Microwave-assisted synthesis of fused heterocycles incorporating trifluoromethyl moiety

Article abstract of DOI:10.1016/j.jfluchem.2008.09.002

4,4,4-Trifluoro-1-(thien-2-yl)butane-1,3-dione (1) reacts with 5-aminopyrazole, 1,2,4-aminotriazole and 2-aminobenzimidazole derivatives, in the presence of triethylorthoformate under pressurized microwave irradiation to afford the corresponding trifluoromethyl derivatives of pyrazolo[1,5-a]pyrimidine, 1,2,4-triazolo[1,5-a]pyrimidine, and pyrimido[1,2-a]benzimidazoles. Also, compound 1 couples readily with azole diazonium salts to give pyrazolo[5,1-c]triazine, benzimidazo[5,1-c]1,2,4-triazine, and triazolo[3,4-c]1,2,4-triazine derivatives incorporating trifluoromethyl group.

Full text of DOI:10.1016/j.jfluchem.2008.09.002

Journal of Fluorine Chemistry 129 (2008) 1156–1161
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Microwave-assisted synthesis of fused heterocycles incorporating
trifluoromethyl moiety
Mohamed R. Shaaban
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
A R T I C L E I N F O
A B S T R A C T
Article history:
4,4,4-Trifluoro-1-(thien-2-yl)butane-1,3-dione (1) reacts with 5-aminopyrazole, 1,2,4-aminotriazole
and 2-aminobenzimidazole derivatives, in the presence of triethylorthoformate under pressurized
microwave irradiation to afford the corresponding trifluoromethyl derivatives of pyrazolo[1,5-
a]pyrimidine, 1,2,4-triazolo[1,5-a]pyrimidine, and pyrimido[1,2-a]benzimidazoles. Also, compound 1
couples readily with azole diazonium salts to give pyrazolo[5,1-c]triazine, benzimidazo[5,1-c]1,2,4-
triazine, and triazolo[3,4-c]1,2,4-triazine derivatives incorporating trifluoromethyl group.
ß 2008 Elsevier B.V. All rights reserved.
Received 9 July 2008
Received in revised form 3 September 2008
Accepted 5 September 2008
Available online 20 September 2008
Keywords:
4,4,4-Trifluoro-1-(thien-2-yl)butane-1,3-
dione
Fluorine building blocks
Trifluoromethyl fused heterocycles
Hetrocyclic amines
Hetrocyclic diazonium salts
Microwave irradiation
1. Introduction
wide variety of trifluoromethyl-substituted heterocyles. These
include pyrazoles [32–34], pyridines [35], pyrimidines [36],
Fluorine-containing heterocyclic compounds have attracted
much interest because of their potent biological and pharmaco-
logical activities [1–3], in addition to their role in the development
of new functional materials [4–10]. Pyrimidine and triazine ring
systems fused with pyrazoles, triazoles and benzimidazoles have
shown diverse biological activities [11–19]. Among these the
important effects are analgesic and antinociceptive activities,
many fluorinated analogues of biologically active molecules have
exhibited dramatic enhancement in their properties. However,
direct fluorination of heterocyclic compounds is not always
straightforward. Recently, new methodologies of fluorination have
been shown to be more elegant and applicable than conventional
fluorination methods such as electrochemical fluorination [20–24]
or using various fluorine-containing building blocks [25–27]. In
this context, trifluoromethylated 1,3-dicarbonyl derivatives con-
stitute important synthetic intermediates, incorporating multiple
functionalities that can be involved either as nucleophilic or
electrophilic species in a large variety of synthetic transformations
[28–31]. Their versatility and effectiveness as potential multi-
component substrates have been proven to be building blocks for a
isoxazoles [37], and thiazoles [38]. However, most of the thermal
syntheses of such compounds consume a lot of time and/or lake of
high selectivity. On the other hand, microwave irradiation has
recently demonstrated its utility as an energy source to improve
yields and/or save reaction conditions, especially in the field of
heterocyclic synthesis [39–41]. The use of the pressurized
microwave irradiation can be very advantageous to many
chemistries where the solvent can be heated up to temperatures
that are 2–4 times their respective boiling points and thus
providing large rate enhancement. In addition, keeping the
atmosphere from moisture that may affect the moisture sensitive
reagents decreases the possibility of formation of the undesired
byproducts. As a part of systematic study on the synthesis of new
fused heterocyclic systems having potential unique properties
[42,43], we report the synthesis of several pyrazolopyrimidine,
triazolopyrimidine, and benzimidazolopyrimidines attached to
trifluoromethyl moiety as well as fused triazine derivatives using
microwaves.
