Green chemical synthesis of fluorinated 1,3,5-triaryl-s-triazines in aqueous medium under microwaves as potential antifungal agents

Article abstract of DOI:10.1016/j.jfluchem.2004.03.002

Reasonable pure fluorinated s-triazines were synthesized in quantitative yield (96-99%) in 2-3 min in aqueous medium under microwaves, by reaction of fluorinated anilines and aqueous formaldehyde. All synthesized compounds have been screened in vitro for

Full text of DOI:10.1016/j.jfluchem.2004.03.002

Journal of Fluorine Chemistry 125 (2004) 1273–1277
Green chemical synthesis of fluorinated 1,3,5-triaryl-s-triazines in
aqueous medium under microwaves as potential antifungal agents
Anshu Dandia*, Kapil Arya, Meha Sati, Pritima Sarawgi
Department of Chemistry, University of Rajasthan, Jaipur 302004, India
Received 28 September 2003; received in revised form 1 March 2004; accepted 3 March 2004
Available online 29 July 2004
Abstract
Reasonable pure fluorinated s-triazines were synthesized in quantitative yield (96–99%) in 2–3 min in aqueous medium under microwaves,
by reaction of fluorinated anilines and aqueous formaldehyde. All synthesized compounds have been screened in vitro for their antifungal
activity against Rhizoctonia solani, Fusarium oxysporum, and Collectotrichum capsici.
# 2004 Published by Elsevier B.V.
Keywords: Fluorinated triaryl-s-triazines; Microwave irradiation; Aqueous medium
1. Introduction
[6,7], long reaction time, low yield, use of strong acids [6]/
base [18]/dehydrating agents [17], use of high boiling
solvents [19] and Dean stark apparatus for azeotropic
removal of water [6,7,18].
1,3,5-Tri-N-substituted hexahydro-1,3,5-triazines have
been focus of attention for the chemists and biologist for
long time due to wide variety of biological activities asso-
ciated with them such as antibacterial [1], antimicrobial [2],
antitumor [3], muscle relaxant properties [4] and are reactive
as azodyes [5]. They have also been used for protection of
amino group [6,7] as well as for the synthesis of poly amines
[8] and most of references are patent showing anti-HIV [9],
herbicidal [10], and fungicidal [11] activity.
Incorporation of fluorine to different heterocycles is
known to affect the course of the reaction besides, influen-
cing the biological/pharmacological activity [12]. Further,
incorporation of a trifluoromethyl substituents have been
shown to increase the phytoxicity along with selectivity and
arenes bearing a trifluoromethyl substituents comprise the
largest sub-group of commercially promising pesticides and
herbicides and more interest has been focused on synthesis
of fluorinated 1,3,5-triazines due to wide variety of their
biological activities such as antimicrobial [13], high oil and
water repellant polymers [14] and some references are
patented as potential herbicides [15] and acidic bifunctional
reactive dyes [16].
Usage of microwave irradiation (MWI) is well known for
the synthesis of variety of compounds [20] wherein chemical
reactions are accelerated because of selective absorption of
microwaves by polar molecules, but microwave assisted
procedures involving the use of solvents are limited as they
give rise to elevated temperatures and consequently high
pressures which can lead to dangerous explosions. In view of
this, more interest has now been focused on dry media
synthesis, involving the coupling of MWI with solid sup-
ported reagents. The method provides unique chemical
process with special attribute to enhanced reaction time,
higher yield, greater selectivity, and ease of manipulation
[21] But, the above technique requires an appreciable
amount of solvent for adsorption of reactants and elution
of products.
Recently, the use of aqueous media for organic reaction
[22] is under extensive investigation for synthesis and also to
exploit hydrophobic effect [23]. Water has high dielectric
constant with a permanent dipole moment, which allows the
coupling between the oscillating electric field and the mole-
cular tumbling to occur with high efficient heating. Hence, at
elevated temperature it acts as a pseudo-organic solvent and
in its use, isolation of products is also facilitated due to
decreased solubility of organic material upon post reaction
cooling.
Conventional syntheses of tri substituted 1,3,5-triazines
suffer from many disadvantages like multistep procedure
* Corresponding author. Tel.: þ91-141-523637; fax: þ91-141-523637.
E-mail address: dranshudandia@eth.net (A. Dandia).
0022-1139/$ – see front matter # 2004 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2004.03.002

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A. Dandia et al. / Journal of Fluorine Chemistry 125 (2004) 1273–1277
Table 1
Physical data of synthesized compounds 3a–f
Compound
X
Reaction time (min)/yield (%)
Molecular formulaa
C21H18N3F3
Melting point (8C)
Classical method
Microwave method
Observed
Reported
3a
3b
3c
3d
3e
3f
3-F
600/75
480/67
1400/78
780/62
720/71
750/65
3/99
86
160
182
125
142
225
84–86 [18]
4-F
2-F
4/99
5/98
C
21H18N3F3
158 [18]
181–182 [18]
C21H18N3F3
C24H18N3F9
C24H18N3F9
C24H15N3F9Cl3
2-CF3
3-CF3
2-CF34-Cl
2.5/99
3/99
2.5/98
–
–
–
Final temperature is measured at the end of microwave irradiation by introducing a glass thermometer in the reaction mixture in the beaker.
a All compounds gave satisfactory elemental analyses (C and H) within Æ0.25% of theoretical value.
In all cases it has been found that reactions proceed with
considerable lower yields under similar thermal conditions
demonstrating that the effect of MW is evidently not purely
thermal [26]. These specific non-thermal effects remain
noticeable even by extended reaction times up to 3 h, are
consistent with the consideration of mechanisms [27] and
with the assumption that MW effects are increased when the
polarity of a system is enhanced. The first step consist of the
nucleophillic addition of aromatic amines (1) on the C¼O of
the formaline (2) to leading a dipolar transition state. One
can expect an important specific microwave effect due to the
evolution of polarity of the system during the reaction
progress, as the transition state (TS) is more polar than
Scheme 1.
In continuation to our earlier interest on the economic and
environmentally benign synthesis of biodynamic hetero-
cycles [24] and particular interest on use of aqueous medium
for heterocyclic synthesis [25] we report herein for the first
time the economic, ecofriendly, facile one pot synthesis of
fluorinated 1,3,5-triaryl hexahydro-1,3,5-triazine by the
condensation of fluorinated amines (1) with formaldehyde
(2) under microwave irradiation in aqueous medium
(Table 1, Scheme 1).
the ground state (GS) in this reaction. The most important
stabilization of the transition state is, therefore, responsible
for an enhancement of reactivity by a decrease of the
activation energy (Scheme 2).
The first step is followed by trimarization of aldimines
under similar conditions to yield 1,3,5-trisubstituted hexa-
hydro-1,3,5-triazines in one step efficiently (Scheme 3)
which also involves polar transition state.
Finally, in order to check the possible intervention of
specific (non-thermal) MW effects, the results obtained
under MW were compared to conventional heating. The
reaction, in the case of compounds 3a and 3d has been
carried out using pre-heated oil bath, under the same con-
ditions as under MW (time, temperature, vessel) (Table 2).
2. Result and discussion
IR spectra of the products (3a–f) displayed characteristic
absorption in the region 2980–2820 (aliphatic CH), 1180–
1150 (CN), and 740–720 (C–F). The 1H NMR spectra of 3b
Table 2
Comparative results obtained for the synthesis of 3a and 3d by reacting aromatic amine with formaldehyde
Entry
Medium
Mode of reaction D/MW (power (W))
Temperaturea (8C)
Time (min)
Yieldb (%)
3b
Aqueous medium
Aqueous medium
Aqueous medium
MW (640)
101
101
101
3
3
99
D
D
No reaction
68c
180
3d
Aqueous medium
Aqueous medium
Aqueous medium
MW (640)
101
101
101
2.5
2.5
99
No reaction
58c
D
D
180
a Final temperature is measured at the end of microwave irradiation by introducing a glass thermometer in the reaction mixture in the beaker.
b Isolated yield of purified compounds that exhibited physical and spectral properties in accordance with the assigned structure.
c Yields obtained after extension of reaction time up to 180 min at similar temperature (under MWs). TLC indicated complete conversion of reactants but
formation of mixture of product causing decrease in yield of required compounds.

A. Dandia et al. / Journal of Fluorine Chemistry 125 (2004) 1273–1277
1275
Scheme 2.
2.1. Evaluation of antifungal activity
The antifungal activity of all synthesized compounds 3a–
e were tested against three pathogenic fungi namely Rhi-
zoctonia solani, Fusarium oxysporum, and Collectotrichum
capsici by the poison plate technique [28]. The stock solu-
tion of 1000 and 500 ppm of all compounds were prepared in
acetone and then incorporated in required quantities to
Potato Dextrose Agar (PDA) medium before dispersing into
petri-plates. One hundred milliliters of PDA was uniformly
distributed into three petri-plates, served as replicates. Three
plates containing unamended PDA were maintained as
control.
The petri-plates were inoculated with a 4 mm disc cut
from a 7 days old fungus culture. The inoculated plates were
incubated at 25 Æ 1 8C for 5 days. The radial growth of the
fungal colonies was measured on sixth day and data were
statistically analyzed. The fungicidal data (Table 4) indi-
cates that some of the compounds were found significantly
superior than control (9.0 cm) in controlling the radial
growth (1.25–5.00 cm) of all the three pathogens. The other
were similar to control.
Scheme 3.
showed singlet at d 4.76 (s, 6H, CH2), 6.93 (d, 6H, Ar–H)
and 6.98 (d, 6H, Ar–H), while in case of compounds 3a and
3c–f it showed a singlet at d 4.76–4.95 (s, 6H, CH2), and
6.86–7.42 (m, Ar–H). Disappearance of C¼O (formalde-
hyde) at 1740 cmÀ1 and primary amino group absorption at
3450–3330 cmÀ1 further confirmed the formation of 3.
13C NMR of 3 showed a sharp signal at d 78.1–79.5
(CH2), 119.2–138.5 (aromatic carbons), 145.5–147.2 (C–
N). The presence of fluorine was confirmed by 19F NMR
spectra, where the C–F signal was observed at d 118.05–
120.42 (compound 3a–c) and CF3 signal at d 63.25–
64.07 ppm in case of compound 3d–f. In the mass spectra
of 3a–c molecular ion peaks were observed at 369 corre-
sponding to their molecular weight along with base peak at
123 (C6H4CH2NF) or at 95 (C6H4F) (Table 3).
Table 3
Spectral data of synthesized compounds 3a–f
Compound IR (cmÀ1
)
1H NMR (d (ppm))
13C NMR (d (ppm))
19F NMR
Mass m/z (%)
(d (ppm))
CH2
Ar–H
3a
3b
3c
3d
3e
3f
2970–2830 (ali. CH),
1170–1150 (C–N),
740 (C–F)
4.85 (s, 2H)
6.95–7.35
78.2 (CH2), 120.8–138.2
(aromatic carbons), 145.2
(C–N), 151.8 (C–F)
À119.20 (s, 3-F)
À118.05 (s, 4-F)
À120.42 (s, 2-F)
369 ([Mþ] 8.8), 246
(m, 12H)
([Mþ À C7H6NF] 40.2),
123 (C7H6NF, 100), 95 (35)
369 ([Mþ] 12.2), 246 (42.2),
123 (30.5), 95 (C6H4F, 100)
2980–2840 (ali. CH),
1180–1150 (C–N),
760 (C–F)
4.76 (s, 2H)
4.95 (s, 2H)
4.92 (s, 2H)
4.82 (s, 2H)
4.90 (s, 2H)
6.93 (d, 6H),
6.98 (d, 6H)
78.9 (CH2 119.2–135.2
(aromatic carbons), 146.5
(C–N), 150.2 (C–F))
2970–2850 (ali. CH),
1180–1160 (C–N),
740 (C–F)
6.98–7.25
79.5 (CH2), 121.2–137.2
(aromatic carbons), 147.2
(C–N), 151.2 (C–F)
369 ([Mþ] 17.8), 246 (35.6),
(m, 12H)
123 (C7H6NF, 100), 95 (28)
2975–2860 (ali. CH),
1170–1150 (C–N),
750 (C–F)
6.95–7.42
78.6 (CH2), 121.8–138.2
(aromatic carbons), 125.3
(CF3), 130.5 (C–CF3)
78.3 (CH2), 120.3–135.7
(aromatic carbons), 126.03
(CF3), 131.2 (C–CF3)
78.7 (CH2), 119.9–135.2
(aromatic carbons), 121.2
(C–Cl) 126.01 (CF3),
131.5 (C–CF3)
À64.02 (s, 2-CF3) 519 ([Mþ] 24.2), 345
([Mþ À C6H4CH2NCF3]),
(m, 12H)
171 (C8H6NCF3, 100)
À63.25 (s, 3-CF3) 519 ([Mþ] 24.2), 345
2980–2830 (ali. CH),
1180–1150 (C–N),
760 (C–F)
6.90–7.35
(m, 12H)
([Mþ-C6H4CH2NCF3]),
171 (C8H6NCF3, 100)
2980–2820 (ali. CH),
1180–1150 (C–N),
760 (C–F), 780 (C–Cl)
6.86–7.35
À64.07 (s, 2-CF3)
–
(m, 9H)

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A. Dandia et al. / Journal of Fluorine Chemistry 125 (2004) 1273–1277
Table 4
Effect of the compounds synthesized on the mean radial growth (cm) of fungi in vitro (poison plate technique)
Compound
Rhizoctonia solani
Fusarium oxysporum
Collectotrichum capsici
1000 (ppm)
500 (ppm)
1000 (ppm)
500 (ppm)
1000 (ppm)
500 (ppm)
3a
3b
3c
3d
3e
3f
1.42a
3.92
1.83a
6.42
5.00
7.08
2.25a
4.57
2.75a
8.83
6.25
9.00
4.00
2.25a
3.67
3.42
1.42a
3.17
5.17
3.33a
3.67
5.37
2.67a
3.58
4.77
3.77
3.25
1.92a
3.83
1.25a
5.17
4.50
5.58
3.25a
6.53
2.08a
a Minimum value.
It was found that compound 3a (X ¼ 3-F) and 3c
(X ¼ 2-F) was the most effective against R. solani (1.42–
1.83 cm), compounds 3e (3-CF3), 3b (X ¼ 4-F) were most
effective against F. oxysporum (1.42–2.25 cm) and 3f (2-
CF3, 4-Cl), 3d (2-CF3) were also found effective against C.
capsici (1.25–1.92 cm).
(1.23 g, 10 mmol) was stirred and heated (oil bath
temperature slowly raised from 90 to 102 8C) with
para formaldehyde (0.32 g, 10 mmol) in anhydrous
benzene (30 ml) with azeotropic removal of water,
using Dean and Stark apparatus for 10 h. The
remaining benzene was removed under reduced
pressure and solid residue was extracted with ether,
the ether layer dried (Na2SO4) and evaporated under
suction to give crude product which was further
recrystallized from hexane to give 3a (mp 84–86;
yield ¼ 75%) [18].
3. Conclusion
In conclusion, we have presented a new economical, safe,
environmentally benign solvent free synthesis of fluorinated
1,3,5-trisubstituted hexahydro-1,3,5-triazines under micro-
wave irradiation using water as aqueous medium. The
operational simplicity, avoiding the use of solvent and solid
support, high yield in significant very short reaction times,
can impose this procedure as a useful and attractive alter-
native to the currently available methods.
Microwave mediated synthesis: A mixture of 1a
(1.23 g, 10 mmol) and aqueous formaldehyde
(4 ml, 12 mmol) in open borosil beaker (100 ml)
was irradiated inside a microwave oven at 640 W
till the completion of reaction (TLC), to give an oil
which was solidified on standing, which was
washed with water and found to be pure by
(TLC), with no need of further purification process
(mp 84–86; yield ¼ 99%).
4. Experimental
Likewise, following the same procedure compounds 3b–f
were prepared under microwaves and their structural char-
Melting points were determined in open glass capillaries
and were uncorrected. Thin layer chromatography on silica
gel ‘G’ coated glass plates using benzene, ethanol (8:2) as
eluent was used for monitoring progress of the reactions. IR
spectra (KBr) were recorded on a Magna FT IR-550 spectro-
photometer, 1H, 19F, and 13C NMR spectra
[CDCl3 þ ðCD3Þ2SO] were taken on a Jeol FX 90Q spectro-
meter at 89.55, 84.25, and 22.49 MHz, respectively, using
TMS as an internal standard for PMR and hexafluoroben-
zene as external standard for 19F NMR and mass spectra
were recorded on Jeol D-300 spectrometer at an ionization
potential of 70 eV. Microwave assisted reactions were car-
ried out on a BPL BMO model, operating at 700 W, gen-
erating 2450 MHz frequency. All anilines were purchased
from Aldrich Chemical Co. and were used as received.
Formaldehyde was of concentration 37–39% (w/w).
1,3,5-Tris (30-flurophenyl)-hexahydro 1,3,5-triazine (3b)
was prepared by two different ways.
1
acterization was done on the basis of IR, H NMR and
spectral and elemental analyses (Table 1).
Acknowledgements
Financial assistance from CSIR (New Delhi) is gratefully
acknowledged. We are also thankful to RSIC, CDRI, Luck-
now for the elemental and spectral analyses.
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