TBHP/TBAI–Mediated simple and efficient synthesis of 3,5-disubstituted and 1,3,5-trisubstituted 1H-1,2,4-triazoles via oxidative decarbonylation of aromatic aldehydes and testing for antibacterial activities

Article abstract of DOI:10.1016/j.tetlet.2020.151989

The author has developed a simple, efficient and eco–friendly convenient general method for synthesis of 3,5–disubstituted–1,2,4–triazoles and 1,3,5–trisubstituted–1,2,4–triazoles from 3–monosubstituted–1,2,4–triazoles and 1,3–disubstituted–1,2,4–triazoles respectively using tetrabutylammonium iodide (TBAI) as catalyst and TBHP as oxidant under mid reaction conditions. This method provides structurally diverse 3,5–disubstituted 1,2,4–triazoes and 1,3,5––trisubstituted–1,2,4–triazoles in good to excellent yields. 3,5–Disubstituted 1,2,4–triazoes and 1,3,5––trisubstituted–1,2,4–triazoles derivatives are biologically and pharmaceutically active molecules, and therefore, this protocol could be of wide applications in medicinal chemistry and organic chemistry.

Full text of DOI:10.1016/j.tetlet.2020.151989

Journal Pre-proofs
TBHP/TBAI–Mediated simple and efficient synthesis of 3,5-disubstituted and
1,3,5-trisubstituted 1H-1,2,4-triazoles via oxidative decarbonylation of aro‐
matic aldehydes and testing for antibacterial activities
Habtamu Abebe Agisho, Habdolo Esatu, Suboot Hairat, Mehvash Zaki
PII:
S0040-4039(20)30432-9
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151989
TETL 151989
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Revised Date:
Accepted Date:
15 March 2020
22 April 2020
27 April 2020
Please cite this article as: Agisho, H.A., Esatu, H., Hairat, S., Zaki, M., TBHP/TBAI–Mediated simple and
efficient synthesis of 3,5-disubstituted and 1,3,5-trisubstituted 1H-1,2,4-triazoles via oxidative decarbonylation of
aromatic aldehydes and testing for antibacterial activities, Tetrahedron Letters (2020), doi: https://doi.org/
10.1016/j.tetlet.2020.151989
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TBHP/TBAI–Mediated simple and efficient synthesis of 3,5-disubstituted and
1,3,5-trisubstituted 1H-1,2,4-triazoles via oxidative decarbonylation of
aromatic aldehydes and testing for antibacterial activities
Habtamu Abebe Agisho,*a Habdolo Esatu,a Suboot Hairat,b Mehvash Zakic
*a
Department of Chemistry, Wachemo University, P.O. Box 667, Hosanna, Ethiopia.
b
Department of Biotechnology, Wachemo University, P.O. Box 667, Hosanna, Ethiopia.
c
Department of Chemistry, King Abdulaziz University, P.O. Box 80203, Jeddah, Saudi Arabia.
Corresponding author’s e-mail address: habtamuabebe83@gmail.com
Abstract
The author has developed a simple, efficient and eco–friendly convenient general method for
synthesis of 3,5–disubstituted–1,2,4–triazoles and 1,3,5–trisubstituted–1,2,4–triazoles from 3–
monosubstituted–1,2,4–triazoles and 1,3–disubstituted–1,2,4–triazoles respectively using
potassium iodide as catalyst and TBHP as oxidant under mid reaction conditions. This method
provides structurally divers 3,5–disubstituted 1,2,4–triazoes and 1,3,5––trisubstituted–1,2,4–
triazoles in good to excellent yields. 3,5–Disubstituted 1,2,4–triazoes and 1,3,5––trisubstituted–
1,2,4–triazoles derivatives are biologically and pharmaceutically active molecules, and therefore,
this protocol could be of wide applications in medicinal chemistry and organic chemistry.
Keywords: 1H–1,2,4–triazoles, antibacterial activity, radical trapping, TBHP.

