An efficient two-step synthesis of novel thiazolo[2,3-b]pyrazolo[3,4-f][1, 3,5]triazepines

Article abstract of DOI:10.1002/jhet.145

(Chemical Equation Presented) In an attempt to carry out a straightforward synthesis of thiazolopyrazolodiazepines from the reaction of 4,5-diamino-3-methyl-1-phenylpyrazole 1 with arylidene derivatives of rhodanine 2, the unplanned (Z)-2′-[(5-amino-3-met

Full text of DOI:10.1002/jhet.145

756
An Efficient Two-Step Synthesis of Novel Thiazolo[2,3-
b]pyrazolo[3,4-f][1,3,5]triazepines
Vol 46
a
Braulio Insuasty, * Alexis Tigreros, Henry Martınez, Jairo Quiroga,
a
a
a
´
Rodrigo Abonia,a Alexander Gutierrez,b Manuel Nogueras,c* and Justo Coboc
aHeterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle,
A.A. 25360, Cali, Colombia
´ ´
Department of Biology and Chemistry, Universidad Tecnologica del Choco, A.A. 292, Quibdo,
b
´
Colombia
c
´
´
Department of Inorganic and Organic Chemistry, Universidad de Jaen, 23071 Jaen, Spain
*E-mail: brainsu@univalle.edu.co or mmontiel@ujaen.es
Received February 28, 2009
DOI 10.1002/jhet.145
Published online 14 July 2009 in Wiley InterScience (www.interscience.wiley.com).
In an attempt to carry out a straightforward synthesis of thiazolopyrazolodiazepines from the reaction
of 4,5-diamino-3-methyl-1-phenylpyrazole 1 with arylidene derivatives of rhodanine 2, the unplanned
(Z)-20-[(5-amino-3-methyl-1-phenylpyrazol-4-yl)imino]-5-arylidenethiazolidin-4-ones 4 were obtained as
unique products. Nevertheless, the treatment of these compounds with aliphatic aldehydes in dimethyl-
formamide provided the novel thiazolo[2,3-b]pyrazolo[3,4-f][1,3,5]triazepines 5 and 6 in good to excel-
lent yields. All the structures of the obtained compounds were assigned on the basis of IR, 1D and 2D
NMR measurements, mass spectrometry, and microanalysis.
J. Heterocyclic Chem., 46, 756 (2009).
INTRODUCTION
be reacted with 4,5-diamino-3-methyl-1-phenylpyrazole
1 as a direct procedure for the synthesis of our target
compounds 3, Scheme 1, approach (a).
In recent years, the synthesis and pharmacological
properties of diverse systems containing heterocycles
To obtain the expected diazepines 3, a mixture of dia-
minopyrazole 1 (1.5 mmol) and (Z)-5-(nitrobenzyli-
dene)-2-thioxothiazolidin-4-one (2a) (Ar ¼ 4-NO2C6H4)
(1.5 mmol) was heated at reflux for 15 h in the presence
of ethanol (20 mL) as solvent and triethylamine (1 mL)
as catalyst, according to previously reported procedures
[7]. This reaction afforded a yellow solid, which after
fused to
a seven-membered diazepine ring have
appeared in the literature [1]. Particularly, good CNS ac-
tivity was reported for various pyrazolodiazepines [2],
some of them acting as psychotropic agents [3].
It is known that the interaction of ortho-diamines
with a,b-unsaturated carbonyl compounds constitutes
one of the more expeditious procedures yielding diaze-
pine systems fused to aromatic rings [4]. In this sense,
we have successfully carried out several reactions
between 4,5-diaminopyrazoles and diaminopyrimidines
with chalcones and b-dimethylaminopropiophenone
hydrochlorides as versatile approaches for the synthesis
of new pyrazolo- and pyrimidodiazepine derivatives,
respectively [5].
1
spectroscopic analysis (IR, H and 13C NMR and mass
spectrum), corresponded unexpectedly to the imine com-
pound 4a (Ar ¼ 4-NO2C6H4) in 87% isolated yield,
Scheme 1, approach (b), but not to the cyclo-condensed
product 3a.
The yellow solid exhibited all the signals expected for
the proposed structure (4a). The IR spectrum showed
mainly absorption bands at 3410, 3285, and 1700 cmꢀ1
assigned to NH, NH2, and C¼¼O functionalities, respec-
tively. The 1H NMR of this compound features the follow-
ing main signals: a broad singlet (2H) at 5.72 ppm assigned
to the 5-NH2 group, a singlet (1H) at 7.64 ppm assigned
to 500-H, and a broad singlet (1H) at 11.04 ppm assigned to
30-NH. In fact, an H,H-NOESY effect was observed
between both 5-NH2 and 30-NH groups in agreement
with the proposed conformational structure. Without
including the methyl carbon atoms, the relevant feature in
RESULTS AND DISCUSSION
Continuing with our studies directed toward the de-
velopment of synthetic methodologies leading to fused
pyrazole systems and in an attempt to obtain the new
thiazolopyrazolodiazepines 3 for biological testing, we
prepared a series of (Z)-arylidene derivatives of rhoda-
nine 2a–f (a,b-unsaturated carbonyl compounds) [6] to
C
V
2009 HeteroCorporation

July 2009
An Efficient Two-Step Synthesis of Novel Thiazolo[2,3-b]pyrazolo[3,4-f][1,3,5]triazepines
757
Scheme 1
Scheme 2. i ¼ HCHO for 5a–f (R ¼ H). i ¼ CH3CHO for 6a–f
(R ¼ CH3).
H and 6-NH, of the triazepine ring appear coupled
between them, and the coupling constants are in the
range of J ¼ 6.2–6.4 Hz.
The analysis of 13C, DEPT-135, and two-dimensional
heteronuclear NMR spectra provided the final structural
elucidation of compounds 5. Thus, the signal for C-5 is
in the range of d ¼ 56.4–63.9 ppm. The HMBC experi-
ments for all derivatives indicate three-bond correlations
between 5-H and quaternary carbons C-10a and C-6a.
Mass spectra of compounds 5 show well-defined molec-
ular ions with a characteristic fragmentation pattern
involving the loss of phenyl group.
the 13C NMR spectrum of this compound is that all signals
appear at aromatic field (120.5–162.3 ppm), which is con-
sistent with the proposed structure (4a). Finally, the molec-
ular ion (m/z ¼ 420), showed in mass spectrum confirmed
that the formation process of this solid effectively involved
the loss of a molecule of H2S but not the loss of a molecule
of H2O, as expected for the synthesis of our compound 3.
