Benedict's solution/ vitamin C: An alternative catalytic protocol for the synthesis of regioselective-1,4-disubstituted-1H-1,2,3-triazoles at room temperature

Article abstract of DOI:10.1002/aoc.4425

A novel and highly efficient method for the synthesis of 1,4-disubstituted-1H-1,2,3-triazoles by copper-catalyzed azide-alkyne cycloaddition has been developed. This economic and sustainable protocol uses a readily available Benedict's solution/Vitamin C

Full text of DOI:10.1002/aoc.4425

Received: 23 January 2018
DOI: 10.1002/aoc.4425
Revised: 5 March 2018
Accepted: 20 April 2018
C O M M U N I C A T I O N
Benedict's solution/ vitamin C: An alternative catalytic
protocol for the synthesis of regioselective‐1,4‐disubstituted‐
1H‐1,2,3‐triazoles at room temperature
Manashjyoti Konwar1 | Roktopol Hazarika1 | Abdul A. Ali1 | Mitali Chetia1 |
Nageshwar D. Khupse2 | Prakash J. Saikia3 | Diganta Sarma1
1 Department of Chemistry, Dibrugarh
A novel and highly efficient method for the synthesis of 1,4‐disubstituted‐1H‐
University, Dibrugarh 786004 Assam, India
2 Centre for Materials for Electronics
Technology, Pashan Road, Pune 411008,
India
3 Analytical Chemistry Division, CSIR‐
North East Institute of Science &
1,2,3‐triazoles by copper‐catalyzed azide‐alkyne cycloaddition has been
developed. This economic and sustainable protocol uses a readily available
Benedict's solution/Vitamin C catalyst system affording a wide range of 1,4‐
disubstituted‐1H‐1,2,3‐triazoles under mild conditions.
Technology, Jorhat 785006 Assam, India
KEYWORDS
Correspondence
1,4‐disubstituted‐1H‐1,2,3‐triazole, azide‐alkyne cycloaddition, Benedict's solution, vitamin C
Diganta Sarma, Department of Chemistry,
Dibrugarh University, Dibrugarh‐786004,
Assam, India.
Email: dsarma22@dibru.ac.in
Funding information
DST, New Delhi, India, Grant/Award
Number: EMR/2016/002345; UGC, New
Delhi for UGC‐BSR
1 | INTRODUCTION
bioconjugation,[10] triazole peptidomimetics[11] and
organocatalysis.[12]
1,2,3‐Triazoles are N‐heterocyclic compounds that have
been found in diverse applications ranging from materials
to biological sciences.[1] Several synthetic methods have
been developed for the preparation of 1,2,3‐triazole deriv-
atives. Among them, the copper‐catalyzed azide‐alkyne
cycloaddition reaction (CuAAC), a premier example of
‘click chemistry’,[2] represents an easy and atom econom-
ical strategy to these heterocycles. The first CuAAC reac-
tion discovered by Sharpless et al. preceded in presence of
CuSO4/ Na ascorbate mixture in water/t‐BuOH solvent
affording triazoles in excellent yields.[2b,c] The click reac-
tion is generally carried out in benign conditions[3] lead-
ing to drug innovation,[4] improvements for
pharmaceutical and biological activities such as antifun-
gal,[5,6] antimicrobial,[7] antitumor,[8] HIV inhibitor[9]
Recently, numerous greener approaches have been
applied to the CuAAC reaction like synthesis in water,[13]
the use of ultrasound,[14] microwave,[15] micro‐flow tech-
nology,[16] etc. Several other techniques have also been
developed including supported catalyst,[17–20] salts/addi-
tives or ligands,[21–33] nanotechnology,[34–39] photo cataly-
sis[40] etc. for 1,2,3‐triazole synthesis.
The Benedict's solution, an aqueous alkaline solution
of copper(II) citrate, proved to be an important reagent in
pharmaceutical and medicinal chemistry for the detec-
tion of presence of reducing sugars in urine,[41] determi-
nation of glucose in a solution.[42] In synthetic organic
chemistry, Benedict's solution acts as a very good catalytic
medium for reactions which are carried out in presence
of copper source in aqueous solution.[13,43] Similarly, L‐
Appl Organometal Chem. 2018;e4425.
wileyonlinelibrary.com/journal/aoc
Copyright © 2018 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4425

