Some novel observations on the reaction of 2-hydrazino-3-methylquinoxaline with trifluoromethyl-β-diketones

Article abstract of DOI:10.1016/j.jfluchem.2009.06.021

The reaction of 2-hydrazino-3-methylquinoxaline 1 with trifluoromethyl-β-diketones 2 not only yields the expected 5-trifluoromethyl-5-hydroxy-Δ²-pyrazolines 3a-3f and/or 3-trifluoromethylpyrazoles 4c-4f but also the unexpected products 1,2,4-tr

Full text of DOI:10.1016/j.jfluchem.2009.06.021

Journal of Fluorine Chemistry 130 (2009) 886–893
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Some novel observations on the reaction of 2-hydrazino-3-methylquinoxaline
with trifluoromethyl-b-diketones
*
Ranjana Aggarwal , Rajiv Kumar, Shiv P. Singh
Department of Chemistry, Kurukshetra University, Kurukshetra 136 119, Haryana, India
A R T I C L E I N F O
A B S T R A C T
Article history:
The reaction of 2-hydrazino-3-methylquinoxaline 1 with trifluoromethyl-b-diketones 2 not only yields
the expected 5-trifluoromethyl-5-hydroxy-D2-pyrazolines 3a–3f and/or 3-trifluoromethylpyrazoles
4c–4f but also the unexpected products 1,2,4-triazolo[4,3-a]quinoxalines 5a–5f and/or 3(5)-
trifluoromethyl-1H-pyrazoles 6c–6f. Furthermore, the acid-catalyzed dehydration of 5-hydroxypyr-
azolines 3a–3b resulted in the formation of unexpected 5a–5b along with the expected corresponding
pyrazoles 7a–7b. These unprecedented observations provide evidence for the existence of equilibrium
between the hydroxypyrazoline 3 and its open chain tautomer, ketoimine 9 in the mechanistic path
leading to the formation of pyrazoles 7 and triazoles 5.
Received 17 May 2009
Received in revised form 27 June 2009
Accepted 29 June 2009
Available online 5 July 2009
Keywords:
3-Trifluoromethylpyrazoles
5-Trifluoromethylpyrazoles
5-Trifluoromethyl-5-hydroxypyrazolines
ß 2009 Elsevier B.V. All rights reserved.
Trifluoromethyl-b-diketones
Triazolo[4,3-a]quinoxalines
1. Introduction
to acidic medium, change of regioselectivity has been observed and
5-aryl-3-trifluoromethylpyrazoles have been found to be the
The reaction of aryl/heteroaryl hydrazines with trifluoro-
methyl- -diketones has been studied extensively by us [1–4]
and others [5–9] in the last two decades. The reaction between
monosubstituted hydrazines and trifluoromethyl- -diketones
major product [1,2]. Also, higher regioselectivity in favour of 5-
aryl-3-trifluoromethylpyrazoles has recently been reported by the
use of fluorinated alcohols such as 2,2,2-trifluoroethanol and
1,1,1,3,3,3-hexafluoro-2-propanol as solvents [6].
b
b
typically furnishes three products: 3-trifluoromethylpyrazoles,
5-hydroxy-5-trifluoromethyl-D2-pyrazolines, and their dehy-
drated products 5-trifluoromethylpyrazoles. It has been estab-
lished that the ratio of the three products formed in the reaction
depends not only upon the relative nucleophilicity of NH and NH2
of the monosubstituted hydrazine and on the equilibrium ratio of
Recent investigation from our laboratory has shown that the
reaction between 2-hydrazino-3-methylquinoxaline 1 with aryl-
b
-diketones leads to the formation of a mixture consisting of
regioisomeric pyrazoles along with a small amount of 1,2,4-
triazolo[4,3-a]quinoxaline [10] rather than the erroneously
reported exclusive formation of the latter in the reaction of 2-
hydrazino-3-methylquinoxaline with phenyl-1,3-butanedione
[11]. Encouraged by these observations and in view of the
biological properties associated with pyrazoles bearing trifluor-
omethyl group [12,13], we now report some novel results of our
studies on the reaction of 2-hydrazino-3-methylquinoxaline 1
the two enolic forms of
upon the substituents present on
b
-diketones [1,2] (which in turn depends
-diketones and hydrazines) but
b
also on the reaction medium. For instance, reaction of aroyltri-
fluoroacetones with phenylhydrazine leads to the formation of 5-
aryl-3-trifluoromethylpyrazoles an exclusive/major product [2,5]
or in varying amount [6] depending upon the solvent and reaction
conditions, while the reaction with heteroaryl/p-nitrophenylhy-
drazines resulted in the production of 5-hydroxy-5-trifluoro-
methyl-D2-pyrazolines as the major product. Similarly, presence of
an electron-withdrawing group (NO2) on the phenyl ring of
with trifluoromethyl-b-diketones 2 leading to the formation of 5-
hydroxy-5-trifluoromethyl-3-substituted-1-(3-methylquinoxa-
lin-2-yl)-D2-pyrazolines 3, 3-trifluoromethyl-5-substituted-1-
(3-methylquinoxalin-2-yl)pyrazoles 4, 1-substituted-4-methyl-
1,2,4-triazolo[4,3-a]quinoxalines 5, 3(5)-trifluoromethyl-5(3)-
aroyltrifluoroacetones resulted in the formation of
a
larger
substituted-1H-pyrazoles
6 and 5-trifluoromethyl-3-substi-
proportion of hydroxypyrazolines [1,2]. On going from neutral
tuted-1-(3-methylquinoxalin-2-yl)pyrazoles 7.
2. Results and discussion
* Corresponding author. Tel.: +91 1744 238734; fax: +91 1744 238277.
