Cu-FeCl3-mediated one-pot multicomponent reaction leading to N-aryl- and N-alkyltriazoles in water

Article abstract of DOI:10.1055/s-2007-982543

A concise, convenient and mild route for the one-pot syntheses of N-aryl- and N-alkyltriazoles in water is reported. The methodology involves the three-component reaction comprising phenylacetylene, sodium azide and aryl/alkyl halide catalyzed by Cu(I) sp

Full text of DOI:10.1055/s-2007-982543

LETTER
1591
Cu–FeCl3-Mediated One-Pot Multicomponent Reaction Leading to N-Aryl-
and N-Alkyltriazoles in Water1
C
u–FeCl -Media
i
d
O
ne
s
-Pot Reac
w
tion to
N
-Aryl- an
a
d
N
-
Alkyltr
j
iazolesit Saha, Sunil Sharma, Devesh Sawant, Bijoy Kundu*
3
Division of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226001, India
Fax +91(522)2623405; E-mail: bijoy_kundu@yahoo.com
Received 4 December 2006
numerous successful examples have been recorded in the
Abstract: A concise, convenient and mild route for the one-pot
syntheses of N-aryl- and N-alkyltriazoles in water is reported. The
methodology involves the three-component reaction comprising
phenylacetylene, sodium azide and aryl/alkyl halide catalyzed by
literature.10 Sharpless and co-workers reported Cu(I)-
catalyzed ligation of azides with terminal alkynes, where-
as Fokin and co-workers developed multicomponent vari-
Cu(I) species generated in situ by a redox reaction between FeCl3 ants in both conventional11 and microwave irradiation
methods.12 Further reports have varied the reaction condi-
and copper metal. Prominent features of our methodology are in-
corporation of aryl fluoride to generate N-aryltriazoles, which are
tions, particularly with respect to generation of the active
rather scarcely reported, use of water as reaction medium, and
Cu(I) species. Sources of Cu(I) include Cu(I) salts, most
avoidance of hazardous aryl azide as a reactant.
commonly copper iodide,8b in situ reduction of Cu(II)
salts, particularly Cu(II) sulfate,8a and comproportion-
Key words: multicomponent reaction, triazole, Cu–FeCl3, redox
reaction
ation of Cu(0) and Cu(II).9 Recent reports suggest that
nitrogen-based ligands can stabilize the Cu(I) oxidation
state under aerobic, aqueous conditions and in turn
promote the desired transformation.13 Recently, a com-
prehensive review on Cu(I)-catalyzed click chemistry
dealing with both mechanistic as well as synthetic aspects
has been described.10
In recent years there has been growing interest in using
specific biologically validated substructures (privileged
structures) as starting points for library design.2 The
resulting library can then be used to address a variety of
biological targets. One way to increase the structural di-
versity of a privileged structure is to generate polycyclic
rigid templates, which in turn will bear structural analogy
to natural products. In view of our continued interest in
the development of synthetic strategies for novel poly-
cyclic structures3 of biological interest, we required poly-
cyclic structures based on N-aryltriazole 3. Triazoles are
an important class of compounds, as they form important
components in pharmacologically active compounds and
are associated with a wide spectrum of activities.4 These
heterocycles function as rigid linking units that can mimic
the atom placement and electronic properties of a peptide
bond without any susceptibility to hydrolytic cleavage.5
Perhaps it is due to their ability to mimic certain aspects
of a peptide bond, that many derivatives of 1,2,3-triazoles
possess varied biological activities, including anti-HIV
activity,4e selective b3-adrenergic receptor inhibition,6 an-
tibacterial activity4d and potent antihistamine activity.4a–c
However, in general all these reports involved the use of
alkyl halide as one of the predominant monomers in con-
trast to the aryl halide, which is rather scarcely reported.11c
We envisioned that the synthesis of our target structure
N-aryltriazole 3 could be affected by replacing alkyl
halides with o-nitrofluorobenzene in the Cu(I)-catalyzed
multicomponent reaction. Our initial experiments with
three-component reaction involving alkyne, o-nitro-
fluorobenzene and NaN3 in the presence of Cu(0)/CuSO4
produced final compound 3a in low yields (Table 1, entry
1). There was no further improvement in yield when
NaHCO3 was used as a base, which is known to facilitate
the reaction.9–11
This led us to develop a modified strategy for the forma-
tion of N-aryltriazoles by optimizing the redox and
reaction conditions (Table 2).
The redox potential of Cu was compared in the electro-
chemical series with elements that would facilitate the
generation of the Cu(I) species in situ. It was found that
use of Fe(III) might assist in improving the generation of
Cu(I) in a more effective manner.14 This phenomenon can
be understood by comparing the reduction potential of the
redox couples. The reduction potential of Cu(I) to Cu(0)
is +0.521 V and Fe(III) to Fe(II) is +0.771 V. Thus, the net
potential is positive (+0.25 V) and therefore the reaction
may be favorable. Armed with these observations, we car-
ried out the three-component reaction involving alkyne, o-
nitrofluorobenzene and NaN3 in the presence of Cu–FeCl3
as catalysts in t-BuOH–H2O, but the reaction furnished 3a
in 10% isolated yield (Table 1, entry 3). Again NaHCO3
The synthesis of 1,2,3-triazoles has been generally carried
out by Huisgen’s 1,3-dipolar cycloaddition reactions in
one pot using three-component format.7 The discovery of
1,4-disubstituted 1,2,3-triazoles under mild conditions
was a welcome advance.8 Perhaps the most powerful click
reaction to date,5a the Cu(I)-catalyzed azide–alkyne cyclo-
addition (CuAAC) has quickly found many applications
in chemistry, biology, and materials science.9 Since the
initial discovery of CuI-catalyzed alkyne–azide coupling,
SYNLETT 2007, No. 10, pp 1591–1594
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8
.0
6
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Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982543; Art ID: D37506ST
© Georg Thieme Verlag Stuttgart · New York