Introduction
Triazoles, also known as pyrrodiazoles are a five membered diunsaturated ring structure
composed of three nitrogen atoms and two carbon atoms.[1]They refer to either one of a pair of
isomeric forms with molecular formula C2H3N3.[2]Based on the position of nitrogen atom they
are classified into 1,2,4–triazoles and 1,2,3–triazoles (Figure 1).[3]
5
1
5
NH
N
1
NH
N
4
N
2
4
2
N
3
3
1,2,4-triazole
1,2,3-triazole
Fig 1. Isomeric forms of triazole.
1,2,4–Triazoles have attracted much attention for their wide range of biological activities
including antibacterial,[4,5] antiinflammatory,[6] antitumor,[7] antitubercular,[8] tyrosinase
inhibitory[9] and cytotoxic activities.[10] They are versatile building blocks for the synthesis of
many commercially available drugs such as maraviroc, sitagliptin, triazolam (Figure 2).[11]
N
N
N
N
HOOC
N
N
N
N
Cl
OH
Et
N
NH
Cl
DL111-IT
Penipanoid A
F
Triazolam
F
F
F
N
F
N
N
N
O
N
N
F
NH
N
O
N
NH2
Sit
ag
lip
tin
F
Ma
ravir
oc
F
Fig 2. Selected examples of bio–active and natural compounds containing 1,2,4–triazole core.

They have also been used as bioisosters of esters, amides and as dipeptidomimetics in a
number of pharmacologically important molecules.[12] Moreover, 1,2,4–triazole motif has
attracted considerable interest in the fields of coordination chemistry and in materials science as
well as natural products.[13–15] 1,2,4–Triazoles have also been extensively studied as ligands for
mononuclear and oligonuclear metal coordination, exhibiting interesting physical properties.[16]
Recent applications illustrate that the incorporation of the 1,2,4–triazole ligand into functional
heteroleptic Ir(III) complexes affords a sky–blue emission with attractive quantum yields for
potential use in organic light emitting diodes (OLEDs).
Among the 1,2,4–triazoles, in this article the author has concentrated on 3,5–
disubstituted 1,2,4–triazoles and 1,3,5–trisubstituted 1,2,4–triazoles because they exhibit wide
applications in pesticides, medicines, functional materials, and organ catalysts as we as natural
products. Furthermore, N–1–aryl–1,2,4–triazoles such as ICL670 (deferasirox), an orally active
iron chelator, is very useful in iron overload therapy.[17,18] In addition, a number of natural
products contain 3,5–disubstituted 1,2,4–triazoles and 1,3,5–trisubstituted 1,2,4–
triazoles.Because of their important properties and applications, various methods for the
synthesis of 3,5–disubstituted 1,2,4–triazoles and 1,3,5–trisubstituted 1,2,4–triazoles and their
derivatives have been developed.
Results and Discussion
In view of the potential applications of these 3,5–disubstituted and 1,3,5–trisubstituted
1H–1,2,4–triazoles and due to the mentioned limitations in the previously reported methods,[16c-e]

the development of new synthetic approaches for synthesis of 3,5–disubstituted and 1,3,5–
trisubstituted 1H–1,2,4–triazoles is still demanding.
Based on the above facts and the author’s interest in developing inexpensive and
environmentally benign methodologies for the synthesis of bioactive molecules herein, the
author has reported a novel and direct synthesis of 3,5–disubstituted and 1,3,5–trisubstituted–
1H–1,2,4–triazoles from 3–substituted and 1,3–disubstituted–1H–1,2,4–triazoles and aromatic
aldehydes via C–C bond formation using TBHP as oxidant and TBAI as catalyst (Scheme 1).
The details of synthesis of 3,5–disubstituted and 1,3,5–trisubstituted–1H–1,2,4–triazoles
discussed in this section and characterization of the synthesized compounds has been discussed
in supporting information.
R1
N
R1
N
O
TBHP (3 eq.)
R2
N
N
N
R2
N
+
TBAI (20 mol%), DCE
120 oC, N2, 5 h
R
R
2
1 R = H
4 R = Phenyl
3 or 5
Scheme 1. Synthesis of 3,5–disubstituted and 1,3,5–trisubstituted 1H–1,2,4–triazoles.
The author has begun his preliminary investigation with the reaction of
3–phenyl–1H–1,2,4–triazole (1a) and benzaldehyde (2a) in the presence of a catalytic amount of
TBAI (10 mol%) and TBHP (70% in water, 1.5 eq. ) in DCE at 120 °C under N2. He was
delighted to observe the formation of the desired product 3aa, albeit in a good yield of 71%
(Table 1, entry 1). Next, he has optimized the reaction conditions in order to increase the yield.
Thus, different solvents were screened and the results are summarized in Table 1. It was found
that DCE was the best solvent in terms of the yield (Table 1, entry 1). Next, various oxidants