E-mail addresses: ranjana67in@yahoo.com (R. Aggarwal),
Results of the reaction between 2-hydrazino-3-methylqui-
rajivchem@yahoo.com (R. Kumar), shivpsingh@rediffmail.com (S.P. Singh).
noxaline 1 and a series of trifluoromethyl-b-diketones 2 are
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.06.021

R. Aggarwal et al. / Journal of Fluorine Chemistry 130 (2009) 886–893
887
Scheme 1. Various products obtained from the reaction of trifluoromethyl-b-diketones and 2-hydrazino-3-methylquinoxaline.
summarized in Scheme 1 and the ratio of different products
obtained in neutral (EtOH, reflux) and acidic conditions (EtOH,
2–3 drops of H2SO4, reflux) has been gathered in Table 1.
This particular pattern is expected from the two methylene
protons (CHAHB) (respectively, cis and trans to the CF3 group) at
position 4 of hydroxypyrazolines as these protons observe a
difference in coupling with CF3 located at position 5. Further
support for the structure of 3 was provided by 13C NMR spectra,
which exhibited signals at
F = 33 Hz) and 151 ppm for hydroxypyrazolines 3 C4, C5 and C3,
respectively (Table 2). Finally, the 19F NMR spectra showed a
Initially, the reaction of 1 with aliphatic trifluoromethyl-b-
diketones (2a–2b) in neutral medium was investigated. The two
reaction products were identified as 5-hydroxy-3-methyl/trifluor-
omethyl-5-trifluoromethyl-1-(3-methylquinoxalin-2-yl)-D2-pyr-
azolines (3a–3b) and 1-methyl/trifluoromethyl-1,2,4-triazolo[4,3-
a]quinoxalines (5a–5b), an unexpected product. However, similar
d
48, 94–95 as a quartet (2JC–
signal in the range
is typical for CF3 bound to saturated carbon. In the case of
3b, second CF3 resonates at
d
ꢀ78.99 to ꢀ79.14 ppm (Table 3), which
treatment of 1 with aryl trifluoromethyl-b-diketones (2c–2f)
yielded four products namely: 5-hydroxy-5-trifluoromethyl-3-
aryl-1-(3-methylquinoxalin-2-yl)-D2-pyrazolines (3c–3f), 3-tri-
fluoromethyl-5-aryl-1-(3-methylquinoxalin-2-yl)pyrazoles (4c–
4f), 1-aryl-4-methyl-1,2,4-triazolo[4,3-a]quinoxalines (5c–5f)
and another unexpected product, 3(5)-trifluoromethyl-5(3)-aryl-
1H-pyrazoles (6c–6f) obtained by C–N bond cleavage (Scheme 1).
All the products were purified by column chromatography and the
ratio of these different products was measured by 1H NMR
spectroscopy of the crude reaction mixture (Table 1).
d
ꢀ66.85, which is the typical
position of CF3 located at position 3 of hydroxypyrazoline
(Table 3) [14–17].
In 1H NMR spectra of 4, a singlet of one proton intensity
appeared in the range
d 6.9–7.0 indicating that this proton is an
aromatic pyrazole proton corresponding to C4–H. Also, the 13C
2
NMR spectra of 4 showed signals at about
d
104, 145 (q, JC–
F = 38 Hz) and 146 ppm corresponding to C4, C3 and C5, respec-
tively (Table 4) and thus providing the firm evidence in support of
the formation of aromatic system. Further support to the position
of CF3 in 3-trifluoromethylpyrazoles 4 was provided by 19F NMR
All the four products have been unambiguously characterized
by a combined application of 1H, 13C and 19F NMR spectroscopy.
The 1H NMR spectra of 3a–3f displayed one doublet of one
spectrum, a sharp singlet for CF3 appeared at about
showing that CF3 is bonded to double bond and located at position
3 (Table 3) [1,2,14–16].
d
ꢀ62 ppm
proton intensity at about
coupling and one doublet of quartet of one proton intensity at
d
3.7 (2JH
¼ 18 Hz) due to geminal
ꢀH
A
B
about
d
3.5 (2JH
¼ 18 Hz, 4JH
¼ 1:2 Hz) due to geminal
ꢀCF
3
Identity of 1-substituted-4-methyl-1,2,4-triazolo[4,3-a]qui-
noxalines 5 was confirmed on the basis of 1H NMR spectra, an
ꢀH
A
B
B
coupling as well as coupling with the CF3 located at position 5.
Table 1
The ratio of different products obtained is calculated by 1H NMR of the crude reaction mixture in neutral (EtOH, reflux) and acidic conditions (EtOH, 2–3 drops of H2SO4,
reflux)a.
Compds.
R
3 (%)
4 (%)
5 (%)
6 (%)
7 (%)
Dehydration of hydroxypyrazoline (3)
a
b
c
d
e
f
CH3
85(0)
80(0)
45(0)
35(0)
37(0)
70
0(9)
0(58)
34(45)
29(67)
33(49)
14
15(73)
20(42)
10(17)
26(<7)
15(<5)
<5
0(0)
0(0)
0(18)
0(0)
0(23)
0(14)
0(36)
0
80%(5a), 20%(7a)
CF3
57%(5b), 43%(7b or 4b)
C6H5
11(15)
10(12)
15(10)
14
7c
7d
7e
7f
p-OCH3C6H4
p-ClC6H4
p-NO2C6H4
a
Percentages in parenthesis are for reaction in acidic medium.

888
R. Aggarwal et al. / Journal of Fluorine Chemistry 130 (2009) 886–893
Table 2
13C NMR data for 5-hydroxy-5-trifluoromethylpyrazolines 3 (ppm).
Compds.
