210
(76), 196 (3). HRMS calcd for C10H16N3OS [MþH]þ 226.1009, found
226.1011.
DMSO-d6): d 47.48, 65.24, 92.85, 128.40, 128.56, 134.79, 140.50,
166.34, 171.76, 180.53. GC–MS (EI, 70 eV): m/z (%): 323 (100), 264
(15), 139 (25), 113 (23), 69 (13). HRMS calcd for C14H15ClN3O2S
[MþH]þ 324.0568, found 324.0585.
4.2.8. 4-Amino-2-(4-morpholinyl)-5-nitro-1,3-thiazole (12)
Yield: 65% (Method B). Brown solid; mp 219 ꢀC. IR: 3348, 3257,
4.2.15. 4-Amino-5-(4-chlorobenzoyl)-2-(1-pyrrolidinyl)-1,3-
thiazole (19)
3137, 1607, 1552 cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
3.56 (br s,
4H, 2ꢂCH2), 3.68 (br s, 4H, 2ꢂCH2), 8.20 (br s, 1H, NH2), 8.93 (br s,
1H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
44.00, 65.15, 109.72,
Yield: 65% (Method B). Yellow solid; mp 210 ꢀC. IR: 3271, 3145,
d
1594, 1542 cmꢁ1 1H NMR (250 MHz, DMSO-d6):
. d 1.95 (m, 4H,
160.16, 168.04. GC–MS (EI, 70 eV): m/z (%): 230 (100), 184 (38), 113
(69), 69 (33). HRMS calcd for C7H10N4O3SNa [MþNa]þ 253.0366,
found 253.0342.
2ꢂCH2), 3.50 (m, 4H, 2ꢂCH2), 7.52 (m, 2H, 2ꢂCH), 7.65 (m, 2H,
2ꢂCH), 8.25 (br s, 2H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
d 24.97,
49.16, 93.00, 128.36, 130.34, 133.97, 140.71, 166.79, 168.16, 179.90.
GC–MS (EI, 70 eV): m/z (%): 307 (100),196 (14),139 (22),111 (22), 97
(27), 55 (25). HRMS calcd for C14H14ClN3OS [MþH]þ 308.0619,
found 308.0603.
4.2.9. 4-Amino-5-nitro-2-(1-pyrrolidinyl)-1,3-thiazole (13)
Yield: 72% (Method B). Brown solid; mp 247 ꢀC. IR: 3401, 3104,
1620, 1571 cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
1.96 (m, 4H,
2ꢂCH2), 3.37 (m, 2H, CH2), 3.58 (m, 2H, CH2), 8.15 (br s, 1H, NH2),
8.94 (br s, 1H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
24.78, 49.18,
4.2.16. 4-Amino-5-(4-chlorobenzoyl)-2-(1-piperidinyl)-1,3-
thiazole (20)
d
109.87, 160.36, 164.77. GC–MS (EI, 70 eV): m/z (%): 214 (100), 140
(40), 97 (92), 72 (27), 55 (48). HRMS calcd for C7H11N4O2S [MþH]þ
215.0597, found 215.0601.
Yield: 76% (Method B). Yellow solid; mp 175 ꢀC. IR: 3336, 3253,
1592, 1538 cmꢁ1 1H NMR (250 MHz, DMSO-d6):
. d 1.57 (m, 6H,
3ꢂCH2), 3.48 (m, 4H, 2ꢂCH2), 7.50 (d, 2H, 2ꢂCH, J¼8.4 Hz), 7.65 (d,
2H, 2ꢂCH, J¼8.4 Hz), 8.25 (br s, 2H, NH2). 13C NMR (62.9 MHz,
4.2.10. 4-Amino-5-nitro-2-(1-piperidinyl)-1,3-thiazole (14)
DMSO-d6): d 23.29, 24.81, 48.60, 92.72, 128.34, 128.64, 133.97,
Yield: 70% (Method B). Brown solid; mp 220 ꢀC. IR: 3413, 3284,
139.62, 166.79, 171.06, 180.06. GC–MS (EI, 70 eV): m/z (%): 321
(100), 139 (25), 111 (40). HRMS calcd for C15H17ClN3OS [MþH]þ
322.0775, found 322.0791.
