Synthesis of substituted [1,3]thiazolo[4,5-b]pyridines and [1,3]thiazolo[4,5-d][1,2,3]triazines

Article abstract of DOI:10.1016/j.tet.2008.07.017

In this work, we described an easy preparation of substituted 4-amino-5-cyano-1,3-thiazoles. These compounds have been used as starting materials to obtain two classes of compounds. New substituted [1,3]thiazolo[4,5-e]pyridines were synthesized in one step via Friedl?nder reaction. Diazotation of 4-amino-5-cyano-1,3-thiazoles afforded 4-chloro[1,3]thiazolo[4,5-d][1,2,3]triazines in one step. The later was substituted by a secondary amine to obtain substituted 4-amino[1,3]thiazolo[4,5-d][1,2,3]triazines.

Full text of DOI:10.1016/j.tet.2008.07.017

Tetrahedron 64 (2008) 9309–9314
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted [1,3]thiazolo[4,5-b]pyridines and [1,3]thiazolo-
[4,5-d][1,2,3]triazines
a
a
a
a,
b
*
´
David Thomae , Enrico Perspicace , Stephanie Hesse , Gilbert Kirsch , Pierre Seck
a Laboratoire d’Inge´nierie Mole´culaire et Biochimie Pharmacologique, Institut Jean Barriol, FR CNRS 2843, 1 Boulevard Arago, 57070 METZ, France
b 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 described an easy preparation of substituted 4-amino-5-cyano-1,3-thiazoles. These
compounds have been used as starting materials to obtain two classes of compounds. New substituted
[1,3]thiazolo[4,5-e]pyridines were synthesized in one step via Friedla¨nder reaction. Diazotation of 4-
amino-5-cyano-1,3-thiazoles afforded 4-chloro[1,3]thiazolo[4,5-d][1,2,3]triazines in one step. The later
was substituted by a secondary amine to obtain substituted 4-amino[1,3]thiazolo[4,5-d][1,2,3]triazines.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 30 May 2008
Received in revised form 3 July 2008
Accepted 4 July 2008
Available online 10 July 2008
Keywords:
Alzheimer disease
Thiazole analogues of Tacrine
Substituted [1,3]thiazolo[4,5-d]-
[1,2,3]triazine
Substituted 4-amino-1,3-thiazole-5-
carbonitrile
Dimethyl cyanodithioimidocarbonate
1. Introduction
NH2
CN
N
N
S
N
R
R
n
Since a few years, we are interested in the many possibilities
that heterocyclic analogs of anthranilonitriles or anthraniloesters
allow. Especially, ortho-amino-cyano-thiophenes were used to
synthesize analogues of Tacrine,1,2 thienopyridinones,3 and thi-
enopyrimidinones.4 Several analogues of Tacrine synthesized in the
thiophene series are currently under biological investigation. As the
1,3-thiazole ring is also present in many pharmacological active
substances,5 we decided to extend our library of Tacrine analogues
to the thiazole series. Those new analogues could be obtained
starting from 4-amino-1,3-thiazole-5-carbonitrile. This interesting
starting material would also allow access to thiazolocondensed
heterocyclic systems like thiazolopyrimidines or thiazolotriazines
(Scheme 1).
S
NH2
N
N
S
N
N
R
N
N
R1
R
N
S
R1
Scheme 1. Targeted compounds starting from amino-cyano-thiazole.
the literature6 and usually, compound 2a is obtained from cyano-
dithiocarbamic acid methyl ester potassium salt and chloro-
acetonitrile.6a,c Here, we proposed an alternative route via
dimethyl cyanodithioimidocarbonate 1 (Scheme 2). As reported in
the literature,7 1 was obtained easily and in good yield from
cyanamide (Scheme 2). We applied the same methodology, we
used few years ago to synthesize amino-cyano-thiophenes from
ketene S,S-dimethylthioacetals:8 compound 1 was reacted with
sodium sulfide, an activated halide and potassium carbonate.
Compound 2a was obtained in good yield with this one-pot three-
step sequential procedure (Scheme 2).
2. Results and discussion
The first step of our strategy was the formation of 4-amino-1,3-
thiazole-5-carbonitriles 2. Their preparation is well described in
* 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 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.07.017

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D. Thomae et al. / Tetrahedron 64 (2008) 9309–9314
NH2
N
CN
S
NH2
CN
i, ii, iii
N
iv, v, vi
N
NH2CN
S
CN
S
HN
S
i, ii, iii
S
NH2CN
92%
1
71%
2a 85%
Scheme 2. Reagents and conditions: (i) KOH; (ii) CS2; (iii) MeI; (iv) Na2S$9H2O, DMF;
2d
(v) ClCH2CN; (vi) K2CO3.
Scheme 5. i) DMF, K2CO3; (ii) phenyl isothiocyanate; (iii) ClCH2CN.
In the literature, 1,3-thiazolopyridines are obtained by cycliza-
tion of the suitable thioacetamidopyridine.12 The second step of our
strategy was to use thiazoles 2(a–d) as starting material to access
new classes of compounds like thiazole analogues of Tacrine and
[1,3]thiazolo[4,5-d][1,2,3]triazines.
Taking advantage of the good leaving group property of the
methylsulfanyl group in compound 2a and as described before on
similar compounds,6k,l,9 SNAr reaction with secondary amines were
realized. Compound 2a was dissolved in 10 equiv of amine and
refluxed overnight to yield 2b and 2c in high yields (method A,
Scheme 3).
Friedla¨nder reaction on thiazoles 2 has allowed formation of
new Tacrine’s analogues. As we have shown recently in the sele-
nophene series,13 Friedla¨nder reaction can be performed under
classical heating or under microwave irradiation. We decided to
study those two methods on thiazoles 2. Using classical heating,
thiazoles 2a and 2d were dissolved in dichloroethane, and cycla-
nones and aluminum chloride were added. For thiazoles 2b and 2c,
we have chosen THF because 2(b and c) were not enough soluble in
dichloroethane. In both cases, the reaction mixture was refluxed for
4 h and compounds 3–5(a–d) were obtained in high yields (Scheme
6 and Table 1). Under microwave irradiation, we choose a mixture
of solvent to be able to finish the reaction in about 30 min (THF for
solubility and DCE for the higher boiling point). With microwave
irradiation, the time of reaction was reduced from 4 h to about
30 min and compounds 4(a–d) were obtained in high yields too
(Scheme 6 and Table 2).