To evaluate the general character of this unplanned
reaction, this approach was extended to the other 5-ary-
lidene-2-thioxothiazolidin-4-ones (2b–f) with similar
results, that is, yielding compounds 4b–f as unique prod-
ucts involving in all the cases the loss of a molecule of
H2S, as shown in Scheme 1 and Table 1.
The extension of this procedure to acetaldehyde pro-
vided the analog triazepine systems 6a–f also in good
yields, as shown in Table 2. It is worth mentioning that
when the compounds 4 were treated with aryl aldehydes
(i.e. benzaldehyde, 4-methylbenzaldehyde and 4-chloro-
benzadehyde), under the same reaction conditions, the
reaction was not observed. Probably, steric effects could
be related to such lack of reactivity, and therefore, this
procedure is limited to aliphatic aldehydes. In short, we
have not yet concluded an explanation why monoamines
reacts with the arylidene derivatives 2 involving the
C¼¼O functionality through its a,b-unsaturated moiety
as previously reported [8], while the analog diamine 1
reacted exclusively by the C¼¼S functionality without
participation of the a,b-unsaturated moiety. Currently,
we are working in other cases to try to give a satisfac-
tory explanation to this matter.
Trying to overcome the aforementioned failed attempt
to obtain compounds 3, we rationalized that according
to NOESY experiments both 5-NH2 and 30-NH groups
in 4 are certainly spatially nearby. Therefore, we consid-
ered the possibility of completing the cyclization process
by treatment of compounds 4 with aldehydes, toward
the formation of a novel, although slightly different
from 3, no less interesting triazepine system 5. In this
sense, the heating of compounds 4a–f with an excess of
formaldehyde in DMF at 70ꢁC enabled us to obtain
the novel pyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepines
(5a–f) in 70 to 92% yield, as shown in Scheme 2 and
Table 2.
1
In summary, we have developed a new and versatile
indirect two-step method for the synthesis of novel thia-
In the H NMR spectra of compounds 5, the proton
20-H appears as a singlet at d ¼ 7.65–7.77 ppm. The
signals for the 9-CH3 protons of the pyrazole ring result
in a singlet at d ¼ 2.19–2.22 ppm. The two protons, 5-
zolopyrazolotriazepines
5 and 6, via the initially
unplanned iminopyrazoles 4, followed by treatment with
Table 1
Table 2
Physical and analytical data of compounds 4a–f.
Physical and analytical data of compounds (5/6)a–f.
Compound
Ar
m.p. (ꢁC)
Yield
Compound
Ar
m.p. (ꢁC)
Yield (%)
4a
4b
4c
4d
4e
4f
4-O2NC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
287–288
265–267
261–263
267–269
189–190
286–288
87
82
70
71
65
62
(5/6)a
(5/6)b
(5/6)c
(5/6)d
(5/6)e
(5/6)f
4-O2NC6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
291–293/262–264
248–250/262–264
310–312/254–256
265–267/209–211
246–248/264–266
222–224/231–233
72/92
70/94
70/88
92/93
90/92
88/85
4-CH3C6H4
4-CF3C6H4
4-CH3C6H4
4-CF3C6H4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

´
B. Insuasty, A. Tigreros, H. Martınez, J. Quiroga, R. Abonia, A. Gutierrez, M. Nogueras,
and J. Cobo
758
Vol 46
m/z (%): 455 (Mþ, 100), 213 (58). Anal. Calcd for
C20H16BrN5OS: C, 52.87; H, 3.55; N, 15.41. Found: C, 52.89;
H, 3.49; N, 15.39.
aliphatic aldehydes. The chemical and biological poten-
tial of the triazepines 5 and 6 described herein are cur-
rently under investigation.
(Z)-20-[(5-Amino-3-methyl-1-phenylpyrazol-4-yl)imino]-50-
(4-chlorobenzylidene)thiazolidin-4-one (4c). This compound
was obtained as yellow solid (ethanol); IR (KBr): (NH, NH2)
3410 and 3285, C¼¼O 1700 cmꢀ1
;
1H NMR (400 MHz,
EXPERIMENTAL
DMSO-d6): d 2.05 (s, 3H, 3-CH3), 5.68 (s, 2H, NH2), 7.33 (t,
1H, Hp-Ph, J ¼ 7.6 Hz), 7.49 (d, 2H, Hm-Ph, J ¼ 8.3 Hz),
7.50 (d, 2H, Ho-Ar, J ¼ 8.3 Hz), 7.62 (d, 2H, Ho-Ph, J ¼ 8.6
Hz), 7.64 (s, 1H, H-500), 7.68 (d, 2H, Hm-Ar, J ¼ 8.3 Hz),
10.96 ppm (s, 1H, 30-NH); 13C NMR (100 MHz, DMSO-d6): d
11.3 (3-CH3), 120.8 (C-4), 122.4 (Co-Ph), 123.0 (Ci-Ar), 126.2
(Cp-Ph), 128.1 (C-50), 128.4 (C-500), 129.1 (Cm-Ph), 131.1 (Co-
Ar), 132.5 (Cm-Ar), 132.8 (Cp-Ar), 138.9 (Ci-Ph), 143.2 (C-5),
144.0 (C-20), 144.9 (C-3), 162.0 ppm (C-40); ms (EI, 70 eV)
m/z (%): 409 (Mþ, 100), 213 (39). Anal. Calcd for
C20H16ClN5OS: C, 58.61; H, 3.93; N, 17.09. Found: C, 58.56;
H, 3.99; N, 17.00.
Melting points were measured using a Stuart SMP3 melting
point apparatus and are uncorrected. IR spectra were recorded
1
on a Shimadzu FTIR 8400 instrument. The H and 13C NMR
spectra were run on a Bruker DPX 400 spectrometer operating
at 400 and 100 MHz, respectively, using dimethyl sulfoxide-d6
as solvent and tetramethylsilane as internal standard. The mass
spectra were scanned on a Hewlett Packard HP Engine-5989
spectrometer (equipped with a direct inlet probe) operating at
70 eV. High-resolution mass spectra (HRMS) were recorded in
a Waters Micromass AutoSpec NT spectrometer (STIUJA).
The elemental analyses have been obtained using a LECO
CHNS-900 and a Thermo Finnigan FlashEA1112 CHNS-O
(STIUJA) elemental analyzers. Thin layer chromatography
(TLC) was performed on a 0.2-mm precoated plates of silica
gel 60GF254 (Merck). The benzylidene derivatives of rhoda-
nine were obtained according to methodology described in the
work [6c].
