Ligand-free copper(0) catalyzed direct C-H arylation of 1,2,4-triazoles and 1,3,4-oxadiazoles with aryl iodides in PEG-400

Article abstract of DOI:10.1016/j.tetlet.2014.12.064

A ligand-free copper catalyzed approach has been developed to the synthesis of 3,4,5-triaryl-1,2,4-triazoles and 2,5-diaryl-1,3,4-oxadiazoles by the direct arylation of corresponding 3,4-diaryl-1,2,4-triazoles and 2-aryl-1,3,4-oxadiazoles with aryl iodides using PEG-400 as reaction medium. The procedure is experimentally simple and free from addition of external chelating ligands or co-catalysts.

Full text of DOI:10.1016/j.tetlet.2014.12.064

Accepted Manuscript
Ligand-free copper(0) catalyzed direct C-H arylation of 1,2,4-triazoles and
1,3,4-oxadiazoles with aryl iodides in PEG-400
Ramu Tadikonda, Mangarao Nakka, Srinuvasarao Rayavarapu, Siva Prasada
Kumar Kalidindi, Siddaiah Vidavalur
PII:
S0040-4039(14)02130-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.064
TETL 45588
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 November 2014
4 December 2014
10 December 2014
Please cite this article as: Tadikonda, R., Nakka, M., Rayavarapu, S., Kalidindi, S.P.K., Vidavalur, S., Ligand-free
copper(0) catalyzed direct C-H arylation of 1,2,4-triazoles and 1,3,4-oxadiazoles with aryl iodides in PEG-400,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.064
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Ligand-free copper(0) catalyzed direct C-H arylation of 1,2,4-triazoles and 1,3,4-oxadiazoles with
aryl iodides in PEG-400.
Ramu Tadikonda, Mangarao Nakka, Srinuvasarao Rayavarapu, Siva Prasada Kumar Kalidindi and Siddaiah
Vidavalur∗
N
N
Z
I
N
N
R2
Z
Cu, K2CO3
PEG - 400
R2
R1
Z= NAr, O
120 o
C
R1
Z= NAr, O

1
Tetrahedron Letters
journal homepage: www.els evier.com
Ligand-free copper(0) catalyzed direct C-H arylation of 1,2,4-triazoles and 1,3,4-
oxadiazoles with aryl iodides in PEG-400
Ramu Tadikonda, Mangarao Nakka, Srinuvasarao Rayavarapu, Siva Prasada Kumar Kalidindi and Siddaiah
Vidavalur∗
Department of Organic Chemistry & FDW, Andhra University, Visakhapatnam-530 003, India
ARTICLE INFO
ABSTRACT
A ligand-free copper catalyzed approach has been developed to the synthesis of 3,4,5-triaryl-
1,2,4-triazoles and 2,5-diaryl-1,3,4-oxadiazoles by the direct arylation of corresponding 3,4-
diaryl-1,2,4-triazoles and 2-aryl-1,3,4-oxadiazoles with aryl iodides using PEG-400 as reaction
medium. The procedure is experimentally simple and free from addition of external chelating
ligands or co-catalysts.
Article history:
Received
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
3,4,5-Triaryl-1,2,4-triazole
2,5-Diaryl-1,3,4-oxadiazole
Ligand-free
Copper powder
Arylation
Coupling reaction
3,4,5-Triaryl-1,2,4-triazoles and 2,5-diaryl-1,3,4-oxadiazoles are
well known to exhibit a wide range of biological activities
including anti-bacterial,1 anti-inflammatory,2 anti-tumour,3 anti-
tubercular,4 tyrosinase inhibitory,5 and cytotoxic6 activities.
Besides their biological properties, these π-conjugated scaffolds
find applications in the field of material science.7 Due to their
unique optoelectronic properties these scaffolds have been
exploited in the development of organic light emitting diodes
(OLEDs) and utilized in energy efficient, full-color, flat-panel
displays.8 Certain suitably conjugated oxadiazoles are also known
to perform as multiphoton absorbing systems.8b
ligand-free, eco-friendly and potential alternative methods for the
synthesis of 3,4,5-triaryl-1,2,4-triazoles and 2,5-diaryl-1,3,4-
oxadiazoles.
On the other hand, poly(ethylene glycols) (PEGs) are known to
be nontoxic, less volatile, thermally stable, eco-friendly, and
inexpensive media for various organic reactions.14 Inspired by
these advances and in continuation of our work15 in development
of environmentally benign methodologies for various biologically
active heterocycles using PEG as a reaction medium, herein, we
report a ligand-free copper catalyzed direct arylation of 3,4-
diaryl-1,2,4-triazoles and 2-aryl-1,3,4-oxadiazoles using aryl
iodides and PEG-400 as reaction medium (Scheme 1).
In outlook of their biological and optoelectronic properties,
numerous methods have been reported for their synthesis.9
Generally, 3,4,5-triaryl-1,2,4-triazoles and 2,5-diaryl-1,3,4-
oxadiazoles are synthesized by the cyclodehydration of
I
N
Z
N
Z
N
N
Cu, K2CO3
PEG - 400
corresponding N-acylamidrazones10 and
diacylhydrazines11
R2
R2
120 o
C
respectively. Recently, transition-metal catalyzed direct arylation
of heterocyclic C-H bonds has received significant attention in
organic synthesis because of their potential for diverse
transformation into a variety of useful derivatives.12 3,4,5-Triaryl-
1,2,4-triazoles and 2,5-diaryl-1,3,4-oxadiazoles are synthesized
by the direct arylation of 1,2,4-triazoles and 1,3,4-oxadiazoles
R1
R1
Z = NAr (3)
= O (5)
Z = NAr (1)
= O (4)
2
Scheme 1. Synthesis of 3,4,5-triaryl-1,2,4-triazoles (3) and 2,5-
diaryl-1,3,4-oxadiazoles (5)
using
CuI/1,10-phenanthroline(phen)
catalytic
system.13
However, this method has some drawbacks such as requirement
of organic ligands which make it difficult for the separation and
purification after the reaction and use of expensive organic
solvents. Therefore, there is a need to develop more economical,
———
Initially, 3,4-diphenyl-4H-1,2,4-triazole (1a) was treated with
iodobenzene (2a) in the presence of a catalytic amount of copper
o
powder (20 mol%) and K2CO3 (2.5 equiv) in diglyme at 120 C.
To our delight, the desired product 3a was formed, albeit in a low
∗ Corresponding author. Tel.: +0891-2544683; fax: +0891-2544682; e-mail: sidduchem@gmail.com