2. Results and discussion
The behavior of 4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-
E-mail address: rabiemohamed@hotmail.com.
dione (1) towards some aminopyrazole derivatives as potential
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.09.002

M.R. Shaaban / Journal of Fluorine Chemistry 129 (2008) 1156–1161
1157
Scheme 1.
precursors for interesting biologically active pyrazolo[1,5-a]pyr-
imidine derivatives was investigated. Thus, when compound 1
was treated with 5-amino-1H-pyrazole derivatives 3a–d in the
presence of excess amount of triethylorthoformate under
pressurized microwave irradiation, it afforded the corresponding
5-(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine derivatives 5a–d
in almost quantitative yield (Scheme 1). The mass spectrum of
compound 5a, taken as an example of the prepared series,
revealed a molecular ion peak at m/z 311. Its 1H NMR spectrum
which undergo intramolecular cyclization and aromatization
to give the final products 5a–d (Scheme 1). This conclusion was
further unequivocally confirmed by X-ray crystallography
(Fig. 1), where single crystal X-ray diffraction of compound 5a
adds sharp evidence for the proposed structure 5a–d rather than
structure 7 or 8.
Similarly, 4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-dione (1)
reacts with 3-amino-1,2,4-triazole (9) and triethylorthoformate
to afford 6-thienoyl-7-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyr-
imidine (10) as shown in Scheme 2. The 1H NMR spectrum of the
revealed a singlet signal at
d
d
9.64 due to pyrimidine-CH and three
3
doublets of doublet at
8.22 (3JHH = 5.0 Hz, JHH = 4.0 Hz),
latter product revealed a singlet at
d 10.13 due to pyrimidine-CH, a
4
7.94 (3JHH = 5.0 Hz, JHH = 1.0 Hz) and 7.29 (3JHH = 4.0 Hz,
4JHH = 0.9 Hz) due to thiophene protons, respectively, in addition
singlet at 9.03 due to the triazole proton and three doublets of
d
doublet in the region of 7.31–8.29 due to thiophene protons. The IR
spectrum of the same compound exhibited absorption band at
1695 cmÀ1 due to a carbonyl function.
Compound 1 reacts also with 2-amino-benzimidazole (11),
under the same experimental conditions to afford only one isolable
product (as examined by TLC). The reaction product was identified
as 6-thienoyl-7-(trifluoromethyl) benzimidazo[1,2-a]pyrimidine
(12) (Scheme 2).
Next, a new and convenient route to some heterocyclic fused
triazines with bridgehead nitrogen atom was also investigated.
Thus, 4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-dione (1) couples
smoothly with the diazonium salt of 1,2,4-aminotriazole 13, in
to a singlet signal at
at
2.51 due to methyl protons. The 19F NMR chemical shift of
the CF3 group at
d 6.94 due to pyrazole proton and a singlet
d
d
À63.69 ppm confirms the presence of the
cyclic structure 5a rather than 8. For the latter compound the
fluorine chemical shift of the CF3 group should be at higher field
[44].
The formation of the products 5a–d is assumed to take place
via an initial addition of the more nucleophilic endocyclic
nitrogen in the aminopyrazole derivatives 3a–d to the
a,b-
unsaturated moiety in the ethoxymethylene derivative 2 to yield
the corresponding acyclic non-isolable intermediates 4a–d

1158
M.R. Shaaban / Journal of Fluorine Chemistry 129 (2008) 1156–1161
Fig. 1. X-ray structure of compound 5a.
Scheme 2.
pyridine at 0 8C, to afford the corresponding hydrazone 14 which
undergoes intramolecular cyclization in pyridine under micro-
wave irradiation to afford the 6-thienoyl-5-(trifluoromethyl)-
[1,2,4]triazolo[3,4-c][1,2,4]triazine (15) (Scheme 3). The IR spec-
trum of the isolated product 15 revealed the disappearance of band
at 3419 cmÀ1 due to the NH function. The 1H NMR spectrum of the
In a similar manner, compound 1 couples readily with the
diazonium salt of 2-aminobenzimidazole and aminopyrazole
derivatives 16a,b and 18, respectively, under the same experi-
mental conditions, to afford, in each case, a single product
according to TLC analysis (Scheme 4).
Based on the elemental analyses and spectral data, the structure
of the isolated products were identified as 6-thienoyl-4-(trifluor-
omethyl)-pyrazolo[5,1-c][1,2,4]triazines 17a,b and 3-thienoyl-4-
latter product displayed a singlet signal at
d 9.31 of the triazole-CH
and signals at 7.25–8.06 due to thiophene protons.
d
Scheme 3.
Scheme 4.

