Fehling solution/DIPEA/hydrazine: an alternative catalytic medium for regioselective synthesis of 1,4-disubstituted-1H-1,2,3-triazoles using azide–alkyne cycloaddition reaction

Article abstract of DOI:10.1016/j.tetlet.2016.08.068

The development of copper catalyzed azide–alkyne cycloaddition in aqueous solvent system at room temperature is a notable contribution to the field of green chemistry. In this work, 1,4-disubstitued-1H-1,2,3-triazoles are synthesized in the Fehling soluti

Full text of DOI:10.1016/j.tetlet.2016.08.068

Accepted Manuscript
Fehling Solution / DIPEA / Hydrazine: An Alternative Catalytic Medium for
Regioselective Synthesis of 1,4-disubstituted-1H-1,2,3-triazoles using Azide-
Alkyne Cycloaddition Reaction
Manashjyoti Konwar, Abdul Aziz Ali, Mitali Chetia, Prakash J. Saikia, Diganta
Sarma
PII:
S0040-4039(16)31095-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.08.068
TETL 48039
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
15 July 2016
19 August 2016
20 August 2016
Please cite this article as: Konwar, M., Ali, A.A., Chetia, M., Saikia, P.J., Sarma, D., Fehling Solution / DIPEA /
Hydrazine: An Alternative Catalytic Medium for Regioselective Synthesis of 1,4-disubstituted-1H-1,2,3-triazoles
using Azide-Alkyne Cycloaddition Reaction, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2
016.08.068
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Fehling Solution / DIPEA / Hydrazine: An Alternative Catalytic Medium for Regioselective
Synthesis of 1,4-disubstituted-1H-1,2,3-triazoles using Azide-Alkyne Cycloaddition Reaction
a
a
a
b
a
Manashjyoti Konwar , Abdul Aziz Ali , Mitali Chetia , Prakash J. Saikia , and Diganta Sarma*
CuSO4
Rochelle salt
COONa
COOK
H
H
H
C
C
O
O
C
C
H
H
Cu
O
O
H
COONa
R
N3
COOK
R'
RT
Air
Hydrazine
DIPEA
Cu complex
in water
R= Benzyl, Substituted benzyl, Phenyl, Substituted phenyl, Phenethyl
/
R = -C
6
H
5
, 4-OMe-C
6
H
4
, 4-Me-C
6
H
4

