Regioselective synthesis of novel 4-aryl-2-ethylthio-7-methyl pyrazolo[1,5-a]-[1,3,5]-triazines

Article abstract of DOI:10.1016/j.tetlet.2006.05.168

Pyrazolo[1,5-a]-[1,3,5]-triazines 6a-d were obtained by an efficient one-step reaction from S,S-diethyl aroyliminodithiocarbonates 4a-d and 5-amino-3-methylpyrazole 5 or by an alternative two-step reaction from 5 and aroyl isothiocyanates 8a-d to give ini

Full text of DOI:10.1016/j.tetlet.2006.05.168

Tetrahedron Letters 47 (2006) 5441–5443
Regioselective synthesis of novel 4-aryl-2-ethylthio-7-methyl
pyrazolo[1,5-a]-[1,3,5]-triazines
a
a
b,
b
Henry Insuasty,a, Martın Estrada, Edward Cortes, Jairo Quiroga, Braulio Insuasty,
*
*
´
´
b
c
c
´
Rodrigo Abonıa, Manuel Nogueras and Justo Cobo
aGrupo de Investigacio´n en Sı´ntesis de Compuestos Heterocı´clicos, Department of Chemistry, Universidad de Narin˜o,
A.A. 1175 Pasto, Colombia
bGrupo de Investigacio´n de Compuestos Heterocı´clicos, Department of Chemistry, Universidad del Valle, A.A. 25360 Cali, Colombia
cDepartment of Inorganic and Organic Chemistry, Universidad de Jae´n, 23071 Jae´n, Spain
Received 10 May 2006; revised 19 May 2006; accepted 30 May 2006
Available online 16 June 2006
Abstract—Pyrazolo[1,5-a]-[1,3,5]-triazines 6a–d were obtained by an efficient one-step reaction from S,S-diethyl aroyliminodithio-
carbonates 4a–d and 5-amino-3-methylpyrazole 5 or by an alternative two-step reaction from 5 and aroyl isothiocyanates 8a–d to
give initially the thiourea derivatives 9a–d, which after S-ethylation and cyclization afforded compounds 6a–d. The intermediate 7a
isolated from reaction between 4a and 5 permitted us to establish the orientation.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
compound 3 (Fig. 1) was reported as a powerful Corti-
cotrophin Releasing Factor type 1 (CFR1) receptor
antagonist.1g CFR1 plays an important role in modulat-
ing the endocrinal, autonomic, behavioural and immune
responses to stress.1h
Derivatives of the ring system pyrazolo[1,5-a]-[1,3,5]-tri-
azine are of great interest as purine analogues.1,2 Addi-
tionally, these compounds are active agents to inhibit
bronchial inflammation (1, Fig. 1)1d and are useful in
the treatment and prevention of central nervous system
disorders,1e such as psychosis, schizophrenia, depres-
sions, memory disorders, Parkinson’s disease, Alzhei-
mer’s disease and Huntington’s chorea (2, Fig. 1).
Other pyrazolotriazines have been used in the treatment
of metabolic and peripheral disorders1f and recently,
The most common strategy for preparing pyrazolo[1,5-a]-
[1,3,5]-triazines is the reaction between 5-aminopyraz-
oles and an appropriate biselectrophilic reagent.1c,2
S,S-Dialkyl aroyliminodithiocarbonates3 and aroyl
isothiocyanates3a,4 are good bielectrophiles that have
been widely used in the synthesis of many heterocyclic
compounds, such as monocyclic 1,3,5-triazines,3c,4c by
reaction with amidines or guanidines. To the best of
our knowledge, their use have not been reported for
the preparation of pyrazolo[1,5-a]-[1,3,5]-triazines. We
describe here the interaction of S,S-diethyl aroylimino-
dithiocarbonates 4a–d and aroyl isothiocyanates 8a–d
with 5-amino-3-methylpyrazole 5 as an efficient and
versatile method to obtain novel 4-aryl-2-ethylthio-7-
methylpyrazolo[1,5-a]-[1,3,5]-triazines 6a–d, interesting
compounds in view of their potential biological
activity.1,2,5
NHCH(CH2OMe)2
NHMe
NH2
N
N
N
N
N
N
N
N
N
Me
SMe
Me
Me
N
N
N
O
Cl
S
O
1
2
3
N
Cl
Figure 1.
Keywords: 5-Amino-3-methylpyrazole; S,S-Diethyl aroyliminodithio-
carbonates; Aroyl isothiocyanates; Pyrazolo[1,5-a]-[1,3,5]-triazines;
2. Results and discussion
Thioureas; Isothioureas.
*
We have devised an efficient one-step procedure for the
Corresponding authors. Fax: +57
2 7313106; e-mail addresses:
synthesis of new pyrazolo[1,5-a]-[1,3,5]-triazines 6a–d,6
hein@udenar.edu.co; jaiquir@univalle.edu.co
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.168