1624, 1566 cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
1.59 (m, 6H,
3ꢂCH2), 3.54 (m, 4H, 2ꢂCH2), 8.17 (br s, 1H, NH2), 8.86 (br s, 1H,

D. Thomae et al. / Tetrahedron 65 (2009) 2982–2988
2987
4.3. Preparation of sodium selenide
58.51, 163.40, 166.72, 167.07, 170.02. GC–MS (EI, 70 eV): m/z (%): 289
(100), 274 (0.5), 261 (12). HRMS calcd for C10H16N3O2Se [MþH]þ
290.0402, found 290.0400.
Selenium (0.01 mol) was added to
a solution of NaOH
(0.056 mol) and sodium formaldehyde sulfoxylate (0.024 mol) in
water (10 mL). After stirring for 1 h at 50 ꢀC, the white precipitate
was filtered under argon atmosphere and rapidly used for the next
step.
4.4.6. 4-Amino-2-(1-piperidinyl)-1,3-selenazole-5-carbonitrile (26)
Yield: 67%. Pale brown solid; mp 236 ꢀC. IR: 3362, 3201, 2170,
1641 cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
1.54 (m, 6H, 3ꢂCH2),
3.35 (m, 4H, 2ꢂCH2), 6.63 (br s, 2H, NH2). 13C NMR (62.9 MHz,
4.4. Synthesis of substituted 4-amino-1,3-selenazoles
DMSO-d6): d 23.32, 24.83, 48.52, 56.29, 116.77, 166.53, 170.29. GC–
MS (EI, 70 eV): m/z (%): 256 (100), 241 (4). HRMS calcd for
Dimethyl cyanodithioimidocarbonate 1 (0.01 mol) was dis-
solved in DMF (15 mL). The secondary amine (0.01 mol) was added
and the mixture was heated at 70 ꢀC for 1 h. Then, fresh sodium
selenide (0.01 mol) was added and heated for 20 min at 70 ꢀC.
Activated halide (0.02–0.03 mol) was added dropwise at 70 ꢀC (0 ꢀC
for bromonitromethane). The mixture was heated at 70 ꢀC for 2 h
and the potassium carbonate was added (0.01 mol). The reaction
was stirred at 70 ꢀC for 1 h more. The mixture was poured onto
water (100 mL) with good stirring. When a precipitate appeared, it
was filtered, washed with water, and dried at room temperature
until constant weight. When a viscous mixture appeared, the so-
lution was extracted with ether (3ꢂ25 mL). The organic layers were
dried with MgSO4, filtered, and evaporated. The isolated solid was
purified by recrystallization in acetonitrile.
C9H13N4Se [MþH]þ 257.0300, found 257.0301.
4.4.7. 4-Amino-5-benzoyl-2-(1-piperidinyl)-1,3-selenazole (27)
Yield: 41%. Green solid; mp 166 ꢀC. IR: 3637, 1598, 1527 cmꢁ1. 1H
NMR (250 MHz, DMSO-d6):
2ꢂCH2), 7.43 (m, 3H, 3ꢂCH), 7.60 (m, 2H, 2ꢂCH), 8.50 (br s, 2H,
NH2). 13C NMR (62.9 MHz, DMSO-d6):
23.21, 24.80, 48.54, 92.79,
d
1.57 (m, 6H, 3ꢂCH2), 3.48 (m, 4H,
d
126.60, 128.28, 130.03, 142.01, 166.51, 172.00, 181.71. GC–MS (EI,
70 eV): m/z (%): 335 (100). HRMS calcd for C15H18N3OSe [MþH]þ
336.0610, found 336.0619.
4.4.8. 4-Amino-5-(4-chlorobenzoyl)-2-(1-piperidinyl)-1,3-
selenazole (28)
Yield: 50%. Green solid; mp 167 ꢀC. IR: 3337, 1670, 1539 cmꢁ1. 1H
NMR (250 MHz, DMSO-d6):
2ꢂCH2), 7.48 (m, 2H, 2ꢂCH), 7.59 (m, 2H, 2ꢂCH), 8.45 (br s, 2H,
NH2). 13C NMR (62.9 MHz, DMSO-d6):
23.39, 24.82, 48.67, 93.22,
128.09, 128.36, 134.39, 140.63, 168.08, 171.89, 181.82. GC–MS (EI,
70 eV): m/z (%): 369 (100). HRMS calcd for C15H17ClN3OSe [MþH]þ
370.0220, found 370.0235.
d
1.57 (m, 6H, 3ꢂCH2), 3.49 (m, 4H,
4.4.1. 4-Amino-2-(4-morpholinyl)-1,3-selenazole-5-
carbonitrile (21)
d
Yield: 55%. Brown solid; mp 209 ꢀC. IR: 3344, 2178, 1658 cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
3.39 (m, 4H, 2ꢂCH2), 3.63 (m, 4H,
2ꢂCH2), 6.72 (br s, 2H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
d
47.36, 56.16, 65.26, 118.30, 166.21, 171.31. GC–MS (EI, 70 eV): m/z
(%): 258 (100), 243 (0.5). HRMS calcd for C8H11N4OSe [MþH]þ
Acknowledgements
259.0093, found 259.0085.