M.R. Shaaban / Journal of Fluorine Chemistry 129 (2008) 1156–1161
1159
(trifluoromethyl)-benzimidazo[2,1-c][1,2,4]triazine (19), respec-
tively (see Section 4).
CF3); EIMS (probe) 70 eV, m/z (rel. int.): 311 [M]+ (54). Anal. Calcd
for C13H8F3N3OS: C, 50.16; H, 2.59; N, 13.50; S, 10.30. Found: C,
50.04; H, 2.53; N, 13.50; S, 10.20.
3. Conclusions
4.1.2. X-ray crystallography
A single crystal of compound 5a was obtained by slow
evaporation from benzene. The crystal structure was solved and
This work shows that trifluoromethylated 1,3-dicarbonyl
derivatives still constitute versatile substrates in fluorine chem-
istry and can be accommodated in many diverse synthetic
pathways. The high synthetic potential of these very easily
accessible reagents has found numerous applications, especially
for the synthesis of fused heterocyclic compounds. Use of
microwaves in new synthetic transformations making use of
trifluoromethylated 1,3-dicarbonyls towards conventional meth-
ods should enlarge the scope of this field, allowing the facile and
selective construction of highly functionalized fused heterocycles
of high synthetic and biological value.
refined using maxus (nonius, Deflt and MacScience, Japan) Mo-K
˚
radiation (l = 0.71073 A) and a graphite monochromator were
a
used for data collection. The chemical formula and ring labeling
system is shown in Fig. 1.
Crystallographic data (excluding structure factors) for the
structure in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number
CCDC 693229. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union, Road, Cambridge CB2 1EZ, UK [fax:
44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
4. Experimental
4.1.2.1. 2-Methyl-3-phenyl-6-thienoyl-5-(trifluoromethyl)pyra-
All melting points were measured on a Gallenkamp melting
point apparatus. The infrared spectra were recorded in potassium
bromide disks on a pye Unicam SP 3300 and Shimadzu FT IR 8101
PC infrared spectrophotometers. The NMR spectra were recorded
on a Varian Mercury VX-300 NMR spectrometer. 1H spectra were
run at 300 MHz and 13C spectra were run at 75.46 MHz in
deuterated dimethyl sulphoxide (DMSO-d6). Chemical shifts were
related to that of the solvent. 19F NMR spectra were obtained using
CFCl3 as an internal standard. Mass spectra were recorded on a
Shimadzu GCMS-QP1000 EX mass spectrometer at 70 eV. Ele-
mental analyses were carried out at the Microanalytical Center of
Cairo University, Giza, Egypt. Microwave experiments were carried
out using CEM Discover LabmateTM microwave apparatus (300 W
with ChemDriverTM Software). 4,4,4-Trifluoro-1-(thien-2-yl)-
butane-1,3-dione (1) was purchased from Fluka chemicals.
Aminopyrazoles 3a–d [45–47], heterocyclic diazonium salts 13,
16a,b, and 18 [48] were prepared according to procedures reported
in the literature.
zolo[1,5-a]pyrimidine (5b). Yield (86%); mp 184 8C; IR (KBr)
y 1658
(C O), 1596 (C N) cmÀ1; 1H NMR (DMSO-d6):
d
2.60 (3H, s), 7.24
3
4
3
(1H, dd, JHH = 4.0 Hz, JHH = 0.9 Hz), 7.25 (1H, dd, JHH = 5.0 Hz,
4JHH = 1.0 Hz), 7.53–7.82 (5H, m), 8.02 (1H, s) 8.22 (1H, dd,
3JHH = 5.0 Hz, JHH = 4.0 Hz); 13C NMR (DMSO-d6):
d (12.76, CH3),
3
(98.51, 126.62, 135.98, 143.05, 146.80, 167.30: pyrazolo[1,5-
a]pyrimidine), (104.60, CF3), (125.32, 127.54, 129.64, 133.09:
phenyl ring), (128.88, 133.33, 136.40, 157.82: thiophene ring),
(182.83, C O); 19F NMR (DMSO-d6):
d
À63.48 (s, CF3); EIMS
(probe) 70 eV, m/z (rel. int.): 387 [M]+ (43). Anal. Calcd for
19H12F3N3OS: C, 58.91; H, 3.12; N, 10.85; S, 8.28. Found: C, 58.88;
C
H, 3.11; N, 10.78; S, 8.29.
