Ecofriendly solventless synthesis and reduction reaction of some triazole compounds and evaluation of their antimicrobial activity

Article abstract of DOI:10.1080/00397911.2011.632831

A number of triazole-3-one compounds have been synthesized, and reduction of the carbonyl group in the molecule has been carried out to give a corresponding hydroxyl group that possesses asymmetric carbon atom in good yields and short reaction times. It is ecofriendly because it is produced by straightforward microwave irradiation in the absence of solvent. All newly synthesized compounds were also screened for their antimicrobial activities. The antimicrobial activity study revealed that 2d, 2i, 3c, and 3g-j showed good activity against a variety of microorganisms. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2011.632831

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Ecofriendly Solventless Synthesis and
Reduction Reaction of Some Triazole
Compounds and Evaluation of Their
Antimicrobial Activity
Musa Özil a , Emre Menteşe a , Şengül Alpay Karaoğlu b & Bahittin
Kahveci c
a Department of Chemistry, Faculty of Sciences and Arts, Recep
Tayyip Erdoğan University, Rize, Turkey
b Department of Biology, Faculty of Sciences and Arts, Recep Tayyip
Erdoğan University, Rize, Turkey
c Department of Nutrition and Dietetics, Faculty of Health Sciences,
Karadeniz Technical University, Trabzon, Turkey
Version of record first published: 21 Feb 2013.
To cite this article: Musa Özil , Emre Menteşe , Şengül Alpay Karaoğlu & Bahittin Kahveci (2013):
Ecofriendly Solventless Synthesis and Reduction Reaction of Some Triazole Compounds and Evaluation
of Their Antimicrobial Activity, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:9, 1328-1336
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Synthetic Communications1, 43: 1328–1336, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.632831
ECOFRIENDLY SOLVENTLESS SYNTHESIS AND
REDUCTION REACTION OF SOME TRIAZOLE
COMPOUNDS AND EVALUATION OF THEIR
ANTIMICROBIAL ACTIVITY
1
1
2
¨
˘
Musa Ozil, Emre Mentes¸e, S¸engu¨l Alpay Karaoglu, and
Bahittin Kahveci3
1Department of Chemistry, Faculty of Sciences and Arts, Recep Tayyip
Erdog˘an University, Rize, Turkey
2Department of Biology, Faculty of Sciences and Arts, Recep Tayyip
Erdog˘an University, Rize, Turkey
3Department of Nutrition and Dietetics, Faculty of Health Sciences,
Karadeniz Technical University, Trabzon, Turkey
GRAPHICAL ABSTRACT
Abstract A number of triazole-3-one compounds have been synthesized, and reduction of the
carbonyl group in the molecule has been carried out to give a corresponding hydroxyl group
that possesses asymmetric carbon atom in good yields and short reaction times. It is eco-
friendly because it is produced by straightforward microwave irradiation in the absence
of solvent. All newly synthesized compounds were also screened for their antimicrobial
Received October 2, 2011.
Address correspondence to Musa Ozil, Department of Chemistry, Faculty of Sciences and Arts,
¨
Recep Tayyip Erdog˘an University, Rize 53100, Turkey. E-mail: musa.ozil@rize.edu.tr
1328