1592
B. Saha et al.
LETTER
Table 1 Synthesis of N-Aryltriazole (3a)
F
O2N
NO2
Cu(0)–FeCl3
N
N
+
NaN3
+
NaHCO3,
H2O, reflux, 7 h
N
1
2
3a
Entry
Reaction conditions
Cu–CuSO4·5H2O
Solvent
Time (h)
Yield of 3 (%)
1
2
3
4
5
H2O, t-BuOH (1:1)
H2O, t-BuOH (1:1)
H2O, t-BuOH (1:1)
H2O, t-BuOH (1:1)
H2O
12
12
12
7
35
36
10
70
72a
Cu–CuSO4·5H2O, NaHCO3
Cu–FeCl3
Cu–FeCl3, NaHCO3
Cu–FeCl3, NaHCO3
7
a Formation of 4-phenyl-1,2,3-triazole was observed in 5% isolated yield.
was added as a base and this time to our delight improve- underwent [3+2]-cycloaddition with alkynes to furnish
ment in the yield to 70% was observed (Table 1, entry 4). the title compound 3a (Figure 1). In order to prove this,
The Cu(I) catalyst was prepared in situ by the redox reac- sodium azide and phenylacetylene were reacted in the
tion of Cu(0) and Fe(III) and the azides were generated in presence of Cu(0)–FeCl3 catalytic system, which fur-
situ from the corresponding halides,15 whereupon they nished 4-phenyl-1,2,3-triazole in 45% isolated yield,
were captured by copper(I) acetylides, forming the corre- hence suggesting the possible reaction pathway depicted
sponding 1,4-disubstituted 1,2,3-triazoles (Table 1). The in Figure 1.
cascade of events must have begun with nucleophilic
substitution of the halide with the azide 2 to generate the
corresponding organoazide 4 derivative, which in turn
Table 2 Synthesis of N-Aryl- and N-Alkyltriazole Derivatives Produced via Table 1
Ar
n
N
N
N
3a–l
Entry
1
Halide
Product
n
0
Ar
Time (h)
7
Yield (%)a
72
MS [M+ + 1] (ES)
267.1
F
3a
NO2
NO2
F
2
3
3b
3c
0
0
7
7
75
74
285.2
281.2
F
NO2
F
NO2
F
NO2
NO2
F
Cl
Cl
4
5
3d
3e
0
0
7
8
70
72
335.1
268.2
Cl
N
NO2
Cl
NO2
N
Cl
NO2
NO2
Synlett 2007, No. 10, 1591–1594 © Thieme Stuttgart · New York