`
We thank the ‘Ministere de l’Education Nationale, de l’En-
4.4.2. 5-Acetyl-4-amino-2-(4-morpholinyl)-1,3-selenazole (22)
´
seignement Superieur et de la Recherche’ for a Ph.D. grant to D.T.
and E.P. We thank also the ‘Universite du Luxembourg’ for financial
support to P.S. We are grateful to Ms. Veronique Poddig for re-
cording NMR.
Yield: 28% (2 equiv of ClCH2COCH3); 36% (3 equiv of
´
ClCH2COCH3). Brown solid; mp 164 ꢀC. IR: 3252, 1588, 1526 cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d 2.04 (s, 3H, CH3), 3.46 (m, 4H,
2ꢂCH2), 3.67 (m, 4H, 2ꢂCH2), 7.62 (br s, 2H, NH2). 13C NMR
(62.9 MHz, DMSO-d6):
d 28.65, 47.35, 65.24, 93.71, 163.68, 170.23,
References and notes
184.57. GC–MS (EI, 70 eV): m/z (%): 275 (100), 260 (64), 246 (0.9).
HRMS calcd for C9H14N3OSe [MþH]þ 276.0246, found 276.0220.
1. (a) Masquelin, T.; Obrecht, D. Tetrahedron 2001, 57, 153; (b) Zabriskie, T. M.;
Mayne, C. L.; Ireland, C. M. J. Am. Chem. Soc. 1988, 110, 7919; (c) Hara, M.; Asano,
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1988, 110, 4365; (e) Metzger, J. V. Chemistry of Heterocyclic Compounds; Wiley:
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Derivatives; Potts, K. T., Ed.; Pergamon: New York, NY, 1984; Vol. 6; (g) Rosowsky,
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4.4.3. 4-Amino-2-(4-morpholinyl)-5-nitro-1,3-selenazole (23)
Yield: 32%. Orange solid; mp 249 ꢀC. IR: 3268, 2360, 1619, 1394,
1274 cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
3.33 (m, 4H, 2ꢂCH2),
3.67 (m, 4H, 2ꢂCH2), 8.45 (br s, 2H, NH2). 13C NMR (62.9 MHz,
DMSO-d6): d 65.15, 65.27, 109.99, 162.12, 168.73. GC–MS (EI, 70 eV):
m/z (%): 278 (93). HRMS calcd for C7H10N4O3SeNa [MþNa]þ
300.9810, found 300.9802.
4.4.4. 4-Amino-2-(1-pyrrolidinyl)-1,3-selenazole-5-
carbonitrile (24)
Yield: 70%. Brown solid; mp 302 ꢀC. IR: 3169, 2165, 1646 cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
1.94 (m, 4H, 2ꢂCH2), 3.36 (m, 4H,
2ꢂCH2), 6.60 (br s, 2H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
d
25.02, 49.11, 118.66, 165.47, 166.51, 166.97. GC–MS (EI, 70 eV): m/z
(%): 242 (100), 227 (0.5). HRMS calcd for C8H11N4Se [MþH]þ
243.0143, found 243.0144.
4.4.5. Ethyl 4-amino-2-(1-pyrrolidinyl)-1,3-selenazole-5-
carboxylate (25)
Yield: 52%. Brown solid; mp 199 ꢀC. IR: 3171, 1727, 1641 cmꢁ1. 1H
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2ꢂCH2), 3.41 (m, 4H, 2ꢂCH2), 4.06 (q, J¼7.5 Hz, 2H, CH2), 6.80 (br s,
2H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
14.61, 25.01, 48.87,
d
1.16 (t, J¼7.5 Hz, 3H, CH3), 1.94 (m, 4H,
d

2988
D. Thomae et al. / Tetrahedron 65 (2009) 2982–2988
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