SYNTHESIS AND REDUCTION OF TRIAZOLES
1329
activities. The antimicrobial activity study revealed that 2d, 2i, 3c, and 3g–j showed good
activity against a variety of microorganisms.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Antimicrobial activity; green chemistry; microwave-assisted synthesis;
solvent-free; 1,2,4-triazole-3-one
INTRODUCTION
A dramatic increase in antibiotic resistance, especially among Gram-positive
bacteria, triggered a clear need for the discovery of new antimicrobials rather than
analogs of the existing ones.[1] Traditionally, small molecules have been a reliable
source for discovering novel biologically active compounds.
1,2,4-Triazole compounds have been found to be useful for applications in
medicine and agriculture.[2] The synthesis, reactions, and biological properties of
substituted triazole constitute a significant part of modern heterocyclic chemistry.[3]
Compounds with the triazole ring system have many pharmacological properties and
play important roles in biochemical processes. There have been reported applications
in a wide spectrum of potential biological properties, such as antifungal,[4] antitu-
mor,[5] analgesic,[6] antibacterial,[7,8] and cancer therapy.[9] Antibacterial activity data
of these structures showed considerable activity against Gram-negative and
Gram-positive bacteria as well as some strains of fungi.[10–12] Thus, the heterocyclic
system is an attractive scaffold to be utilized for exploiting chemical diversity.
The application of microwave (MW) irradiation as an effective energy source for
activation of reactions has now become a very popular and useful technology in
organic chemistry.[13] Nowadays economical and environmental conditions are forcing
the chemical community to search for more efficient ways of performing chemical
transformations in a single operation by reusing catalysts and avoiding toxic and costly
reagents, large amounts of solvents, and expensive purification techniques.[14] Reac-
tions using solid-supported reagents and scavengers have created considerable interest
among synthetic chemists around the world.[15] Because of several advantages in terms
of yield, purity, and selectivity, supported reagents have been used under solvent-free
conditions for the synthesis of various important synthetic intermediates.[16]
The combination of microwave irradiation and solvent-free reaction conditions
leads to enhanced reaction rates, greater yields of pure products, easier workup, and
selective conversions, all advantages of the ecofriendly approach.[17,18] Consequently,
this protocol should be welcomed in these environmentally conscious times.
The growing importance of triazole compounds has led to the development of
new methods for their synthesis, including microwave-assisted synthesis. Thus, the
development of simple, convenient, safe, and efficient methods for the preparation
of these molecules still continues to be an interesting and attractive area of research
in synthetic chemistry.
In the present work, we studied the triazole formation, taking different para-
meters of solid supports like (i) montmorillonite KSF, (ii) montmorillonite K10,
(iii) alumina, and (iv) silica gel. However, no reaction occurred. Encouraged by
recent focus on the green chemical theme of eliminating the use of solvents, we

¨
M. OZIL ET AL.
1330
extended our studies to neat reactions, those that could be made successful without
any solid supports. It did not lead to any side reactions and no detectable by-product
was observed. Consequently, we extended this condition to the synthesis of com-
pounds (2a–j).
RESULTS AND DISCUSSION
Recently, we reported the synthesis of triazole compounds by both microwave
irradiation and conventional heating.[19,20] However, poor reaction yields, selectivity,
and long reaction times dissuade more systematic study of the reaction. Therefore,
we planned to focus our study on the synthesis and reduction of triazole compounds
via conventional and microwave-assisted synthesis under solvent-free media.
(N0-Ethoxycarbonyl)-4-alkyl(aryl)hydrazonic acid ethyl ester can be considered
as useful intermediate leading to the formation of heterocycles, such as 1,2,4-
triazole-3-ones. We synthesized some (N0-ethoxycarbonyl)-4-alkyl(aryl)hydrazonic
acid ethyl ester (1a–j) according to the literature.[20–22]
At first, we had to optimize the reaction conditions for the synthesis of
5-aryl(alkyl)-4-(4-benzoylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2a–j) by the
reaction of (N0-ethoxycarbonyl)-4-alkyl(aryl)hydrazonic acid ethyl ester (1a–j) with
p-aminobenzophenone. We tried different reaction conditions to carry out this reac-
tion under microwave irradiation in the absence of solvent. For this we used solid
support, such as montmorillonite KSF, montmorillonite K10, alumina, and silica
gel, but no reaction occurred. However, reaction occurred when heated neat above
the melting points under microwave irradiation (Scheme 1).
The polarity of the system is increased during the reaction progress from the
neutral ground state (GS) to the dipolar transition state (TS) for cyclization. Conse-
quently, microwave stabilizing effects by dipole–dipole interactions with the electric
Scheme 1. Pathway for the formation of the 3H-1,2,4-triazol-3-ones.