NH2
NH2
CN
N
R1
i
N
CN
N
R2
S
1
90-95%
S
S
2a
2b, 2c
Scheme 3. Method A: synthesis of 3 (R1–R2¼4-morpholinyl) and 4 (R1–R2¼1-pyrro-
lidinyl) starting from 2. Reagents: (i) excess of amine, reflux.
Ried et al. described the synthesis of 4-amino-2-morpholin-4-
yl-thiazole-5-carboxylic acid methyl ester from methyl N-cyano-4-
morpholinecarbimidothioate and methylthioglycolate.10 We have
presumed that compounds 2b and 2c could be synthesized directly
from 1 via a one-pot four-step sequential procedure (method B,
Scheme 4). Compound 1 was dissolved in DMF, then morpholine or
pyrrolidine was added and heated at 70 ꢀC during 1 h. After this
time, sodium sulfide was introduced to form the thiolate that
reacted with chloroacetonitrile and finally, potassium carbonate
was added to complete the cyclization (Scheme 4). Compounds 2(b
and c) were obtained in good yields. In the literature, there is only
one example of solid phase synthesis to access 2,4,5-trisubstituted
thiazoles in a one-pot four-step reaction.11 In terms of overall yields,
methods A and B were equivalent but method B was shorter.
O
N
NH2
CN
N
S
n
N
R
(CH2)2Cl2/THF
n
R
S
AlCl3
Δ
NH2
2 (a-d)
3 (a-d) n=0
4 (a-d) n=1
5 (a-d) n=2
O
CN
S
CN
S
N
N
CN
S
N
i
ii
N
NH2
N
R1
R1
N
R2
N
R2
Na
N
R
S
(CH2)2Cl2/THF
AlCl3
MW 100W
S
R
CN
S
1
NH2
2 (a-d)
4 (a-d)
iii
Scheme 6. Friedla¨nder reaction: R¼MeS–, 4-morpholinyl, 1-pyrrolidinyl, PhNH–.
NH2
CN
CN
As explained before, amino-cyano-thiazoles could also be used
to synthesize thiazolocondensed systems. For example, thiazolo-
pyrimidines have shown interesting biological activity such as
antagonist of CXCR2 receptor.14 This bicyclic core has been built
starting either from substituted pyrimidines15 or from 4-amino-5-
cyanothiazole.16 On another hand, in several publications, aza an-
alogues of condensed pyrimidines were synthesized for studying
the modulation of biological activities: pyrazolo[3,4-d]-1,2,3-
triazin-4-one nucleosides17 or pyrrolo[2,3-d]-1,2,3-triazine18 were
explored for their antiviral/antitumor activity.
N
N
iv
R1
R1
N
R2
S
CN
N
R2
S
2b, 2c
Scheme 4. Method B: synthesis of 3 (R1–R2¼4-morpholinyl) and 4 (R1–R2¼1-pyrro-
lidinyl) starting from 1. Reagents: (i) morpholine or pyrrolidine, DMF; (ii) Na2S$9H2O;
(iii) ClCH2CN; (iv) K2CO3.
Thiazole 2d was synthesized by a method described by
Gewald.6d Cyanamide, potassium carbonate, phenyl isothiocyanate,
and chloroacetonitrile afforded in one step and in high yield thia-
zole 2d (Scheme 5).
So we planned to synthesize new thiazolotriazines. Few years
ago, pyridothienotriazines were described as anti-histaminic19 and
antifungal20 compounds; in these publications, the 4-chloro-
triazine ring was prepared in one-pot starting from 3-amino-2-

D. Thomae et al. / Tetrahedron 64 (2008) 9309–9314
9311
Table 1
N
N
N
Friedla¨nder reaction under classical heating
N
N
N
N
i
O
N
Thiazole
Solvent Substituted
[1,3]thiazolo
Yield (%)
N
N
S
N
Ketone (n)
MeS
S
Cl
[4,5-b]pyridine
n
7
55%
6a
2a, R¼MeS–
0
1
2
(CH2)2Cl2 3a
96
77
87
4a
5a
N
N
N
N
N
N
N
2b, R¼4-morpholinyl
2c, R¼1-pyrrolidinyl
2d, R¼Ph–NH–
0
1
2
THF
THF
3b
4b
5b
98
98
92
i
N
N
S
N
O
N
N
S
Cl
O
8
63%
0
1
2
3c
4c
5c
98
95
97
6b
N
N
N
N
N
N
N
i
0
1
2
(CH2)2Cl2 3d
85
80
97
N
4d
5d
S
N
S
Cl
O
6c
9
66%
N
N
N
Table 2
N
N
N
N
S
Friedla¨nder reaction under microwave irradiation
N
i
Ph
NH
Thiazole
Solvent
Substituted [1,3]thiazolo Time Yield
N
Ph
HN
S
Cl
[4,5-b]pyridine
(min) (%)
O
6d
2a, R¼MeS–
(CH2)2Cl2
4a
3ꢂ8 93
2ꢂ16 93
2ꢂ16 80
1ꢂ16 79
10
Scheme 8. (i) RR0NH 10 mL, reflux.
76%
2b, R¼4-morpholinyl (CH2)2Cl2/THF (4:1) 4b
2c, R¼1-pyrrolidinyl (CH2)2Cl2/THF (4:1) 4c
2d, R¼Ph–NH–
(CH2)2Cl2/THF (3:1) 4d
5.3.1. 1H and 13C NMR spectra (
d in parts per million) were recorded
cyanothiophenes. To the best of our knowledge, chlorothiazolo-
triazines are not described in the literature. 2-Substituted 4-amino-
5-cyanothiazoles 2(a–d) were converted into chlorothiazolo-
triazines 6(a–d) in moderate to good yields via a one-pot process of
diazotation and dediazo-chlorination (Scheme 7).21
on an AC 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, 6890 N gas chromato-
graph and a 5973 mass selective detector. The mass spectrometer
was operated in EI mode at 70 eV and MS spectra were recorded
from m/z 50 to 650. A CEM Discover oven was used for Friedla¨nder’s
reaction under microwave irradiation.