2
Tetrahedron
Table 2. Synthesis of 3,4,5-triaryl-1,2,4-triazoles (3)a
yield of 18% (Table 1, entry 1) after 24 h. Next, we optimized
the reaction conditions in order to increase the yield. Thus,
different solvents and bases were screened and the results are
summarized in Table 1. It was found that PEG-400 was the most
superior solvent and K2CO3 was the most effective base in terms
of the reaction time and yield of the product (Table 1, entry 6).
Once we had established suitable solvent and base, we then
focused on the quantity of copper powder. By decreasing the
quantity of copper powder from 20 mol% to 10 mol% the yield
was dropped to 80% even after prolonged reaction time also
(Table 2, entry 12). In contrast, no improvement of the yield was
observed by increasing the catalyst loading (Table 2, entry 13).
The effect of temperature on the reaction was also investigated.
Faster reactions occurred on increasing the temperature but the
product yields were not satisfactory (Table 1, entries 14). The
progress of the reactions was monitored by TLC analysis (using
EtOAc-hexane as the eluents).
N
N
N
N
N
N
N
N
N
Cl
Cl
3a (88%)
3b (85%)
3c (87%)
N
N
N
N
N
OMe
OMe
OMe
N
N
N
OMe
OMe
N
Cl
3d (81%)
3e (82%)
N
3f (85%)
N
N
N
N
N
N
N
N
Table 1. Optimization of reaction conditions to 3aa
Cl
N
N
N
N
I
3h (81%)
N
3g (82%)
Cl
3i (81%)
N
N
N
N
N
Br
NO2
N
N
N
N
N
3a
1a
2a
3k (80%)
3j (82%)
3l (86%)
(a) Reaction conditions: 3,4-diaryl-1,2,4-triazole (1) (1.0 equiv.), iodobenzene
(2) (1.2 equiv.), copper powder (0.2 equiv.), base (2.5 equiv.), solvent (5 vol.)
and temperature 120 oC. Reported yields are isolated yields.
Entry
Catalyst
(mol %)
20
Base
Solvent
Temp
(oC)
120
reflux
reflux
120
120
120
120
120
120
rt
Time
(h)
24
24
24
24
24
12
24
24
24
36
12
30
12
8
Yield
(%)b
18
1
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
KOtBu
KOH
Diglyme
Toluene
Dioxane
DMSO
20
20
trace
25
27
Motivated by this result, next we undertook the direct arylation of
1,3,4-oxadiazoles by taking 2-phenyl-1,3,4-oxadiazole as
3
4
20
20
a
5
DMF
39
88
representative example under the optimized conditions.
Fortunately, we were able to synthesize various 2,5-diaryl-1,3,4-
oxadiazoles (5a-5h) in reasonably high yields (85-89%)
following the above protocol and the results are presented in
Table 3.
6
20
20
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
7
14
9
8
20
20
9
trace
-
24
10c
11d
12
13
14
20
20
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
120
120
120
150
Table 3. Synthesis of 2,5-diaryl-1,3,4-oxadiazolesa
10
30
20
80
88
82
N
O
N
O
N
O
N
N
(a) Reaction conditions: 3,4-diphenyl-4H-1,2,4-triazole (1.0 equiv.),
iodobenzene (1.2 equiv.), base (2.5 equiv.), solvent (5 vol.).
(b) Isolated yield.
N
O
NO2
(c) Reaction performed at room temperature.
(d) Reaction was performed in air.
5c (88%)
5b (89%)
5a (87%)
Br
N
N
N
N
Subsequently, with the optimal conditions in hand,16 we
examined the structural diversity of the various aryl iodides as the
coupling partners. Notably, a wide variety of functionalities
regardless of the electronic nature of the substituents were
compatible with the reaction conditions. For example, chloro and
bromo substituents (Table 2, entries 3j and 3k), electron-
donating groups such as methoxy (Table 2, entry 3d and 3f) and
methyl (Table 2, 3g-3i) and electron-withdrawing groups
including a nitro substituent on the aromatic ring (Table 2, entry
3l) were well tolerated in direct C-H arylation of 1,2,4-triazoles.
Interestingly, steric bulk of the aryl iodides didn’t affect the
reactivity, and 82% yield of the product was achieved with 2-
chloro iodobenzene (Table 2, entry 3j). Only aryl iodides are
effective coupling partners, with aryl bromides and chlorides
giving little or no product. This result suggests that this method
should be useful for the chemoselective arylation at iodide-
substituted centers when other halogen substituents are present
(Table 2, 3j and 3k). To further probe the scope of the reaction,
a range of 1,2,4-triazoles were converted into corresponding
products with excellent yields under the established conditions
(Table 2, entries 3a-3c and 3e). All the synthesized compounds
are well characterized by advanced spectroscopic analysis (1H
NMR, 13C NMR and Mass).are well characterized by advanced
spectroscopic analysis (1H NMR, 13C NMR and Mass).
N
N
O
O
O
Cl
Cl
5e (87%)
5f (88%)
5d (85%)
Br
N
N
N
O
N
NO2
O
Cl
Cl
5h (85%)
5g (86%)
(a) Reaction conditions: 2-aryl-1,3,4-oxadiazole (4) (1.0 equiv), iodobenzene
(2) (1.2 equiv.), copper powder (0.2 equiv), base (2.5 equiv.), solvent (5 vol.)
and temperature 120 oC. Reported yields are isolated yields.
In summary, we have developed a ligand-free copper powder
catalyzed direct arylation of 3,4-diaryl-1,2,4-triazoles and 2-aryl-
1,3,4-oxadiazoles with aryl iodides in PEG-400. The present
method allows a wide range of aryl iodides as arylating reagents
and provides an easy access to a variety of 3,4,5-triaryl-1,2,4-
triazoles and 2,5-diaryl-1,3,4-oxadiazoles. The use of inexpensive
copper powder, simple experimental procedure and free from
addition of external ligands or co-catalyst are the major
advantages of this method.