3a
3b
3c
3d
3e
3f
Pyrazole carbons
2
C-3
C-4
C-5
151.08
48.08
94.33
141.18(q, JC–F = 39Hz)
150.78
44.32
94.68
149.52
43.36
93.44
150.13
44.19
94.84
150.04
43.90
95.26
42.15
95.75
2
2
2
2
2
2
(q, JC–F = 33 Hz)
(q, JC–F = 33 Hz)
(q, JC–F = 33 Hz)
(q, JC–F = 28.5 Hz)
(q, JC–F = 33 Hz)
(q, JC–F = 33 Hz)
Quinoxaline carbons
C-20
151.41
150.08
150.86
149.76
150.54
150.08
C-30
150.86
149.56
150.18
149.20
149.71
148.44
C-50, 60, 70, 80
129.70, 128.06,
128.01, 126.56
138.63, 136.74
130.23, 129.23,
128.48, 126.84
139.68, 136.46
130.45, 130.15,
128.44, 125.99
137.01, 130.57
128.98, 127.17,
126.57, 125.45
136.77, 135.93
130.12, 128.49,
127.83, 126.61
138.30, 136.39
130.01, 128.62,
128.40, 126.69
139.43, 136.65
C-4a0, 8a0
Aryl carbons
C-100
C-200, 600
C-300, 500
C-400
127.57
128.89
126.25
126.61
122.14
126.76
113.21
160.31
129.63
127.43
129.16
136.89
133.20
126.80
124.16
148.30
Other carbons
Qux-CH3
CF3
24.07
23.72
24.15
23.32
24.18
123.6
24.29
123.74
123.14
123.68
124.33
123.47
1
1
1
1
1
1
(q, JC–F = 283.5 Hz)
(q, JC–F = 269.25 Hz)
(q, JC–F = 285 Hz)
(q, JC–F = 285 Hz)
(q, JC–F = 284.25 Hz)
(q, JC–F = 284.25 Hz)
30-CF3
119.50
1
(q, JC–F = 261.75 Hz)
CH3
15.53
OCH3
54.32
Table 3
about ꢀ58 ppm indicating that CF3 is located at position 5 of the
pyrazole ring (Table 3).
19F NMR data for 5-hydroxy-5-trifluoromethylpyrazolines 3,3-trifluoromethylpyr-
azoles 4 and 5-trifluoromethylpyrazoles 7 (ppm).
It was also observed that the position of CH3 protons signal
located at position 3 of quinoxaline ring is significantly affected by
the position of trifluoromethyl group on the hydroxypyrazoline/
pyrazole ring attached to quinoxaline at position 2. The signal for
CH3 protons is deshielded when CF3 group is present at position 5,
Compds.
3
4
7
a
b
c
d
e
f
ꢀ78.99
ꢀ58.21
ꢀ79.14, ꢀ66.85
ꢀ79.02
–
ꢀ58.25, ꢀ66.51
ꢀ58.28
ꢀ62.40
ꢀ62.48
ꢀ62.45
–
ꢀ78.94
ꢀ58.23
and appeared as a singlet at
d 2.95 (except in the case of 3b where
ꢀ71.10
ꢀ58.25
this CH3 appears at
d
2.76 ppm) and 2.80 ppm in 1H NMR spectra of
ꢀ78.93
ꢀ58.31
3 and 7, respectively. However, this methyl resonates at about
d
2.45 in 1H NMR spectra of 4, when the CF3 group is present at
position 3 of pyrazole ring.
We also explored alternate reaction conditions hoping to
change the ratio of products by changing the solvent of the
reaction from ethanol to THF. When 1 and 2c were refluxed in THF
for 5 h, a mixture consisting of the pyrazoline 3c, pyrazole 4c and
triazole 5c was obtained in the percentage ratio 46:42:12 without
any trace of 6c. Further, the reaction between 1 and 2e was carried
out in solvent-free conditions, in a conical flask at 180 8C for 30–
35 min, and again pyrazole 6e was excluded from the reaction
mixture and it contained pyrazoline 3e, pyrazole 4e and triazole
5e in the ratio 49:38:13. This result finds precedence in the
literature where it has been observed that the 2-hydrazinoben-
zoxazole on reaction with pentan-2,4-dione in EtOH/HCl results
into the formation of 3,5-dimethyl-1H-pyrazole. It has been
proposed that ethanol acts as a nucleophile and results in the
cleavage of C–N bond [18]. Also, pyrazole 4c was recovered
unchanged when it was refluxed in a mixture of EtOH:H2O (1:1)
for 6 h indicating the stability of the pyrazole ring under the
reaction conditions. It can thus be concluded that C–N bond
cleavage occurs in the intermediate(s) leading to the formation of
the pyrazole ring.
alternative synthesis of 5a [10] and mix Mp. The signal for CH3
protons on quinoxaline ring is deshielded and appears at about
3.1 ppm in 1H NMR spectra of 5. Also, in 19F NMR spectrum of 5b, a
sharp singlet for CF3 appeared at about
Trifluoromethyl-5(3)-aryl-1H-pyrazoles 6 obtained by C–N bond
cleavage were identified on the basis of their 1H NMR spectra,
literature Mp., mix Mp. and co-tlc.
5-Hydroxy-5-trifluoromethyl-D2-pyrazolines 3 are resistant to
elimination of water under the reaction conditions. However,
treatment of 3c–3f in EtOH/H2SO4 furnished the dehydrated
product i.e. 3-aryl-5-trifluoromethylpyrazoles (7c–7f) in good
yields (Scheme 1). However, surprisingly, 3a and 3b under similar
reaction conditions afforded a mixture consisting of corresponding
pyrazoles (7a–7b) and 1,2,4-triazolo[4,3-a]quinoxalines (5a–5b)
(Table 1).
d
d
ꢀ57.85 ppm. 3(5)-
Structure of compound 7 was established on the basis of 1H, 13
and 19F NMR spectra. 1H NMR displayed a singlet of one proton
intensity in the range 7.1–7.3 ppm corresponding to the
C
d
pyrazole 4-position [14–17], which is about 0.2 ppm downfield
as compared to the corresponding proton in the regioisomer 4.