5442
H. Insuasty et al. / Tetrahedron Letters 47 (2006) 5441–5443
Scheme 1.
from S,S-diethyl aroyliminodithiocarbonates3 4a–d and
5-aminopyrazole 5. Thus, equimolar amounts of 4a–d
and 5 were refluxed in dimethylformamide (DMF) to
give compounds 6a–d in a short time and with good
yields (Scheme 1).
by other means, as described below. So, we skipped this
latter step to obtain 6, and so proved our previous
assumption. To confirm the formation of intermediate
7a–d, we repeated the S-ethylation reaction and, when
TLC monitoring indicated the formation of compounds
7a–d, the reaction mixture was refluxed for 0.5–1.5 h
yielding the desired compounds 6a–d6 (Scheme 1).
The regioselectivity and the mechanism path of reaction
between 4 and 5 were established after isolation of inter-
mediate 7a,7 which was prepared by reaction between 4a
and 5 in DMF at room temperature for 24 h. Com-
pound 7a was refluxed in DMF for 1 h to yield the
expected compound 6a (Scheme 1).
The structures of all new compounds were established
by spectroscopic methods (IR, NMR 1H and 13C), mass
spectrometry. Additionally, the isolation of single crys-
tals of compounds 6b and 6d allowed us to corroborate
unambiguously the proposed structure by X-ray diffrac-
tion analysis.9
Hence, the formation of 6a is assumed to proceed
through an initial addition–elimination: first, the C@N
double bond of compound 4a suffers an addition from
exocyclic nitrogen at pyrazole 5, which after subsequent
ethanethiol elimination, affords the adduct 7a, which
after further intramolecular cyclocondensation between
endocyclic NH and carbonyl group, leads to pyrazolo-
triazine 6a.
3. Conclusion
The two reported routes are simple and practical meth-
ods for the preparation of novel 4-aryl-2-ethylthio-7-
methylpyrazolo[1,5-a]-[1,3,5]-triazines in a short reac-
tion time and with good yields, under mild conditions.
Our findings are an important contribution to confirm
the selectivity and the mechanism of this kind of
reactions.
In order to provide further evidence to support the above
assumption, we have devised an alternate two-step reac-
tion to prepare compounds 6a–d. In the first step, 5-
aminopyrazole 5 and aroyl isothiocyanates3a,4 8a–d were
refluxed in acetonitrile for 2 h to give thiourea derivatives
9a–d8 (Scheme 1). In the second step, compounds 9a–d
were treated with ethyl bromide in the presence of
sodium hydride in DMF at room temperature for 1 h to
render the intermediate isothiourea 7a–d, which although
was impossible to isolate; their formation was confirmed
Acknowledgements
Authors wish to thank Universidad de Narino, COL-
˜
´
CIENCIAS, Universidad del Valle and Servicios Tecni-
´
cos of Universidad de Jaen for financial support.

