Solvent-free one-pot synthesis of 1,2,3-triazole derivatives by the 'Click' reaction of alkyl halides or aryl boronic acids, sodium azide and terminal alkynes over a Cu/Al2O3 surface under ball-milling

Article abstract of DOI:10.1039/c2gc36521a

A one-pot procedure for the synthesis of 1,2,3-triazole derivatives by a three-component coupling of alkyl (benzyl) halides or aryl boronic acids, sodium azide and terminal alkynes over copper(ii) sulfate supported on alumina (Cu/Al₂O₃) under ball-milling in the absence of any solvent and additive has been developed. The product was isolated by simple washing of the crude reaction residue with ethanol followed by evaporation of the solvent. No chromatographic purification is required. The catalyst is recycled for subsequent reactions. The azides are produced in situ and thus this procedure avoids the handling of hazardous azides. This protocol offers broad scope for access to a variety of diversely substituted 1,2,3-triazoles. The use of no hazardous organic solvent, the use of ball-milling, and cost efficiency, recyclability of the catalyst up to eight runs without appreciable loss of activity and high yields of products make this procedure greener.

Full text of DOI:10.1039/c2gc36521a

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Graphical Abstract
Solvent–free one–pot synthesis of 1,2,3-triazole derivatives by ‘Click’ reaction of alkyl
halides or aryl boronic acids, sodium azide and terminal alkynes over Cu/Al2O3 surface
under ball-milling
Nirmalya Mukherjee, Sabir Ahammed, Sukalyan Bhadra and Brindaban C. Ranu*
R1
N
R2
X
N
N
R1
Cu/Al2O3
NaN3
R2
N
R3
R3 B(OH)2
+ K2CO3
N
N
R1
R1 = aryl, heteroaryl,alkyl
R2 = benzyl, substituted benzyl, alkyl
R3 = aryl, heteroaryl, alkenyl
An efficient solvent-free synthesis of 1,2,3-triazole derivatives has been achieved by ‘Click’
reaction over Cu/Al2O3 surface under ball- milling.

Green Chemistry
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Journal Name
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Cite this: DOI: 10.1039/c0xx00000x
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ARTICLE TYPE
Solvent–free one–pot synthesis of 1,2,3-triazole derivatives by ‘Click’
reaction of alkyl halides or aryl boronic acids, sodium azide and
terminal alkynes over Cu/Al2O3 surface under ball-milling
Nirmalya Mukherjee, Sabir Ahammed, Sukalyan Bhadra and Brindaban C.
Ranu*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A oneꢀpot procedure for the synthesis of 1,2,3ꢀtriazole derivatives by a threeꢀcomponent coupling of alkyl
(benzyl) halides or aryl boronic acids, sodium azide and terminal alkynes over cooper(II) sulfate supported on
10 alumina (Cu/Al2O3) under ballꢀmilling in absence of any solvent and additive, has been developed. The product
was isolated by simple washing of the crude reaction residue with ethanol followed by evaporation of solvent.
No chromatographic purification is required. The catalyst is recycled for subsequent reactions. The azides are
produced in situ and thus this procedure avoids the handling of hazardous azides. This protocol offers a broad
scope for an access to a variety of diversely substituted 1,2,3ꢀtriazoles. The use of no hazardous organic solvent,
15 ballꢀmilling, cost efficiency, recyclability of the catalyst up to eight runs without appreciable loss of activity
and high yields of products make this procedure greener.
their thermodynamic instability and initiation of
1. Introduction
40 undesired alkyneꢀalkyne coupling, the direct use of
Cu(I) salts was restricted.4 Instead, in situ reduction
1,2,3ꢀTriazoles have received considerable interest
of Cu(II) salts,3a,3d oxidation of Cu(0) metal,2cꢀ2i,
because of their useful applications as pharmaceutical
copper(II)/copper(0) comproportionation,5 were
20 agents, agrochemicals, dyes, corrosion inhibitors,
photostabilizers and photographic materials.1 The
encouraged. Nevertheless, various nitrogenꢀ or
classical method for their synthesis involved thermal
45 phosphorusꢀbased ligands have been employed to
1,3ꢀdipolar cycloaddition of organic azides with
protect the metal centre and enhancing its catalytic
alkynes.2 However, this procedure was associated
25 with elevated temperature, low yields and lack of
selectivity. Thus to overcome these drawbacks an
improved procedure involving Cu(I)ꢀcatalyzed azideꢀ
alkyne 1,3ꢀdipolar cycloaddition was reported,3
which provided high regioselectivity, room
30 temperature reaction and enlarged scope. Because of
activity.6 To check the contamination of metal with
the end product and improve the recovery and reuse
of Cuꢀcatalyst, heterogeneous copper salt supported
50 on activated carbon,7 polymers,8 zeolites,9 and
silica,10 have received significant attention in recent
times.
The handling of organic azides are not safe
because of their toxic and hazardous nature. Although
55 alkyl azides are prepared easily by the displacement
reaction of alkyl halides and sodium azide, their
isolation and purification are problematic in certain
cases. On the other hand, the preparation of aryl
azides from aromatic amines is not so
60 straightforward. Thus a oneꢀpot procedure involving
reaction of in situ generated azides from the
corresponding precursors, and alkynes for the
----------------------------------------------------
a
Department of Organic Chemistry, Indian Association for the
Cultivation of Science, Jadavpur, Kolkata, 700 032, India. Fax: 91-33-
24732805; Tel: 91-33-24734971; E-mail: ocbcr@iacs.res.in
1
35 † Electronic Supplementary Information (ESI) available: [Copies of H
NMR
and
13C
NMR
spectra
of
all
products].
See
DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
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synthesis of triazoles is highly desirable. A number of
best yield was obtained using 10 mol% of catalyst
45 (400 mg) and running the operation for 60 min.
(Table 1, entry 3). No product was obtained in
absence of catalyst under ballꢀmilling in identical
conditions (Table 1, entry 6). The reaction also did
not initiate at all at room temperature under
50 conventional stirring using a magnetic stirrer for 24 h.
such oneꢀpot procedures catalyzed by different Cuꢀ
derivatives have been reported recently.11 These
catalysts include nanoferiteꢀglutathioneꢀcopper under
microwave irradiation,11a copper nanoparticles on
activated carbon,11b,11c CuFe2O4 nanoparticles,11d
ionic liquid supported Cu(I),11e Cu(I)/aminoacids
ionic liquids,11f CuSO4/cyclodextrin,11g and bimetallic
CuꢀFe nanoparticles.11h
5
In a typical experimental procedure, a
mixture of benzyl halide (bromide or chloride),
phenylacetylene and sodium azide over a surface of
aluminaꢀsupported Cu(II)ꢀcatalyst was subjected to
55 ballꢀmilling at 600 rpm for 1 h (TLC). Elution of the
reaction residue by ethanol followed by evaporation
of solvent provided the pure product.
10
Recently, ballꢀmilling (intense mechanical
grinding) has emerged as a powerful tool for
effecting a chemical reaction in a greener way.12
A
variety of reactions such as homocoupling of terminal
alkynes,13 Sonogashira,14 Michael,15 aldol reaction16
15 among others17 have been performed efficiently by
this technique. We have recently developed an
efficient means of transꢀesterification by ballꢀmilling
without any catalyst and solvent18 and now we report
a simple oneꢀpot threeꢀcomponent reaction of
20 benzyl/alkyl halides, sodium azide, alkyne on the
surface of aluminaꢀsupported Cu(II) catalyst19 under
ballꢀmilling without any additive and solvent
(Scheme 1).
Table 1 Standardisation of reaction conditions
N
N
Cu/Al2O3, NaN3
600 rpm, 6 balls
N
Br
+
60
65
70
Entry
Yield [%]a
51
Time ( min.)
Catalyst
Cu/Al2O3
10 mol%
(mol%)
R1
N
N
R2
H
R1
N
+
NaN
+
X
3
600 rpm,
25
2
60
60
60
30
1
2
3
4
6 balls,1 h
R2
R1= benzyl, alkyl, cinnamyl
R2= aryl, alkyl,heteroaryl
X = Br, Cl
72
5
10
10
96b
Scheme 1 Cu/Al2O3 catalyzed one-pot Click reaction in ball-milling
Recently, a Cuꢀ catalyzed reaction of benzyl azide
and phenylacetylenes under ballꢀmilling has also
62
30 been reported.20
5
6
80
0
10
0
45
60
2. Results and discussion
(a) Yield of isolated pure products (by 1H and
The supported Cuꢀcatalyst was prepared by
13C-NMR).
stirring an aqueous solution of CuSO4.5H2O (1 g, 4
mmol) and basic alumina (15 g) for 2 h at room
35 temperature followed by evaporation of water and
drying. The copper content in the fresh catalyst was
found to be 18.78 mg/g (as detected by ICPꢀMS).
(b) best condition.
A wide range of diversely substituted
phenylacetylenes were reacted with a mixture of
benzyl bromides/chlorides and sodium azide by this
75 procedure to produce the corresponding 1,4ꢀ
disubstitutedꢀ1,2,3ꢀtriazoles. The results are
To optimize the reaction conditions a series
of experiments were carried out under varying
40 catalyst loading and time for a representative reaction
of benzyl bromide, sodium azide and phenyl
acetylene on the surface of aluminaꢀsupported Cu(II)
under ballꢀmilling at 600 rpm. It was found that the
summarized in Table 2. The substitution of electron
withdrawing and electron donating groups on the
phenyl ring of phenyl acetylenes did not have any
80 appreciable influence on the outcome of the reaction
(Table 2, entries 4 and 6). The reaction went
2
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Table 2 Cu/Al2O3 catalyzed one-pot azide preparation and cycloaddition of alkyl halides with terminal
alkyne
Cu/Al2O3
10 mol%
R1
N
N
R2
H
N
R1
X
NaN3
+
+
600 rpm,
6 balls,1 h
R2
5
10
15
20
25
30
35
Entry
1
Yield [%]a
Ref b.
Alkyne
Aliphatic Halide
Triazole
N
N
N
X
X= Cl
X= Br
92
96
14d
F
N
N
N
Br
N
2
3
87
23a
23b
40
45
50
55
60
F
N
X
X= Cl
X= Br
N
88
90
Br
Br
NO2
N
N
X
X= Cl
X= Br
N
4
5
91
94
23b
23c
NO2
N
N
N
X
X= Cl
X= Br
N
84
87
N
N
N
X
X= Cl
X= Br
N
6
7
11a
23d
83
86
O
O
N
N
N
N
Br
81
87
S
S
N
N
Br
8
23e
N
N
N
Br
N
78
80
N
9
11a
11b
N
N
N
N
N
N
N
10
I
I
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Table 2 (Contd.)
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Cu/Al2O3
10 mol%
R1
N
N
R2
H
N
R1
X
NaN3
+
+
600 rpm,
6 balls,1 h
R2
40
Ref b
Alkyne
Entry
11
Yield [%] a
Aliphatic Halide
Triazole
5
10
15
20
N
Br
N
N
11a
85
OH
OH
N
N
Br
Br
N
45
50
55
11a
11a
12
13
80
88
N
O
N
O
N
N
O
O
Br
N
N
14
15
70
92
23d
23a
N
N
Br
Br
N
N
N
N
Br
Br
91
16
23g
CF3
CF3
(a) Isolated yields of pure products (by 1H and 13C-NMR)
(b) This denotes the earlier reference of the corresponding product
uniformly for all oꢀ, mꢀ, and pꢀ substituted
alkyl halides such as cyclohexyl bromides
phenylacetylenes (Table 2, entries 4, 2, and 5). The 60 and diꢀiodo methane also react with phenylacetylene
25 1,4ꢀdiethynylbenzene produced the corresponding
bisꢀtriazole derivatives (Table 2, entry 8). The heteroꢀ
aryl substituted acetylene, 3ꢀethynylthiophene
underwent clean reaction to produce 1ꢀbenzylꢀ4ꢀ
(thiophenꢀ3ꢀyl)ꢀ1,2,3ꢀtriazole (Table 2, entry 7). The
30 alkyl acetylenes such as propargyl alcohol (Table 2,
entry 11), hexyne (Table 2, entry 12) and ethyl
propiolate (Table 2, entry 13) also participated in this
reaction to provide the corresponding products. The
reaction of cinnamyl bromide by this procedure
35 furnished the 1ꢀcinnamylꢀ4ꢀphenylꢀ1,2,3ꢀtriazole in
relatively low yield (70%) (Table 2, entry 14). The
without any difficulty to produce the corresponding
triazoles (Table 2, entries 9 and 10).
Unfortunately, the aryl halides failed to
undergo this oneꢀpot reaction to produce the
65 corresponding triazoles. We then focussed our
attention on using aryl boronic acids in place of aryl
halides to open an access to the very valuable 1ꢀarylꢀ
1,2,3ꢀtriazoles.
Our
investigation
towards
optimization of reaction conditions revealed that best
70 yield was obtained using 10 mol% of catalyst in
presence of one equivalent of K2CO3 (Table 3, entry
4
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3). Following this procedure phenylacetylene and 3ꢀ
thienylacetylene (heteroaryl) underwent reactions
with phenyl, substituted phenyl, alkenyl and
heteroaryl boronic acids to provide the corresponding
triazoles. The results are reported in Table 4.
Cu/Al2O3 catalyst was recovered and dried after
washing with ethanol followed by acetone before
reuse. We have found recyclability up to eight runs
although there is marginal linear loss of activity of
45 the catalyst due to lower mass recovery in each step
(Figure 1).
5
10
15
Table 3 Standardisation of reaction conditions of one-pot
aryl azide preparation and cycloaddition with terminal alkyne
In comparison to a related procedure reported
by Stolle et al earlier,20 our procedure offers
significant green advantages avoiding handling of
50 hazardous and toxic azides involving its in situ
generation, use of environment friendly ethanol for
isolation of product and recyclability of catalyst.
1. Cu/Al2O3
N
K2CO3, NaN3
600 rpm, 6 ball,
1 h
N
N
B(OH)2
2. Ph
600 rpm, 1 h
Entry
K2CO3 (equiv.)
Yield [%]a
42
100
Catalyst
(mol%)
80
1
2
10
0
0
60
55
40
20
0
1
1
0
3
0
91b
0
3
4
5
10
0
0
1
2
3
4
5
6
7
8
9
No. of Cycle
Fig. 1 Recyclability Chart (Recyclability of the
60 catalyst was tested on the reaction with benzyl
bromide and phenylacetylene).
10
90
(a) Yield of isolated pure products (by 1H and
13C-NMR).
We have observed that in our catalyst,
Cu/Al2O3, copper remains in +2 oxidation state in the
fresh, intermediate and in the recovered stage, as
65 established by EPR studies (Figure 2). The XPS (Xꢀ
ray Photoelectron Spectroscopy) study of the fresh,
intermediate and recovered catalyst also supports the
+2 oxidation state of the Cu (Figure 3). Thus we
assume that our reaction proceeds via a similar
70 reaction pathway involving Cu+2 as postulated by
Pitchumani et al.22 Further, we did not detect
formation of diynes, usually generated by Cu(I)
catalysis during reduction of Cu(II) to Cu(I).
(b) best condition.
20 The participation of aryl boronic acids in the
synthesis of triazoles by this route using Cuꢀcatalysts
in H2O and other solvents was reported earlier too.21
However, to the best of our knowledge no report of
this reaction under ballꢀmilling on a supported Cuꢀ
25 catalyst in absence of any solvent is known. In
addition, the reactions of alkylꢀ and heteroaryl
boronic acids were not addressed earlier.
In general the reactions are clean and highꢀyielding.
Several functional groups such as F, Br, NO2, CN,
30 OMe, CO2Et, CF3, CHO are compatible under the
reaction conditions. No rigorous extraction of product
by solvent and work up are necessary. A simple
washing of the reaction residue by ethanol followed
by evaporation of solvent furnished pure product. The
35 ICPꢀMS measurement of Cu content in both the
products obtained with halogenides and with the
boronic acids showed the absence of copper.
Chromatographic purification/separation is usually
not required. Thus this procedure avoids use of
40 hazardous organic solvent in the whole process. The
3. Experimental
75 IR spectra were recorded on a Shimadzu 8300 FTIR
1
spectrometer. H NMR and 13C NMR spectra were
run on Bruker DPXꢀ300 and DPXꢀ500 instruments.
HRMS were acquired on a Microtek Qtof Micro YA
263 spectrometer. All commercial reagents were
80 distilled before use. A PM 100, Retsch GmbH,
Germany, ballꢀmilling apparatus was used for all
reactions.
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Table 4 Cu/Al2O3 catalyzed one-pot aryl azide preparation and cycloaddition with terminal alkyne
Cu/Al2O3 (10mol%)
K2CO3 (1 equiv.)
N
35
N
N
1 h, 600 rpm
Triazole
R1 B(OH)2
R1 N3 + R2
R2
NaN3 (3-equiv.)
1 h, 600 rpm
R1
Yield [%]a Ref.b
Acetylene
Entry
Boronic acid
40
45
50
5
10
15
OH
B
N
N
N
OH
20c
23f
1
2
3
91
90
88
88
OH
B
N
N
OH
N
O
OH
B
N
N
O
N
H
O
OH
H
55
OH
B
N
N
OH
N
4
O
60
O
O
HO
OH
OH
B
B
N
N
N
5
6
7
S
S
87
83
85
S
65
70
75
HO
20
N
N
N
S
S
S
N
N
N
OH
B
OH
25
(a) Isolated yields of pure products (by 1H and 13C-NMR)
(b) This denotes the earlier reference of the corresponding product
Preparation of Cu/Al2O3 catalyst
Basic alumina (15 g, SRL, India) was added
80
evaporated on a rotary evaporator under
30 to a wellꢀstirred aqueous solution (30 mL) of
CuSO4.5H2O (1 g, 4 mmol) and the mixture was
stirred at 25 OC for 2 h. The excess water was
reduced pressure followed by drying under vacuum at
140 C for 8 h to get the catalyst as a light green
powder.
O
6
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35
5
.
40
45
10
50 Fig. 3 XPS data of the (a) fresh, (b) intermediate and
(c) recovered catalyst
Fig. 2 Xꢀband EPR spectrum of Cu+2 in (a) fresh
catalyst, (b) after 1st run, (c) after 8th run, (d) at
intermediate stage after 30 minutes reaction
XPS analysis: The XPS study of the fresh,
intermediate and recovered catalyst at the Cu 2p level
55 showed the 2p3/2 lines at 934.5, 932.7 and 932.4 eV
respectively with characteristic shake up features
indicating +2 oxidation state of Cu throughout the
reaction. A slight variation (higher) in the binding
energy of Cu in the fresh catalyst is possibly due to a
60 combined contribution of CuSO4 and Cu(OH)2 on the
surface of alumina.
15 EPR data: The Xꢀband EPR spectrum of the fresh
catalyst shows four wellꢀdefined hyperfine lines for a
solid sample at nitrogen atmosphere resulting from
the coupling of the unpaired electron with the nuclear
spin of Cu(II) (Figure 2). The regenerated and
20 intermediate catalyst also show very similar EPR
spectrum as observed in the fresh catalyst
65
70
Fig. 4 SEM image of Cu/Al2O3 catalyst
25
SEM analysis: The tuned basic Al2O3 supported Cu
75 (II) catalyst are analysed by FESEM (Field Emission
Scanning Electron Microscopy) (Fig. 4). The
particles show very uniform spherical morphology.
Inset pic. shows a selected area scanning.
30
80
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50 twoꢀdimensional (2 D) and threeꢀ dimensional (3 D)
AFM images (Figure 6). By achieving a good
dispersion of the particles it is assumed that the
particles are spherical in nature.
55 Representative experimental procedure for the
synthesis of 1,4-disubstituted 1,2,3-triazole (Table
2, entry 1)
5
A mixture of benzyl bromide (171 mg, 1 mmol) and
phenylacetylene (102 mg, 1 mmol), NaN3 (65 mg, 1
60 mmol) and Cu/Al2O3 (400 mg, 10 mol%) was
subjected to ballꢀmilling at 600 rpm using a 25 mL
stainless steel beaker with six balls (d = 10 mm) of
the same material for 60 min. Ballꢀmilling operation
was performed using inverted rotation directions,
65 with interval of 10 min. and taking interval break of
30 sec. Extraction of the reaction residue by simple
elution with ethanol followed by evaporation of
solvent furnished an ivory solid (96 %), mp = 133
OC; IR (KBr) 3121, 1466, 1356, 1225, 1074, 1049,
10
Fig. 5 EDX spectra of the catalyst
15 EDX analysis: Energy Dispersive Xꢀray (EDX)
analysis on various regions confirmed the presence of
copper on the support, with energy bands of 8.04,
8.90 Kev ( K lines) and 0.92 K (L line) (Fig 5).
1
70 766, 729, 692 cmꢀ1; H NMR (500 MHz, DMSOꢀd6 )
20
25
30
35
40
δ 5.63 (s, 2H), 7.31ꢀ7.43 (m, 8H), 7.82 (d, J = 7.5 Hz,
2H), 8.63 (s, 1H); 13C NMR (125 MHz, DMSOꢀd6) δ
52.9, 121.4, 125.0, 127.7, 128.0, 128.6, 128.7, 130.5,
135.8, 146.5. These spectroscopic data are in good
75 agreement with those of an authentic sample of 1ꢀ
benzylꢀ4ꢀphenylꢀ1Hꢀ1,2,3ꢀtriazole.14d
This procedure was followed for all the
reactions listed in Table 2. All of these triazoles are
known compounds and were easily identified by
80 comparison of their spectroscopic data with those
previously reported. These data were provided in the
Supplementary Information.
The residual catalyst was further washed
with ethanol followed by acetone, dried under
85 vacuum and reused.
Representative experimental procedure for the
synthesis of 1,4-diaryl-1,2,3-triazole from aryl
boronic acid (Table 4, entry 1)
Fig. 6 AFM image of the Cu/Al2O3 catalyst (top),
AFM topological image of the catalyst (bottom)
45
A mixture of phenylboronic acid (122
90 mg, 1 mmol), potassium carbonate (138 mg, 1
mmol), NaN3 (195 mg, 3 mmol) and Cu/ Al2O3 (400
mg, 10 mol%) was subjected to ballꢀmilling at 600
AFM analysis: The AFM method is used to provide
an independent and quantitative measurement of
catalyst particle size and morphology. The
morphology of the catalyst is clearly seen from the
8
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rpm using six balls (d = 10 mm) for 60 min. Then
4-Phenyl-1-(thiophen-3-yl)-1H-1,2,3-triazole
45 (Table 4, entry 5)
phenylacetylene (102 mg, 1 mmol) was added to the
mixture and the mixture was further submitted to
ballꢀmilling at the same condition for one hour, as
required for maximum conversion (TLC/NMR). The
product was extracted from the reaction mixture by
simple filtration through sintered funnel followed by
washing with ethyl acetate (30 ml). The ethyl acetate
extract was washed with brine, dried and evaporated
Dirty white solid (87%), mp = 164ꢀ166 OC, IR (KBr)
1
3103, 1558, 1456, 1231, 1092, 1074 cmꢀ1; H NMR
5
(300 MHz, CDCl3) δ 7.34ꢀ7.39 (m, 1H), 7.43ꢀ7.53
(m, 4H), 7.61 (dd, J = 1.5, 3 Hz, 1H), 7.88ꢀ7.91 (m,
50 2H), 8.11 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
114.3, 121.0, 126.0, 127.5, 128.6, 129.1, 130.3;
HRMS calcd for C12H9N3S [M+H]+ : 228.0595,
found: 228.0591.
10 to leave the crude product which was crystallized
from ethanolꢀhexane mixture to provide a white solid
O
(91% ), mp = 168ꢀ171 C; IR (KBr) 3120, 3090,
1,4-Di-(thiophen-3-yl)-1H-1,2,3-triazole (Table 4,
55 entry 6)
1
1605, 1510, 1412, 1220, 1025, 768 cmꢀ1, H NMR
(500 MHz, CDCl3) δ 7.37 (t, J = 7.5 Hz, 1H), 7.46
15 (td, J = 2 and 7.5 Hz, 3H), 7.56 (t, J = 8 Hz, 2H),
7.79ꢀ7.81 (m, 2H), 7.91ꢀ7.93 (m, 2H), 8.19 (s, 1H);
13C NMR (125 MHz, CDCl3), δ 117.7, 120.7, 126.0,
128.6, 128.9, 129.0, 130.0, 130.4, 137.3, 148.6. These
data are in good agreement with the reported
20 values.20c
Ivory solid (83%), mp = 184ꢀ186 OC; IR (KBr) 3105,
1
1229, 1194, 1092 cmꢀ1; H NMR (300 MHz, CDCl3)
δ 7.40ꢀ7.42 (m, 1H), 7.46ꢀ7.51 (m, 3H), 7.58ꢀ7.60
(m, 1H), 7.76 (d, J = 2.1 Hz, 1H), 8.00 (s, 1H); 13C
60 NMR (75 MHz, CDCl3), δ 114.3, 117.9, 121.0, 121.8,
126.0, 126.7, 127.5, 131.5; HRMS calcd for
C10H7N3S2 [M+H]+ : 234.0159, found: 234.0155.
3-(4-Phenyl-1H-1,2,3-triazol-yl)benzaldehyde
(Table 4, entry 3)
1-((E)-Pent-1-enyl)-4-phenyl-1H-1,2,3-triazole
(Table 4, entry 7)
Dirty white solid (88%), mp = 158ꢀ160 OC; IR (KBr)
3140, 3086, 1699, 1595, 1499, 1454, 1236, 1203,
25 1176, 1014 cmꢀ1; 1H NMR (300 MHz, CDCl3) δ 7.36ꢀ
7.50 (m, 3H), 7.75 (t, J = 7.8 Hz, 1H), 7.90ꢀ7.98 (m,
3H), 8.15ꢀ8.19 (m, 1H), 8.26ꢀ8.27 (m, 1H), 8.30 (s,
1H), 10.12 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
117.5, 120.2, 126.0, 126.1, 128.8, 129.1, 130.0,
30 130.2, 130.9, 137.9, 138.0, 149.0, 190.9; HRMS
calcd for C15H11N3O [M+H]+: 250.0980, found:
250.0976.
O
65 White solid (85%), mp = 86ꢀ90 C; IR (KBr) 3127,
3096, 2957, 2872, 1460, 1234, 1082, 1039 cmꢀ1; H
1
NMR (500 MHz, CDCl3) δ 0.99 (t, J = 7.5 Hz, 3H),
1.52ꢀ1.59 (m, 2H), 2.24 (q, J = 7.5 Hz, 2H), 6.23ꢀ6.29
(m, 1H), 7.16 ( d, J = 14 Hz, 1H), 7.30ꢀ7.36 (m, 1H),
70 7.43 (t, J = 7.5 Hz, 2H), 7.84 (d, J = 7.5 Hz, 2H),
7.93 (s, 1H); 13C NMR (125 MHz, CDCl3), 13.7,
22.3, 31.8, 123.4, 124.5, 126.0, 128.5, 129.0, 130.4;
HRMS calcd for C13H15N3 [M+H]+ : 214.1344,
found: 214.1338.
Ethyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)benzoate
(Table 4, entry 4)
75 4. Conclusion
35 White solid (88%), mp = 165ꢀ168 OC; IR (KBr) 3121,
3098, 2995, 1715, 1607, 1454, 1435, 1273, 1225,
In conclusion, we have developed a
general procedure for the synthesis of 1,4ꢀ
disubstitutedꢀ1,2,3ꢀtriazoles by a simple one pot
threeꢀcomponent reaction of alkyl halide/aryl boronic
80 acid, sodium azide and terminal alkyne on the surface
of Cu/Al2O3 catalyst under ballꢀmilling in absence of
any solvent and additive. This protocol offers a broad
scope for an access to a wide spectrum of diversely
substituted 1,2,3ꢀtriazoles. The simplicity in
1
1174, 1103 cmꢀ1; H NMR (500 MHz, CDCl3) δ 1.43
(t, J = 7 Hz, 3H), 4.42 (q, J = 7 Hz, 2H), 7.38 (t, J = 7
Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.89ꢀ7.95 (m, 4H),
40 8.22ꢀ8.26 (m, 3H); 13C NMR (125 MHz, CDCl3) δ
14.4, 61.6, 117.5, 120.0, 126.1, 128.8, 129.1, 130.0,
130.8, 131.5, 140.2, 148.9, 165.6; HRMS calcd for
C17H15N3O2 [M+H]+ : 294.1242, found: 294.1237.
This journal is © The Royal Society of Chemistry [year]
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Page 11 of 14
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use of no toxic organic solvent in the entire process, 45
reusability of the catalyst for the more than eight
times, no need for chromatographic purification,
reaction at ambient temperature under ballꢀmilling,
good purity, excellent regioselectivity and high yields
of products make this procedure greener and more 50
cost effective.
5
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814.
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Acknowledgments
10 We are pleased to acknowledge financial support
from DST, New Delhi in the form of the award of
J.C. Bose National Fellowships to B.C. R. (Grant no.
SR/S2/JCBꢀ11/2008) and CSIR [Grant no.
01(2365)/10/EMRꢀII]. S. A. and S. B. are also
15 thankful to CSIR for their fellowships. We thank Dr.
T.K. Paine of our Institute for his help in getting EPR
spectrum.
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35
5
Graphical Abstract
40
10 Solvent–free one–pot synthesis of 1,2,3-
triazole derivatives by ‘Click’ reaction of alkyl
halides or aryl boronic acids, sodium azide
and terminal alkynes over Cu/Al2O3 surface
under ball-milling
15 Nirmalya Mukherjee, Sabir Ahammed,
Sukalyan Bhadra and Brindaban C. Ranu*
45
R1
N
R2
X
N
N
R1
Cu/Al2O3
NaN3
R2
N
R3
R3 B(OH)2
+ K2CO3
20
N
N
50
R1
R1 = aryl, heteroaryl,alkyl
R2 = benzyl, substituted benzyl, alkyl
R3 = aryl, heteroaryl, alkenyl
An efficient solventꢀfree synthesis of 1,2,3ꢀ 55
triazole derivatives has been achieved by ‘Click’
25 reaction over Cu/Al2O3 surface under ballꢀ
milling.
60
65
70
30
12 | Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]