such as TBPB, H2O2, DDQ and K2S2O8 were tested and TBHP was proven to be the most
powerful oxidant (Table 1, entries 6–9). Upon using different catalysts such as, n–Bu4NBr, n–
Bu4NCl, I2, CuI and FeCl3 no better yield was observed (Table 1, entries 10–14). Once the
author has established a suitable solvent, oxidant and catalyst for the synthesis of 3,5–
disubstituted 1,2,4–triazoles, then focused on the quantity of TBAI and TBHP. An increase in
the amount of TBAI (from 10 mol% to 20 mol %) increased the product yield from good to very
good (Table 1, entry 15). Further increasing the quantity of TBAI to 30 mol% led to a decrease
in
the
product
yield
to
good
(Table
1,
entry
16).
And
increase in the quantity of TBHP from 1.5 eq. to 3.0 eq. increased the product yield from very
good to excellent (Table 1, entry 17). But further increasing the quantity of TBHP to 4.5 eq. led
a decrease in the product yield (Table 1, entry 18). The effect of temperature on the reaction
rate as well as on the yields of the products was also investigated. Faster reactions occurred on
increasing the temperature but the product yields were not satisfactory. Therefore, the author has
decided to perform the subsequent reactions of the 3–phenyl–1H–1,2,4–triazole with different
benzaldehyde in the presence of TBAI (20 mol %) as the catalyst and TBHP (70% in water,
3eq.) as oxidant in DCE at 120 °C under N2. The progress of the reactions was monitored by
TLC analysis (using EtOAc–hexane as the eluent).
Table1. Optimization of the reaction conditionsa
Entry Catalyst (mol %)
Oxidant (eq.)
TBHP (1.5)
T (oC)
120
Solvent
DCE
Yield (%)b
71
1.
2.
TBAI (10)
TBAI (10)
TBHP (1.5)
120
DMSO
27

3.
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
TBAI (10)
n–Bu4NBr (10)
n–Bu4Cl (10)
I2 (10)
TBHP (1.5)
TBBP (1.5)
TBHP (1.5)
TBPB (1.5)
H2O2 (1.5)
DDQ (1.5)
K2S2O8 (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (1.5)
TBHP (3)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
DMF
EtOAc
H2O
34
4.
39
5.
ND
51
6.
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
7.
cND
cND
cND
41
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
33
59
CuI (10)
36
FeCl3 (10)
TBAI (20)
TBAI (30)
TBAI (20)
TBAI (20)
41
83
65
91
TBHP (4.5)
80
aReaction conditions: 1a (0.4 mmol.), 2a (0.6 mmol.), oxidant (3 eq.) and catalyst (20 mol%)
were heated at 120 °C in 4 ml of solvent under N2 atm. for 5 h. bIsolated yield. cNot detected

With the optimized conditions in hand, the scope of the reaction substrates was
investigated. First, the author has examined the reaction with different 3–phenyl–1,2,4–triazoles
and the results are listed in Table 2. It was found that various substrates were converted into the
corresponding products with excellent yields under the given conditions (Table 2). Next, the
author has examined the scope of benzaldehydes with different substitutions (both electron
donating and electron withdrawing) provided the corresponding products in moderate to
excellent yields (Table 2, 3aa–3aj and 3ba–3bd). Benzaldehydes with electron–donating groups
such as 4-tolualdehyde (2b), 2-tolualdehyde (2c) and 4-anisaldehyde (2d) gave the desired
products in very good yields (Table 2, 3ab and 3ad). Benzaldehydes with moderate electron–
withdrawing groups such as 4-chlrobenzaldehyde (2e), 2-chlrobenzaldehyde (2f), 2-
bromobenzaldehyde (2g) gave the corresponding products in moderate yields (Table 2, 3ae-
3ag), whereas, benzaldehydes with strong electron–withdrawing groups such as 4-
nitrobenzaldehyde (2h), 2-nitrobenzaldehyde (2i) and 4-(trifluoromethyl) benzaldehyde (2j) gave
the corresponding products comparatively lesser yields (Table 2, 3ah-3aj). It is noteworthy to
mention that heterocyclic aromatic aldehydes, such as isonicotinaldehyde and picolinaldeheyde
also reacted smoothly and afforded the corresponding products in good yields (Table 2, 3ak-
3al).
After successfully synthesizing a wide range of 3,5–disubstituted–1H–1,2,4–triazoles in
good to excellent yields, the author turned his attention towards the synthesis of 1,3,5–
trisubstituted from 1,3–disubstituted–1H–1,2,4–triazoles and benzaldehydes with the optimized
reaction conditions.