General procedure for the synthesis of (Z)-20-[(5-amino-
3-methyl-1-phenylpyrazol-4-yl)imino]-50-arylidenethiazolidin-
4-ones (4a–f). To a mixture of 4,5-diamino-3-methyl-1-phenyl-
pyrazole 1 (1.5 mmol), ethanol (20 mL) and triethylamine
(1 mL) was added to the corresponding 5-arylidene-2-thioxo-
thiazolidin-4-one (1.5 mmol). The mixture was refluxed for 15
h. The formed precipitate was filtered off and washed with
ethanol and recrystallized from ethanol.
(Z)-20-[(5-Amino-3-methyl-1-phenylpyrazol-4-yl)imino]-50-
(4-fluorobenzylidene)thiazolidin-4-one (4d). This compound
was obtained as yellow solid (ethanol); IR (KBr): (NH, NH2)
3425 and 3290, C¼¼O 1680 cmꢀ1
;
1H NMR (400 MHz,
DMSO-d6): d 2.07 (s, 3H, 3-CH3), 5.71 (s, 2H, NH2), 7.34 (t,
1H, Hp-Ph, J ¼ 6.2 Hz), 7.52 (d, 2H, Hm-Ph, J ¼ 7.4 Hz),
7.55 (d, 2H, Ho-Ar, J ¼ 8.7 Hz), 7.60 (d, 2H, Ho-Ph, J ¼ 8.7
Hz), 7.69 (s, 1H, H-500), 7.70 (dd, 2H, Hm-Ar, J ¼ 5.29 Hz, J
¼ 8.7 Hz), 10.89 ppm (s, 1H, 30-NH); 13C NMR (100 MHz,
DMSO-d6): d 11.3 (3-CH3), 120.7 (C-4), 122.9 (Co-Ph), 122.9
(Ci-Ar), 125.9 (Cp-Ph), 128.8 (C-50), 129.0 (C-500), 129.1 (Cm-
3
2
Ph), 132.3 (d, JCAF ¼ 8.0 Hz, Co-Ar), 133.9 (d, JCAF ¼ 22.0
1
Hz, Cm-Ar), 139.3 (d, JCAF ¼ 242.0 Hz, Cp-Ar), 140.2 (Ci-
Ph), 143.4 (C-5), 144.8 (C-20), 144.9 (C-3), 163.2 ppm (C-40);
ms (EI, 70 eV) m/z (%): 393 (Mþ, 100), 213 (47). Anal. Calcd
for C20H16FN5OS: C, 61.06; H, 4.10; N, 17.80. Found: C,
61.10; H, 4.02; N, 17.75.
(Z)-20-[(5-Amino-3-methyl-1-phenylpyrazol-4-yl)imino]-50-
(4-nitrobenzylidene)thiazolidin-4-one (4a). This compound
was obtained as yellow solid (ethanol); IR (KBr): (NH, NH2)
3410 and 3285, C¼¼O 1700 cmꢀ1
;
1H NMR (400 MHz,
(Z)-20-[(5-Amino-3-methyl-1-phenylpyrazol-4-yl)imino]-50-
(4-methylbenzylidene)thiazolidin-4-one (4e). This compound
was obtained as yellow solid (ethanol); IR (KBr): (NH, NH2)
DMSO-d6): d 2.07 (s, 3H, 3-CH3), 5.72 (s, 2H, NH2), 7.34 (t,
1H, Hp-Ph, J ¼ 7.5 Hz), 7.48 (t, 2H, Hm-Ph, J ¼ 8.2 Hz),
7.50 (d, 2H, Ho-Ar, J ¼ 8.2 Hz), 7.62 (d, 2H, Ho-Ph, J ¼ 8.6
Hz), 7.64 (s, 1H, H-500), 7.67 (d, 2H, Hm-Ar, J ¼ 8.2 Hz),
11.04 ppm (s, 1H, 30-NH); 13C NMR (100 MHz, DMSO-d6): d
11.3 (3-CH3), 120.5 (C-4), 122.5 (Co), 126.3 (Cp), 128.2 (C-
50), 128.5 (C-500), 129.0 (Ci-Ar), 129.2 (Cm-Ph), 131.1 (Co-Ar),
132.2 (Cm-Ar), 134.0 (Cp-Ar), 139.0 (Ci-Ph), 143.3 (C-5),
144.9 (C-20), 147.0 (C-3), 162.3 ppm (C-40); ms (EI, 70 eV)
m/z (%): 420 (Mþ, 100), 213 (39). Anal. Calcd for
C20H16N6O3S: C, 57.13; H, 3.84; N, 19.99. Found: C, 57.01;
H, 3.79; N, 19.91.
3446 and 3286, C¼¼O 1695 cmꢀ1
;
1H NMR (400 MHz,
DMSO-d6): d 2.07 (s, 3H, 3-CH3), 2.31 (s, 3H, CH3Ar), 5.68
(s, 2H, NH2), 7.29 (d, 2H, Ho-Ar, J ¼ 8.1 Hz), 7.33 (t, 1H,
Hp-Ph, J ¼ 7.4 Hz), 7.43 (d, 2H, Hm-Ar, J ¼ 8.1 Hz), 7.45 (d,
2H, Hm-Ph, J ¼ 7.4 Hz), 7.51 (d, 2H, Ho-Ph, J ¼ 6.4 Hz),
7.63 (s, 1H, H-500), 10.82 ppm (s, 1H, 30-NH); 13C NMR (100
MHz, DMSO-d6): d 11.4 (3-CH3), 21.0 (CH3Ar), 120.9 (C-4),
122.4 (Co-Ph), 122.6 (Ci-Ar), 126.3 (Cp-Ph), 127.4 (C-50),
127.6 (Cp-Ar), 127.9 (Cm-Ph), 129.2 (C-500), 129.6 (Co-Ar),
131.0 (Cm-Ar), 140.4 (Ci-Ph) 143.2 (C-5), 143.6 (C-20), 144.9
(C-3), 162.4 ppm (C-40); ms (EI, 70 eV) m/z (%): 389 (Mþ,
100), 213 (69), 148 (32). Anal. Calcd for C21H19N5OS: C,
64.76; H, 4.92; N, 17.98. Found: C, 64.70; H, 4.90; N, 17.95.