H. Insuasty et al. / Tetrahedron Letters 47 (2006) 5441–5443
5443
column chromatography on silica gel, using a mixture of
hexanes/ethyl acetate (4:1) as eluent. Method B. A solution
of ethyl bromide (0.002 mol) was added dropwise to a
suspension of the corresponding thiourea 9a–d (0.002 mol)
and sodium hydride (0.002 mol) in dimethylformamide
(2 mL). The reaction mixture was then stirred at room
temperature for 1 h and refluxed for 0.5–1.5 h. After the
dilution of the mixture with cold water, precipitated crystals
were filtered and recrystallized from ethanol. Data for 6a.
Yellow solid, mp 94 °C (90%). 1H NMR (400 MHz,
DMSO): d 1.36 (t, 3H, CH3), 2.43 (s, 3H, 7-CH3), 3.16 (c,
2H, CH2), 6.41 (s, 1H, 8-H), 7.62 (t, 2H, Hm), 7.70 (t, 1H,
Hp), 8.57 (d, 2H, Ho). 13C NMR (DMSO): d 14.3 (CH3),
14.6 (7-CH3), 24.8 (CH2), 94.2 (C-8), 128.4 (Cm), 129.6 (Ci),
130.9 (Co), 133.1 (Cp), 150.8 (C-9), 152.0 (C-4), 157.4 (C-7),
165.0 (C-2). EIMS: m/z: 270 (M+, 100), 255 (24), 242 (10),
237 (57), 210 (12), 139 (43%), 105 (33), 77 (18), 51 (20), 39
(16). HMRS (EI): C14H14N4S: requires 270.0944; found:
270.0939.
References and notes
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3. Preparation and chemistry of S,S-dialkyl aroyliminodithio-
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Synthesis 1981, 554–557.
4. Isothiocyanates in the chemistry of heterocycles, see: (a)
Rajappa, S. Heterocycles 1977, 7, 507; (b) Sharma, S. Sulfur
Rep. 1989, 8, 327–470; (c) Mukerjee, A. K.; Ashare, R.
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6. Preparation of 4-aryl-2-ethylthio-7-methylpyrazolo[1,5-a]-
1,3,5-triazines (6a–d). Method A. A solution of appropriate
S,S-diethyl aroyliminodithiocarbonate 4a–d (0.003 mol)
and 5-amino-3-methylpyrazole 5 (0.003 mol) in dimethyl-
formamide (2 mL) was refluxed for 0.5–1.5 h. The solid
products were precipitated by the addition of cold water to
the reaction mixture, collected by filtration and purified by
7. Preparation of 1-benzoyl-2-ethyl-3-(3-methylpyrazol-5-yl)-
isothiourea (7a). A solution of 4a (0.003 mol) and 5
(0.003 mol) in dimethylformamide (2 ml) was stirred at
room temperature for 24 h. The solid product was precip-
itated by the addition of cold water to the reaction mixture,
collected by filtration and purified by column chromato-
graphy on silica gel, using a mixture of hexanes/ethyl acetate
(4:1) as eluent. Colourless crystals, mp 123 °C (76%). 1H
NMR (400 MHz, DMSO): d 1.28 (t, 3H, CH3), 2.23 (s, 3H,
3-CH3), 3.00 (c, 2H, CH2), 5.92 (s, 1H, 4-H), 7.58 (t, 2H,
Hm), 7.68 (t, 1H, Hp), 7.96 (d, 2H, Ho), 12.58 (s, 1H, 1-
NH), 13.26 (s, 1H, 3-NH). 13C NMR (DMSO): d 10.5 (3-
CH3), 13.6 (CH3), 24.3 (CH2), 101.3 (C-4), 127.4 (Cm),
128.2 (Ci), 129.0 (Co), 132.9 (Cp), 139.3 (C-3), 151.1 (C-5),
155.7 (C-2), 163.9 (C@O). EIMS: m/z: 288 (M+, 5), 271 (5),
255 (6), 227 (6), 142 (12), 105 (100), 77 (54), 51 (17), 39 (8).
HMRS (EI): C14H16N4OS: requires 288.1049; found:
288.1045.
8. Preparation of 1-aroyl-3-(3-methylpyrazol-5-yl)-thioureas
(9a–d). A solution of compound 5 (0.019 mol) in aceto-
nitrile (10 mL) was added dropwise to a suspension of proper
aroyl isothiocyanates 8a–d (0.019 mol) (prepared in situ
from corresponding aroyl chloride and potassium thio-
cyanate) in acetonitrile (20 mL) and then the mixture was
refluxed for 2 h. After cooling overnight, the resulting white
solid was filtered, washed with ethanol and recrystallized
from ethanol. Data for 9a. White crystals, mp 209 °C
(95%). 1H NMR (400 MHz, DMSO): d 2.25 (s, 3H, 3-CH3),
6.87 (s, 1H, 4-H), 7.52 (t, 2H, Hm), 7.64 (t, 1H, Hp), 7.96 (d,
2H, Ho), 11.52 (s, 1H, exocyclic 1-NH), 12.45 (s, 1H,
endocyclic 1-NH), 13.09 (s, 1H, 3-NH). 13C NMR
(DMSO): d 10.7 (3-CH3), 97.4 (C-4), 128.4 (Cm), 128.7
(Co), 132.1 (Ci), 133.1 (Cp), 138.4 (C-3), 146.9 (C-5), 168.7
(C@O), 176.5 (C@S). EIMS: m/z: 260 (M+, 30), 139 (37),
105 (100), 97 (25), 77 (94), 51 (31), 39 (13). HMRS (EI):
C12H12N4OS: requires 260.0732; found: 260.0732.
9. Insuasty, H.; Estrada, M.; Cobo, J.; Low, J. N.; Glidewell,
C. Acta Crystallogr. 2006, C62, 122–124.