SYNTHESIS AND REDUCTION OF TRIAZOLES
1331
field are increased with the polarity of reactants. Such an explanation of microwave
effects is supported by calculations suggesting a relation between microwave
irradiation and the polarity of the transition state,[23] so we can say that in our reac-
tions specific microwave effects occur when the reaction mixture is melting.
Encouraged by these findings, we next investigated the optimum reaction con-
dition for the synthesis of 3H-1,2,4-triazol-3-ones (2a–j) under conventional conditions
and a monomodal microwave oven. For conventional conditions, the reaction
occurred in an oil bath for 5 h at 170 ꢀC. For a Discover monomodal microwave oven,
mixture was irradiated in closed vessels with pressure control at 150ꢀC for 3 min (hold
time) at 300W maximum power.
By comparision of data, it is obvious that the microwave irradiation protocol
resulted in much faster reactions and significantly greater yields (Table 1) than the
thermal heating process.
Here, we report our further investigations concerning the reduction of the car-
bonyl group in the molecule, which have been carried out to produce a corresponding
hydroxyl group that possesses asymmetric carbon atoms under microwave irradiation
as well as conventional methods. However, there was no reduction of carbonyl in the
triazole ring but only a reduction of carbonyl in the substitute group bounding the
N-4 nitrogen atom. Thus, in a conventional experiment, we obtained reductive pro-
ducts 3a–j in the presence of an ion exchange solid (Amberlyst-15 Hþ) in the aprotic
solvent tetrahydrofuran (THF). Amberlyst-15 (Hþ) is an effective material for
reduction of hindered and unreactive ketones.[24] However, we obtained 3a–j in the
presence of alumina under microwave irradiation in the absence of solvent (Scheme 2).
Varma and Saini[25] demonstrated the reduction of the carbonyl group in a
solid state under microwave irradiation. Here, we synthesized 3a–j in a monomode
microwave synthesizer for 2 min at 300 W maximum power with high yield (Table 2).
A comparison of the spectral data gave some information as to the nature of
the products. In this context, a comparison of the infrared (IR) spectral data clearly
=
indicates the formation of compounds 3a–j by the disappearance of the C O band at
Table 1. Comparison of yields under microwave irradiation and conven-
tional heating (for compounds 2a–j)
Yield (%)
Compound
Oil batha
Microwaveb
2a
2b
2c
2d
2e
2f
48
56
54
54
64
58
53
67
59
63
78
81
75
85
88
76
83
77
91
70
2g
2h
2i
2j
a5 h at 170 ꢀC.
b3 min at 150 ꢀC.

¨
M. OZIL ET AL.
1332
Scheme 2. Pathway for the reduction reaction of the carbonyl group.
about 1649–1668 cmꢁ1 in compounds 2a–j and the appearance of the OH band at
about 3375–3439 cmꢁ1 and C—O band at about 1013–1059 cmꢁ1 in compounds
1
3a–j. In addition, in the H NMR spectrum of 3a–j revealed for OH group doublet
signals at about 5.91–6.08 ppm in the dimethylsulfoxide (DMSO-d6) and broad
singlet signal at about 2.88–3.38 ppm in the CDCl3 and revealed for CH group doub-
let signals at about 5.70–5.77 ppm in the DMSO-d6 and singlet signals at about
5.80–5.86 ppm in the CDCl3. The 13C NMR spectrum of 3a–j shows a signal that
indicates the appearance of CH groups at about 73.52–75.81 ppm and the disappear-
=
ance of the C O group at about 194.84–195.69 ppm in compounds 2a–j.
Antibacterial Activities
While antibacterial, antituberculotic, and antifungal activity were shown on
some tested compounds, some of compounds did not show any antimicrobial
Table 2. Comparison of yields under microwave irradiation and conven-
tional heating (for compounds 3a–j)
Yield (%)
Compound
THFa
Microwaveb
3a
3b
3c
3d
3e
3f
45
58
56
52
54
56
47
36
41
42
72
75
80
68
75
65
70
63
78
81
3g
3h
3i
3j
a12 h at rt.
b2 min at 150 ꢀC.