1
Tetrahedron Letters
Fehling Solution / DIPEA / Hydrazine: An Alternative Catalytic Medium for
Regioselective Synthesis of 1,4-disubstituted-1H-1,2,3-triazoles using Azide-Alkyne
Cycloaddition Reaction
a
a
a
b
a
Manashjyoti Konwar , Abdul Aziz Ali , Mitali Chetia , Prakash J. Saikia , and Diganta Sarma*
a
Department of Chemistry, Dibrugarh University, Dibrugarh, Assam, India 786004
Analytical Chemistry Division, CSIR-North East Institute of Science & Technology, Jorhat-785006, Assam, India.
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The development of copper catalyzed azide-alkyne cycloaddition in aqueous solvent system at
room temperature is a notable contribution to the field of green chemistry. In this work, 1,4-
disubstitued-1H -1,2,3-triazoles are synthesized in Fehling solution, a widely used system in
practical laboratory classes but totally unexplored in research field, with N,N-
diisopropylethylamine/hydrazine without using any organic solvent under mild reaction
conditions.
Available online
©
2009 Elsevier Ltd. All rights reserved.
Keywords:
Fehling solution
Azide-alkyne Cycloaddition
Regioselectivity
1
,4- disubstituted- 1,2,3-Triazoles
Introduction
Later, Sharpless and co-workers in 2002 developed the copper
catalyzed version of azide-alkyne cycloaddition with the
formation of regioselective product 1,4-disustituted-1H-1,2,3-
triazole and they named the reaction as the “Click reaction”
Over the recent decades, a great deal of attention has been
paid to develop sustainable strategies for synthetic organic
chemistry. In accordance with the 12 principles of green
chemistry, several environmentally acceptable concepts in
chemical synthesis have been recognized. In this context
enormous efforts have been made to use water or other non-
classical solvents instead of traditional organic solvents for
chemical transformations. Especially water is more favorable
since water is cheap, non-flammable, nontoxic and readily
which is also known as “Cu-catalyzed Azide-Alkyne
11-12
Cycloaddition
Reaction”
(CuAAC).
Azide-alkyne
1
-2
cycloaddition reaction in presence of Cu (I) salt has a significant
advantage in the synthesis of 1,2,3- triazoles since it has 100%
regioselectivity (only 1,4- disubstituted regioisomer), proceeds
under mild reaction conditions and has a wide range of substrate
scope. By using the click reaction, the synthesis of triazoles
becomes very easier and efficient and hence it gains a remarkable
interest in biological science, polymer science and material
3
available solvent.
The 1,2,3- triazoles are versatile heterocycles which are absent
in nature, while the synthetic molecules containing 1,2,3-triazole
unit find large applications in drug discovery, material science,
1
3-16
chemistry.
Much attention has been paid to the development
of copper (I) catalytic systems for CuAAC reactions including
4
reduction of Cu(II) salts, oxidation of Cu(0) metal, Cu(I)/ligands
bioconjugation and polymer chemistry. The 1,2,3-triazole unit
17-18
and so on.
Typically in CuAAC reactions, a mixture of water
has the useful properties like high chemical stability (generally
inert to severe hydrolytic, oxidizing, and reducing conditions,
even at high temperature), strong dipole moment (4.8–5.6
Debye), aromatic character, and hydrogen bond accepting
and water-miscible organic solvents such as DMSO, THF, and
t
19-20
BuOH have been used.
Reviewing on the topic of triazoles
synthesis in presence of copper sources, lots of experiments are
done using different copper sources in organic solvents but there
are only few reports describing triazoles synthesis in aqueous
5
ability. A lot of 1,2,3-triazole compounds have the clinical
significance such as carboxyamidotriazole (CAI) as anticancer
agent, tert-butyldimethylsilylspiroaminooxathioledioxide (known
as TSAO) as the non-nucleoside reverse transcriptase inhibitor,
Tazobactam as β-lactum antibiotic, the cephalosporine
21-22
medium.
Results and discussion
6
-7
Cefatrizine etc.
In continuation to our interest in developing milder methodology
for click reactions, herein we developed an alternative synthetic
The classical synthetic procedure for the synthesis of 1,2,3-
triazole is the Huisgen cycloaddition reaction of dipolarophile
23
method towards the synthesis of triazoles in aqueous medium.
In this work, we carried out the click reaction in Fehling solution
at room temperature in presence of air. Fehling solution is a
widely used system in organic laboratory classes, but to the best
of our knowledge it has not been explored in research fields so
far. In view of the fact that Fehling solution is a complex salt of
(acetylene) with the 1,3-dipoles (azides). Nevertheless, the
traditional Huisgen cycloaddition reaction typically requires high
temperatures and proceeds with limited regioselectivity.
8
-10
2
4
*
Corresponding author. Tel.: +91 373-2370210
2
copper and it is reduced to Cu O from Fehling solution, its
E-mail address: dsarma22@gmail.com; dsarma22@dibru.ac.in