(Z)-20-[(5-Amino-3-methyl-1-phenylpyrazol-4-yl)imino]-50-
(4-trifluoromethylbenzylidene)-thiazolidin-4-one (4f). This
compound was obtained as yellow solid (ethanol); IR (KBr):
(Z)-20-[(5-Amino-3-methyl-1-phenylpyrazol-4-yl)imino]-50-
(4-bromobenzylidene)thiazolidin-4-one (4b). This compound
was obtained as yellow solid (ethanol); IR (KBr): (NH, NH2)
3442 and 3288, C¼¼O 1698 cmꢀ1
;
1H NMR (400 MHz,
DMSO-d6): d 2.05 (s, 3H, 3-CH3), 5.68 (s, 2H, NH2), 7.34 (t,
1H, Hp-Ph, J ¼ 7.6 Hz), 7.49 (d, 2H, Hm-Ph, J ¼ 8.3 Hz),
7.50 (d, 2H, Ho-Ar, J ¼ 8.0 Hz), 7.63 (d, 2H, Ho-Ph, J ¼ 8.7
Hz), 7.64 (s, 1H, H-500), 7.68 (d, 2H, Hm-Ar, J ¼ 8.0 Hz),
10.88 ppm (s, 1H, 30-NH); 13C NMR (100 MHz, DMSO-d6): d
11.4 (3-CH3), 120.3 (C-4), 122.4 (Co-Ph), 122.9 (Ci-Ar), 126.2
(Cp-Ph), 128.0 (C-500), 128.4 (C-500), 129.1 (Cm-Ph), 131.3 (Co-
Ar), 132.2 (Cm-Ar), 133.1 (Cp-Ar), 139.0 (Ci-Ph), 143.2 (C-5),
143.5 (C-20), 144.9 (C-3), 161.8 ppm (C-40); ms (EI, 70 eV)
(NH, NH2) 3449 and 3296, C¼¼O 1700 cmꢀ1
;
1H NMR (400
MHz, DMSO-d6): d 2.07 (s, 3H, 3-CH3), 5.70 (s, 2H, NH2),
7.34 (t, 1H, Hp-Ph, J ¼ 7.6 Hz), 7.50 (d, 2H, Hm-Ph, J ¼ 7.7
Hz), 7.64 (d, 2H, Ho-Ph, J ¼ 7.7 Hz), 7.74 (s, 1H, H-500), 7.77
(d, 2H, Hm-Ar, J ¼ 8.3 Hz), 7.84 (d, 2H, Ho-Ar, J ¼ 8.3 Hz),
10.97 ppm (s, 1H, 30-NH); 13C NMR (100 MHz, DMSO-d6): d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
An Efficient Two-Step Synthesis of Novel Thiazolo[2,3-b]pyrazolo[3,4-f][1,3,5]triazepines
759
11.3 (3-CH3), 120.3 (C-4), 122.4 (Co-Ph), 122.7 (Ci-Ar), 126.0
3
Ph), 138.5 (C-10a), 143.2 (C-6a), 145.4 (C-9), 165.1 ppm (C-
(Cp-Ph), 126.0 (q, JCAF ¼ 5.2 Hz, Cm-Ar), 127.4 (C-50),
3); ms (EI, 70 eV) m/z (%): 421 (Mþ, 100), 225 (30), 168
(40). Anal. Calcd for C21H16ClN5OS: C, 59.78; H, 3.82; N,
16.60. Found: C, 59.75; H, 3.76; N, 16.50.
1
127.9 (Cm-Ph), 128.5 (q, JCAF ¼ 268.0 Hz, CF3), 128.9 (q,
2
00
0
JCAF ¼ 31.2 Hz Cp-Ar), 129.2 (Co ), 130.0 (C-5 ), 138.9 (Ci-
Ar), 143.2 (C-5), 143.5 (C-20), 144.9 (C-3), 162.3 ppm (C-40);
ms (EI, 70 eV) m/z (%): 443 (Mþ, 100), 213 (77), 145 (40).
Anal. Calcd for C21H16F3N5OS: C, 56.88; H, 3.64; N, 15.79.
Found: C, 56.82; H, 3.65; N, 15.84.
(Z)-2-(4-Fluorobenzylidene)-9-methyl-7-phenyl-5,6-dihydro-
pyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-one (5d). This
compound was obtained as orange solid (ethanol); IR (KBr):
1
NH 3304, C¼¼O 1677 cmꢀ1; H NMR (400 MHz, DMSO-d6):
d 2.21 (s, 3H, 9-CH3), 5.03 (d, 2H, H-5, J ¼ 6.2 Hz), 7.13 (t,
1H, 6-NH, J ¼ 6.2 Hz), 7.35 (t, 1H, Hp-Ph, J ¼ 7.5 Hz), 7.37
(d, 2H, Ho-Ar, J ¼ 8.9 Hz), 7.48 (t, 2H, Hm-Ph, J ¼ 8.3 Hz),
General procedure for the synthesis of (Z)-2-arylidene-9-
methyl-7-phenyl-5-R-5,6-dihydropyrazolo[3,4-f][1,3]thiazolo
[2,3-b][1,3,5]triazepin-3-ones (5a–f and 6a–f). A mixture
of 2-(5-amino-3-methyl-1-phenylpyrazol-4-ylimino)-5-arylide-
nethiazolidin-4-one 4 (1 mmol), formaldehyde or acetaldehyde
(2 mmol), and DMF (2.0 mL) was heated at 70ꢁC for 2 h. The
formed products were precipitated by adding water, filtered off
under vacuum, washed with water and recrystallized from
ethanol.
7.61 (d, 2H, Ho-Ph, J ¼ 8.7 Hz), 7.63 (dd, 2H, Hm-Ar, JF
¼
5.38 Hz, J ¼ 8.9 Hz), 7.72 ppm (s, 1H, H-20); 13C NMR (100
3
MHz, DMSO-d6): d 11.1 (9-CH3), 56.4 (C-5), 116.3 (d, JCAF
¼ 8.0 Hz, Co-Ar), 118.4 (C-9a), 122.5 (Co-Ph), 123.5 (C-6a),
126.4 (Cp-Ph), 127.6 (C-20), 128.9 (Cm-Ph), 130.3 (Ci-Ar),
2
132.1 (d, JCAF ¼ 22.0 Hz, Cm-Ar), 138.5 (Ci-Ph), 143.3 (C-
1
(Z)-9-Methyl-2-(4-nitrobenzylidene)-7-phenyl-5,6-dihydro-
pyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-ona (5a). This
compound was obtained as brown solid (ethanol); IR (KBr):
9), 145.4 (C-10a), 161.1 (C-2), 162.4 (d, JCAF ¼ 248.0 Hz,
Cp-Ar), 165.2 ppm (C-3); ms (EI, 70 eV) m/z (%): 405 (Mþ,
100), 225 (31), 152 (66). Anal. Calcd for C21H16FN5OS: C,
62.21; H, 3.98; N, 17.27. Found: C, 62.27; H, 3.99; N, 17.37.