Table 2. Synthesis of 3,5–disubstituted 1H–1,2,4–triazoles.a
S.No Reactant 1
Reactant 2
Product
Code
3aa
Yield
O
1.
91%
N
N
H
N
NH
N
NH
O
H
2.
89%
85%
3ab
3ac
N
N
N
NH
N
NH
O
H
3.
N
N
N
NH
N
NH
O
4.
94%
82%
80%
3ad
3ae
3af
O
N
N
O
H
N
NH
N
N
NH
O
5.
Cl
N
N
Cl
H
N
NH
NH
O
H
6.
N
N
N
Cl
N
N
NH
NH
Cl
O
H
7.
78%
69%
60%
3ag
3ah
3ai
Br
N
Br
N
NH
N
NH
O
8.
NO2
N
N
NO2
H
N
NH
N
NH
O
H
9.
N
N
N
O2N
N
NH
NH
O2N

O
H
10.
54%
3aj
CF3
N
N
CF3
N
N
N
NH
NH
O
H
11.
12.
77%
71%
3ak
3al
N
N
N
N
NH
N
NH
O
H
N
N
N
N
N
N
NH
N
N
NH
O
H
13.
75%
3ba
N
N
NH
NH
O
N
14.
15.
65%
70%
3bb
3bc
N
N
N
N
NH
H
NH
O
N
N
Cl
Cl
Br
N
NH
H
O
NH
N
16.
62%
3bd
N
Br
N
N
NH
H
NH
aReaction conditions: 1 (0.4 mmol.), 2 (0.6 mmol.), TBHP (3 eq.) and TBAI (20 mol%) were
heated at 120 °C in 4 ml of solvent under N2 atm. for 5 h. Isolated yield.
The obtained results are detailed in Table 3. As shown in Table 3, benzaldehydes having
electron donating and with drawing groups on the phenyl ring were reacted smoothly with 1,3–
disubstituted– 1H–1,2,4–triazoles and gave the corresponding products in moderate to good
yields.

Table 3. Synthesis of 1,3,5–trisubstituted–1H–1,2,4–triazolesa
S.No
Reactant 1
Reactant 2
Product
Code Yield
O
N
1.
88%
81%
82%
5aa
5ab
5ac
N
N
N
H
N
N
O
H
N
2.
3.
N
N
N
N
N
O
N
O
O
N
N
H
N
N
N
O
N
Cl
4.
5.
6.
82%
80%
78%
5ad
5ae
5af
Cl
N
N
H
N
N
N
O
H
N
B r
Br
N
N
N
N
N
O
H
N
F
F
N
N
N
N
N
aReaction conditions: 4 (0.4 mmol), 2 (0.6 mmol.), TBHP (3 eq.) and TBAI (20 mol%) were
heated at 120 °C in 4 ml of solvent under N2 atm. for 5 h. Isolated yield.

To verify whether the reaction proceeded through a radical pathway, radical trapping
experiments were conducted. The addition of radical inhibitors TEMPO and BHT, a drastic
suppression of reaction was observed and only a trace amount of desired product 3aa
wasdetected (Scheme 2(a) and (b)). Furthermore, the replacement of TBAI by I2, or NaI gave
59% yield of the product (Scheme 2(c)).
Standard conditions
a)
b)
1a
2a
+
3aa, trace
3aa, trace
TEMPO (1 eq.)
Standard conditions
+
2a
1a
BHT (1 eq.)
I2, NaI (20 mol%)
+
c)
2a
1a
3aa, 59%
TBHP (3 eq.), N2
120 oC, 4 h
Scheme 2. Radical trapping experiment with free radical scavengers
The exact mechanism for the product formation is not clear at the present stage it further
warrants detailed studies. However, based on the above observations as well as from the previous
reports,19a–c a plausible mechanism for this oxidative transformation is illustrated in Scheme 3.
Initially, t–BuO• (A) and t–BuOO• (B) were generated in situ from TBHP and TBAI.
Subsequently, acyl radical C was formed from the aldehyde 2a by means of oxidative activation.
2a undergoes decarboxylation to afford phenyl radical D. addition of the phenyl radical to 3–
phenyl–1,2,4–tiazole gives radical E. Due to the ‘‘persistent radical effect’’19d the direct tertiary
hydrogen abstraction of radical E by a tert–butoxy radical to realize re–aromatization is
dynamically unbeneficial. Instead, radical E transfers an electron to produce cation F whichis
further deprotonated by a tert–butoxide anion to afford the desired product 3aa.