N
N
N
NH2
CN
N
N
4.2. Synthesis of dimethyl cyanodithioimidocarbonate (1)
R
S
Cl
R
S
Cyanamide (0.02 mol, 50% aqueous solution) was dissolved in
80 mL of water. Potassium hydroxide (0.04 mol) was added and the
solution was stirred for 45 min at room temperature. Carbon
disulfide was added. The reaction was heated at 40 ꢀC. When all
carbon disulfide was dissolved (2 h are required), methyl iodide
(0.04 mol) was added and the reaction was stirred at room tem-
perature overnight. The precipitate was filtered and the solid was
washed with water, dried at room temperature until constant
weight, and purified by recrystallization in EtOH.
2 (a-d)
R = SMe
6a
83%
47%
44%
71%
R = 4-morpholinyl
R = 1-pyrrolidinyl
R = NHPh
6b
6c
6d
Scheme 7. NaNO2, HCl 37%, 0–5 ꢀC.
We next wanted to study the reactivity of the chlorine atom in
compounds 6(a–d). When compound 6a was subjected to the ac-
tion of pyrrolidine, both the methylsulfanyl group and the chlorine
atom were displaced (Scheme 8). The chlorine atom was also
substituted by a secondary amine in compounds 6b–d (Scheme 8).
Yield: 71%. Colorless solid; mp: 58 ꢀC; mplit: 57 ꢀC.8 IR: 2176
(s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
2.70 (s, 6H, 2ꢂCH3). 13
C
NMR (62.9 MHz, DMSO-d6):
d 15.82, 112.25, 193.77. GC–MS (EI,
3. Conclusion
70 eV): m/z (%): 143 (23), 99 (100), 74 (23).
We have developed a one-pot four-steps sequential synthesis of
trisubstituted [1,3]thiazoles. Those 4-amino[1,3]thiazole-5-car-
bonitriles have allowed access to several thiazolocondensed sys-
tems. We have prepared 12 new analogues of Tacrine in thiazole
series and 8 new thiazolotriazines in good yields.
4.3. Synthesis of 4-amino-2-(methylsulfanyl)-1,3-thiazole-5-
carbonitrile (2a)
Na2S$9H2O (0.04 mol) was suspended in DMF (53 mL), dimethyl
cyanodithioimidocarbonate 1 (0.04 mol) was dissolved in 13 mL of
DMF and added. The mixture is heated at 70 ꢀC for 2 h. Chloro-
acetonitrile (0.08 mol) is slowly dropped at 70 ꢀC. The reaction
was stirred for 2 h and potassium carbonate was added (0.04 mol).
The reaction was stirred at 70 ꢀC for 1 h more. The mixture was
poured onto water (400 mL) under good stirring. The precipitated
was filtered, washed with water, dried at room temperature until
constant weight, and purified by recrystallization in EtOH.
4. Experimental section
4.1. General
Melting points were determined on a Stuart SMP3 apparatus
and are uncorrected. IR spectra were performed on a Perkin–Elmer
FTIR Baragon 1000PC equipped with a Graseby-Specac golden gate
and treated with the Spectrum (Perkin–Elmer) software version
Yield: 85%. Colorless solid; mp: 205 ꢀC; mplit: 204–206 ꢀC.2 IR:
3308 (s), 3171 (s), 2192 (s), 1641 (s), 1534 (s) cmꢁ1 1H NMR
.

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D. Thomae et al. / Tetrahedron 64 (2008) 9309–9314
(250 MHz, DMSO-d6):
(62.9 MHz, DMSO-d6):
(EI, 70 eV): m/z (%): 171 (100), 156 (30), 138 (48).
d
2.62 (s, 3H, CH3), 7.22 (s, 2H, NH2). 13C NMR
15.52, 67.16, 114.43, 165.52, 172.25. GC–MS
dichloroethane/THF. After stirring 5 min at room temperature,
aluminum chloride (4 mmol) was added and the mixture was
heated at reflux for 2 h. The mixture was cooled at room temper-
ature and 4 mmol of aluminum chloride was added, the mixture
was heated at reflux 2 h more. The solvent was removed under
reduced pressure. An aqueous solution of sodium hydroxide
(50 mL, 10%) was added. After stirring for 30 min, the precipitate
was filtered, washed twice with 25 mL of water and washed twice
with 10 mL of ether, and dried at room temperature until constant
weight, purified in 5 mL of acetonitrile, and filtered while hot.
d
4.4. Synthesis of 2-substituted 4-amino-1,3-thiazole-5-
carbonitrile 2(b and c)
4.4.1. Method A
4-Amino-2-(methylsulfanyl)-1,3-thiazole-5-carbonitrile
2a
(2.92 mmol) and corresponding amine (10 mL) were refluxed for
6 h. The mixture was poured onto water (80 mL) under stirring. The
precipitated was filtered, washed with water, and dried at room
temperature overnight.
4.6.2. Microwave irradiation (method D)
In a round bottom flask of 100 mL equipped with a condenser,
cyclohexanone (1.4 mmol) was added to
a solution of 2-
4.4.2. Method B
substituted-1,3-thiazole-5-carbonitrile 2–4 (1 mmol) in 25–40 mL
of a mixture of dichloroethane/THF. Aluminum chloride (4 mmol
otherwise specified) was added and the mixture was heated at
reflux during 16 and 32 min (Table 2) under microwave irradiation
(at a constant power of 100–150 W). The solvent was removed
under reduce pressure. An aqueous solution of sodium hydroxide
(30 mL, 10%) was added. After stirring for 30 min, the precipitate
was filtered, washed twice with 12 mL of water and washed twice
with 5 mL of ether, and dried at room temperature until constant
weight, purified in 2 mL of acetonitrile, and filtered while hot.