(Z)-9-Methyl-2-(4-methylbenzylidene)-7-phenyl-5,6-dihydro-
pyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-one (5e). This
compound was obtained as orange solid (ethanol); IR (KBr):
1
NH 3371, C¼¼O 1690 cmꢀ1; H NMR (400 MHz, DMSO-d6):
d 2.19 (s, 3H, 9-CH3), 5.04 (d, 2H, H-5, J ¼ 6.3 Hz), 7.18 (t,
1H, 6-NH, J ¼ 6.2 Hz), 7.34 (t, 1H, Hp-Ph, J ¼ 7.6 Hz), 7.48
(t, 2H, Hm-Ph, J ¼ 8.4 Hz), 7.61 (d, 2H, Ho-Ph, J ¼ 8.7 Hz),
7.77 (s, 1H, H-20), 7.82 (d, 2H, Ho-Ar, J ¼ 8.1 Hz), 8.30 ppm
(d, 2H, Hm-Ar, J ¼ 8.0 Hz); 13C NMR (100 MHz, DMSO-d6):
d 11.1 (9-CH3), 56.5 (C-5), 118.2 (C-9a), 122.5 (Co-Ph), 124.1
(Cm-Ar), 125.9 (C-20), 126.5 (Cp-Ph), 128.6 (C-2), 129.0 (Cm-
Ph), 130.5 (Co-Ar), 138.4 (C-6a), 138.5 (Ci-Ph), 139.9 (Ci-Ar),
142.5 (C-10a), 145.5 (C-9), 146.7 (Cp-Ar), 164.8 ppm (C-3);
ms (EI, 70 eV) m/z (%): 432 (Mþ, 100), 225 (27), 131 (28).
Anal. Calcd for C21H16N6O3S: C, 58.32; H, 3.73; N, 19.43.
Found: C, 58.36; H, 3.67; N, 19.50.
1
NH 3357, C¼¼O 1708 cmꢀ1; H NMR (400 MHz, DMSO-d6):
d 2.22 (s, 3H, 9-CH3), 2.37 (s, 3H, CH3Ar), 5.03 (d, 2H, H-5,
J ¼ 6.0 Hz), 6.82 (t, 1H, 6-NH, J ¼ 6.0 Hz), 7.32 (t, 1H, Hp-
Ph, J ¼ 7.3 Hz), 7.34 (t, 2H, Hm-Ph, J ¼ 7.1 Hz), 7.46 (d, 2H,
Ho-Ph, J ¼ 8.3 Hz), 7.48 (d, 2H, Ho-Ar, J ¼ 7.7 Hz), 7.61 (d,
2H, Hm-Ar, J ¼ 7.7 Hz), 7.65 ppm (s, 1H, H-20); 13C NMR
(100 MHz, DMSO-d6): d 11.4 (9-CH3), 21.3 (CH3Ar), 57.1
(C-5), 118.9 (C-10a), 123.0 (Cm-Ar), 123.5 (Ci-Ar), 126.8 (Cp-
Ph), 129.3 (C-20), 129.3 (Co-Ph), 130.1 (Co-Ar), 130.2 (Cm-
Ph), 131.6 (Ci-Ph), 139.2 (C-2), 139.4 (C-6a), 140.2 (Cp-Ar),
143.9 (C-10a), 145.9 (C-9), 165.7 ppm (C-3); ms (EI, 70 eV)
m/z (%): 401 (Mþ, 71), 225 (21), 148 (100), 77 (100). Anal.
Calcd for C22H19N5OS: C, 65.82; H, 4.77; N, 17.44. Found: C,
65.72; H, 4.71; N, 17.38.
(Z)-2-(4-Bromobenzylidene)-9-methyl-7-phenyl-5,6-dihydro-
pyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-one (5b). This
compound was obtained as red solid (ethanol); IR (KBr): NH
;
3394, C¼¼O 1682 cmꢀ1 1H NMR (400 MHz, DMSO-d6): d
2.20 (s, 3H, 9-CH3), 5.02 (d, 2H, H-5, J ¼ 6.0 Hz), 7.15 (t,
1H, 6-NH, J ¼ 6.0 Hz), 7.34 (t, 1H, Hp-Ph, J ¼ 7.5 Hz), 7.48
(t, 2H, Hm-Ph, J ¼ 8.2 Hz), 7.53 (d, 2H, Ho-Ar, J ¼ 8.0 Hz),
7.61 (d, 2H, Ho-Ph, J ¼ 8.6 Hz), 7.66 (s, 1H, H-20), 7.70 ppm
(d, 2H, Hm-Ar, J ¼ 8.0 Hz); 13C NMR (100 MHz, DMSO-d6):
d 11.1 (9-CH3), 56.4 (C-5), 118.3 (C-9a), 122.4 (Co-Ph), 122.9
(Cp-Ar), 124.7 (C-20), 126.4 (Cp-Ph), 127.4 (C-2), 129.0 (Cm-
Ph), 131.5 (Ci-Ar), 132.1 (Co-Ar), 132.8 (Cm-Ar), 138.4 (C-
6a), 138.5 (Ci-Ph), 143.1 (C-10a), 145.4 (C-9), 165.1 ppm (C-
3); ms (EI, 70 eV) m/z (%): 465 (Mþ, 83), 225 (52), 212 (52),
77 (100). Anal. Calcd for C21H16BrN5OS: C, 54.09; H, 3.46;
N, 15.02. Found: C, 54.00; H, 3.39; N, 15.10.