SYNTHESIS AND REDUCTION OF TRIAZOLES
1333
Table 3. Antimicrobial activity of the compounds (mg=ml)
Microorganism and minimal inhibition concentration
Compound
Ec
Yp
Pa
Sa
Ef
Bc
Ms
Ca
Sa
2a
2b
2c
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
2
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
32
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
>128
—
—
—
—
—
—
—
—
—
—
—
250
—
—
—
—
31.3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
125
—
—
—
—
31.3
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
2d
2e
—
—
—
—
—
—
—
—
2f
2g
2h
2i
—
—
—
—
—
—
—
—
—
—
—
—
—
—
15.6
—
2j
3a
3b
3c
—
—
—
—
—
—
—
—
125
—
125
—
62.5
—
125
—
3d
3e
—
—
—
—
—
—
—
—
3f
3g
3h
3i
62.5
125
250
250
2
62.5
125
250
250
2
62.5
125
250
250
<1
31.3
15,6
62,5
62.5
3j
Amp.
Strep.
Flu.
4
<8
<8
Notes. Ec, E. coli ATCC 25922; Yp, Y. pseudotuberculosis ATCC 911; Pa, P. aeruginosa ATCC 43288;
Sa, S. aureus ATCC 25923; Ef, E. faecalis ATCC 29212; Bc, B. cereus 702 Roma; Ms, M. smegmatis
ATCC607; Ca, C. albicans ATCC 60193; S. cerevisiae RSKK 251; Amp., ampicillin; Strep., streptomycin;
Flu., fluconazole; —, no activity.
activity. Compounds 2i, 3c, 3g–3j demonstrated antitubercolitic activity (M. smeg-
matis) in 15.6–250 mg=ml concentration. Compound 2d exhibited antimicrobial
activity against only yeast (C. albicans, S. cerevisiae) fungals. Compounds 3c and
3g–3j exhibited antimicrobial activity against Gram-positive M. smegmatis in
15–250 mg=ml concentration. The results are shown in Table 3.
CONCLUSION
We have developed a novel and efficient approach for the synthesis of some
3H-1,2,4-triazol-3-ones and reduction of carbonyl group in these molecules under
microwave irradiation in the absence of solvent. The important advantages of this
procedure include (a) operational simplicity (ease of setup and workup), (b) safe
and environmentally benign solvent-free procedure (eliminating toxic organic
solvents as reaction medium), (c) good yield of the products with high purity, (d)
mild reaction conditions, (e) good selectivity, (f) general applicability, accommodat-
ing a variety of substitution patterns, and (g) effective antibacterial activities
(Table 3) for the compounds 3a–j.[26]

¨
M. OZIL ET AL.
1334
EXPERIMENTAL
Chemistry
Melting points were determined in open capillaries on a Buchi digital melting-point
¨
apparatus and were uncorrected. Infrared (IR) spectra were recorded in KBr pellets on a
1
Perkin–Elmer 100 Fourier transform (FT)-IR spectrophotometer. H NMR and 13C
NMR spectra were measured on a Varian 400 spectrometer using CDCl3 and DMSO-
d6 as solvent and tetramethylsilane (TMS) as internal standard. Chemical shifts are given
in parts per million, and coupling constants J are in hertz. Elemental analyses were per-
formed on a Carlo Erba 1106 CHN analyzer. A monomode CEM-Discover microwave
was used in the standard configuration as delivered, including proprietary software.
All experiments were carried out in microwave process vials (30 mL) with control of
the temperature by IR detection temperature sensor. The temperature was computer
monitored and maintained by discrete modulation of delivered microwave power. After
completion of the reaction, the vial was cooled to 60ꢀC by air jet cooling.
General Procedure for the Synthesis of Compounds 2a–j Under
Conventional Conditions
A mixture of the corresponding (N0-ethoxycarbonyl)-4-alkyl(aryl)hydrazonic
acid ethyl ester (1a–j) (0.01 mol) and p-aminobenzophenone (0.01 mol) was heated
in an oil bath for 5 h (monitored by TLC, ethylacetate–hexane, 3:1) at 170 ꢀC. The
crystals formed on cooling were recrystallized from ethyl acetate–petroleum ether
(3:1) to give pure 2a–j.
General Procedure for the Synthesis of Compounds 2a–j in a
Monomode Microwave Synthesizer
A mixture of the corresponding (N0-ethoxycarbonyl)-4-alkyl(aryl)hydrazonic
acid ethyl ester (1a–j) (0.01 mol) and p-aminobenzophenone (0.01 mol) was irra-
diated in closed vessels with pressure control at 150 ꢀC for 3 min (hold time) at
300 W maximum power. After the completion of the reaction (monitored by TLC,
AcOEt=hexane, 3:1) the crystals formed on cooling were recrystallized from ethyl
acetate–petroleum ether (3:1) to give pure 2a–j.
General Procedure for the Synthesis of Compounds 3a–j Under
Conventional Condition
A mixture of the 2a–j (0.01 mol), NaBH4 (0.03 mol), and amberlyst-15 (Hþ)
(5 g) was stirred at room temperature for 12 h in dry tetrahydrofurane (100 mL)
(monitored by TLC, ethylacetate–hexane, 3:1). The reaction mixture was filtered.
The solvent was removed under reduced pressure. The residue was recrystallized
from ethyl acetate–petroleum ether (3:1) to give pure 3a–j.
General Procedure for the Synthesis of Compounds 3a–j in a
Monomode Microwave Synthesizer
A mixture of 2a–j (0.01 mol), NaBH4 (0.03 mol) and neutral alumina (9.5 g)
was added in a pyrex open vessel (30 mL) and microwave irradiated at 150 ꢀC for