Dimethyl cyanodithioimidocarbonate 1 (0.04 mol) was dis-
solved in DMF (53 mL). Amine (0.04 mol) was added and the
mixture was heated at 70 ꢀC for 1 h. Then, Na2S$9H2O (0.04 mol)
was added and heated for 2 h at 70 ꢀC. Chloroacetonitrile (0.12 mol)
was added dropwise at 50 ꢀC. The mixture was heated at 50 ꢀC for
2 h and the potassium carbonate was added (0.04 mol). The re-
action was stirred at 50 ꢀC for 1 h more. The mixture was poured
onto water (400 mL) with good stirring. The precipitated was fil-
tered, washed with water, dried at room temperature until constant
weight, and purified by recrystallization in EtOH.
4.6.3. 8-Amino-2-(methylsulfanyl)-6,7-dihydro-5H-
4.4.3. 4-Amino-2-(4-morpholinyl)-1,3-thiazole-5-carbonitrile (2b)
cyclopenta[b][1,3]thiazolo[4,5-b]pyridine (3a)
Yield: 90% (method A), 78% (method B). Colorless solid; mp:
Yield: 96% (method C: 60 mL of (CH2)2Cl2). Colorless solid; mp:
236 ꢀC. IR: 3320 (s), 3205 (s), 1641 (s), 1563 (s) cmꢁ1 1H NMR
.
266 ꢀC (dec). IR: 3320 (s), 3205 (s), 1641 (s), 1563 (s) cmꢁ1. 1H NMR
(250 MHz, DMSO-d6):
d
3.39 (t, J¼5.0 Hz, 4H, 2ꢂCH2), 3.65 (t,
(250 MHz, DMSO-d6):
2H, CH2), 2.73 (s, 3H, CH3), 2.82 (t, J¼7.5 Hz, 2H, CH2), 6.34 (s, 2H,
NH2). 13C NMR (62.9 MHz, DMSO-d6):
15.31, 22.33, 27.26, 33.98,
d
2.03 (q, J¼7.5 Hz, 2H, CH2), 2.72 (t, J¼7.5 Hz,
J¼5.0 Hz, 4H, 2ꢂCH2), 6.81 (s, 2H, NH2). 13C NMR (62.9 MHz, DMSO-
d6):
d
47.36, 56.92, 65.15, 116.49, 165.06, 170.01.
d
109.65, 114.42, 144.87, 163.75, 164.72, 167.66. GC–MS (EI, 70 eV):
4.4.4. 4-Amino-2-(1-pyrrolidinyl)-1,3-thiazole-5-carbonitrile (2c)
Yield: 99% (method A), 67% (method B). Colorless solid; mp:
299 ꢀC; mplit: 303–305 ꢀC.2 IR: 3323 (s), 3168 (s), 2170 (s) cmꢁ1. 1H
m/z (%): 237 (100), 204 (19), 191 (28).
4.6.4. 9-Amino-2-(methylsulfanyl)-5,6,7,8-
NMR (250 MHz, DMSO-d6):
d
1.94 (t, J¼7.5 Hz, 4H, 2ꢂCH2), 3.33 (t,
tetrahydro[1,3]thiazolo[4,5-b]quinoline (4a)
J¼5.0 Hz, 4H, 2ꢂCH2), 6.75 (s, 2H, NH2). 13C NMR (62.9 MHz, DMSO-
Yield: 77% (method C: 60 mL of (CH2)2Cl2). Yield: 93% (method
D: 25 mL of (CH2)2Cl2, 6 mmol AlCl3, 150 W, 3ꢂ8 min). Colorless
solid; mp: 215 ꢀC. IR: 3318 (s), 32 (s), 1643 (s), 1571 (s), 1541
d6):
d 25.03, 49.10, 56.18, 116.90, 165.47, 166.18. GC–MS (EI, 70 eV):
m/z (%): 194 (100), 166 (43), 139 (16), 97 (17), 70 (18), 55 (24).
(s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
1.76 (m, 4H, 2ꢂCH2), 2.45
4.5. Synthesis of 4-amino-2-anilino-1,3-thiazole-5-
carbonitrile (2d)
(m, 2H, CH2), 2.73 (m, 5H, CH2þCH3), 6.22 (s, 2H, NH2). 13C NMR
(62.9 MHz, DMSO-d6):
d 15.27, 22.26, 22.52, 23.14, 32.72, 109.06,
110.06, 146.87, 154.57, 162.50, 168.10. GC–MS (EI, 70 eV): m/z (%):
Cyanamide 99% (0.01 mol) was dissolved in 53 mL of dry DMF.
Potassium carbonate (0.01 mol) was added and the reaction was
stirred for 2 h at room temperature. Phenyl isothiocyanate was
added dropwise and the reaction was heated at 60 ꢀC for 1 h.
Chloroacetonitrile (0.01 mol) is slowly dropped and the tempera-
ture increased to 75 ꢀC. The mixture was stirred for 1 h more at this
temperature. After completion, the mixture was poured onto water
(60 mL) with good stirring. The precipitated was filtered, washed
with water, dried at room temperature until constant weight, and
purified by recrystallization in EtOH.
251 (100).
4.6.5. 10-Amino-2-(methylsulfanyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b][1,3]thiazolo[4,5-b]pyridine (5a)
Yield: 87% (method C: 60 mL of (CH2)2Cl2). Colorless solid; mp:
234 ꢀC. IR: 3323 (s), 3202 (s), 1645, 1564 (s), 1543 (s) cmꢁ1. 1H NMR
(250 MHz, DMSO-d6):
d
1.52 (m, 4H, 2ꢂCH2), 1.76 (m, 2H, CH2), 2.72
(m, 5H, CH2þCH3), 2.88 (m, 2H, CH2), 6.22 (s, 2H, NH2). 13C NMR
(62.9 MHz, DMSO-d6):
d 15.35, 24.71, 26.30, 27.16, 31.68, 31.80,
110.76, 115.37, 146.03, 161.79, 161.89, 167.78. GC–MS (EI, 70 eV): m/z
(%): 265 (100), 250 (19), 236 (28).
Yield: 92% (method B). Yellow solid; mp: 212 ꢀC. IR: 2171
(s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d 6.92 (s, 2H, NH2), 7.03 (t,
J¼7.5 Hz, 1H, CH), 7.32 (t, J¼7.5 Hz, 2H, 2ꢂCH), 7.57 (d, J¼7.5 Hz, 2H,
4.6.6. 8-Amino-2-(4-morpholinyl)-6,7-dihydro-5H-
2ꢂCH), 10.63 (s, 1H, NH). 13C NMR (62.9 MHz, DMSO-d6):
d
56.68,
cyclopenta[b][1,3]thiazolo[4,5-b]pyridine (3b)
116.28, 118.24, 124.36, 129.46, 139.70, 164.46, 164.52. GC–MS (EI,
70 eV): m/z (%): 216 (100), 119 (31), 77 (19).