Also, in 13C NMR spectra signals at 107, 135 (q, 2JC–F = 40 Hz) and
d
150 ppm were assigned to the C4, C5 and C3 positions of 7,
respectively. The two regioisomeric pyrazoles 4 and 7 can be
The reaction between diketones 2 and hydrazine 1 was also
carried out in acidic conditions by adding a few drops of H2SO4
to the reaction mixture. Work-up of the reaction mixture
showed the predominance of the 3-trifluoromethylpyrazoles 4
obviously due to the change in regioselectivity as has already
distinguished on the basis of these signals [1,2,14–16].
A
comparative 13C NMR data of both the pyrazoles are given in
Table 4. In 19F NMR spectra of compound 7, a signal appears at
been observed by us [1,2]. 5-Trifluoromethylpyrazoles
7

R. Aggarwal et al. / Journal of Fluorine Chemistry 130 (2009) 886–893
889
(obviously formed by the dehydration of hydroxypyrazolines 3),
triazoles 5 and pyrazoles 6 were other isolable products. In a
typical reaction between 1 and 2a, three products namely: 3-
trifluoromethylpyrazole 4a, triazole 5a and 5-trifluoromethyl-
pyrazole 7a were observed in the ratio 9:73:18. While with
symmetrical diketone 2b, only two products 4b (or 7b) and 5b
were observed. However, with aryl diketones 2c–2e, as
expected, four products 4, 5, 6 and 7 were observed (Table 1).
A
graphical representation of the composition of different
products formed in neutral and acidic media has been indicated
in Fig. 1.
The plausible mechanism for the formation of these products
is given in Scheme 2. With 1,1,1-trifluoropentane-2,4-diones 2a
only two products 3a and 5a were formed. Since, in diketone 2a,
COCF3 carbonyl is known to exist predominantly in enolized
form A [19–21] so that terminal nitrogen of hydrazine attacks on
the carbonyl carbon remote to CF3 (pathway a) generating
hydrazone 8. It is worth mentioning here that nucleophilicity of
nitrogen attached to the quinoxaline ring (NH) is poor due to
electron-withdrawing nature of quinoxaline ring. Thus the
possibility of the first nucleophilic attack of this nitrogen is
almost negligible. There may now be competition between two
possibilities of cyclization of hydrazone 8. One of the routes
through the intermediacy of 9 and 10 leads to the formation of
triazole 5 and other gives hydroxypyrazoline 3. The fact that
triazoles (5a–5b) were also obtained during dehydration of
hydroxypyrazolines (3a–3b) can only be explained if hydro-
xypyrazoline 3 ring opens up and exists in equilibrium with its
open chain tautomer ketoimine 9. It thus looks attractive to
speculate that during the dehydration of 3, pyrazoline ring
opened up and again cyclized along the other path to give the
fused triazole 5. Existence of equilibrium between hydroxypyr-
azoline and ketoimine, established by the 1H NMR of the super-
cooled reaction mixture of 1-hydrazinophthalazine with
b-
diketones, has also been reported by Zimmer and Amer [22].
Since the diketone 2b is symmetrical, the reaction leads to
formation of only two products 3b and 5b through the same
path.
However, in the case of aroyltrifluoroacetones (2c–2f) ratio of
enol tautomer B increases due to extended conjugation between
the C55C–C55O and arenes [19–21]. The terminal nitrogen (NH2) of
quinoxaline then attacks on the CF3 carbonyl (pathway b) and
further cyclization gives rise to the regioisomer 4.
An interesting correlation between product composition
and the substituent effect on
b-diketones was also noted e.g.
strong electron-withdrawing group like p-NO2 present on
arenes of the diketone increases the ratio of hydroxypyrazoline
3e up to 70%, which is minimum in the case of p-methox-
yphenyltrifluoromethyl-b-diketone where 3d was formed
only to the extent of 35%. The percentage of triazole 5 also
decreases when the electron-withdrawing substituents are
present on the aryl ring. As the cleaved pyrazoles 6 were
formed only with aryldiketones 2c–2f, this indicates that its
formation may take place by initial attack on the COCF3 carbonyl
(pathway b) or may be due to slow reaction rate of diketones
2c–2f.
In acidic medium, the ratio of 5-trifluoromethylpyrazole 7
(dehydrated product of 5-hydroxy-5-trifluoromethylpyrazoline 3)
decreases and that of corresponding regioisomeric 3-trifluoro-
methylpyrazole 4 increases which is maximum (67%) when p-OMe
group is present on arene of
regioselectivity in acidic medium may be either due to alteration
of electrophilicity of carbonyl group of -diketones [23] or may be
b-diketones. The change in
b
due to change in nucleophilicity of the nitrogens of the hydrazine.
As, more basic nitrogen (NH2) will be protonated more easily than
less basic one (NH) [1,2,24].

890
R. Aggarwal et al. / Journal of Fluorine Chemistry 130 (2009) 886–893
Fig. 1. Graphical representation of percentage of different products in neutral and acidic medium.
Scheme 2. Plausible mechanism for the formation of 3, 4, 5, 6 and 7.
3. Conclusion
omethyl-D2-pyrazolines 3, 3-trifluoromethyl-5-substituted-1-
(3-methylquinoxalin-2-yl)pyrazoles 4 and 5-trifluoromethylpyr-
azole 7. Through the unprecedented formation of triazolo[4,3-
a]quinoxaline 5 while dehydration of hydoxypyrazoline 3 in
acidic medium, we propose the existence of equilibrium between
5-hydroxy-5-trifluoromethylpyrazoline 3 and its open chain
tautomer 9. The study also shows the role of ethanol as a solvent
in C–N bond cleavage which results into the production of cleaved
pyrazoles 6.