t-BuO + OH
t-BuOOH
A
1
/2 I2
I
t-BuOOH + OH
H2O + t-BuOO
B
Ph
N
O
PhC
C
N
N
1a
t-BuO/ t-BuOO
TBHP
Ph
N
H
Ph
PhCHO
Ph
2a
N
D
N
H
CO
E
SET
Ph
N
Ph
N
Ph
N
N
H
Ph
N
N
H
3aa
F
t-BuOH
Scheme 3. Plausible mechanism.
Antibacterial activity
Preliminary tests for the antibacterial activities of the synthesized compounds were conducted
using the disc diffusion methodagainst Escherichia coli i.e. a Gram–negative bacterium,
Staphylococcusaureusi.e. a Gram–positive bacterium. Standard antibiotic gentamycin was used
as a positive control and solvent was used as a negative control. Sterilized 5 mm paper disc from
Whatmann paper was immersed in different compounds solutions and placed on petri plates
contained bacteria. The petri plates were incubated at 37°C for 24 h and the zone of inhibition
was measured.

Fig3. Antibacterial activity of triazole compounds A. 3aj, B. 3ad, C. 3aa, D. 3ae, E. Antibiotic
control, F. Solvent control.
The synthesized triazole complexes were tested for their inhibitory effect on the growth of E. coli
and S. aureus. The antibacterial activities for the different compounds are summarized in the
Table 4. All the samples showed antibacterial activity. Higher antimicrobial activity was
observed for E. coli as compared to S. aureus. The complexes showed observable inhibition zone
diameter (Figure 3). These complexes might be acting as bactericidal or bacteriostatic agent.
Table 4: Disc diffusion essay for compounds highlighting zone of inhibition against E. Coli and
S. aureaus.
Compound
Zone of inhibition (mm)
E. coli
12
S. aureus
3aj
8
3ad
10
8
3aa
12
8
3ae
8
12
NZ
10
12
NZ
Control (Positive)
Control (Negative)
Conclusions
In conclusion, the author has developed a simple, efficient and eco–friendly method for
synthesis of 3,5–disubstituted–1,2,4–triazoles and 1,3,5–trisubstituted–1,2,4–triazoles by the
reaction of aldehydes with 3–monosubstituted–1,2,4–triazoles and 1,3–disubstituted–1,2,4–

triazoles respectively using TBAI as catalyst and TBHP as oxidant. This method provides
structurally divers 3,5–disubstituted 1,2,4–triazoes and 1,3,5––trisubstituted–1,2,4–triazoles in
good to excellent yields. 3,5–Disubstituted 1,2,4–triazoes and 1,3,5––trisubstituted–1,2,4–
triazoles derivatives are biologically and pharmaceutically active molecules, and therefore, this
protocol could be of wide applications in medicinal chemistry and organic chemistry.
Furthermore, investigations on the reaction mechanism and to expand the scope of these
reactions are underway in our laboratory.
Acknowledgments
The authors thank Wachemo University, Ethiopia, for financial support to Dr. Habtamu Abebe
Agisho and Mr. Habdolo Esatu.
Supporting information summary
Supporting information contains an NMR and Mass spectra of some compounds.
Conflicts of interest
Authors declare no conflicts of interest.
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Highlights

Eco–friendly synthetic route to substituted 1,2,4–triazoles.
 Attachment of moderate electron–withdrawing groups gives products in good yields.
 Mechanism involves the oxidative radical pathway.
 Compound exhibit high antimicrobial activity towards E. coli compared to S. aureus.

GRAPHICAL ABSTRACT