LETTER
Cu–FeCl3-Mediated One-Pot Reaction to N-Aryl- and N-Alkyltriazoles
1593
Table 2 Synthesis of N-Aryl- and N-Alkyltriazole Derivatives Produced via Table 1 (continued)
Ar
n
N
N
N
3a–l
Entry
6
Halide
Product
n
0
Ar
HO
Br
Time (h)
8
Yield (%)a
68
MS [M+ + 1] (ES)
283.3
F
3f
NO2
NO2
HO
Br
NO2
F
7
8
3g
3h
3i
0
1
1
1
7
71
74
71
69
345.2
236.1
281.2
250.1
NO2
Br
2
Br
NO2
9
2
NO2
Br
10
3j
2.5
Br
11
3k
3l
1
1
2
75
70
281.2
250.2
NO2
NO2
Br
12
2.5
a Isolated yield.
and aryl azide in water has been reported;18 however, it
suffers from the use of the hazardous aryl azides.
O2N
F
Interestingly, the three-component click chemistry when
carried out in water using Cu(0)–FeCl3 as a source of
Cu(I), furnished 3 in good isolated yield. In our sub-
sequent experiments,19 we conducted a broader in-
vestigation of this reaction in water by utilizing a variety
of o-fluoronitrobenzenes and alkyl halides with the aim to
synthesize both N-aryl- and N-alkyltriazoles (Table 1).
Both o-fluoronitrobenzenes and alkyl halides furnished 3
with equal ease. The crude N-derivatized triazoles were
purified on silica gel column furnishing pure compounds
in 68–75% isolated yields. HPLC and MS analyses of the
crude products showed presence of 4-phenyl-1,2,3-tri-
azole in less than 8% yield.
N3
N
N
NO2
NO2
N
1
NaN3
+
2
4
3a
Figure 1 Proposed reaction pathway.
After successfully optimizing the reaction conditions for
the synthesis of N-aryltriazole 3, we next decided to carry
out the reaction using water as the sole solvent. Recently,
we successfully demonstrated the use of water as solvent
for the formation of b-carbolines using the Pictet–Speng-
ler reaction.16 Water has clear advantages as a solvent
because it is cheap, readily available and nontoxic. More-
over, it has been argued that reactants that dislike water
tend to come closer (the hydrophobic effect) in order to
realize the reaction at a faster rate than in the absence of
water.17 Recently, a Cu(I)-catalyzed three-component re-
action to form triazoles using an amine, propargyl halide
In summary, we have developed a mild and efficient
protocol for the synthesis of N-aryl- and N-alkyltriazoles
using three-component click chemistry. The use of Fe(III)
to generate Cu(I) has been reported for the first time for
the synthesis of N-aryltriazoles. Studies are in progress to
use the functionalized N-aryltriazoles for the preparation
of polyheterocyclic structures via C–C bond formation.
Synlett 2007, No. 10, 1591–1594 © Thieme Stuttgart · New York

1594
B. Saha et al.
LETTER
(11) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 114, 2708. (b) Chan, T.
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Acknowledgment
BS, SS and DS are grateful to CSIR, New Delhi, India for fel-
lowships.
(12) Prasad, A.; Wim, D.; Fokin, V. V.; Eycken, E. V. Org. Lett.
2004, 6, 4223.
References and Notes
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(19) General Procedure for the Preparation of 1-(2-
Nitrophenyl)-4-phenyl-1H-[1,2,3]triazole (3a): 1-Fluoro-
2-nitrobenzene (2.0 mmol), phenylacetylene (2.2 mmol),
sodium azide (2.2 mmol) and NaHCO3 (2.2 mmol) were
suspended in H2O (10 mL) in a 50-mL round-bottomed flask
equipped with a small magnetic stirring bar. To this was
added copper powder (100 mg) and ferric chloride (100 mg).
The mixture was then heated to reflux for 7 h. The reaction
mixture was cooled and EtOAc (50 mL) was added. The
suspension was passed through a bed of celite and the filtrate
was partitioned in a separating funnel. The organic layer was
separated, dried (Na2SO4) and concentrated to afford a
residue, which was purified by silica gel chromatography
using hexane–EtOAc (70:30) as eluent to afford 3a as a
yellow solid. Yield: 72%; mp 144–145 °C. IR (KBr): 1604,
1534, 1351 cm–1. 1H NMR (300 MHz, CDCl3): d = 8.12 (dd,
J = 1.2, 7.9 Hz, 1 H, ArH), 8.09 (s, 1 H, ArH), 7.91–7.94 (m,
2 H, ArH), 7.81–7.84 (m, 1 H, ArH), 7.69–7.76 (m, 2 H,
ArH), 7.46–7.51 (m, 2 H, ArH), 7.40–7.43 (m, 1 H, ArH).
13C NMR (75.5 MHz, CDCl3): d = 148.54, 144.60, 134.01,
130.91, 130.41, 129.96, 129.11, 128.81, 128.03, 126.15,
125.73, 121.18. MS (ES+): m/z = 267.1 [M+ + 1]. Anal. Calcd
for C14H10N4O2: C, 63.15; H, 3.79; N, 21.04. Found: C,
63.26; H, 3.57; N, 21.40.
1-(4-fluoro-2-nitrophenyl)-4-phenyl-1H-[1,2,3]triazole
(3b): Yield: 75%; mp 178–180 °C. IR (KBr): 1601, 1523,
1347 cm–1. 1H NMR (300 MHz, DMSO): d = 9.14 (s, 1 H,
ArH), 8.28 (dd, J = 2.4, 8.0 Hz, 1 H, ArH), 8.04–8.08 (m, 1
H, ArH), 7.89–7.94 (m, 3 H, ArH), 7.51 (t, J = 7.2 Hz, 2 H,
ArH), 7.27–7.42 (m, 1 H, ArH), 13C NMR (75.5 MHz,
DMSO): d = 147.08, 144.75, 129.78, 129.60, 129.03,
128.43, 125.79, 125.37, 122.91, 121.60, 121.30, 113.80,
113.42. MS (ES+): m/z = 285.2.
(10) Bock, V. D.; Hiemstra, H.; Maarseveen, J. H. V. Eur. J. Org.
Chem. 2006, 51.
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