2
Tetrahedron
mechanistic cycle is quite similar to that of the original one of
was obtained by the use of N,N-diisopropylethylamine as base,
hydrazine as reducing agent in Fehling solution at room
25
the click reaction (Scheme 1). DIPEA plays a dual role of
ligand as well as base in the reaction condition of CuAAC
reaction.
2
9
temperature (Table 1, entry 8). We also used sodium ascorbate
(Table 1, entries 4-5) as an alternative of hydrazine but it was
found to be less efficient than hydrazine. Fehling solution is the
coordination complex salt of Cu(II) which was reduced to Cu(I)
26
27
COONa
COONa
H
COOK
31
H
H
C
C
OH
OH
H
H
C
O
by hydrazine. A plausible mechanism is depicted in Scheme 2.
O
C
C
H
H
2
+
CuSO4
+
2NaOH
Cu
C
O
O
H
Table 1: Optimization of the base and reducing agent for azide-
alkyne cycloaddition.
Copper sulphate
in NaOH (Fehling B)
a
COOK
COONa
COOK
Sodium Potassium
Tartarate (Fehling A)
Complex copper salt of Sodium
potassium tartarate (Fehling solution)
N
N3
Fehling solution, RT Bn
Base, reducing agent
N
N
+
Ph
Hydrazine
COONa
[
b]
Entry
Reducing
Base
Time
Yield (%)
agent
H
H
C
C
OH
OH
+
Cu2O
1
2
3
4
5
6
7
8
-
-
-
-
12 hrs
12 hrs
12 hrs
6 hrs
20 min
2 hrs
5
Red
colour
NEt
DIPEA
3
10
20
20
70
50
60
98
COOK
Sodium Potassium
Tartarate
Na-ascorbate
Na-ascorbate
Hydrazine
Hydrazine
Hydrazine
-
DIPEA
-
NEt
DIPEA
Scheme 1. Formation of the catatlytic species Cu (I)
3
30 min
20 min
The use of Fehling solution as catalytic medium for the synthesis
of 1,2,3-triazoles has been proven to be excellent, high yielding,
simple and very efficient. Fehling solution is a complex salt of
copper and is prepared in aqueous medium by simple mixing of
a
Reaction conditions: benzyl azide (1 mmol), phenyl acetylene
1.5 mmol), Base (1 mmol), reducing agent (1 mmol) in Fehling
solution (1.5 ml Fehling A+ 1.5 ml Fehling B) at room
(
b
2
7-28
temperature. Isolated yields
equal volume of Fehling A & Fehling B solution.
By using
this catalytic system (Figure 1) for triazole synthesis, the yield
obtained was very high in short reaction time. The system is
highly economic and the most important point is that it becomes
friendly to the environment with greater selectivity, and has
enormous substrate scope.
a
Figure 2: Effect of substituent on Azide-alkyne cycloaddition.
Fehling solution, DIPEA
N
R
N
N
R N3
1
+
R'
Hydrazine, RT
R'
3
2
N
N
N
N
N
N
N
N
OMe
OMe
N
Bn
Bn
Ph
Bn
3
c, 30min, 92%
N
3
a, 15 min, 95%
3b, 30 min, 60%
N
N
N
N
N
N
N
Ph
N
Ph
3d, 30 min, 90%
3e, 1 hr, 80%
3f, 1 hr, 85%
N
N
(
A)
(B)
N
N
N
N
OMe
N
N
N
R
N3
R'
Br
Br
Br
3g, 3 h, 80%
3i, 3h, 80%
3h, 3h, 70%
N
N
N
N
N
N
OMe
N
RT
N
Air
N
N
N
N
Hydrazine
DIPEA
R
3
l, 2h, 60%
3j, 2h, 80%
3k, 2h, 50%
R'
Fehling solution
N
N
N
O2N
N
N
N
2
O N
N
N
(
D)
(C)
N
Cl
3m, 1h, 90%
3n, 30 min, 70%
3
o, 2h, 100%
Figure 1. (A) Fehling A and Fehling B (B) Fehling solution (C)
Reaction mixture (D) 1,2,3-triazoles
N
N
N
N
N
N
OMe
N
N
N
Primarily, the cycloaddition reaction between benzyl azide and
phenyl acetylene was chosen for the optimization of the reaction
condition by using 3 ml Fehling solution which acts both as
catalyst and solvent system at room temperature (Table 1). The
CuAAC reaction in presence of Fehling solution afforded the 1,4-
disubstituted-1H-1,2,3-triazole product in negligible yields
Bn
Cl
Cl
3r, 3h, 95%
3p, 2h, 96%
3q, 3h, 96%
a
Reaction conditions: azide (1 mmol), acetylene (1.5 mmol),
DIPEA (1 mmol), Hydrazine (1 mmol) in Fehling solution (1.5
ml Fehling A+ 1.5 ml Fehling B) at room temperature.
(Table 1, entry 1). To investigate the better reaction condition we
used some bases in the reaction but it also gave inferior yields of
the triazoles (Table 1 entries 2-3). After many efforts best result