(Z)-9-Methyl-7-phenyl-2-(4-trifluoromethylbenzylidene)-5,
6-dihydropyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-one
(5f). This compound was obtained as orange solid (ethanol);
IR (KBr): NH 3341, C¼¼O 1689 cmꢀ1
;
1H NMR (400 MHz,
DMSO-d6): d 2.22 (s, 3H, 9-CH3), 5.81 (m, 2H, H-5), 7.14 (t,
1H, 6-NH), 7.33 (t, 1H, Hp-Ph, J ¼ 7.5 Hz), 7.48 (t, 2H, Hm-
Ph, J ¼ 7.9 Hz), 7.58 (d, 2H, Ho-Ph, J ¼ 8.3 Hz), 7.75 (s, 1H,
H-20), 7.80 (d, 2H, Ho-Ar, J ¼ 8.3 Hz), 7.85 ppm (d, 2H, Hm-
Ar, J ¼ 8.3 Hz); 13C NMR (100 MHz, DMSO-d6): d 11.2 (9-
3
CH3), 63.6 (C-5), 118.8 (C-9a), 123.1 (Co-Ph), 125.7 (q, JCAF
1
¼ 5.6 Hz Cm-Ar), 125.9 (q, JCAF ¼ 274.0 Hz, CF3,), 126.4
2
(Z)-2-(4-Chlorobenzylidene)-9-methyl-7-phenyl-5,6-dihydro-
pyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-one (5c). This
compound was obtained as red solid (ethanol); IR (KBr): NH
(q, JCAF ¼ 30.6 Hz, Cp-Ar), 126.5 (Cp-Ph), 126.6 (C-20),
129.2 (C-6a), 129.5 (Ci-Ar), 130.6 (Cm-Ph), 132.4 (Co-Ar),
138.1 (Ci-Ph), 138.9 (C-2), 142.2 (C-10a), 145.8 (C-9), 165.05
ppm (C-3); ms (EI, 70 eV) m/z (%): 455 (Mþ, 100), 225 (20),
77 (34). Anal. Calcd for C22H16F3N5OS: C, 58.02; H, 3.54; N,
15.38. Found: C, 58.11; H, 3.60; N, 15.48.
3382, C¼¼O 1704 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6): d
2.21 (s, 3H, 9-CH3), 5.02 (d, 2H, H-5, J ¼ 5.9 Hz), 7.21 (t,
1H, 6-NH, J ¼ 5.9 Hz), 7.33 (t, 1H, Hp-Ph, J ¼ 7.6 Hz), 7.48
(t, 2H, Hm-Ph, J ¼ 8.3 Hz), 7.60 (d, 2H, Ho-Ar, J ¼ 8.2 Hz),
7.62 (d, 2H, Ho-Ph, J ¼ 8.7 Hz), 7.64 (d, 2H, Hm-Ar, J ¼ 8.3
Hz), 7.71 ppm (s, 1H, H-20); 13C NMR (100 MHz, DMSO-d6):
d 11.2 (9-CH3), 56.5 (C-5), 118.3 (C-9a), 122.5 (Co-Ph), 124.6
(C-20), 124.7 (Cp-Ar), 126.4 (Cp-Ph), 127.3 (C-2), 129.0 (Cm-
Ph), 129.3 (Co-Ar), 131.5 (Cm-Ar), 132.6 (Ci-Ar), 134.1 (Ci-
(Z)-5,9-Dimethyl-2-(4-nitrobenzylidene)-7-phenyl-5,6-dihydro-
pyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-one (6a). This
compound was obtained as red solid (ethanol); IR (KBr): NH
3318, C¼¼O 1691 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6): d
1.35 (d, 3H, 5-CH3, J ¼ 7.0 Hz), 2.21 (s, 3H, 9-CH3), 5.81
(m, 1H, H-5), 7.16 (d, 1H, 6-NH, J ¼ 6.1 Hz), 7.34 (t, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

´
B. Insuasty, A. Tigreros, H. Martınez, J. Quiroga, R. Abonia, A. Gutierrez, M. Nogueras,
and J. Cobo
760
Vol 46
Hp-Ph, J ¼ 7.9 Hz), 7.48 (t, 2H, Hm-Ph, J ¼ 7.0 Hz), 7.58 (d,
2H, Ho-Ph, J ¼ 7.9 Hz), 7.76 (s, 1H, H-20), 7.83 (d, 2H, Ho-
Ar, J ¼ 7.9 Hz), 8.29 ppm (d, 2H, Hm-Ar, J ¼ 7.9 Hz); 13C
NMR (100 MHz, DMSO-d6): d 11.6 (9-CH3), 21.0 (5-CH3),
63.7 (C-5), 118.7 (C-9a) 123.1 (Co-Ph), 124.7 (Cm-Ar), 126.4
(C-20), 127.1 (Cp-Ph), 128.7 (C-2), 129.6 (Cm-Ph), 131.0 (Co-
Ar), 136.5 (C-6a), 138.9 (Ci-Ph), 140.5 (Cp-Ar), 141.9 (C-
10a), 145.80 (C-9), 147.3 (Ci-Ar), 164.9 ppm (C-3); ms (EI,
70 eV) m/z (%): 446 (Mþ, 100), 413 (30), 239 (20). Anal.
Calcd for C22H18N6O3S: C, 59.18; H, 4.06; N, 18.82. Found:
C, 59.10; H, 4.01; N, 18.90.
(86). Anal. Calcd for C22H18FN5OS: C, 62.99; H, 4.33; N,
16.70. Found: C, 62.91; H, 4.39; N, 16.78.
(Z)-5,9-Dimethyl-2-(4-methylbenzyliden)-7-phenyl-5,6-dihy-
dropyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-one (6e). This
compound was obtained as yellow solid (ethanol); IR (KBr):
1
NH 3442, C¼¼O 1701 cmꢀ1; H NMR (400 MHz, DMSO-d6):
d 1.35 (d, 3H, 5-CH3, J ¼ 6.4 Hz), 2.24 (s, 3H, 9-CH3), 2.39
(s, 3H, CH3Ar), 5.83 (m, 1H, H-5), 7.10 (d, 1H, 6-NH, J ¼
5.0 Hz), 7.34 (t, 1H, Hp-Ph, J ¼ 6.2 Hz), 7.35 (t, 2H, Hm-Ph,
J ¼ 7.4 Hz), 7.38 (d, 2H, Ho-Ph, J ¼ 8.5 Hz), 7.49 (d, 2H,
Ho-Ar J ¼ 7.7 Hz), 7.61 (d, 2H, Hm-Ar, J ¼ 7.7 Hz), 7.67
ppm (s, 1H, H-20); 13C NMR (100 MHz, DMSO-d6): d 11.1
(9-CH3), 20.5 (5-CH3), 21.3 (CH3Ar), 62.9 (C-4), 118.5 (C-
9a), 124.2 (Cm-Ar), 125.5 (Ci-Ar), 126.7 (Cp-Ph), 128.4 (C-20),
129.3 (Co-Ph), 130.1 (Co-Ar), 131.2 (Cm-Ph), 131.6 (Ci-Ph),
139.7 (C-2), 141.0 (C-6a), 141.2 (Cp-Ar), 142.5 (C-10a), 145.2
(C-9), 165.7 ppm (C-3); ms (EI, 70 eV) m/z (%): 415 (Mþ,
100), 239 (46), 148 (57), 77 (73). Anal. Calcd for
C23H21N5OS: C, 66.48; H, 5.09; N, 16.85. Found: C, 66.39; H,
5.17; N, 16.84.