4.1.2.2. 2-Phenyl-6-thienoyl -5-(trifluoromethyl)pyrazolo[1,5-a]pyr-
imidine (5c). Yield (82%); mp 202 8C; IR (KBr)
y 1660 (C O), 1596
(C N) cmÀ1 1H NMR (DMSO-d6):
; d 6.90 (1H, s), 7.26 (1H, dd,
3JHH = 4.0 Hz, 4JHH = 0.9 Hz), 7.27 (1H, dd, 3JHH = 5.0 Hz,
4JHH = 1.0 Hz), 7.54–7.80 (5H, m), 8.24 (1H, dd, JHH = 5.0 Hz,
3
3JHH = 4.0 Hz), 9.73 (1H, s); 13C NMR (DMSO-d6):
d (98.53, 126.63,
4.1. Reaction with heterocyclic amines
133.33, 135.98, 145.80, 167.30: pyrazolo[1,5-a]pyrimidine),
(118.60, CF3), (125.32, 127.54, 129.63, 133.10: phenyl ring),
(128.88, 136.40, 143.05, 157.82: thiophene ring), (182.84, C O);
4.1.1. General procedure
To a mixture of 4,4,4-trifluoro-1-(thien-2-yl)-butane-1,3-dione
(1) (2.22 g, 10 mmol) and the appropriate heterocyclic amine
(aminopyrazoles 3a–d, 3-amino-l,2,4-triazole (9) and 2-amino-
benzimidazole (11)) (10 mmol) in triethylorthoformate (0.5 ml)
was mixed in a process vial. The vial was capped properly and
irradiated by microwaves using pressurized conditions (17.2 bar,
100 8C) for 5 min. The excess triethylorthoformate was evaporated
in vacuo and the residual solid was taken in EtOH then collected by
filtration, washed with ethanol, dried and finally recrystallized
from EtOH/DMF to afford the corresponding pyrazolo[1,5-a]pyr-
imidine 5a–d, 1,2,4-triazolo[4,3-a]pyrimidine 10, and pyri-
mido[1,2-a]benzimidazole derivatives 12, respectively. The
physical and spectral data of the synthesized compounds 5a–d,
10 and 12 are listed below.
19F NMR (DMSO-d6):
d
À63.01 (s, CF3); EIMS (probe) 70 eV, m/z (rel.
int.): 373 [M]+ (50). Anal. Calcd for C18H10F3N3OS: C, 57.91; H, 2.70;
N, 11.25; S, 8.59. Found: C, 57.87; H, 2.71; N, 11.35; S, 8.49.
4.1.2.3. 2-(4-Chlorophenyl)-6-thienoyl-5-(trifluoromethyl)pyra-
zolo[1,5-a]pyrimidine (5d). Yield (75%); mp 214 8C; IR (KBr)
y 1654
(C O), 1596 (C N) cmÀ1; 1H NMR (DMSO-d6):
d
6.90 (1H, s), 7.26
3
4
3
(1H, dd, JHH = 4.0 Hz, JHH = 0.9 Hz), 7.27 (1H, dd, JHH = 5.0 Hz,
4JHH = 1.0 Hz), 7.74–8.10 (4H, m), 8.31 (1H, dd, JHH = 5.0 Hz,
3
3JHH = 4.0 Hz), 8.79 (1H, s); 13C NMR (DMSO-d6):
d (98.54, 126.63,
133.09, 133.33, 146.80, 167.40: pyrazolo[1,5-a]pyrimidine),
(119.91, CF3), (125.32, 127.54, 129.65, 136.40: phenyl ring),
(128.98, 135.98, 143.15, 157.82: thiophene ring), (182.83, C O);
19F NMR (DMSO-d6):
d
À62.19 (s, CF3); EIMS (probe) 70 eV, m/z (rel.
int.): 407 [M]+ (38). Anal. Calcd for C18H9ClF3N3OS: C, 58.91; H,
3.12; N, 10.85; S, 8.28. Found: C, 58.88; H, 3.11; N, 10.78; S, 8.26.