Yield: 98% (method C: 50 mL of THF). Colorless solid; mp 311 ꢀC.
IR: 1628 (s), 1569 (s), 1534 (s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
2.03 (q, J¼7.5 Hz, 2H, CH2), 2.68 (t, J¼7.5 Hz, 2H, CH2), 2.74 (t,
¨
4.6. General procedure for Friedlander’s reaction
J¼7.5 Hz, 2H, CH2), 3.47 (t, J¼5.0 Hz, 4H, 2ꢂCH2), 3.72 (t, J¼5.0 Hz,
4H, 2ꢂCH2), 6.01 (s, 2H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
4.6.1. Classical conditions (method C)
d 22.22, 27.28, 33.94, 47.55, 65.41, 104.13, 112.98, 144.68, 162.06,
Cyclanone (2.8 mmol) was added to a solution of 2-substituted-
164.13, 168.28. GC–MS (EI, 70 eV): m/z (%): 276 (100), 219 (100),
1,3-thiazole-5-carbonitrile 2–4 (2 mmol) in
a
mixture of
190 (15).

D. Thomae et al. / Tetrahedron 64 (2008) 9309–9314
9313
4.6.7. 9-Amino-2-(4-morpholinyl)-5,6,7,8-tetrahydro[1,3]-
4.6.13. 9-Amino-2-anilino-5,6,7,8-tetrahydro[1,3]-
thiazolo[4,5-b]quinoline (4b)
thiazolo[4,5-b]quinoline (4d)
Yield: 98% (method C: 50 mL of THF). Yield: 93% (method D:
20 mL of (CH2)2Cl2þ5 mL of THF, 4 mmol AlCl3, 100 W, 2ꢂ16 min).
Colorless solid; mp: 318 ꢀC. IR: 3302 (s), 3209 (s), 1629 (s), 1567 (s),
Yield: 80% (method C: 50 mL of (CH2)2Cl2þ10 mL of THF). Yield:
79% (method D: 30 mL of (CH2)2Cl2þ10 mL of THF, 2 mmol AlCl3,
100 W,16 min). Orange solid; mp: 280 ꢀC. IR: 1617 (s), 1563 (s), 1519
1532 (s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
1.72 (m, 4H, 2ꢂCH2),
(s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
1.75 (m, 4H, 2ꢂCH2), 2.43
2.41 (m, 2H, CH2), 2.63 (m, 2H, CH2), 3.48 (t, J¼5.0 Hz, 4H, 2ꢂCH2),
(m, 2H, CH2), 2.68 (m, 2H, CH2), 5.99 (s, 2H, NH2), 7.00 (m, 1H, CH),
7.33 (m, 2H, 2ꢂCH), 7.76 (m, 2ꢂCH), 10.48 (s, 1H, NH). 13C NMR
3.72 (t, J¼5.0 Hz, 4H, 2ꢂCH2), 5.87 (s, 2H, NH2). 13C NMR (62.9 MHz,
DMSO-d6):
d
22.45, 22.68, 23.01, 32.61, 47.60, 65.42, 104.05, 108.76,
(62.9 MHz, DMSO-d6): d 22.45, 22.69, 23.07, 32.56, 103.76, 109.44,
146.45, 153.14, 162.03, 168.30. GC–MS (EI, 70 eV): m/z (%): 290
117.77, 121.83, 128.80, 140.73, 146.48, 153.05, 16.73, 161.87.
(100), 233 (88), 204 (17).
4.6.14. 10-Amino-2-anilino-6,7,8,9-tetrahydro-5H-
cyclohepta[b][1,3]thiazolo[4,5-b]pyridine (5d)
4.6.8. 10-Amino-2-(4-morpholinyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b][1,3]thiazolo[4,5-b]pyridine (5b)
Yield: 97%. Colorless solid; mp: 275 ꢀC. IR: 1634 (s), 1564 (s),
Yield: 92% (method C: 50 mL of THF). Colorless solid; mp:
1542 (s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
1.50 (m, 4H, 2ꢂCH2),
314 ꢀC. IR: 1633 (s), 1565 (s), 1526 (s) cmꢁ1
.
1H NMR (250 MHz,
1.77 (m, 2H, CH2), 2.66 (m, 2H, CH2), 2.84 (m, 2H, CH2), 5.92 (s, 2H,
NH2), 6.99 (m, 1H, CH), 7.33 (m, 1H, 2ꢂCH), 7.75 (m, 2H, 2ꢂCH),
DMSO-d6):
d
1.51 (m, 4H, 2ꢂCH2), 1.75 (m, 2H, CH2), 2.65 (m, 2H,
CH2), 2.80 (m, 2H, CH2), 3.47 (t, J¼5.0 Hz, 4H, 2ꢂCH2), 3.72 (t,
10.42 (s, 1H, NH). 13C NMR (62.9 MHz, DMSO-d6):
d 24.75, 26.39,
J¼5.0 Hz, 4H, 2ꢂCH2), 5.87 (s, 2H, NH2). 13C NMR (62.9 MHz, DMSO-
27.34, 31.84, 40.48, 105.23, 114.73, 117.71, 121.81, 128.82, 140.71,
145.73, 160.38, 161.17, 161.67.
d6):
d 24.69, 26.38, 27.37, 31.81, 40.48, 47.70, 65.40, 105.53, 114.03,
145.70,160.47,161.32,168.32. GC–MS (EI, 70 eV): m/z (%): 304 (100),
247 (63).