(Z)-2-(4-Bromobenzylidene)-5,9-dimethyl-7-phenyl-5,6-dihy-
dropyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-one (6b). This
compound was obtained as yellow solid (ethanol); IR (KBr):
1
NH 3298, C¼¼O 1688 cmꢀ1; H NMR (400 MHz, DMSO-d6):
d 1.35 (d, 3H, 5-CH3, J ¼ 5.6 Hz), 2.23 (s, 3H, 9-CH3), 5.84
(m, 1H, H-5), 6.81 (d, 1H, 6-NH, J ¼ 6.2 Hz), 7.33 (t, 1H,
Hp-Ph, J ¼ 7.1 Hz), 7.48 (t, 2H, Hm-Ph, J ¼ 7.3 Hz), 7.52 (d,
2H, Ho-Ar, J ¼ 8.0 Hz), 7.62 (d, 2H, Ho-Ph, J ¼ 8.2 Hz),
7.65 (s, 1H, H-20), 7.74 ppm (d, 2H, Hm-Ar, J ¼ 8.0 Hz); 13C
NMR (100 MHz, DMSO-d6): d 11.3 (9-CH3), 20.9 (5-CH3),
63.9 (C-5), 118.2 (C-9a), 122.3 (Co-Ph), 123.0 (Cp-Ar), 124.6
(C-20), 127.4 (Cp-Ph), 127.8 (C-2), 128.6 (Cm-Ph), 131.7 (Ci-
Ar), 132.1 (Co-Ar), 132.8 (Cm-Ar), 138.8 (C-6a), 139.3 (Ci-
Ph), 143.1 (C-10a), 145.4 (C-9), 165.2 ppm (C-3); ms (EI, 70
eV) m/z (%): 479 (Mþ, 100), 481 (98), 239 (50), 168 (44), 77
(75). Anal. Calcd for C22H18BrN5OS: C, 55.01; H, 3.78; N,
14.58. Found: C, 55.09; H, 3.83; N, 14.67.
(Z)-5,9-Dimethyl-7-phenyl-2-(4-trifluoromethylbenzyli-dene)-
5,6-dihydropyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]tri-azepin-3-one
(6f). This compound was obtained as orange solid (ethanol);
IR (KBr): NH 3341, C¼¼O 1689 cmꢀ1
;
1H NMR (400 MHz,
DMSO-d6): d 1.35 (d, 3H, 5-CH3, J ¼ 6.5 Hz), 2.21 (s, 3H, 9-
CH3), 5.04 (m, 1H, H-5), 7.17 (s, 1H, 6-NH), 7.34 (t, 1H, Hp-
Ph, J ¼7.3 Hz), 7.49 (t, 2H, Hm-Ph, J ¼ 7.8 Hz), 7.63 (d, 2H,
Ho-Ph, J ¼ 8.3 Hz), 7.77 (s, 1H, H-20), 7.81 (d, 2H, Ho-Ar, J
¼ 8.3 Hz), 7.87 ppm (d, 2H, Hm-Ar, J ¼ 8.3 Hz); 13C NMR
(100 MHz, DMSO-d6): d 11.1 (9-CH3), 21.0 (5-CH3), 56.5 (C-
(Z)-2-(4-Chlorobenzylidene)-5,9-dimethyl-7-phenyl-5,6-dihy-
dropyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-one (6c). This
compound was obtained as yellow solid (ethanol); IR (KBr):
3
5), 118.8 (C-9a), 122.2 (Co-Ph), 125.3 (q, JCAF ¼ 4.3 Hz,
2
1
1
Cm-Ar), 125.8 (q, JCAF ¼ 31.6 Hz, Cp-Ar), 126.0 (q, JCAF ¼
NH 3296, C¼¼O 1687 cmꢀ1; H NMR (400 MHz, DMSO-d6):
276.0 Hz, CF3), 126.5 (Cp-Ph), 126.6 (C-20), 127.0 (C-5a),
128.7 (Ci-Ar), 128.9 (Cm-Ph), 130.2 (Co-Ar), 137.6 (Ci-Ph),
138.5 (C-2), 142.8 (C-10a), 145.5 (C-9), 164.9 ppm (C-3); ms
(EI, 70 eV) m/z (%): 469 (Mþ, 100), 239 (23), 145 (17). Anal.
Calcd for C23H18F3N5OS: C, 58.84; H, 3.86; N, 14.92. Found:
C, 58.91; H, 3.79; N, 14.99.
d 1.35 (d, 3H, 5-CH3, J ¼ 6.6 Hz), 2.23 (s, 3H, 9-CH3), 5.82
(m, 1H, H-5), 7.13 (d, 1H, 6-NH, J ¼ 5.0 Hz), 7.34 (t, 1H,
Hp-Ph, J ¼ 7.2 Hz), 7.49 (t, 2H, Hm-Ph, J ¼ 7.4 Hz), 7.59 (d,
2H, Ho-Ph, J ¼ 8.2 Hz), 7.62 (d, 2H, Ho-Ar, J ¼ 8.2 Hz),
7.63 (d, 2H, Hm-Ar, J ¼ 8.2 Hz), 7.71 ppm (s, 1H, H-20); 13C
NMR (100 MHz, DMSO-d6): d 11.1 (9-CH3), 20.5 (5-CH3),
56.5 (C-5), 118.4 (C-9a), 122.6 (Co-Ph), 124.3 (C-20), 126.6
(Cp-Ar), 127.4 (Cp-Ph), 129.1 (C-2), 129.3 (Cm-Ph), 131.3 (Co-
Ar), 132.6 (Cm-Ar), 134.1 (Ci-Ar), 135.9 (Ci-Ph), 138.5 (C-
10a), 142.0 (C-6a), 145.2 (C-9), 164.7 ppm (C-3); ms (EI, 70
eV) m/z (%): 435 (Mþ, 100), 239 (52), 168 (47), 77 (86).
Anal. Calcd for C22H18ClN5OS: C, 60.62; H, 4.16; N, 16.06.
Found: C, 60.55; H, 4.23; N, 16.15.