4.1.1.1. 3-Methyl-6-thienoyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyri-
midine (5a). Yield (89%); mp 170–171 8C; IR (KBr)
y 1655 (C O),
1596 (C N) cmÀ1; 1H NMR (DMSO-d6):
d
2.51 (3H, s), 6.94 (1H, s),
4.1.2.4. 6-Thienoyl-7-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrimi-
3
4
7.29 (1H, dd, JHH = 4.0 Hz, JHH = 0.9 Hz), 7.94 (1H, dd,
3JHH = 5.0 Hz, 4JHH = 1.0 Hz), 8.22 (1H, dd, 3JHH = 5.0 Hz,
dine (10). Yield (91%); mp > 300 8C; IR (KBr)
1596 (C N) cmÀ1 1H NMR (DMSO-d6):
y
1695 (C O) and
;
d 7.31 (1H, dd,
3JHH = 4.0 Hz), 9.64 (1H, s); 13C NMR (DMSO-d6):
d
(14.37, CH3),
3JHH = 4.5 Hz, 4JHH = 1.0 Hz), 7.93 (1H, dd, 3JHH = 5.0 Hz,
3
3
(98.51, 120.54, 137.89, 138.33, 143.05, 158.42: pyrazolo[1,5-
4JHH = 1.0 Hz), 8.29 (1H, dd, JHH = 5.0 Hz, JHH = 4.5 Hz), 9.03
(1H, s), 10.13 (1H, s); 13C NMR (DMSO-d6):
(119.32, CF3),
(123.88, 124.43, 135.88, 146.14, 151.28: triazolo[4,3-a]pyrimi-
a]pyrimidine), (116.32, CF3), (122.88, 141.98, 142.40, 146.20:
d
thiophene ring), (182.03, C O); 19F NMR (DMSO-d6):
d
À63.69 (s,

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M.R. Shaaban / Journal of Fluorine Chemistry 129 (2008) 1156–1161
dine), (128.73, 131.99, 136.58, 141.00: thiophene ring), (179.31,
O); 19F NMR (DMSO-d6):
m/z (rel. int.): 298 [M]+ (64). Anal. Calcd for C11H5F3N4OS: C, 44.30;
H, 1.69; N, 18.79; S, 10.75. Found: C, 44.27; H, 1.71; N, 18.76; S,
10.78.
4.2.1.3. 7-Phenyl-3-thienoyl-4-(trifluoromethyl)pyrazolo[5,1-
c][1,2,4]triazine (17a). Yield (82%); mp > 300 8C; IR (KBr)
(C O), 1596 (C N) cmÀ1; 1H NMR (DMSO-d6):
6.90 (1H, s), 7.26
C
d
À67.69 (s, CF3); EIMS (probe) 70 eV,
y 1662
d
3
4
3
(1H, dd, JHH = 4.0 Hz, JHH = 0.9 Hz), 7.27 (1H, dd, JHH = 5.0 Hz,
3
4JHH = 1.0 Hz), 7.54–7.80 (5H, m), 8.24 (1H, dd, JHH = 5.0 Hz,
3JHH = 4.0 Hz), 9.73 (1H, s); 13C NMR (DMSO-d6):
d (119.33, CF3),
4.1.2.5. 6-Thienoyl-7-(trifluoromethyl)benzimidazo[1,2-a]pyrimi-
(98.53, 125.52, 126.62, 135.97, 136.40, 143.15, 146.70, 157.82,
dine (12). Yield (83%); mp 244 8C; IR (KBr)
y
1656 (C O), 1596
167.40: pyrazolo[5,1-c][1,2,4]triazine), (127.54, 128.78, 129.64,
(C N) cmÀ1
;
1H NMR (DMSO-d6):
d
7.15 (1H, d), 7.27 (1H, dd,
133.19: thiophene ring), (182.83, C O); 19F NMR (DMSO-d6):
d
4
3JHH = 4.5 Hz, JHH = 1.0 Hz), 7.45 (1H, m), 7.93 (1H, dd,
À65.45 (s, CF3); EIMS (probe) 70 eV, m/z (rel. int.): 374 [M]+ (65).
Anal. Calcd for C17H9F3N4OS: C, 54.54; H, 2.42; N, 14.97; S, 8.57.
Found: C, 54.57; H, 2.40; N, 14.95; S, 8.60.
3JHH = 5.0 Hz, JHH = 1.0 Hz), 7.45 (2H, m), 8.29 (1H, dd,
4
3
3JHH = 5.0 Hz, JHH = 4.5 Hz), 9.02 (1H, s); 13C NMR (DMSO-d6):
d
(102.37, 113.60, 116.32, 120.24, 120.58, 121.42, 133.44, 143.51,
146.20, 158.42: benzimidazo[1,2-a]pyrimidine), (117.62, CF3),
(122.90, 128.25, 130.77, 134.03: thiophene ring), (180.03, C O);
4.2.1.4. 7-Methyl-8-phenyl-3-thienoyl-4-(trifluoromethyl)pyra-
zolo[5,1-c][1,2,4]triazine (17b). Yield (86%); mp 274 8C; IR (KBr)
y
19F NMR (DMSO-d6):
d
À68.45 (s, CF3); EIMS (probe) 70 eV, m/z (rel.
1653 (C O), 1596 (C N) cmÀ1; 1H NMR (DMSO-d6):
d
2.60 (3H, s),
int.): 347 [M]+ (56). Anal. Calcd for C16H8F3N3OS: C, 55.33; H, 2.32;
N, 12.10; S, 9.23. Found: C, 55.23; H, 2.42; N, 12.08; S, 9.13.
7.24 (1H, dd, JHH = 4.0 Hz, JHH = 0.9 Hz), 7.25 (1H, dd,
3
4
4
3JHH = 5.0 Hz, JHH = 1.0 Hz), 7.53–7.82 (5H, m), 8.02 (1H, s) 8.22
(1H, dd, 3JHH = 5.0 Hz, 3JHH = 4.0 Hz); 13C NMR (DMSO-d6):
d (12.76,
4.2. Coupling with azole diazonium salts
CH3), (98.52, 127.64, 133.23, 146.82, 167.30: pyrazolo[5,1-
c][1,2,4]triazine), (120.60, CF3), (125.42, 126.72, 129.65, 143.15:
phenyl ring), (128.88, 135.98, 136.42, 157.82: thiophene ring),
4.2.1. General procedure
To a cold solution of 4,4,4-trifluoro-1-(thien-2-yl)butane-1,3-
dione (1) (2 mmol) in pyridine (25 ml) was added the appropriate
heterocyclic diazonium salt 13, 16a,b, or 18 (2 mmol) portion-
wise over a period of 1/2 h. After stirring for further 3 h at 0–5 8C,
the reaction mixture was left to stand in an ice-box for 12 h then
diluted with water. The solid that precipitated was filtered off
washed with water and dried. Crystallization from the proper
solvent gave the corresponding coupling products. The coupling
products were taken in pyridine and irradiated with microwaves
in a vial for 5 min under the same experimental conditions in the
pervious section. The excess pyridine was evaporated in vacuo
and the residual solid was taken in EtOH then collected by
filtration, washed with ethanol, dried and finally recrystallized
from EtOH/DMF to afford the corresponding triazolo[3,4-
c][1,2,4]triazine 15, benzimidazo[2,1-c][1,2,4]triazine 19, and
pyrazolo[5,1-c][1,2,4]triazines 17a,b. The physical and spectral
data of the synthesized compounds 14, 15, 17a,b and 19 are listed
below.
(182.93, C O); 19F NMR (DMSO-d6):
d
À66.33 (s, CF3); EIMS
(probe) 70 eV, m/z (rel. int.): 388 [M]+ (62). Anal. Calcd for
18H11F3N4OS: C, 55.67; H, 2.85; N, 14.43; S, 8.26. Found: C, 55.63;
C
H, 2.83; N, 14.45; S, 8.22.
4.2.1.5. 3-Thienoyl-4-(trifluoromethyl) benzimidazo[2,1-c][1,2,4]tria-
zine (19). Yield (83%); mp > 300 8C; IR (KBr)
y 1650 (C O), 1596
(C N) cmÀ1 1H NMR (DMSO-d6):
; d 7.15 (1H, d), 7.27 (1H, dd,
3JHH = 4.5 Hz, 4JHH = 1.0 Hz), 7.45 (1H, m), 7.93 (1H, dd, 3JHH = 5.0 Hz,
4JHH = 1.0 Hz), 7.45 (2H, m), 8.29 (1H, dd, JHH = 5.0 Hz,
3
3JHH = 4.5 Hz), 9.02 (1H, s); 13C NMR (DMSO-d6):
d (102.38,
113.61, 116.32, 120.25, 122.93, 130.77, 134.03, 158.43, 143.54,:
benzimidazo[2,1-c][1,2,4]triazine), (117.63, CF3), (121.42, 128.35,
133.44, 146.24: thiophene ring), (180.53, C O); 19F NMR (DMSO-
d6):
d
À64.34 (s, CF3); EIMS (probe) 70 eV, m/z (rel. int.): 348 [M]+
(64). Anal. Calcd for C15H7F3N4OS: C, 51.73; H, 2.03; N, 16.09; S,
9.21. Found: C, 51.75; H, 2.05; N, 16.12; S, 9.24.
References
4.2.1.1. 2-(2-(1H-1,2,4-Triazol-5-yl)hydrazono)-4,4,4-trifluoro-1-
[1] G. Resnati, Tetrahedron 49 (1993) 9385–9445.
(thien-2-yl)butane-1,3-dione (14). Yield (91%); mp 254 8C; IR (KBr)
y
3419 (NH), 1705 (C O), 1691 (C O), 1596 (C N) cmÀ1; 1H NMR
[2] L. Kenneth, Kirk, J. Fluorine Chem. 127 (2006) 1013–1029.
[3] G. Lal, S. Pez, G.P. Syvret, Chem. Rev. 96 (1996) 1737–1756.
[4] J. Mann, Chem. Soc. Rev. 16 (1987) 381–436.
[5] K. Burger, U. Wucherpfennig, E. Brunner, Adv. Heterocycl. Chem. 60 (1994) 1–23.