4.7. Synthesis of chlorothiazolotriazines 6(a–d): general
procedure
4.6.9. 8-Amino-2-(1-pyrrolidinyl)-6,7-dihydro-5H-
cyclopenta[b][1,3]thiazolo[4,5-b]pyridine (3c)
Yield: 98% (method C: 50 mL of THF). Colorless solid; mp:
A solution of sodium nitrite (11.4 mmol) in water (7 mL) was
added over 15 min to a suspension of the foregoing 2-substituted 4-
amino-1,3-thiazole-5-carbonitrile (8.1 mmol) at 0–5 ꢀC in concen-
trated hydrochloric acid (16 mL). The resulting mixture was stirred
at 0 ꢀC for a further 40 min and then allowed to stand at room
temperature overnight. The reaction mixture was quenched in
water (100 mL). The precipitate was washed twice with 15 mL of
water, and dried under room temperature, purified in 2 mL of
acetonitrile, and filtered while hot.
369 ꢀC. IR: 1632 (s), 1573 (s), 1535 (s) cmꢁ1 1H NMR (250 MHz,
.
DMSO-d6):
d
1.99 (m, 6H, 3ꢂCH2), 2.67 (t, J¼7.5 Hz, 2H, CH2), 2.72 (t,
J¼7.5 Hz, 2H, CH2), 3.43 (m, 4H, 2ꢂCH2), 5.91 (s, 2H, NH2). 13C NMR
(62.9 MHz, DMSO-d6):
d 22.24, 24.79, 27.25, 33.96, 67.22, 104.10,
112.35, 144.54, 161.71, 164.13, 164.92. GC–MS (EI, 70 eV): m/z (%):
260 (100), 232 (42), 205 (74), 55 (19).
4.6.10. 9-Amino-2-(1-pyrrolidinyl)-5,6,7,8-tetrahydro[1,3]-
thiazolo[4,5-b]quinoline (4c)
Yield: 95% (method C: 50 mL of THF). Yield: 80% (method D:
20 mL of (CH2)2Cl2þ5 mL of THF, 4 mmol AlCl3, 100 W, 2ꢂ16 min).
Colorless solid; mp: 346 ꢀC. IR: 1629 (s), 1576 (s), 1522 (s) cmꢁ1. 1H
4.7.1. 4-Chloro-6-(methylsulfanyl)[1,3]thiazolo[4,5-d]-
[1,2,3]triazine (6a)
Yield: 83%. Orange solid; mp: 190 ꢀC. IR: 1516 (s), 1460 (s), 1359
NMR (250 MHz, DMSO-d6):
2ꢂCH2), 2.40 (m, 2H, CH2), 2.62 (m, 2H, CH2), 3.43 (m, 4H, 2ꢂCH2),
5.77 (s, 2H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
22.51, 22.73,
d
1.73 (m, 4H, 2ꢂCH2), 1.98 (m, 4H,
(br) cmꢁ1 1H NMR (250 MHz, DMSO-d6): 2.49 (s, 3H, CH3). 13C
. d
NMR (62.9 MHz, DMSO-d6):
d 16.65, 129.18, 150.73, 165.18, 183.03.
d
GC–MS (EI, 70 eV): m/z (%): 190 (97), 175 (23), 157 (100).
22.95, 25.06, 32.62, 48.79, 104.07, 108.16, 146.27, 152.76, 162.06,
164.14. GC–MS (EI, 70 eV): m/z (%): 274 (100), 246 (45), 219 (49),
70 (12).
4.7.2. 4-Chloro-6-(4-morpholinyl)[1,3]thiazolo[4,5-d]-
[1,2,3]triazine (6b)
Yield: 47%. Beige solid; mp: 243 ꢀC. IR: 1592 (s), 1530 (s), 1417
4.6.11. 10-Amino-2-(1-pyrrolidinyl)-6,7,8,9-tetrahydro-5H-
cyclohepta[b][1,3]thiazolo[4,5-b]pyridine (5c)
(s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
3.47 (m, 4H, 2ꢂCH2), 3.76
(m, 4H, 2ꢂCH2). 13C NMR (62.9 MHz, DMSO-d6):
d 65.25, 105.89,
Yield: 97% (method C: 50 mL of THF). Colorless solid; mp:
124.53, 148.41, 166.07, 171.87. GC–MS (EI, 70 eV): m/z (%): 229 (100),
336 ꢀC. IR: 1630 (s), 1571 (s), 1524 (s) cmꢁ1
.
1H NMR (250 MHz,
171 (83), 144 (36).
DMSO-d6):
d
1.50 (m, 4H, 2ꢂCH2), 1.75 (m, 2H, CH2), 1.99 (m, 4H,
2ꢂCH2), 2.63 (m, 2H, CH2), 2.78 (m, 2H, CH2), 3.41 (t, J¼5.0 Hz, 4H,
4.7.3. 4-Chloro-6-(1-pyrrolidinyl)[1,3]thiazolo[4,5-d]-
[1,2,3]triazine (6c)
2ꢂCH2), 5.77 (s, 2H, NH2). 13C NMR (62.9 MHz, DMSO-d6):
d 24.69,
25.07, 26.40, 27.44, 31.87, 40.48, 48.82, 105.47, 113.42,145.57, 160.10,
162.06, 164.18. GC–MS (EI, 70 eV): m/z (%): 288 (100), 273 (16), 260
(44), 233 (25).
Yield: 44%. Orange solid; mp: 219 ꢀC. IR: 1560 (s), 1526 (s), 1412
(s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d
2.52 (m, 4H, 2ꢂCH2), 3.56
(m, 2H, CH2), 3.80 (m, 2H, CH2). 13C NMR (62.9 MHz, DMSO-d6):
25.12, 50.83, 124.64, 148.15, 166.07, 167.80. GC–MS (EI, 70 eV): m/z
d
4.6.12. 8-Amino-2-anilino-6,7-dihydro-5H-cyclo-
(%): 213 (97), 185 (100), 158 (60).