In summary, we have studied the reaction of 2-hyrazino-3-
methylquinoxaline
1 with trifluoromethyl-b-diketones 2 in
different reaction conditions. The reaction resulted in the
formation of the unexpected products 1-substituted-4-methyl-
1,2,4-triazolo[4,3-a]quinoxalines
5 and 3(5)-trifluoromethyl-
5(3)-substituted-1H-pyrazoles 6 in addition to the expected 5-
hydroxy-3-substituted-1-(3-methylquinoxalin-2-yl)-5-trifluor-

R. Aggarwal et al. / Journal of Fluorine Chemistry 130 (2009) 886–893
891
4. Experimental
(2 mmol) in the ethanol (30 ml), and the mixture was refluxed for
6 h. The reaction was monitored by tlc. The solvent was evaporated
and the tlc and 1H NMR of residue showed the formation of
products in the ratio given in Table 1. Column chromatography
separation using silica gel (100–200 mesh) with petroleum
ether:ethyl acetate (99:1) afforded 3, further elution of column
with petroleum ether:ethyl acetate (98:2) afforded 4, elution with
petroleum ether:ethyl acetate (96:4) afforded 6 and further elution
with petroleum ether:ethyl acetate (90:10) afforded 5.
TheIRspectraofthe compoundswererecordedonBuckScientific
IR M-500 spectrophotometer using KBr pellets (nmax in cmꢀ1), 1H
and 13C NMR spectra on a Bruker instrument at 300 and 75 MHz,
respectively; chemical shifts are expressed in
d-scale downfield
from TMS as an internal standard. 19F NMR spectra were run on DRX
300 and DPX 400 at 282 and 376 MHz, respectively, using
deuteriochloroform as a solvent. The internal standard for 19F
spectra was fluorotrichloromethane, setting the CFCl3 signal at d0.0.
Elemental analyses were performed at Sophisticated Analytical
Instrument Facility Central Drug Research Institute, Lucknow, India.
4.2.1. 5-Hydroxy-1-(3-methylquinoxalin-2-yl)-3-phenyl-5-
trifluoromethyl-D2-pyrazoline 3c
(43%) Mp. 144–146 8C; IR: (KBr, cmꢀ1) 3550
n(O–H), 1565
Fluorinated
b-diketones 2a–2c are available commercially and
n
(C55N); 1H NMR (CDCl3, 300 MHz)
d: 2.96 (s, 3H, CH3), 3.53 (dq,
other 2d–2f were prepared according to the literature procedure
[25,26]. 2-Hydrazino-3-methylquinoxaline 1 was also synthesized
according to the literature procedure [11].
1H, 2JH
¼ 18:6 Hz, 4JH
¼ 1:2 Hz, 4-HB), 3.69 (d, 1H,
ꢀCF
ꢀH
A
B
B
3
2JH
¼ 18:6 Hz, 4-HA), 7.38–7.40 (m, 3H, 300, 400, 500-H), 7.59–
ꢀH
A
B
7.75 (m, 5H, 50, 60, 70, 200, 600-H), 7.99–8.01 (m, 1H, 80-H), 8.80 (bs,
1H, 50-OH, exchangeable with D2O); MS (EI) m/z: 373 [M+1]+. Anal.
Calcd. for C19H15F3N4O: C, 61.29; H, 4.06; N, 15.05. Found: C, 61.26;
H, 4.02; N, 14.89.
4.1. General procedure for the preparation of 5-hydroxy-3-
substituted-1-(3-methylquinoxalin-2-yl)-5-trifluoromethyl-D2
-
pyrazolines 3a–3b, and 1-substituted-4-methyl-1,2,4-triazolo[4,3-
a]quinoxalines 5a–5b
4.2.2. 5-Hydroxy-1-(3-methylquinoxalin-2-yl)-3-(p-
methoxyphenyl)-5-trifluoromethyl-D2-pyrazoline 3d
An ethanolic solution (30 ml) of 2-hydrazino-3-methylqui-
noxaline 1 (0.35 g, 2 mmol) and trifluoromethyl-b-diketones 2a–
(31%) Mp. 94–96 8C; IR: (KBr, cmꢀ1) 3480
n
(O–H), 1509
n(C55N);
1H NMR (CDCl3, 300 MHz)
d: 3.00 (s, 3H, CH3), 3.58 (d, 1H,
2b (2 mmol) was refluxed for 6 h. The reaction was monitored by
tlc. On completion of reaction solvent was evaporated completely.
The tlc and 1H NMR of the reaction mixture showed the formation
of products in the ratio given in Table 1. Column chromatography
separation using silica gel (100–200 mesh) with petroleum
ether:ethyl acetate (99:1) afforded 3, and further elution with
petroleum ether:ethyl acetate (90:10) afforded 5.
2JH
¼ 18 Hz, 4-HB), 3.74 (d, 1H, 2JH
¼ 18 Hz, 4-HA), 3.88 (s,
ꢀH
ꢀH
A
B
A
B
3H, OCH3), 6.97 (d, 2H, 300, 500-H, J = 8.7 Hz), 7.66–7.69 (m, 4H, 60, 70,
200, 600-H), 7.78–7.81 (m, 1H, 50-H), 8.03–8.05 (m, 1H, 80-H), 8.60 (bs,
1H, 50-OH, exchangeable with D2O; MS (EI) m/z: 403 [M+1]+. Anal.
Calcd. for C20H17F3N4O2: C, 59.70; H, 4.26; N, 13.92. Found: C,
59.65; H, 4.21; N, 13.90.