[6] R. Filler, Y. Kobayashi (Eds.), Biomedicinal Aspects of Fluorine Chemistry, Kon-
dansha and Elsevier Biomedical, Tokyo, 1982.
[7] J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry, Wiley, New York,
1991.
[8] I. Ojima, J.R. McCarthy, J.T. Welch (Eds.), Biomedical Frontiers of Fluorine Chem-
istry, ACS Symposium Series 639, , American Chemical Society, Washington, DC,
1996.
3
4
(DMSO-d6):
d 7.25 (1H, dd, JHH = 4.5 Hz, JHH = 1.0 Hz), 7.89 (1H,
3
4
3
dd, JHH = 5.0 Hz, JHH = 1.0 Hz), 8.06 (1H, dd, JHH = 5.0 Hz,
3JHH = 4.5 Hz), 9.31 (1H, s), 13.49 (2H, broad, D2O exchangable);
13C NMR (DMSO-d6):
d
(122.32, CF3), (123.98, 128.73, 132.99,
135.88: thiophene ring), (136.68, 141.00: triazole ring), (151.28
C
d6):
N hydrazone), (180.32, C O), 189.32, COCF3); 19F NMR (DMSO-
d
À77.08 (s, CF3); EIMS (probe) 70 eV, m/z (rel. int.): 317 [M]+
(34). Anal. Calcd for C10H6F3N5O2S: C, 37.86; H, 1.91; N, 22.08; S,
10.11. Found: C, 37.82; H, 1.93; N, 22.12; S, 10.13.
[9] S. Narizuka, T. Fuchigami, Bioorg. Med. Chem. Lett. 5 (1995) 1293–1294.
[10] T. Hiyama, Organofluorine Compounds: Chemistry and Applications, Springer,
Berlin, 2000.
[11] J. Elguero, in: A.R. Katritzky, C.W. Rees (Eds.), Comprehensive Heterocyclic
Chemistry, vol. 5, Pergamon, Oxford, 1984.
4.2.1.2. 6-Thienoyl-5-(trifluoromethyl)-[1,2,4]triazolo[3,4-
[12] J. Elguero, in: A.R. Katritzky, C.W. Rees, E.F. Scriven (Eds.), Comprehensive
Heterocyclic Chemistry, vol. 2, Pergamon, Oxford, 1996.
[13] T.D. Penning, J.J. Talley, S.R. Bertenshaw, J.S. Carter, P.W. Collins, J. Med. Chem. 40
(1997) 1347–1365.
[14] C. Almanza, F.A. Arriba, F.L. Cavalcanti, L.A. Go´mez, A. Miralles, M. Merlos, J.G.
Rafanell, J. Forn, J. Med. Chem. 44 (2001) 350–361.
[15] T. Novinson, R.K. Robins, T.R. Matthews, J. Med. Chem. 20 (1977) 296–299.
[16] C.F.P. George, Lancet 358 (2001) 1623–1630.
[17] A. Thomas, M. Chakraborty, H. Ila, H. Junpappa, Tetrahedron 46 (1990) 577–586.
[18] A.C. Sheker, B. Narsaiah, R.V. Venkataratnam, J. Fluorine Chem. 86 (1997) 127–
130.
c][1,2,4]triazine (15). Yield (91%); mp 240 8C; IR (KBr)
(C O), 1596 (C N) cmÀ1 1H NMR (DMSO-d6):
7.25 (1H, dd,
3JHH = 4.5 Hz, 4JHH = 1.0 Hz), 7.89 (1H, dd, 3JHH = 5.0 Hz,
y 1650
;
d
4JHH = 1.0 Hz), 8.06 (1H, dd, JHH = 5.0 Hz, JHH = 4.5 Hz), 9.31
(1H, s); 13C NMR (DMSO-d6):
(119.33, CF3), (123.80, 135.88,
141.10, 151.38: triazolo[3,4-c][1,2,4]triazine), (128.76, 132.99,
136.58, 146.34: thiophene ring), (179.41,
O); 19F NMR
(DMSO-d6):
3
3
d
C
d
À62.69 (s, CF3); EIMS (probe) 70 eV, m/z (rel. int.):
299 [M]+ (47). Anal. Calcd for C10H4F3N5OS: C, 40.14; H, 1.35; N,
23.40; S, 10.72. Found: C, 40.18; H, 1.33; N, 23.42; S, 10.75.
[19] M.R. Shaaban, T.S. Saleh, A.M. Farag, Heterocycles 71 (2007) 1765–1777.
[20] M.R. Shaaban, T. Fuchigami, Tetrahedron Lett. 43 (2002) 273–276.

M.R. Shaaban / Journal of Fluorine Chemistry 129 (2008) 1156–1161
1161
[21] N. Iwayasu, M.R. Shaaban, T. Fuchigami, Heterocycl. Commun. 57 (2002) 623–629.