3
Once we had the optimized condition for click reaction, the scope
H. C.; Finn M. G.; Sharpless K. B.; Elder J. H.; Fokin V. V.
Angew. Chem. Int. Ed. 2006, 45, 1435–1439.
32
of this process was examined (Figure 2). Several aryl and
benzyl azides reacted efficiently with terminal alkynes under our
catalytic condition affording 1,2,3-triazoles in good to excellent
yields. However the presence of substituent (electron
withdrawing, electron rich) either on the azide or on the alkyne
had negligible effect on the outcome of this reaction. The ability
to form the desired triazole moiety in aqueous solvent system at
room temperature in short reaction time will have a great
importance in the field of synthetic organic chemistry.
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R
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N N N
N
1
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Conclusion
In summary, an efficient and alternative protocol was developed
for regioselective synthesis of 1,4-disubstituted-1H-1,2,3-
triazoles using Fehling solution/DIPEA/Hydrazine as catalytic
system in aqueous medium at room temperature. The simplicity
and efficiency of this catalytic system has been successfully
established and hence it can be used for further various synthetic
applications.
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Acknowledgments
2
2
3. (a) Ali A. A.; Chetia M.; Saikia P. J.; Sarma D. RSC Adv. 2014, 4,
4388. (b) Chetia M.; Ali A. A.; Bhuyan D.; Saikia L.; Sarma D.
6
MK is thankful to UGC, New Delhi for UGC-BSR fellowship.
D.S. is thankful to CSIR, New Delhi, India for a research grant
New J. Chem. 2015, 39, 5902. (c) Ali A. A.; Chetia M.; Saikia B.;
Saikia P.J.; Sarma D. Tetrahedron Lett. 2015, 56, 5892. (d) Ali A.
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4. Synthesis of Fehling solution:
[No. 02(0154)/13/EMR-II]. The authors acknowledge the De-
partment of Science and Technology for financial assistance
under DST-FIST program and UGC, New Delhi for Special
Assistance Programme (UGC-SAP) to the Department of
Chemistry, Dibrugarh University.
Fehling Solution A: 3.464 g of Copper sulphate pentahydrate
(CuSO
4 2
. 5H O) was dissolved in 50 mL of deionized water
containing a few drops of concentrated H SO .
2
4
Fehling Solution B: 17.3 g of Sodium Potassium Tartarate
Rochelle salt) and 6g of NaOH in minimum amount of water was
(
mixed and make the solution upto 50 mL with water. Fehling
Solution was prepared by dissolving equal volume of the two
solutions (Fehing A and B).
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2. General procedure for the synthesis of 1,4-disubstituted-1H-
,2,3-triazole: To a mixture of aromatic azide (1 mmol, 1 equiv.),
2
3
1
aromatic acetylene (1.5 mmol, 1.5 equiv.), DIPEA (1 mmol),
Hydrazine (1 mmol) in Fehling solution (3 mL) was added. The
mixture was stirred at room temperature for the given time period
as mentioned in Table 2. The progress of the reaction was
monitored by TLC. After completion of the reaction it was
extracted with diethyl ether (2x20 mL), washed with deionized
water, dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The resulting residue was purified
through silica gel column chromatography (10–20%
EtOAc/hexane) to afford the desired product.