penta[b][1,3]thiazolo[4,5-b]pyridine (3d)
Yield: 85% (method C: 50 mL of (CH2)2Cl2þ10 mL of THF). Or-
4.7.4. 4-Chloro-N-phenyl[1,3]thiazolo[4,5-d][1,2,3]-
triazin-6-amine (6d)
ange solid. Colorless solid; mp: 274 ꢀC. IR: 1623 (s), 1564 (s), 1526
(s) cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
2.01 (q, J¼7.5 Hz, 2H,
Yield: 71%. Orange solid; mp: 208 ꢀC. IR: 1602 (s), 1567 (s), 1500
CH2), 2.70 (t, J¼7.5 Hz, 2H, CH2), 2.77 (t, J¼7.5 Hz, 2H, CH2), 6.01 (s,
(s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d 7.22 (m, 1H, CH), 7.47 (m,
2H, NH2), 6.97 (m, 1H, CH), 7.31 (m, 2ꢂCH), 7.73 (m, 2H, 2ꢂCH),
2H, 2ꢂCH), 7.78 (m, 2H, 2ꢂCH), 12.03 (s, 1H, NH). 13C NMR
10.50 (s, 1H, NH). 13C NMR (62.9 MHz, DMSO-d6):
d
22.26, 27.32,
(62.9 MHz, DMSO-d6): d 118.70, 119.68, 124.97, 129.38, 138.39,
33.89, 103.82, 113.48, 117.88, 121.67, 128.80, 141.21, 144.60, 161.90,
164.11.
140.37, 148.85, 166.19. GC–MS (EI, 70 eV): m/z (%): 235 (100),
200 (52).

9314
D. Thomae et al. / Tetrahedron 64 (2008) 9309–9314
4.8. Synthesis of aminothiazolotriazine derivatives
recording NMR spectra and Dr. Serge Schneider and Dr. Marc
Schuman from Gabriel Lipmann for recording IR and GC–MS
analyses.
The chlorothiazolotriazines 6(a–d) (1 mmol) and corresponding
amine (10 mL) were refluxed for 6 h. The mixture was cooled at
room temperature and poured onto water (80 mL) under stirring.
When a precipitated was formed, it was filtered, washed twice with
15 mL of water and twice with 8 mL of diethyl ether, and dried at
room temperature overnight. When a precipitated wasn’t formed,
the aqueous layer was extracted trice with 25 mL of CH2Cl2. The
organic layers were washed twice with 30 mL of HCl 2 N and once
with 80 mL of water, dried over MgSO4 and concentrated under
reduce pressure. The products were purified in 2 mL of acetonitrile
and filtered while hot to give products 7–10.
References and notes
1. Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2007, 1027.
2. Seck, P.; Thomae, D.; Kirsch, G. J. Heterocycl. Chem. 2008, 45, 853.
3. Thomae, D.; Kirsch, G.; Seck, P.; Kaminski, T. Synthesis 2007, 2153.
4. Hesse, S.; Perspicace, E.; Kirsch, G. Tetrahedron Lett. 2007, 48, 5261.
5. (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,
K.; Kawamoto, I.; Takiguchi, I.; Katsumata, S.; Takahashi, K.; Nakano, H. J.
J. Antibiot. 1988, 42, 1768; (d) Crews, P.; Kakou, Y.; Quinoa, E. J. Am. Chem. Soc.
1988, 110, 4365; (e) Metzger, J. V. Chemistry of Heterocyclic Compounds; Wiley:
New York, NY, 1979; p 34; (f) Metzger, J. V. In Thiazoles and their Benzo
Derivatives; Potts, K. T., Ed.; Pergamon: New York, NY, 1984; Vol. 6.
6. (a) Walek, W.; Pallas, M.; Augustin, M. Tetrahedron 1976, 32, 623; (b) Evers, R.
J. Prakt. Chem. 1985, 327, 604; (c) Wobig, D. Justus Liebigs Ann. Chem. 1972, 764,
125; (d) Gewald, K. J. Prakt. Chem. 1967, 35, 97; (e) Hartke, K.; Seib, B. Arch.
Pharm. 1970, 303, 625; (f) Gewald, K.; Hain, U. J. Prakt. Chem. 1975, 317, 329; (g)
Lloyd, D.; Millar, R. W. Tetrahedron 1980, 36, 2675; (h) Gewald, K.; Hain, U.;
Hartung, P. Monatsh. Chem. 1981, 112, 1393; (i) Fuchigami, T.; Yeh, M. Y.; Nonaka,
T.; Tien, H. J. Bull. Chem. Soc. Jpn. 1983, 56, 3851; (j) Middleton, W. J. J. Org. Chem.
1966, 31, 3731; (k) Seybold, G.; Eilingsfeld, H. Justus Liebigs Ann. Chem. 1979, 9,
1271; (l) Eilingsfeld, H.; Swybold G. DE 2713573, 1978.
4.8.1. 4,6-Di(1-pyrrolidinyl)[1,3]thiazolo[4,5-d][1,2,3]triazine (7)
Yield: 55%. Pale yellow solid; mp: 178 ꢀC. IR: 1556 (s), 1457 (s),
1422 (s), 1325 (s) cmꢁ1. 1H NMR (250 MHz, DMSO-d6):
d 1.97–2.03
(m, 8H, 4ꢂCH2), 3.32 (m, 4H, 2ꢂCH2), 3.71 (m, 4H, 2ꢂCH2). 13C NMR
(62.9 MHz, DMSO-d6):
d 24.68, 25.08, 46.91, 49.74, 102.98, 150.90,
164.05, 167.51.
4.8.2. 6-(4-Morpholinyl)-4-(1-pyrrolidinyl)[1,3]thiazolo-
[4,5-d][1,2,3]triazine (8)
7. (a) Timmons, R. J.; Wittenbrook, L. S. J. Org. Chem. 1967, 32, 1566; (b) Buckman,
J.; Pera, J. D.; Appling, J. W. U.S. Patent 2,881,071, 1959; Chem. Abstr. 1959, 53,
20678d; (c) Yokoyama, M.; Kumata, K.; Yamada, N.; Noro, H.; Sudo, Y. J. Chem.
Soc., Perkin Trans. 1 1988, 2309; (d) Suyama, T.; Suzuki, N.; Nishimura, M.;
Saitoh, Y.; Ohkoshi, H.; Yamaguchi, J. I. Bull. Chem. Soc. Jpn. 2005, 78, 873; (e)
Elgemeie, G. H.; Sood, S. A. Synth. Commun. 2006, 36, 743; (f) Alqaradawi, S. Y.;
Elgemeie, G. H. Synth. Commun. 2004, 34, 805.