4.1.1. 5-Hydroxy-3-methyl-1-(3-methylquinoxalin-2-yl)-5-
4.2.3. 5-Hydroxy-1-(3-methylquinoxalin-2-yl)-3-(p-chlorophenyl)-
trifluoromethyl-D2-pyrazoline 3a
5-trifluoromethyl-D2-pyrazoline 3e
(67%) Mp. 116–118 8C; IR: (KBr, cmꢀ1) 3448
n(O–H), 1501
(29%) Mp. 110–112 8C; IR: (KBr, cmꢀ1) 3406
n(O–H), 1511
(C55N); 1H NMR (CDCl3, 300 MHz)
d: 2.13 (s, 3H, CH3), 2.86 (s, 3H,
n
(C55N); 1H NMR (CDCl3, 300 MHz)
d: 2.96 (s, 3H, CH3), 3.57 (d, 1H,
n
CH3), 3.10 (dq, 1H, 2JH
¼ 18 Hz, 4JH
¼ 1:2 Hz, 4-HB), 3.38 (d,
ꢀCF
2JH
¼ 18 Hz, 4-HB), 3.74 (d, 1H, 2JH
¼ 18 Hz, 4-HA), 7.43 (d,
ꢀH
ꢀH
ꢀH
A
B
B
3
A
B
A
B
1H,2JH
¼ 18 Hz, 4-HA), 7.59–7.67 (m, 2H, 60, 70-H), 7.75–7.78(m,
2H, J = 8.7 Hz, 300, 500-H), 7.65–7.69 (m, 4H, 60, 70, 200, 600-H), 7.78–
7.81 (m, 1H, 50-H), 7.99–8.01 (m, 1H, 80-H), 8.81 (bs, 1H, 50-OH,
exchangeable with D2O); MS (EI) m/z: 407/409 [M+1]+. Anal. Calcd.
for C19H14ClF3N4O: C, 56.15; H, 3.47; N, 13.79. Found: C, 56.20; H,
3.35; N, 13.54.
ꢀH
A
B
1H, 50-H), 7.96–7.99 (m, 1H, 80-H), 8.9 (bs, 1H, 50-OH, exchangeable
with D2O); MS (EI) m/z: 311 [M+1]+. Anal. Calcd. for C14H13F3N4O: C,
54.19; H, 4.22; N, 18.06. Found: C, 54.53; H, 3.99; N, 19.05.
4.1.2. 5-Hydroxy-1-(3-methylquinoxalin-2-yl)-3,5-
bis(trifluoromethyl)-D2-pyrazoline 3b
4.2.4. 5-Hydroxy-1-(3-methylquinoxalin-2-yl)-3-(p-nitrophenyl)-5-
(75%) Mp. 84–86 8C; IR: (KBr, cmꢀ1) 3455
n
(O–H), 1505
n(C55N);
trifluoromethyl-D2-pyrazoline 3f
1H NMR (CDCl3, 300 MHz)
d: 2.76 (s, 3H, CH3), 3.31 (d, 1H,
(64%) Mp. 173–176 8C; IR: (KBr, cmꢀ1) 3466
n(O–H), 1551
n
(C55N); 1H NMR (CDCl3, 300 MHz)
d: 2.88 (s, 3H, CH3), 3.53 (dq,
2JH
¼ 18:6 Hz, 4-HB), 3.54 (d, 1H, 2JH
¼ 18:6 Hz, 4-HA),
ꢀH
ꢀH
A
B
A
B
7.61–7.64 (m, 2H, 60, 70-H), 7.72–7.75 (m, 1H, 50-H), 7.94–7.97 (m,
1H, 80-H), 8.6 (bs, 1H, 50-OH, exchangeable with D2O); MS (EI) m/z:
365 [M+1]+. Anal. Calcd. for C14H10F6N4O: C, 46.16; H, 2.77; N,
15.38. Found: C, 46.10; H, 2.85; N, 16.02.
1H, 2JH
¼ 18 Hz, 4JH
¼ 1:5 Hz, 4-HB), 3.71 (d, 1H,
ꢀCF
ꢀH
A
B
B
3
2JH
¼ 18 Hz, 4-HA), 7.57–7.64 (m, 2H, 60, 70-H), 7.72–7.75 (m,
ꢀH
A
B
1H, 50-H), 7.78 (d, 2H, J = 8.7 Hz, 200, 600-H), 7.92–7.95 (m, 1H, 80-H),
8.23 (d, 2H, J = 8.7 Hz, 300, 500-H), 8.67 (bs, 1H, 50-OH, exchangeable
with D2O); MS (EI) m/z: 418 [M+1]+. Anal. Calcd. for C19H14F3N5O3:
C, 54.54; H, 3.38; N, 16.78. Found: C, 54.49; H, 3.34; N, 16.85.
4.1.3. 1-Trifluoromethyl-4-methyl-1,2,4-triazolo[4,3-a]quinoxaline
5b
(19%) Mp. 190–92 8C; 1H NMR (CDCl3, 300 MHz)
d
: 3.10 (s, 3H,
CH3), 7.54–7.57 (m, 2H, 60, 70-H), 7.99–8.02 (m, 1H, 50-H), 8.06–8.09
(m, 1H, 80-H); 19F NMR (CDCl3, 282 MHz)
: ꢀ57.85 (s, CF3).
4.2.5. 1-(3-Methylquinoxalin-2-yl)-5-phenyl-3-
trifluoromethylpyrazole 4c
(30%) Mp. 122–124 8C; IR: (KBr, cmꢀ1) 3116, 1498; 1H NMR
d
(CDCl3, 300 MHz) d: 2.50 (s, 3H, CH3), 6.91 (s, 1H, 4-H), 7.26–7.30 (m,
5H, 200, 300, 400, 500, 600-H), 7.77–7.90 (m, 2H, 60, 70-H), 8.04–8.15 (m, 2H,
50, 80-H); MS (EI) m/z: 355 [M+1]+. Anal. Calcd. for C19H13F3N4: C,
64.77; H, 3.70; N, 15.81. Found: C, 64.36; H, 3.68; N, 15.47.
