Room-temperature ionic liquid-DMSO promoted and improved one-pot synthesis of 5,6-diaryl-1,2,4-triazines

Article abstract of DOI:10.1080/00397911.2014.891040

An improved and rapid one-pot synthesis of 5,6-diarylsubstituted-1,2,4- triazines in a mixture of room-temperature ionic liquid 1,3-dibutylimidazolium bromide [Bbim]⁺Br^- and dimethylsulfoxide (DMSO) is described without the need for

Full text of DOI:10.1080/00397911.2014.891040

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Room-Temperature Ionic Liquid–DMSO
Promoted and Improved One-Pot
Synthesis of 5,6-Diaryl-1,2,4-triazines
Riyaj S. Tamboli a , Rajani Giridhar a , Hemant M. Mande b , Shailesh
R. Shah b & Mange Ram Yadav a
a Pharmacy Department, Faculty of Technology and Engineering ,
Kalabhavan, Maharaja Sayajirao University of Baroda , Vadodara ,
Gujarat , India
b Department of Chemistry, Faculty of Science , Maharaja Sayajirao
University of Baroda , Vadodara , Gujarat , India
Accepted author version posted online: 03 Apr 2014.Published
online: 09 Jun 2014.
To cite this article: Riyaj S. Tamboli , Rajani Giridhar , Hemant M. Mande , Shailesh R. Shah
& Mange Ram Yadav (2014) Room-Temperature Ionic Liquid–DMSO Promoted and Improved
One-Pot Synthesis of 5,6-Diaryl-1,2,4-triazines, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 44:15, 2192-2204, DOI:
10.1080/00397911.2014.891040
To link to this article: http://dx.doi.org/10.1080/00397911.2014.891040
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Synthetic Communications1, 44: 2192–2204, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.891040
ROOM-TEMPERATURE IONIC LIQUID–DMSO
PROMOTED AND IMPROVED ONE-POT SYNTHESIS
OF 5,6-DIARYL-1,2,4-TRIAZINES
Riyaj S. Tamboli,1 Rajani Giridhar,1 Hemant M. Mande,2
Shailesh R. Shah,2 and Mange Ram Yadav1
1Pharmacy Department, Faculty of Technology and Engineering,
Kalabhavan, Maharaja Sayajirao University of Baroda, Vadodara,
Gujarat, India
2Department of Chemistry, Faculty of Science, Maharaja Sayajirao
University of Baroda, Vadodara, Gujarat, India
GRAPHICAL ABSTRACT
Abstract An improved and rapid one-pot synthesis of 5,6-diarylsubstituted-1,2,4-triazines in
a mixture of room-temperature ionic liquid 1,3-dibutylimidazolium bromide [Bbim]þBrꢀ
and dimethylsulfoxide (DMSO) is described without the need for any added catalyst. Dif-
ferent polar aprotic solvents were screened along with ionic liquids and a synergistic effect
with DMSO has been found. The predominance of one regioisomer over the other has also
been studied with varying reaction temperatures. The one-pot methodology leading to
excellent isolated yields in short span of time is achieved by simple workup procedure.
The ionic liquid was efficiently recovered and reused three times without the loss of
catalysis. All the compounds were characterized by infrared, NMR, mass spectrometry, and
elemental analysis.
Keywords 5,6-Diaryl-1,2,4-triazines; 1,2-diketones; DMSO; ionic liquid (IL); regioisomers
Received November 26, 2013.
Address correspondence to Rajani Giridhar and Mange Ram Yadav, Pharmacy Department,
Faculty of Technology and Engineering, Kalabhavan, Maharaja Sayajirao University of Baroda,
Vadodara, Gujarat, India. E-mail: rajanimsu@rediffmail.com; mryadav11@yahoo.co.in
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2192

IL-DMSO-PROMOTED SYNTHESIS OF 1,2,4-TRIAZINES
2193
INTRODUCTION
1,2,4-Triazine moiety has been widely studied because of its occurrence in
natural antibiotics such as fervenulin, toxoflavin, and reurhycin.[1] 1,2,4-Triazines
are an important class of compounds which show different physical, chemical,
and biological properties.[2] Their medicinal and agricultural uses have been well
documented.[3] The 1,2,4-triazine scaffold has been associated with diversified
pharmacological activities such as antiplatelet,[4] antihypertensive,[5] thromboxane
synthetase inhibition,[5] anti-inflammatory,[6] and antimalarial[7] activities. Because
of its cytotoxic potential it has also showed anticancer activity.[8] Recently 5,6-diaryl
triazine derivatives have been evaluated as potent adenosine A2A antagonists in
Parkinson’s disease[9] and as anticytokines.[10] The neuropharmacological applications
of 1,2,4-triazines attracted wide attention from scientific community because of their
potent activity, particularly in neuroinflammatory diseases such as Alzheimer’s
disease[11] and as neuroprotective agents.[12] Tirapazamine, a benzotriazine N-oxide,
is being used as an experimental lead for selective hypoxic cytotoxins as an anticancer
drug.[13] Lamotrigine, 6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine, is used as an
anticonvulsant drug in the treatment of epilepsy and bipolar disorder.[14] Vardenafil,
a fused imidazotriazine derivative, acts as a potent PDE5 inhibitor (Figure 1).[15]
A number of patents have been granted for the syntheses and pharmacological uses
of 1,2,4-triazine derivatives, namely as topical antithrombotic agents,[16a] anti-
inflammatory agents,[16b] GABA activators,[16c] and sodium channel blockers.[16d]
Various methods have been reported to date for the synthesis of 1,2,4-triazines.
A survey of the literature revealed several attempts involving condensation of sub-
stituted 1,2-dicarbonyl compounds with acid hydrazides in different solvents
such as acetic acid,[17] n-butanol, ethanol, and methanol for prolonged time
periods[18,7c,19] to yield trisubstituted-1,2,4-triazines. Other variations include reac-
tion of the dicarbonyl compounds with monoarylhydrazones in alkaline ammonia
under pressure;[20] refluxing with ammonium bicarbonate,[21] sodium tert-butoxide,[22]
or with hydrazides=amidrazones;[23a,23b] microwave irradiation;[24] using metal salt
catalysts such as ZrOCl2 ꢁ 8H2O at 100 ꢂC;[25] using cuprous iodide,[26] and refluxing
in the presence of NaOAc=KOAc=AgOAc.[27] Srinivasan and coworkers have
reported this condensation in monobutylimidazolium ionic liquids alone.[28] Generally
3-methylthio-1,2,4-triazine synthesis has been reported with either S-methylthio-
semicarbazide hydroiodide[29] or in two steps with thiosemicarbazide and then
with alkyl halides in the presence of a base.[10–12,16]
Figure 1. Some important drug molecules containing the 1,2,4-triazine scaffold.

2194
R. S. TAMBOLI ET AL.
In the past decade, significant attention has been given to synthetic protocols
using room-temperature ionic liquids (RTILs). Imidazolium ILs are becoming
solvents of choice because they have shown great promise as an alternative to
conventional solvents, due to their low volatility and vapor pressure, larger liquidous
range, and thermal stability.[30] Herein we report a rapid synthesis of 5,6-
diarylsubstituted-1,2,4-triazines by one-pot condensation reaction of 1,2-diketones,
thiosemicarbazide, and methyl iodide in a fixed ratio (1:10) of Brønsted acidic IL
1,3-dibutylimidazolium bromide ([Bbim]þBrꢀ) and dimethylsulfoxide (DMSO) at
ambient temperatures. The effect of temperature variations on the formation of both
of the regioisomers is also discussed.
RESULTS AND DISCUSSION
Although many synthetic protocols for 1,2,4-triazines have been reported in
the past, as mentioned, there still exists a need for the development of more efficient
processes for the synthesis of 1,2,4-triazines. All of the mentioned procedures have
one or more disadvantages, such as formation of undesired condensed jelly-like
masses as side products, harsh reaction conditions, formation of more than one
regioisomer, activation by toxic metals, use of inorganic supports such as silica,
use of NaOAc or AgOAc, longer reaction times, use of corrosive acids, high
temperature or reflux conditions, multistep procedures such as preliminary isolation
of the 1,2-diketone-monoacylhydrazones followed by ring closure, and use of
scarcely available substituted carbazides as starting materials. Modifications have
been done by substituting solvents and acids=bases, but problems including longer
reaction times, high-temperature conditions, and low to moderate reaction yields still
persisted. Additionally, almost all of the known methods make use of volatile
organic solvents, leading to complex isolation and recovery procedures. Therefore,
we sought to develop a more efficient and convenient method that was flawless
and amenable to both laboratory and industrial scales.
Recently, we reported the synthesis of five-, six-, and seven-membered cyclic
guanidines by the synergy of specific ratio of IL and DMSO at ambient conditions.[31]
Hence, to utilize this synergistic phenomenon of the mixture, we envisaged evaluating
its effect on the formation of 5,6-diaryl-substituted 1,2,4-triazines from nonsymmetri-
cal diketones and thiosemicarbazide. We extended the investigation of this system
towards the synthesis of 1,2,4-triazines by a one-pot condensation of thiosemicarba-
zide, substituted diketones, and methyl iodide to afford the 5,6-diaryl substituted
3-methylthio-1,2,4-triazines in excellent yields in much shorter reaction times without
any added catalyst (Scheme 1).
Scheme 1. One-pot synthesis of 3-methylthio-5,6-diphenyl-1,2,4-triazine.

IL-DMSO-PROMOTED SYNTHESIS OF 1,2,4-TRIAZINES
2195
Table 1. Screening of different molar ratios of reactants
Entry
Molar ratioa
Yieldb (%)
Time (min)
1
2
3
4
1.0:1.0:1.0
1.0:1.5:1.2
1.0:1.0:1.2
1.0:1.0:0.0
75
27
17
21
15
25
96
85 (thiol)
aBenzil=thiosemicarbazide=methyl iodide.
bIsolated yields.
To determine the optimum conditions for the one-pot synthesis of alkylthio-
triazines, the model reaction of benzil, thiosemicarbazide, and methyl iodide was
selected. The optimum yields were found with equimolar quantities of benzil and
thiosemicarbazide with 1.2 eq. of methyl iodide at 70 ꢂC (Table 1, entry 3). When
the ratio of benzil and thiosemicarbazide was changed to 1:1.5, the mixture of sticky
polymeric complex was observed after workup, which showed a spot at the base
(with low Rf value) in thin-layer chromatography (TLC) with trace amounts of
desired cyclized product. This is probably because formation of bishydrazones or
dimers which failed further cyclization (Table 1, entry 2).
For ascertaining the role of solvent for the reaction, different polar aprotic sol-
vents with and without IL were employed to the model reaction as shown in Table 2.
DMSO gave the best results and hence was used for subsequent reactions (Table 2,
entry 5).
DMSO was further investigated as the most desired solvent with different ionic
liquids. In each case, the ionic liquid used was in catalytic ratio of 1:10 to DMSO.
Different ionic liquids (viz. 1-butylimidazolium tetrafluoroborate ½HbImꢃþBF4ꢀ,
1,3-dibutylimidazolium tetrafluoroborate ½BbImꢃþBF4ꢀ, 1-butyl-3-methylimidazo-
lium bromide [BmIm]þBrꢀ, and 1-butyl-2,3-dimethylimidazolium tetrafluoroborate
½BmmImꢃþBFꢀ4 ) were evaluated, and the results are given in Table 3. The ionic liquid
[Bbim]þBrꢀ in DMSO gave the best results. To justify these results and to scour
down the possibility of catalysis of ionic liquid or DMSO alone, the reaction was
performed in pure IL without DMSO and separately in DMSO alone. Longer reac-
tion times and moderate yields were observed in both these cases (Table 2, entries 6
and 7).
Table 2. Screening of different solvents with IL [Bbim]þBrꢀ
Entry
Solvent
Time
Yieldb (%)
1
2
3
4
5
6
7
DMFa
>2.5 h
>5 h
>3 h
42
69
62
65
96
65
45
THFa
Acetonea
Acetonitrilea
DMSOa
>2 h
15 min
>1.5 h
>2.5 h
DMSO alone
[Bbim]þBr- alone
a1:10 ratio with IL.
bIsolated yields.

2196
R. S. TAMBOLI ET AL.
Table 3. Screening of different ILs with DMSO
Entry
IL with DMSO (1:10)
Time
Yield (%)a
1
2
3
4
5
½HbImꢃþBFꢀ4
½BbImꢃþBFꢀ4
[Bbim]þBrꢀ
[BmIm]þBrꢀ
½BmmImꢃþBFꢀ4
48 min
42 min
15 min
45 min
>1 h
75
81
96
75
45
aIsolated yields.
It is interesting to note that when the reaction was carried out with both
the reactants without methyl iodide to form triazine-3-thiol derivative, the reaction
time increased in comparison to that of alkylthiotriazine (Table 1, entry 4).
It was observed that under similar conditions, a wide range of diketones
containing electron-withdrawing as well as electron-donating groups such as halo,
methyl, thiomethyl, and nitro easily underwent condensation with thiosemicarbazide
and methyl iodide to give 5,6-diaryl substituted 1,2,4-triazines in 10–45 min with
excellent isolated yields. The results are summarized in Table 4.
The unsymmetrical diketones were also explored for the synthesis of 1,2,4-triazines
(Scheme 2). In each case a mixture of regioisomers was obtained, which was separated by
flash chromatography. The predominance of one isomer over the other has been
observed depending on the substituent on the aryl ring. When the reaction temperature
was increased to 100ꢂC both isomers were observed in approximately equal proportions
with trace quantities of bishydrazones. When the same reaction was performed at room
temperature, only one isomer was obtained with minor quantity of the other one while at
0 ꢂC only one isomer was exclusively obtained. This observation can be utilized to syn-
thesize only one isomer selectively by varying the temperature of the reaction. As we
intended to use both of these isomers we performed all the reactions at 70 ꢂC. The struc-
tures of all 16 newly synthesized compounds 3d–k0 were characterized on the basis of
1
infrared (IR), H NMR spectral data, and elemental analyses. The known compounds
3a–c were identified by the comparison of their 1H NMR with those reported in the litera-
ture.[11,12] The structure of compound 3e has been confirmed by its crystal structure
(Figure 2). The rest of the isomers were assigned their structures accordingly.
It may be postulated that the inherent Brønsted acidity of the ionic liquid
plays an important role in the formation of hydrazone and high polarity of
combined solvents serves to form S-methyl-thiosemicarbazide in situ and facilitates
the cycloaddition reaction.
In the case of unsymmetrical diketones, the relatively enhanced solvent polarity
gave rise to the formation of one hydrazone exclusively by route ‘‘a’’ as shown in
Scheme 3, which resulted in the formation of one isomer predominantly. It was
reported that use of highly polar solvents and either acidic=basic conditions might
give predominantly one isomer.[26,32] Because of the superior polarity of the said mix-
ture (IL-DMSO) at ambient temperatures in combination with Brønsted acidity of IL
one isomer predominantly was obtained, achieving the regioselective synthesis at 0 ꢂC.
The mechanism of IL-promoted synthesis has also been postulated. The
hydrogen bonding of amine with molecular solvents may hinder the reaction rate,
while IL enhances the reaction rate due to lesser degree of hydrogen bonding

2197

2198

2199

2200
R. S. TAMBOLI ET AL.
Scheme 2. One-pot synthesis of 1,2,4-triazine isomers from unsymmetrical diketones.
and stabilization of transient states. The acidic C2-H of imidazolium cation could assist
carbonyl carbon to have higher electrophilicity, resulting in rapid hydrazone formation.
The methods reported so far for the synthesis of 1,2,4-triazines utilize either acidic
conditions using acids such as acetic, hydrochloric, trifluoroacetic and sulfuric or
solvents such as methanol and ethanol, requiring very harsh reaction conditions such
as refluxing for 8–24h. Compared to the reported methods, this method allowed safe,
convenient, and easy isolation procedures under ambient conditions by simple workup
of the reaction mixture in ice-cold water. The use of catalytic amounts of IL in DMSO
as a cosolvent is significant as compared to the previously reported method[28] in which
excess of IL was utilized as reaction medium and promoter. There were noteworthy
improvements in yields observed in the current method in comparison to the previously
reported method.[28] Another advantage of the method reported herein is that a pure
regioisomer can be obtained when the reaction is performed at low (0ꢂC) temperature.
The IL could be recovered easily from the aqueous filtrate by subjecting it
to evaporation on rotary evaporator and removal of DMSO in high vacuum.
The recovered IL has been used for the same reaction three times and showed no loss
of its catalytic activity. In conclusion, we have developed a mild, convenient,
and efficient protocol for the synthesis of 1,2,4-triazines by the condensation
of diketones, thiosemicarbazide, and methyl iodide using a mixture of IL and DMSO
(1:10 proportions) as a solvent as well as a promoter. The process gave excellent
isolated yields of 1,2,4-triazines in 10–45 min under ambient reaction conditions
in shorter reaction times than hitherto reported synthetic procedures.
Figure 2. ORTEP diagram of crystal structure of 3e (with 50% probability).

IL-DMSO-PROMOTED SYNTHESIS OF 1,2,4-TRIAZINES
2201
Scheme 3. Plausible mechanism of regioselective synthesis of 1,2,4-triazines in IL=DMSO (1:10).
EXPERIMENTAL
Melting points were determined in capillaries using Veego programmable
melting-point apparatus and are uncorrected. IR (in cmꢀ1) spectra in KBr pellets
1
on a Bruker ALPHA-T instrument and H NMR spectra were recorded in CDCl3
on a Bruker Avance II spectrometer (400 MHz), using Tetramethylsilane (TMS)
as an internal standard. Chemical shift data are reported in parts per million
(d in ppm). Elemental analyses were recorded on a Thermoscientific Flash-2000
CHN analyzer. Mass spectra were recorded on Thermoscientific DSQ-II mass spec-
trometer equipped with an electron-impact ionization (EI) interface. Flash column
chromatography was carried out Combiflash RF 200 (Teledyne Esco) using flash-grade
silica gel (230–400 mesh). The IL [Bbim]þBrꢀ was synthesized as per the earlier
reported procedure.[33] The diketones 1a–k were obtained by our previous protocol.[34]
General Procedure for Synthesis of 3-Methylthio-1,2,4-triazines in
IL þ DMSO (1:10) (3e and 3e’ as Examples)
A mixture of diketone 1e (2.0 mmol), thiosemicarbazide 2 (2.0 mmol), and
methyl iodide (2.4 mmol) in DMSO and [Bbim]þBrꢀ in 10:1 (5 g : 0.5 g) proportions
was stirred at 70 ꢂC for 20 min. The progress of the reaction was monitored by TLC
with an eluent mixture of n-hexane and ethyl acetate (4.5:0.5). After completion, the
reaction mixture was added to ice-cold water. The precipitated product was filtered,
washed with water, and dried. This regioisomeric mixture was subjected to flash
chromatographic purification using 5% ethyl acetate in n. hexane as eluent, to obtain
first fraction as 3e and second fraction as 3e0.
3-Methylthio-5-(4-fluorophenyl)-6-phenyl-1,2,4-triazine (3e)
Mp 104–106 ꢂC; IR (KBr, cmꢀ1) 3116, 3061, 1599, 698; m=z 296.96 (Mþ);
1H NMR (CDCl3, 400 MHz): d (ppm) 2.77 (s, 3H, SCH3); 7.05–7.56 (m, 9H,
Ar-H). Anal. calcd. for C16H12FN3S: C, 64.63; H, 4.07; N, 14.13. Found: C,
64.71; H, 4.06; N, 14.07.

2202
R. S. TAMBOLI ET AL.
Crystal Data
C16H12S1N3F1, CCDC 969264, Mr ¼ 297.36, T ¼ 293(2) K, space group ¼
3
˚
˚
˚
˚
P21=c, a ¼ 6.1928(2)A, b ¼ 10.6279(3)A, c ¼ 22.6088(8)A, V ¼ 1474.14(8)A ,
Z ¼ 4, R1 ¼ 0.0768, wR2 ¼ 0.2794 [I > 2r (I)].
3-Methylthio-5-phenyl-6-(4-fluorophenyl)-1,2,4-triazine (3e’)
Mp 95–97 ꢂC; IR (KBr, cmꢀ1) 3116, 3061, 1599, 698; m=z 296.96 (Mþ). 1H NMR
(CDCl3, 400 MHz): d (ppm) 2.79 (s, 3H, SCH3); 7.02–7.61 (m, 9H, Ar-H). Anal. calcd.
for C16H12FN3S: C, 64.63; H, 4.07; N, 14.13. Found: C, 64.74; H, 4.02; N, 14.09.
FUNDING
We thank the All India Council for Technical Education (AICTE), New Delhi,
India, for the National Doctoral Fellowship to R. S. T. [File No. 1–10=RID=NDF=
PG=36=2009–2010].
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
REFERENCES
1. Yoneda, F.; Nagamatsu, T. Transformation of toxoflavin into fervenulin via 1-demethyl-
toxoflavin. Tetrahedron Lett. 1973, 17, 1577–1580.
2. Neunhoeffer, H. Comprehensive Heterocyclic Chemistry; A. R. Katrizky, and C. W. Rees
(Eds.); Pergamon Press: Oxford, UK, 1984; vol. 3; Chapter 2.19; pp. 385–456.
3. Neunhoeffer, H. Comprehensive Heterocyclic Chemistry II; A. R. Katrizky, C. W. Rees, and
E. F. V. Scriven (Eds.); Pergamon Press: Oxford, UK, 1996; vol. 6; Chapter 6.11; pp. 507–573.
4. (a) Tanaka, A.; Sakai, H.; Ishikawa, T.; Motoyama, Y.; Takasugi, H. Studies on
anti-platelet agents, V: Synthesis and structure–activity relationship of 3-substituted
5,6-bis(4-methoxyphenyl)-1,2,4-triazines. Chem. Pharm. Bull. (Tokyo) 1994, 42, 1835–
1840; (b) Konno, S.; Kokubo, T.; Amano, M.; Yoshida, N.; Sagi, M.; Yamanaka, H.
Studies on as-triazine derivatives, XVIII: Synthesis of 5,6-diaryl-1,2,4-triazine derivatives
as blood platelet aggregation inhibitors. Yakugaku Zasshi 1992, 112, 729–741.
5. Monge, A.; Palop, J.; Ramirez, C.; Font, M.; Fernandez-Alvarez, E. New 5H-
1,2,4-triazino[5,6-b]indole and aminoindole derivatives: Synthesis and studies as inhibitors
of blood platelet aggregation, anti-hypertensive agents, and thromboxane synthetase
inhibitors. Eur. J. Med. Chem. 1991, 26, 179–188.
6. O’Rourke, M.; Lang Jr., S. A.; Cohen, E. 3-Aryl-as-triazines as potential anti-
inflammatory agents. J. Med. Chem. 1977, 20, 723–726.
7. (a) Ban, K.; Duffy, S.; Khakham, Y.; Avery, V. M.; Hughes, A.; Montagnat, O.; Katneni,
K.; Ryan, E.; Baell, J. B. 3-Alkylthio-1,2,4-triazine dimers with potent antimalarial
activity. Bioorg. Med. Chem. Lett. 2010, 20, 6024–6029; (b) Rees, R. W.; Russell, P. B.;
Foell, T. J.; Bright, R. E. Antimalarial activities of some 3,5-diamino-as-triazine deriva-
tives. J. Med. Chem. 1972, 15, 859–861; (c) March, L. C.; Bajwa, G. S.; Lee, J.; Wasti,
K.; Joullıe, M. M. Antimalarials, 3: 1,2,4-Triazines. J. Med. Chem. 1976, 19, 845–848.
´

IL-DMSO-PROMOTED SYNTHESIS OF 1,2,4-TRIAZINES
2203
8. Abdel-Rahman, R. M. Role of uncondensed 1,2,4-triazine compounds and related
heterobicyclic systems as therapeutic agents: A review. Pharmazie 2001, 56, 18–22.
´
9. Congreve, M.; Andrews, S. P.; Dore, A. S.; Hollenstein, K.; Hurrell, E.; Langmead, C. J.;
Mason, J. S.; Ng, I. W.; Tehan, B.; Zhukov, A.; Weir, M.; Marshall, F. H. Discovery of
1,2,4-triazine derivatives as adenosine A2A antagonists using structure-based drug design.
J. Med. Chem. 2012, 55, 1898–1903.
10. Khoshneviszadeh, M.; Ghahremani, M. H.; Foroumadi, A.; Miri, R.; Firuzi, O.;
Madadkar-Sobhani, A.; Edraki, N.; Parsa, M.; Shafiee, A. Design, synthesis, and biologi-
cal evaluation of novel anti-cytokine 1,2,4-triazine derivatives. Bioorg. Med. Chem. 2013,
21, 6708–1717.
11. Ansari, N.; Khodagholi, F.; Ramin, M.; Amini, M.; Irannejad, H.; Dargahi, L.;
Amirabad, A. D. Inhibition of LPS-induced apoptosis in differentiated-PC12 cells by
new triazine derivatives through NF-jB-mediated suppression of COX-2. Neurochem.
Int. 2010, 57, 958–968.
12. Irannejad, H.; Amini, M.; Khodagholi, F.; Ansari, N.; Tusi, S. K.; Sharifzadeh, M.;
Shafiee, A. Synthesis and in vitro evaluation of novel 1,2,4-triazine derivatives as
neuroprotective agents. Bioorg. Med. Chem. 2010, 18, 4224–4230.
13. (a) Brown, J. M. SR4233 (tirapazamine): A new anticancer drug exploiting hypoxia
in solid tumours. Br. J. Cancer. 1993, 67, 1163–1170; (b) Wilson, W. R.; Hay, M. P.
Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 2011, 11, 393–410.
14. Baxter, M. G.; Elphick, A. R.; Miller, A. A.; Sawyer, D. A. Substituted aromatic
compounds. U.S. Patent 4,560,687, 1985.
15. Haning, H.; Niewo¨hner, U.; Schenke, T.; Es-Sayed, M.; Schmidt, G.; Lampe, T.; Bischoff,
E. Imidazo[5,1-f]triazin-4(3H)-ones, a new class of potent PDE 5 inhibitors. Bioorg. Med.
Chem. Lett. 2002, 12, 865–868.
16. (a) Lacefield, W. B. 5,6-Diaryl-1,2,4-triazines as topical antithrombotic agents. U.S.
Patent 4,318,911, 1982; (b) Lacefield, W. B. 5,6-Diaryl-1,2,4-triazines. U.S. Patent
4,190,725, 1977; (c) Wong, D. T.; Lacefield, W. B. 1,2,4-Triazine derivatives. U.S. Patent
4,585,861, 1986; (d) Leach, M.; Harbige, L.; Riddall, D.; Barraclough, P. Medical use of
triazine derivatives. U.S. Patent 2009=0291954 A1, 2012.
17. Laakso, P. V.; Robinson, R.; Vandrewala, H. P. Studies in the triazine series including
a new synthesis of 1,2,4-triazines. Tetrahedron 1957, 1, 103–118.
18. Musatov, D. M.; Kurilov, D. V.; Rakishev, A. K. Efficient synthesis of 3-amino-5,6
diphenyl-1,2,4-triazine. Ukrainica Bioorg. Acta 2008, 1, 61–62.
19. Misra, U.; Hitkari, A.; Saxena, A. K.; Gurtu, S.; Shanker, K. Biologically active
indolylmethyl-1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 4H-1,3,4-triazoles, and 1,2,4-triazines.
Eur. J. Med. Chem. 1996, 31, 629–634.
¨
20. (a) Metze, R. Uber 1.2.4-Triazine, II: Mitteil.: Die Synthese di-und trialkyl-substituierter
und alkylaryl-substituierter 1.2.4-Triazine. Chem. Ber. 1955, 88, 772–778; (b) Metze, R.
¨
Uber 1.2.4-Triazine, III: Mitteil.: 1.2.4- Triazine mit substituierten und heterocyclischen
¨
Resten in 3-Stellung. Chem. Ber. 1956, 89, 2056–2060; (c) Metze, R.; Meyer, S. Uber 1.2.
4-Triazine, V: Seitenkettenoxydationenam 1.2.4-Triazin ring. Chem. Ber. 1957, 90,
¨
481–485; (d) Metze, R.; Kort, W. Uber 1.2.4-Triazine, VI: Triazinsynthesen mit
Dicarbonsauren. Chem. Ber. 1958, 91, 417–421.
¨
21. Orlek, B. S.; Cassidy, F.; Clark, M. S. G.; Faulkner, R. E. Design and synthesis of novel
muscarinic agonists containing the 1,2,4-triazine ring as an ester bioisostere. Bioorg. Med.
Chem. Lett. 1994, 4, 1411–1414.
22. Phucho, T.; Nongpiur, A.; Tumtin, S.; Nongrum, R.; Myrboh, B.; Nongkhlaw, R. L.
Novel one-pot synthesis of substituted 1,2,4-triazines. Arkivoc 2008, 15, 79–87.
23. Neunhoeffer, H.; Hennig, H.; Fruhauf, H.-W.; Mutterer, M. Zur synthese von 1,2,4-
triazinen. Tetrahedron Lett. 1969, 37, 3147–3150.

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R. S. TAMBOLI ET AL.
24. (a) Rauf, A.; Sharma, S.; Gangal, S. Microwave-assisted efficient one-pot synthesis of
3,5,6-trisubstituted-1,2,4-triazines from fatty acid hydrazides under solvent-free conditions
and their antimicrobial activity. Arkivoc 2007, 16, 137–147; (b) Zhao, Z.; Leister, W. H.;
Strauss, K. A.; Wisnoski, D. D.; Lindsley, C. W. Broadening the scope of 1,2,4-triazine
synthesis by the application of microwave technology. Tetrahedron Lett. 2003, 44, 1123–1127;
(c) Saad, H. A.; Youssef, M. M.; Mosselhi, M. A. Microwave-assisted synthesis of some
new fused 1,2,4-triazines bearing thiophene moieties with expected pharmacological activity.
Molecules 2011, 16, 4937–4957.
25. Sangshetti, J. N.; Shinde, D. B. One-pot synthesis and SAR of some novel 3-substituted
5,6-diphenyl-1,2,4-triazines as antifungal agents. Biorg. Med. Chem. Lett. 2010, 20, 742–745.
26. Lee, J. K.; Kim, H. G.; Kim, K. A.; Neunhoffer, H. 1,2,4-Triazine(VII): Synthesis of 6,50-
bis-1,2,4-triazinyls and 6,60-bis-1,2,4-triazinyls. Bull. Korean. Chem. Soc. 1998, 19, 391–394.
27. Saraswathi, T. V.; Srinivasan, V. R. A novel synthesis of 1,2,4-triazines. Tetrahedron Lett.
1971, 25, 2315–2316.
28. Potewar, T. M.; Lahoti, R. J.; Daniel, T.; Srinivasan, K. V. Efficient synthesis of 3,5,6-
trisubstituted-1,2,4-triazines in the Brønsted acidic ionic liquid, 1-n-butylimidazolium
tetrafluoroborate ([HBIM]BF4). Synth. Commun. 2007, 37, 261–269.
29. Huang, J. J. Synthesis of fused 1,2,4-triazines: 6- and 7-azapteridine and 6-azapurine
ring systems. J. Org. Chem. 1985, 50, 2293–2298.
30. For ionic liquids please see (a) Welton, T. Room-temperature ionic liquids: Solvents
for synthesis and catalysis. Chem. Rev. 1999, 99, 2071–2084; (b) Wasserscheid, P.;
Welton, T. Ionic Liquids in Synthesis, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2007.
31. Verma, A.; Giridhar, R.; Modh, P.; Yadav, M. R. A facile IL-DMSO-assisted synthesis
of 5-, 6-, and 7-membered benzo-annelated cyclic guanidines. Tetrahedron Lett. 2012,
53, 2954–2958.
32. Limanto, J.; Desmond, R. A.; Gauthier, D. R. Jr.; Devine, P. N.; Reamer, R. A.; Volante,
R. P. A regioselective approach to 5-substituted-3-amino-1,2,4-triazines. Org. Lett. 2003,
5, 2271–2274.
33. Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Ionic
liquid–promoted regiospecific Friedlander annulation: Novel synthesis of quinolines and
fused polycyclic quinolines. J. Org. Chem. 2003, 68, 9371–9378.
34. Shirude, S. T.; Patel, P.; Giridhar, R.; Yadav, M. R. An efficient and time-saving
microwave-assisted selenium dioxide oxidation of 1,2-diarylethanones. Ind. J. Chem.
2006, 45(B), 1080–1085.