SYNTHESIS AND REDUCTION OF TRIAZOLES
1335
2 min (hold time) at 300 W maximum power. Completion of the reaction was indi-
cated by TLC (ethylacetate–hexane, 3:1). The reaction mass was eluted with ethanol
and 25 mL of water was added and heated for 10 min. The solvent was removed
under reduced pressure. The residue was recrystallized from ethyl acetate–petroleum
ether (3:1) to give pure 3a–j.
MICROBIOLOGY
All test microorganisms were obtained from the Hifzissihha Institute of Refik
Saydam (Ankara, Turkey) and were as follows: Escherichia coli (E. coli)
ATCC35218, Yersinia pseudotuberculosis (Y. pseudotuberculosis) ATCC911, Pseudo-
monas aeruginosa (P. aeruginosa) ATCC43288, Enterococcus faecalis (E. faecalis)
ATCC29212, Staphylococcus aureus (S. aureus) ATCC25923, Bacillus cereus (B. cer-
eus) 709 Roma, Mycobacterium smegmatis (M. smegmatis) ATCC607, Candida albi-
cans (C. albicans) ATCC60193, and Saccharomyces cerevisiae (S. cerevisia) RSKK
251. All the newly synthesized compounds were weighed and dissolved in dimethyl-
sulfoxide (DMSO) to prepare extract stock solution of 10.000 mg=ml.
The antimicrobial effects of the substances were tested quantitatively in respect-
ive broth media by using double microdilution, and the minimal inhibition concen-
tration (MIC) values (mg=ml) were determined.[27] The antibacterial and antifungal
assays were performed in Mueller-Hinton broth (MH) (Difco, Detroit, MI) at pH
7.3 and buffered yeast nitrogen base (Difco, Detroit, MI) at pH 7.0, respectively.
The microdilution test plates were incubated for 18–24 h at 35 ꢀC. Brain heart
infusion broth (BHI) (Difco, Detriot, MI) was used for M. smegmatis and incubated
for 48–72 h at 35 ꢀC.[28] The MIC was defined as the lowest concentration that showed
no growth. Ampicillin (10.000 mg g=ml), streptomycin 10.000 mg g=ml, and flucona-
zole (2.000 mg g=ml) were used as standard antibacterial and antifungal drugs,
respectively. Dimethylsulfoxide with dilution of 1:10 was used as solvent control.
SUPPLEMENTARY INFORMATION
Full experimental details for all experiments are given in the Supplementary
Information, available online.
ACKNOWLEDGMENT
Financial support from the Scientific and Technical Research Council of
˙
Turkey (TUBITAK) through Project 108T221 is gratefully acknowledged.
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