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KONWAR ET AL.
Ascorbic acid or more commonly known as vitamin C is
one of the most effective alternative reducing agents,
which is environmentally friendly in nature.[44] The basic
structure of L‐ascorbic acid is the five‐membered lactone
sugar and due to this, it has some physiological activities
towards organic synthesis.[45] More importantly, L‐
ascorbic acid is water soluble and hence it can be used
in aqueous reaction generating metal ascorbate com-
plexes through in‐situ mechanism.[46] Herein we describe
a cheap and readily available Benedict's solution (diluted
up to 2 mol%)/ascorbic acid system as a homogeneous
catalyst for the CuAAC reaction. The current strategy
TABLE 1 Optimization of the catalytic and solvent systema
Entry
[Cu]
Solvent
Time (h)
Yieldb(%)
1
Benedict solution +Na ascorbate
‐
‐
4
12
6
4
8
3
3
5
2
2
3
2
90
‐
2
H2O
3
Copper Citrate
H2O
70
85
70
70
85
50
70
90
88
85
4
Benedict solution + Glucose
Copper Citrate
‐
5
Ethylene glycol
6
Copper Citrate + Glucose
Copper Citrate + Ascorbic acid
Benedict solutionc
Ethylene glycol
7
Ethylene glycol
8
‐
‐
‐
9
Benedict solutionc + Glucose
Benedict solutionc + Ascorbic acid
Benedict solutionc+ Na ascorbate
CuSO4+ Na ascorbate
10
11
12
t
H2O: BuOH
t
H2O: BuOH
aReaction condition: Benzyl azide (1 mmol), phenyl acetylene (1.2 mmol), catalyst (2 mol%), reducing agent (1 mmol), solvent (5 ml) at room temperature.
bIsolated yield.
c3 ml of Benedict solution (2 mol%) is added.
FIGURE 1 a) Benedict Reagent; b)
Benedict solution (2 mol% copper
loading); c) Optimized reaction in 2 mol%
Bendict solution/ Ascorbic acid system
through in‐situ generated copper(II)
complex; d) completion of reaction
mixture and formation of copper(I) as
colour changes from light blue to red

KONWAR ET AL.
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TABLE 3 Substrate scope studya
offers a wide range of corresponding 1,4‐disubstituted‐
1H‐1,2,3‐triazoles in good to excellent yields at room tem-
perature with very low loading of copper.
2 | EXPERIMENTAL
Entry
R
R/
Time (h) Yieldb(%)
1
Bn
Ph
2
2
2
4
3
2
2
2
3
3
3
4
3
4
4
5
2
3.5
6
6
90
95
60
85
90
85
95
93
72
90
60
88
82
90
75
60
92
80
70
78
2.1 | General procedure for the synthesis
of 1,4‐disubstituted‐1H‐1,2,3‐triazole
2
Ph
Ph
3
4‐NO2‐Bn
PhCH2CH2
3‐Cl‐Ph
4‐F‐Ph
4‐OCH3‐Ph
Bn
Ph
To a mixture of azide (1 mmol), acetylene (1.2 mmol) and
Ascorbic acid (1 mmol) in 3 ml of Benedict's solution
(2 mol%) was added. The mixture was stirred at room
temperature for the given time period as mentioned in
Table 3. The progress of the reaction was monitored by
TLC. After completion of the reaction it was extracted
with ethyl acetate (3 x 20 ml), washed with deionized
water, dried over anhydrous sodium sulfate and concen-
trated under reduced pressure. The resulting residue
was purified through silica gel column chromatography
(15–20% EtOAc/hexane) to get the desired product and
confirmed through 1H & 13CNMR analysis (details in
Supporting Information).
4
Ph
5
Ph
6
Ph
7
Ph
8
4‐OCH3‐C6H4
Ph
9
2‐CH3‐Ph
4‐OCH3‐Ph
3‐Cl‐Ph
3‐Cl‐Ph
Bn
10
11
12
13
14
15
16
17
18
19
20
3‐CH3‐C6H4
4‐CH3‐C6H4
4‐OCH3‐C6H4
‐CH2OOC‐Ph
‐CH2OOC‐Ph
3‐CH3‐C6H4
4‐OCH3‐C6H4
‐CH2OOC‐Ph
4‐NO2‐Ph
Bn
PhCH2CH2
3‐Cl‐Ph
3 | RESULTS AND DISCUSSION
To search out the optimized condition, we took the model
reaction of benzyl azide and phenyl acetylene in various
conditions as shown in Table 1 (Entries 1–10). From the
study of the optimization conditions, it was seen that
copper(II) source devoid of reducing agent slowed down
the reaction kinetics whereas in presence of reducing
agent it gave an enhanced product yield. Among the var-
ious reducing agents used (as mentioned in Table 1),
ascorbic acid gave better results to Benedict's solution
than the others and this is believed to be due to the
CH3(CH2)7‐ ‐CH2OOC‐Ph
Ph
‐(CH2) CH3
3
4‐Br‐Ph
‐(CH2)3CH3
aReaction condition: azide (1 mmol), acetylene (1.2 mmol), Ascorbic acid
(1 mmol), 3 ml Benedict solution (2 mol%) at room temperature.
bIsolated yield.
enhanced activity of the enediol moiety present in ascor-
bic acid (Table 1, entry 10). Moreover, use of copper
TABLE 4 One pot protocol for triazole synthesisa
TABLE 2 Optimization of the copper loadinga
Entry
Copper loading (mol%)
Time (h)
Yieldb(%)
Entry
R
R/
Time (h)
Yieldb(%)
1
2
3
4
5
10
6
2
2
2
2
2
92
91
90
90
75
1
2
3
4
5
Ph‐CH2
Ph‐CH2
Ph‐CH2
4‐Br‐Bn
4‐NO2‐Bn
Ph
4
4
4
4
4
95
85
90
88
92
‐CH2OOC‐Ph
4
3‐CH3‐Ph
2
Ph
Ph
1
aReaction condition: Benzyl azide (1 mmol), phenyl acetylene (1.2 mmol),
reducing agent (1 mmol) with 3 ml of Benedict solution(1–10 mol%) at room
temperature.
aReaction Conditions: bromide (1 mmol), NaN3 (1.2 mmol), alkynes
(1.2 mmol), Ascorbic acid (1 mmol), 3 ml Benedict solution (2 mol%),
0.2 ml of Ethylene Glycol at room temperature.
bIsolated yield.
bIsolated yield.