4.2. General procedure for the preparation of 5-hydroxy-3-aryl-1-(3-
methylquinoxalin-2-yl)-5-trifluoromethyl-D2-pyrazolines 3c–3f, 3-
trifluoromethyl-5-aryl-1-(3-methylquinoxalin-2-yl)pyrazoles 4c–4f,
3(5)-trifluoromethyl-5(3)-arylpyrazoles 6c–6f and 1-aryl-4-methyl-
1,2,4-triazolo[4,3-a]quinoxalines 5c–5f
4.2.6. 1-(3-Methylquinoxalin-2-yl)-5-(p-methoxyphenyl)-3-
trifluoromethylpyrazole 4d
(19%) Mp.118–1208C; IR: (KBr, cmꢀ1) 3120, 1501; 1H NMR
2-Hyrazino-3-methylquinoxaline
1
(0.35 g, 2 mmol) was
-diketone 2
slowly added to the corresponding trifluoromethyl-
b
(CDCl3, 300 MHz) d: 2.46 (s, 3H, CH3), 3.76 (s, 3H, OCH3), 6.78 (d,

892
R. Aggarwal et al. / Journal of Fluorine Chemistry 130 (2009) 886–893
2H, 300, 500-H, J = 8.4 Hz), 6.84 (s, 1H, 4-H), 7.17 (d, 2H, 200, 600-H,
J = 8.4 Hz), 7.88–7.90 (m, 2H, 60, 70-H), 8.08–8.15 (m, 2H, 50, 80-H);
MS (EI) m/z: 385 [M+1]+. Anal. Calcd. for C20H15F3N4O: C, 62.50; H,
3.93; N, 14.58. Found: C, 62.49; H, 3.85; N, 13.50.
4.4.2. 1-(3-Methylquinoxalin-2-yl)-3-(p-methoxyphenyl)-5-
trifluoromethylpyrazole 7d
(83%) Mp. 96–98 8C; IR: (KBr, cmꢀ1) 3220, 1503; 1H NMR
(CDCl3, 300 MHz) d: 2.80 (s, 3H, CH3), 3.88 (s, 3H, OCH3), 7.00 (d,
2H, 300, 500-H, J = 8.7 Hz), 7.17 (s, 1H, 4-H), 7.79–7.89 (m, 4H, 60, 70,
200, 600-H), 8.09–8.12 (m, 1H, 50-H), 8.15–8.18 (m, 1H, 80-H); MS (EI)
m/z: 385 [M+1]+. Anal. Calcd. for C20H15F3N4O: C, 62.50; H, 3.93; N,
14.58. Found: C, 62.40; H, 3.91; N, 14.36.
4.2.7. 1-(3-Methylquinoxalin-2-yl)-5-(p-chlorophenyl)-3-
trifluoromethylpyrazole 4e
(28%) Mp. 130–132 8C; IR: (KBr, cmꢀ1) 3116, 1498; 1H NMR
(CDCl3, 300 MHz) d: 2.62 (s, 3H, CH3), 6.99 (s, 1H, 4-H), 7.28 (d, 2H,
300, 500-H, J = 8.4 Hz), 7.35 (d, 2H, 200, 600-H, J = 8.4 Hz), 7.89–7.97 (m,
2H, 60, 70-H), 8.09–8.12 (m, 1H, 50-H), 8.20–8.22 (m, 1H, 80-H); MS
(EI) m/z: 389/391 [M+1]+. Anal. Calcd. for C19H12ClF3N4: C, 58.76;
H, 3.11; N, 14.93. Found: C, 58.69; H, 3.14; N, 14.51.
4.4.3. 1-(3-Methylquinoxalin-2-yl)-3-(p-chlorophenyl)-5-
trifluoromethylpyrazole 7e
(85%) Mp. 104–106 8C; IR: (KBr, cmꢀ1) 3145, 1495; 1H NMR
(CDCl3, 300 MHz) d: 2.70 (s, 3H, CH3), 7.12 (s, 1H, 4-H), 7.36 (d, 2H,
300, 500-H, J = 8.4 Hz), 7.74 (d, 2H, 200, 600-H, J = 8.4 Hz), 7.77–7.82 (m,
2H, 60, 70-H), 8.00–8.03 (m, 1H, 50-H), 8.06–8.09 (m, 1H, 80-H); MS
(EI) m/z: 389/391 [M+1]+. Anal. Calcd. for C19H12ClF3N4: C, 58.76;
H, 3.11; N, 14.43. Found: C, 58.64; H, 3.05; N, 14.75.
4.3. General procedure for the preparation of 1-(3-methylquinoxalin-
2-yl)-3-alkyl-5-trifluoromethylpyrazoles 7a–7b
An ethanolic solution of 5-hydroxy-3-substituted-1-(3-methyl-
quinoxalin-2-yl)-5-trifluoromethyl-D2-pyrazoline 3a or 3b
(1 mmol), 2–3 drops of H2SO4 were added and refluxed for 4–
5 h. The reaction was monitored by tlc. On completion, reaction
mixture was neutralized using aq. NaOH and extracted with ethyl
acetate (3ꢁ 20 ml). The combined organic extracts were dried over
anhydrous sodium sulphate, filtered and concentrated to give 7a–
7b and 5a–5b ratio calculated from their 1H NMR is given in
Table 1. Column chromatography separation using silica gel (100–
200 mesh) with petroleum ether:ethyl acetate (98:2) as eluent
afforded 7, and further elution with petroleum ether:ethyl acetate
(90:10) afforded 5.