3
Reddy, N. R. Org. Lett. 2002, 4, 4399; (c) Namboodiri, V. V.,
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Acknowledgments
The authors pleased to thank Department of Science and
Technology (DST), New Delhi for financial assistance (through a
project SB/EMEQ-348/2013) and UGC, New Delhi for the award
of SRF to the authors T. R and N. M.
15. (a) Mangarao, N.; Ramu, T.; Srinuvasarao, R.; Prasanthi, S.; Siddaiah,
V. Synthesis (accepted); (b) Siddaiah, V.; Mahaboob Basha, G.; Ramu,
T.; Mangarao, N.; Sudhakar, D.; Santosh, K. Y.; Christopher, V.
Tetrahedron Lett. 2014, 55, 2691; (c) Mangarao, N.; Mahaboob Basha,
G.; Ramu, T.;
Srinuvasarao, R.; Prasanthi, S.; Siddaiah, V.
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Commun. 2012, 42, 627.
Supplementary Information
Supplementary information associated with general experimental
procedure, characterization data and 1H, 13C NMR and Mass
spectra of all new compounds.
16. General experimental procedure for the synthesis of 3 and 5:
Copper powder (0.2 equiv) and K2CO3 (2.5 equiv) were added to a
solution of 3,4-diaryl-1,2,4-triazole (1) or 2-aryl-1,3,4-oxadiazole
(4) (1.0 equiv) and iodobenzene (2) (1.2 equiv) in PEG-400 (5 vol.).
The reaction mixture was stirred at 120 oC under nitrogen atmosphere
for 12 h. After completion of the reaction as indicated by TLC, the
reaction mixture was cooled to room temperature and partitioned
between water and ethyl acetate. The organic and aqueous layers were
then separated and aqueous layer was extracted with ethyl acetate
twice. The combined organic extracts were dried over anhydrous
sodium sulfate and concentrated under reduced pressure to afford the
crude compound. The crude was further purified by silica gel
chromatography using EtOAc/hexane as eluents to furnish the desired
product 3 or 5.
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