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KONWAR ET AL.
FIGURE 2 Redox reaction mechanism
of L‐ascorbic acid
citrate instead of Benedict solution also catalyzed the
reaction to some extent but the reaction requires the pres-
ence of a solvent (Table 1, entries 5–7).
Various derivatives of both azide and acetylene were
employed to investigate the scope of the formation of
1,4‐disubstitued‐1H‐1,2,3‐triazoles
under
optimized
Benedict reagent is a commercially available alkaline
solution containing copper sulphate, sodium carbonate
and sodium citrate with very high amount of copper
source (1 litre of Benedict solution contains 69 mmol of
copper). We have minimized the copper loading in the
Benedict solution by subsequent dilution method. For
these, we made solutions of Benedict reagent that contains
1, 2, 4, 6 and 10 mol% of copper source and applied it in the
model reaction of benzyl azide and phenyl acetylene
(Figure 1 and Table 2). From the optimized condition of
the catalyst loading, it is seen that the reactions containing
10, 6, 4, 2 mol% of Benedict solution gave almost identical
yield of 92, 91, 90 and 90% respectively (Table 2, entries
1–4). Further reduction of copper loading to 1 mol%, the
product yield reduced to 75% (Table 2, entry 5).
conditions (Table 3). Electron withdrawing as well as
electron donating substituents were introduced on both
substrates (azides and alkynes) to study the effects of
the functional group on the click transformation
(Table 3, entries 1–20). Irrespective of the electronic
behaviour of the azide and alkyne, good to excellent
results of the triazoles were obtained under this catalytic
condition. The reaction rate decreased in the presence
of ortho substituent in the aromatic azide owing to the
steric effect of the functional group (Table 3, entry 9).
To avoid the handling and isolation of organic azides,
a one‐pot protocol for the synthesis of 1,2,3‐triazoles is
desirable. In this context, several methodologies have
been developed for the simultaneous in situ generation
of azides and [3 + 2] cycloaddition reaction with
FIGURE 3 Plausible catalytic cycle

KONWAR ET AL.
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alkynes.47 For the one‐pot protocol, the reaction was carried
out by the multicomponent reaction of benzyl bromide,
sodium azide and phenyl acetylene under the above‐men-
tioned reaction conditions using a little amount of ethylene
glycol as a co‐solvent, affording 95% of the desired triazoles
in 4 h. Therefore, attempts were made to synthesize 1,2,3‐
triazoles from the benzyl bromide derivatives by this one
pot protocol (Table 4, entries 1–5) affording desired prod-
ucts in good to excellent yields in relatively shorter time.
The Benedict's solution / Vitamin‐C catalyzed AAC
reaction is believed to proceed through an in‐situ gener-
ated copper ascorbate complex (Figure 3). Vitamin C
has very peculiar structure containing 2,3‐enediol moiety,
steric lactone ring, four hydroxyl groups with different
reactivity and has hydrophilic character. The most signif-
icant 2,3‐enediols moiety of vitamin C has the ability to
reduce the oxidation state of a metal ion (Figure 2). In
this regard, vitamin C is used along with the Benedict
solution to reduce Cu2+ ion to Cu+ ion as insoluble
copper(I) oxide which catalyzes the AAC reaction.
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research grant [No. EMR/2016/002345]. The authors
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ORCID
Diganta Sarma http://orcid.org/0000-0001-5174-418X

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