[22] M.R. Shaaban, H. Ishii, T. Fuchigami, J. Org. Chem. 65 (2000) 8685–8689.
[23] M.R. Shaaban, H. Ishii, T. Fuchigami, Synlett 10 (2001) 1644–1646.
[24] M.R. Shaaban, H. Ishii, T. Fuchigami, J. Org. Chem. 66 (2000) 5633–5636.
[25] J.T. Welch, Tetrahedron 43 (1987) 3123–3197.
[36] J.P. Edwards, R.I. Huguchi, D.T. Winn, C.L.F. Pooley, T.R. Caferro, L.G. Zhi, L.
Hamman, K.B. Marschke, M.E. Goldman, T.K. Jones, Bioorg. Med. Chem. Lett. 9
(1999) 1003–1008.
[37] L. Zhi, C.M. Tegly, K.B. Marschke, T.K. Jones, Bioorg. Med. Chem. Lett. 9 (1999)
1009–1012.
[26] A.L. Krasovsky, A.S. Hartulyari, V.J. Nenajdenko, E.S. Balenkova, Synthesis (2002)
133–137.
[38] J.P. Edwards, S.J. Weat, C.L.F. Pooley, K.B. Marschke, L.J. Farmer, T.K. Jones, Bioorg.
Med. Chem. Lett. 8 (1998) 745–750.
[27] D.M. Volochnyuk, A.O. Pushechnikov, D.G. Krotko, D.A. Sibgatulin, S.A. Kovalyova,
A.A. Tolmachev, Synthesis 10 (2003) 1531–1540.
[28] Y.V. Burgart, A.S. Fokin, O.G. Kuzueva, O.N. Chupakhin, V.I. Saloutin, J. Fluorine
Chem. 92 (1998) 101–108.
[29] Y.V. Burgart, O.G. Kuzueva, M.V. Pryadeina1, C.O. Kappe, V.I. Saloutin, Russ. J. Org.
Chem. 37 (2001) 869–880.
[39] S. Caddick, Tetrahedron 51 (1995) 10403–10432.
[40] A.K. Bose, M. Jayaraman, A. Okawa, S.S. Barie, E.W. Robb, M.S. Manhas, Tetra-
hedron Lett. 37 (1996) 6989–6992.
[41] O. Kappe, Angew. Chem. Int. Ed. 43 (2004) 6250–6284.
[42] M.R. Shaaban, T.S. Saleh, F. Osman, A.M. Farag, J. Heterocycl. Chem. 44 (2007)
177–181.
[30] D.A. Sibgatulin, D.M. Volochnyuk, A.N. Kostyuk, Tetrahedron Lett. 48 (2007)
2775–2779.
[43] M.R. Shaaban, T.S. Saleh, A.S. Mayhoub, A. Mansour, A.M. Farag, Bioorg. Med.
Chem. 16 (2008) 6344–6352.
[31] O.G. Khudina, Y.V. Burgart, V.I. Saloutin, O.N. Chupakhin, J. Fluorine Chem. 125
(2004) 401–407.
[32] A. Touzot, M. Soufyane, H. Berber, L. Toupet, C. Mirand, J. Fluorine Chem. 125
(2004) 1299–1304.
[33] D. Bonnet-Delpon, J.-P. Begue, T. Lequeux, M. Ourevitch, Tetrahedron 52 (1996)
59–70.
[44] O.G. Khudina, E.V. Shchegol’kov, Y.V. Burgart, M.I. Kodess, O.N. Kazheva, A.N.
Chekhlov, G.V. Shilov, O.A. Dyachenko, V.I. Saloutin, O.N. Chupakhin, J. Fluorine
Chem. 126 (2005) 1230–1238.
[45] A. Takamizawa, Y. Hamashima, Yakugaku Zasshi 84 (1964) 1113–1117.
[46] M.H. Elnagdi, H.A. Elfahham, S.A.S. Ghozlan, G.E. Elgemeie, J. Chem. Soc., Perkin
Trans. 1 (1982) 2663–2666.
[34] V.I. Saloutin, Y.V. Burgart, O.G. Kuzueva, C.O. Kappe, O.N. Chupakhin, J. Fluorine
Chem. 103 (2000) 17–23.
[47] M.H. Elnagdi, E.M. Kandeel, E.M. Zayed, Z.E. Kandeel, J. Heterocycl. Chem. 14
(1977) 155–0157.
[35] C.M. Tice, L.M. Bryman, Tetrahedron 57 (2001) 2689–2700.
[48] R.N. Butler, Chem. Rev. 75 (1975) 241–257.