Yield: 63%. Pale orange solid; mp: 178 ꢀC (dec). IR: 1536 (s), 1413
(br), 1329 (s) cmꢁ1 1H NMR (250 MHz, DMSO-d6):
. d 1.86 (m, 2H,
CH2), 1.97 (m, 2H, CH2), 3.42 (m, 2H, CH2), 3.51 (m, 2H, CH2), 3.66
(m, 4H, 2ꢂCH2), 3.72 (m, 4H, 2ꢂCH2). 13C NMR (62.9 MHz, DMSO-
8. Sommen, G.; Comel, A.; Kirsch, G. Synthesis 2003, 735.
d6):
d 24.96, 47.37, 48.58, 65.28, 117.77, 161.26, 168.83, 171.76.
9. (a) Gewald, K.; Schaefer, H.; Eckert, K.; Jeschke, T. J. Prakt. Chem. 1996, 338, 206;
(b) Gruner, M.; Rehwald, M.; Eckert, K.; Gewald, K. Heterocycles 2000, 53, 2363;
(c) Walczynski, K.; Zuiderveld, O. P.; Timmerman, H. Eur. J. Med. Chem. 2005,
40, 15.
10. (a) Ried, W.; Kuhnt, D. Justus Liebigs Ann. Chem. 1986, 4, 780; (b) Ried, W.; Broft,
G. W.; Bats, J. W. Chem. Ber. 1983, 116, 1547; (c) Ried, W. Kuhnt Synthesis 1987,
10, 940.
11. Lee, I. Y.; Lee, J. Y.; Lee, H. J. L.; Gong, Y. D. Synlett 2005, 2483.
12. (a) Giorgi, G.; Salvini, L.; Ponticelli, F.; Tedeschi, P. J. Heterocycl. Chem. 1996, 33,
1895; (b) Takashi, T.; Yatsuka, T.; Onuma, Y. J. Pharm. Jpn. 1943, 63, 153; (c)
Couture, A.; Grandelaudon, P. Heterocycles 1984, 22, 1383; (d) Couture, A.;
Grandelaudon, P. J. Heterocycl. Chem. 1996, 33, 1895; (e) Smith, K.; Anderson, D.;
Matthews, I. Sulfur Lett. 1995, 18, 79.
GC–MS (EI, 70 eV): m/z (%): 264 (100).
4.8.3. 4-(4-Morpholinyl)-6-(1-pyrrolidinyl)[1,3]thiazolo-
[4,5-d][1,2,3]triazine (9)
Yield: 66%. Pale orange solid; mp: 203 ꢀC. IR: 1543 (br), 1489 (s),
1421 (s) cmꢁ1 1H NMR (250 MHz, DMSO-d6):
. d 1.95–2.03 (m, 4H,
2ꢂCH2), 3.32 (m, 8H, 4ꢂCH2), 3.75 (m, 4H, 2ꢂCH2). 13C NMR
(62.9 MHz, DMSO-d6):
d 25.06, 45.30, 49.74, 65.73, 112.61, 147.37,
166.80, 167.32. GC–MS (EI, 70 eV): m/z (%): 213 (98), 185 (100), 158
(58).
13. Thomae, D.; Kirsch, G.; Seck, P. Synthesis 2008, 1600.
14. (a) Baxter, A.; Cooper, A.; Kinchin, E.; Moakes, K.; Unitt, J.; Wallace, A. Bioorg.
Med. Chem. Lett. 2006, 16, 960; (b) Hunt, F.; Austin, C.; Austin, R.; Bonnert, R.;
Cage, P.; Christie, J.; Christie, M.; Dixon, C.; Hill, S.; Jewel, R.; Martin, I.;
Robinson, D.; Willis, P. Bioorg. Med. Chem. Lett. 2007, 17, 2731.
15. Liu, J.; Patch, R. J.; Schubert, C.; Player, M. R. J. Org. Chem. 2005, 70, 10194.
16. Wobig, D. Justus Liebigs Ann. Chem. 1989, 409.
17. Manfredini, S.; Bazzanini, R.; Baraldi, P. G.; Guarneri, M.; Simoni, D.; Marongiu,
M. E.; Pani, A.; Tramontano, E.; La Colla, P. J. Med. Chem. 1992, 35, 917.
18. Migawa, M. T.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2005, 48, 3840.
19. Quintela, J. M.; Peinador, C.; Veiga, M. C.; Botana, L. M.; Alfonso, A.; Riguera, R.
Eur. J. Med. Chem. 1998, 33, 887.
4.8.4. 4-(4-Morpholinyl)-N-phenyl[1,3]thiazolo[4,5-d]-
[1,2,3]triazin-6-amine (10)
Yield: 76%. Pale brown solid; mp: 297 ꢀC. IR: 1535 (s), 1417
(s) cmꢁ1
.
1H NMR (250 MHz, DMSO-d6):
d
3.47 (m, 4H, 2ꢂCH2),
3.70–3.79 (m, 4H, 2ꢂCH2), 7.15 (m, 1H, CH), 7.43 (m, 2H, 2ꢂCH), 7.74
(m, 2H, 2ꢂCH). 13C NMR (62.9 MHz, DMSO-d6):
d 45.35, 65.72,
103.43, 119.19, 123.97, 129.28, 139.21, 153.16, 165.14, 166.60.
20. (a) Hunt, J. C. A.; Briggs, E.; Clarke, E. D.; Whittingham, W. G. Bioorg. Med. Chem.
Lett. 2007, 17, 5222; (b) Paronikyan, E. G.; Noravyan, A. S.; Akopyan, S. F.;
Arsenyan, F. G.; Stepanyan, G. M.; Garibdzhanyan, B. T. Pharm. Chem. J. 2006, 40,
293.
21. (a) Guerrera, F.; Sarva, M. C.; Siracusa, M. A.; Caruso, A.; Leone, M. G.; Cutuli,
V.; Oliveri, S. Farmaco 1991, 46, 33; (b) El-Saghier, A. M. M. Molecules 2002,
7, 756; (c) Blanco, G.; Quintela, J. M.; Peinador, C. J. Heterocycl. Chem. 2006,
43, 1051.
Acknowledgements
`
We thank to the ‘Ministere de l’Education Nationale, de l’En-
seignement Supe´rieur et de la Recherche’ for a PhD 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
´