4.4.4. 1-(3-Methylquinoxalin-2-yl)-3-(p-nitrophenyl)-5-
trifluoromethylpyrazole 7f
(90%) Mp. 128–130 8C; IR: (KBr, cmꢀ1) 3201, 1518; 1H NMR
(CDCl3, 300 MHz) d: 2.79 (s, 3H, CH3), 7.34 (s, 1H, 4-H), 7.82–7.93
(m, 2H, 60, 70-H), 8.07 (d, 2H, 200, 600-H, J = 8.7 Hz), 8.10–8.19 (m, 2H,
50, 80-H), 8.35 (d, 2H, 300, 500-H, J = 8.7 Hz); MS (EI) m/z: 400 [M+1]+.
Anal. Calcd. for C19H12F3N5O2: C, 57.15; H, 3.03; N, 17.54. Found: C,
57.12; H, 3.09; N, 17.68.
4.5. General procedure of the reaction performed under acidic
condition EtOH/H2SO4
4.3.1. 1-(3-Methylquinoxalin-2-yl)-3-methyl-5-
trifluoromethylpyrazole 7a
To an ethanolic solution of 2 (2 mmol) was added two drops of
H2SO4 and stirred for a while, then 1 (0.35 g, 2 mmol) was added to
this solution and refluxed for 5 h. Reaction was monitered by tlc.
On completion of reaction solvent was evaporated completely. The
tlc and 1H NMR of the reaction mixture showed the formation of
products in the ratio given in Table 1. Different products formed
were identified from their NMR spectra as described above.
(17%) Mp. 92–94 8C; IR: (KBr, cmꢀ1) 3125, 1509; 1H NMR
(CDCl3, 300 MHz) d: 2.35 (s, 3H, CH3), 2.62 (s, 3H, CH3), 6.64 (s, 1H,
4-H), 7.68–7.79 (m, 2H, 60, 70-H), 7.99–8.01 (m, 1H, 50-H), 8.04–8.07
(m, 1H, 80-H); MS (EI) m/z: 293 [M+1]+. Anal. Calcd. for C14H11F3N4:
C, 57.53; H, 3.79; N, 19.17. Found: C, 57.43; H, 3.74; N, 19.15.
4.3.2. 1-(3-Methylquinoxalin-2-yl)-3,5-bis(trifluoromethyl)pyrazole
4.6. Reaction between 1,1,1-trifluoromethyl-4-(p-
chlorophenyl)butan-2,4-dione 2e and 2-hydrazino-3-
methylquinoxaline 1 under solvent-free condition
7b
(29%) Mp. 100–102 8C; IR: (KBr, cmꢀ1) 3156, 1548; 1H NMR
(CDCl3, 300 MHz) d: 2.72 (s, 3H, CH3), 7.21 (s, 1H, 4-H), 7.80–7.92
(m, 2H, 60, 70-H), 8.09–8.12 (m, 1H, 50-H), 8.16–8.18 (m, 1H, 80-H);
MS (EI) m/z: 347 [M+1]+. Anal. Calcd. for C14H8F6N4: C, 48.57; H,
2.33; N, 16.18. Found: C, 49.21; H, 2.45; N, 17.01.
1
(0.35 g, 2 mmol) and 2e (0.5 g, 2 mmol) were ground
vigorously using pestle and mortar. The contents were
a
transferred to a conical flask and heated to 180–90 8C for 30–
35 min. The reaction was monitored by tlc. The tlc and 1H NMR of
reaction mixture showed the formation of three products 5-
trifluoromethyl-5-hydroxypyrazoline 3e, 3-trifluoromethylpyra-
zole 4e and 1-(p-chlorophenyl)triazolo[4,3-a]quinoxaline 5e in a
percentage ratio 49:38:13. Spectral data have already been given
above.
4.4. General procedure for the preparation of 1-(3-methylquinoxalin-
2-yl)-3-aryl-5-trifluoromethylpyrazoles 7c–7f
To an ethanolic solution of 5-hydroxy-3-substituted-1-(3-
methylquinoxalin-2-yl)-5-trifluoromethyl-D2-pyrazolines
3
(1 mmol), 2–3 drops of H2SO4 were added and refluxed for 4–
5 h. The reaction was monitored by tlc. On completion, reaction
mixture was neutralized using aq. NaOH and extracted with
ethyl acetate (3ꢁ 20 ml). The combined organic extracts were
dried over anhydrous sodium sulphate, filtered and concentrated
to give 7.
Acknowledgements
We thank the Council of Scientific and Industrial Research, New
Delhi for financial assistance and a Senior Research Fellowship to
Rajiv Kumar. Thanks are also due to SAIF, CDRI, Lucknow, India for
providing 19F NMR spectra, mass spectrometry and elemental
analysis.
4.4.1. 1-(3-Methylquinoxalin-2-yl)-3-phenyl-5-
trifluoromethylpyrazole 7c
(85%) Mp. 94–96 8C; IR: (KBr, cmꢀ1) 3201, 1499; 1H NMR
References
(CDCl3, 300 MHz) d: 2.78 (s, 3H, CH3), 7.23 (s, 1H, 4-H), 7.41–7.49
(m, 3H, 300, 400, 500-H), 7.80–7.90 (m, 4H, 60, 70, 200, 600-H), 8.08–8.11
(m, 1H, 50-H), 8.13–8.15 (m, 1H, 80-H); MS (EI) m/z: 355 [M+1]+.
Anal. Calcd. for C19H13F3N4: C, 64.40; H, 3.70; N, 15.81. Found: C,
64.35; H, 3.72; N, 15.31.
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