Acknowledgments. The authors are grateful to Colciencias,
´
Universidad del Valle, the Spanish ‘‘Consejerıa de Innovacion,
Ciencia y Empresa, Junta de Andalucıa,’’ and ‘‘Servicios Tecni-
´
´
´
´
cos de Investigacion de la Universidad de Jaen’’ for the financial
support, and Dr Fabio Zuluaga for reviewing this manuscript.
´
REFERENCES AND NOTES
(Z)-5,9-Dimethyl-2-(4-fluorobenzylidene)-7-phenyl-5,6-dihy-
dropyrazolo[3,4-f]thiazolo[2,3-b][1,3,5]triazepin-3-one (6d). This
compound was obtained as yellow solid (ethanol); IR (KBr):
[1] (a) Fray, M. J.; Bull, D. J.; Cooper, K.; Parry, M. J.; Stefa-
niak, M. H. J Med Chem 1995, 38, 3524; (b) Kelly, T. A.; McNeil, D.
W.; Rose, J. M.; David, E.; Shih, C.-K.; Grob, P. M. J Med Chem
1997, 40, 2430.
1
NH 3398, C¼¼O 1692 cmꢀ1; H NMR (400 MHz, DMSO-d6):
d 1.35 (d, 3H, 5-CH3, J ¼ 6.6 Hz), 2.23 (s, 3H, 9-CH3), 5.83
(m, 1H, H-5), 7.12 (d, 1H, 6-NH, J ¼ 5.0 Hz), 7.34 (t, 1H,
Hp-Ph, J ¼ 6.1 Hz), 7.38 (d, 2H, Ho-Ar, J ¼ 8.7 Hz), 7.49 (t,
2H, Hm-Ph, J ¼ 8.1 Hz), 7.61 (d, 2H, Ho-Ph, J ¼ 7.4 Hz),
7.68 (dd, 2H, Hm-Ar, J ¼ 8.7 Hz, J ¼ 5.38 Hz), 7.72 ppm (s,
1H, H-20); 13C NMR (100 MHz, DMSO-d6): d 11.1 (9-CH3),
[2] De Wald, A. H.; Lobbestaell, S.; Poschel, B. P. H. J Med
Chem 1981, 24, 982.
[3] (a) Sternbach, L. M. Prog Drug Res 1978, 22, 229; (b)
Sharp, J. T. In Comprehensive Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Lwowski, W., Eds; Pergamon Press: Oxford, 1984;
Vol. 1, p 593; (c) Chimirri, A.; Gitto, R.; Grasso, S.; Monforte, A. M.;
Romero, G.; Zappala, M. Heterocycles 1993, 36, 601; (d) Tsuchiya, T.
Yuki Gosei Kagaku Kyokaishi 1983, 41, 641; Chem Abstr 1983, 99,
212426n.
2
20.5 (5-CH3), 63.1 (C-5), 116.2 (d, JCAF ¼ 21.0 Hz, Co-Ar),
118.4 (C-9a), 122.6 (Co-Ph), 123.1 (C-6a), 127.7 (C-20), 127.8
(Cp-Ph), 128.6 (C-2), 129.1 (Cm-Ph), 131.0 (Ci-Ar), 132.1 (d,
3JCAF ¼ 9.0 Hz, Cm-Ar), 138.5 (Ci-Ph), 142.2 (C-10a), 145.2
1
(C-9), 162.4 (d, JCAF ¼ 248.0 Hz, Cp-Ar), 164.8 (C-3); ms
[4] Insuasty, B.; Quiroga, J.; Meier, H. Trends Heterocycl
Chem 1997, 5, 83.
(EI, 70 eV) m/z (%): 419 (Mþ, 100), 239 (49), 152 (66), 77
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
An Efficient Two-Step Synthesis of Novel Thiazolo[2,3-b]pyrazolo[3,4-f][1,3,5]triazepines
761
´
´
[5] (a) Insuasty, B.; Rodrıguez, R.; Quiroga, J.; Martınez, R.;
Angeles, E. J Heterocycl Chem 1997, 34, 1131; (b) Orlov, V. D.;
Quiroga, J.; Kolos, N. N. Khim Geterotsikl Soedin 1987, 304; (c)
Orlov, V. D.; Quiroga, J.; Marrugo, A.; Kolos, N. N.; Iksanova, S. V.
Khim Geterotsikl Soedin 1987, 1254; (d) Orlov, V. D.; Kolos, N. N.;
Quiroga, J.; Kaluski, Z.; Figas, E.; Potekhin, A. Khim Geterotsikl Soe-
Commun 2004, 10, 103; (i) Abonia, R.; Insuasty, B.; Quiroga, J.;
Nogueras, M.; Meier, H. Mini Rev Org Chem 2004, 1, 387; (j)
´
Insuasty, B.; Ramos, M.; Quiroga, J.; Sanchez, A.; Nogueras, M.; Han-
old, N.; Meier, H. J Heterocycl Chem 1994, 31, 61.
[6] (a) Delgado, P.; Quiroga, J.; Cobo, J.; Low, J. N.; Glide-
well, C. Acta Crystallogr C 2005, 61, 477; (b) Delgado, P.; Quiroga,
J.; de la Torre, J.; Cobo, J.; Low, J. N.; Glidewell, C. Acta Crystallogr
´
´
din 1992, 424; (e) Insuasty, B.; Rodrıguez, R.; Quiroga, J.; Abonıa,
R.; Saitz, C.; Jullian, C. Heterocycl Commun 2000, 6, 231; (f)
Insuasty, B.; Insuasty, H.; Quiroga, J.; Saitz, C.; Jullian, C. J Hetero-
´
C 2006, 62, 382; (c) Sortino, M.; Delgado, P.; Juarez, S.; Quiroga, J.;
´
Abonıa, R.; Insuasty, B.; Nogueras, M.; Rodero, L.; Gariboto, F.;
´
cycl Chem 1999, 36, 635; (g) Insuasty, B.; Rodrıguez, R.; Quiroga, J.;
´ ´
Abonıa, R.; Martınez, R.; Toscano, A.; Angeles, E. Molecules 2001, 6,
Enriz, R.; Zacchino, S. Bioorg Med Chem 2007, 15, 484.
[7] Insuasty, B.; Abonia, R.; Quiroga, J. An Quim 1992, 88, 718.
[8] Delgado, P.; Cruz, S.; Cobo, J.; Low, J. N.; Glidewell, C.
Acta Crystallogr E 2005, 61, 3998.
´
710; (h) Insuasty, B.; Quiroga, J.; Abonıa, R.; Insuasty, H.; Mosquera,
M.; Cruz, S.; Nogueras, M.; Sortino, M.; Zacchino, S. Heterocycl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet